The UK High-End Computing Consortium for Biomolecular Simulation
Lead Research Organisation:
University of Bristol
Department Name: Chemistry
Abstract
Simulations using powerful computers can show how biological molecules 'work' in atomic detail. For example, molecular simulations can show drugs bind to their biological targets, how enzymes catalyse reactions, and how proteins fold into their functional forms. Biomolecular simulation is a vibrant and growing area, making increasingly significant contributions to biology. It is an area of growing international importance. Simulations of biological molecules complement experiments in building a molecular-level understanding of biology: they can test hypotheses and interpret and analyse experimental data in terms of interactions at the atomic level. A wide variety of simulation techniques have been developed, applicable to a range of different problems in biomolecular science. Biomolecular simulations have already shown their worth in helping to analyse how enzymes catalyse biochemical reactions, and how proteins adopt their functional structures e.g. within cell membranes. They contribute to the design of drugs and catalysts, and in understanding the molecular basis of disease. Simulations have played a key role in developing the conceptual framework now at the heart of biomolecular science, that is, the understanding that the way that biological molecules move and flex - their dynamics - is central to their function. Developing methods from chemical physics and computational science will open exciting new opportunities in biomolecular science, including in drug development and biotechnology. Much biomolecular simulation demands high end computing (HEC) resources: e.g. large-scale simulations of biological machines such as the ribosome, proton pumps and motors, membrane receptor complexes and even whole viruses. A particular challenge is the integration of simulations across length and timescales: different types of simulation method are required for different types of problems).
Biomolecular Simulations are contributing increasingly to areas such as biotechnology, drug design, biocatalysis and biomedicine. The UK has a strong community in this field, recognized by the recent (2011) establishment by EPSRC of CCP-BioSim (ccpbiosim.ac.uk), the UK Collaborative Computational Project for Biomolecular Simulation at the Life Sciences Interface (and the subsequent award of 'widening participation' funds in 2012). We believe there is a clear, growing and demonstrable need for high-end computing in this field, and propose a new HEC Consortium in biomolecular simulation. Working with CCP-BioSim, this Consortium will help bring HEC to a wider community, including non-traditional users and experimental bioscientists, and engage physical and computer scientists in biological applications.
Biomolecular Simulations are contributing increasingly to areas such as biotechnology, drug design, biocatalysis and biomedicine. The UK has a strong community in this field, recognized by the recent (2011) establishment by EPSRC of CCP-BioSim (ccpbiosim.ac.uk), the UK Collaborative Computational Project for Biomolecular Simulation at the Life Sciences Interface (and the subsequent award of 'widening participation' funds in 2012). We believe there is a clear, growing and demonstrable need for high-end computing in this field, and propose a new HEC Consortium in biomolecular simulation. Working with CCP-BioSim, this Consortium will help bring HEC to a wider community, including non-traditional users and experimental bioscientists, and engage physical and computer scientists in biological applications.
Planned Impact
Who will benefit from this research?
As well as biosimulation specialists, a broad cross-section of bioscientists who are concerned, in some way or other, with the nature and behaviour of biomolecules at the atomic level e.g. X-ray crystallographers, NMR spectroscopists, single-molecule biophysicists, mass spectrometrists, enzymologists, medicinal chemists, chemical biologists. It will contribute to synthetic biology, biocatalysis and drug design. The UK High-End Computing Consortium for Biomolecular Simulation will help achieve maximum benefit from national HEC investment. It will assist the biological community to use high-end computing facilities and help physical scientists tackle biological problems. In the longer term, there is the potential for the project to impact on the general public through improvements in health and quality of life.
How will they benefit from this research?
The "molecule-oriented" bioscience community will benefit through access to tools, training, and trained simulation specialists that enable novel and more effective multidisciplinary projects where computational methods enhance and extend their core experimental approaches. Such integrated studies have a higher probability of producing high-impact discoveries and developments and so fostering such activities will enhance UK competitiveness in the international research arena. The Consortium will provide tools and resources to facilitate this. These tools should give rise to major benefits (e.g. high-impact papers, major international grant awards) over the term of the project, and in future. In the longer term the Consortium will be helping train a new generation of bioscientists who can work confidently and knowledgeably across the theory/experimental divide. What is 'state-of-the-art' today with regard to computational power and methodology, and so might be regarded as somewhat esoteric, will be on the desktop of bioscientists in 5-10 years time. Impacts on the health and quality of life of the general public are likely to come primarily from the application of the methodologies fostered and disseminated (e.g. by CCP-BioSim) to drug design and discovery. Computational methods are already well-established in Pharma, since they can hasten and cheapen the process of drug discovery and development. The more computationally-intensive methods of biomolecular simulation are gaining ground, as improvements in computational power make accuracy and time-to-solution competitive with 'wet' methods. The Consortium will help improve this by a) helping train new generations of researchers with the necessary HEC skills and b) providing a forum to enhance industrial-academic research links (members of the Consortium have established links with many large and smaller pharmaceutical/biotech companies (e.g. AZ, Vernalis, Phaminox, GSK, Evotec, J&J, Pfizer, Oxford Nanopore). The benefits to the public in the longer term come from new and/or cheaper medicinal products, plus the potential for simulations has in addressing the 3Rs and biosecurity.
What will be done to ensure that they benefit from this research?
Through close coordination with CCP-BioSim and other bodies:
- The programme of workshops, co-organised with leading experimentalists in key disciplines, examining and fostering links across the simulation/experimental interface
- The annual conference focused on exemplifying and encouraging the highest quality interdisciplinary research.
- Training workshops introducing non-specialist bioscientists to high quality simulation methods, and specialists to the latest technological advances.
- Associated on-line training packages, available any time, any place.
- Training workshops and tools developed to aid access to HPC resources for those with a bioscience background.
Tools, software and data from development work will be made freely available, and disseminated via the web. Involvement of a wide community will ensure broad uptake
As well as biosimulation specialists, a broad cross-section of bioscientists who are concerned, in some way or other, with the nature and behaviour of biomolecules at the atomic level e.g. X-ray crystallographers, NMR spectroscopists, single-molecule biophysicists, mass spectrometrists, enzymologists, medicinal chemists, chemical biologists. It will contribute to synthetic biology, biocatalysis and drug design. The UK High-End Computing Consortium for Biomolecular Simulation will help achieve maximum benefit from national HEC investment. It will assist the biological community to use high-end computing facilities and help physical scientists tackle biological problems. In the longer term, there is the potential for the project to impact on the general public through improvements in health and quality of life.
How will they benefit from this research?
The "molecule-oriented" bioscience community will benefit through access to tools, training, and trained simulation specialists that enable novel and more effective multidisciplinary projects where computational methods enhance and extend their core experimental approaches. Such integrated studies have a higher probability of producing high-impact discoveries and developments and so fostering such activities will enhance UK competitiveness in the international research arena. The Consortium will provide tools and resources to facilitate this. These tools should give rise to major benefits (e.g. high-impact papers, major international grant awards) over the term of the project, and in future. In the longer term the Consortium will be helping train a new generation of bioscientists who can work confidently and knowledgeably across the theory/experimental divide. What is 'state-of-the-art' today with regard to computational power and methodology, and so might be regarded as somewhat esoteric, will be on the desktop of bioscientists in 5-10 years time. Impacts on the health and quality of life of the general public are likely to come primarily from the application of the methodologies fostered and disseminated (e.g. by CCP-BioSim) to drug design and discovery. Computational methods are already well-established in Pharma, since they can hasten and cheapen the process of drug discovery and development. The more computationally-intensive methods of biomolecular simulation are gaining ground, as improvements in computational power make accuracy and time-to-solution competitive with 'wet' methods. The Consortium will help improve this by a) helping train new generations of researchers with the necessary HEC skills and b) providing a forum to enhance industrial-academic research links (members of the Consortium have established links with many large and smaller pharmaceutical/biotech companies (e.g. AZ, Vernalis, Phaminox, GSK, Evotec, J&J, Pfizer, Oxford Nanopore). The benefits to the public in the longer term come from new and/or cheaper medicinal products, plus the potential for simulations has in addressing the 3Rs and biosecurity.
What will be done to ensure that they benefit from this research?
Through close coordination with CCP-BioSim and other bodies:
- The programme of workshops, co-organised with leading experimentalists in key disciplines, examining and fostering links across the simulation/experimental interface
- The annual conference focused on exemplifying and encouraging the highest quality interdisciplinary research.
- Training workshops introducing non-specialist bioscientists to high quality simulation methods, and specialists to the latest technological advances.
- Associated on-line training packages, available any time, any place.
- Training workshops and tools developed to aid access to HPC resources for those with a bioscience background.
Tools, software and data from development work will be made freely available, and disseminated via the web. Involvement of a wide community will ensure broad uptake
Organisations
- University of Bristol (Lead Research Organisation)
- Ryerson University (Collaboration)
- Complutense University of Madrid (Collaboration)
- Vertex Pharmaceuticals (Collaboration)
- European Cooperation in Science and Technology (COST) (Collaboration)
- University College Dublin (Collaboration)
- Novartis (Collaboration)
- Budapest University of Technology and Economics (Collaboration)
- UCB Pharma (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
- University of Waikato (Collaboration)
- UNIVERSITY OF EDINBURGH (Collaboration)
- EVOTEC (Collaboration)
- University of Bath (Collaboration)
- Marlow Foods (Collaboration)
- Heriot-Watt University (Collaboration)
- Johnson & Johnson (Collaboration)
- Immunocore Ltd (Collaboration)
- Sanofi (Collaboration)
- Research Complex at Harwell (Collaboration)
- Evotec (UK) Ltd (Collaboration)
- Autonomous University of Barcelona (UAB) (Collaboration)
- University of Bristol (Collaboration)
People |
ORCID iD |
| Adrian Mulholland (Principal Investigator) |
Publications
Hedger G
(2016)
Free Energy Landscape of Lipid Interactions with Regulatory Binding Sites on the Transmembrane Domain of the EGF Receptor.
in The journal of physical chemistry. B
Sampson C
(2015)
A "Stepping Stone" Approach for Obtaining Quantum Free Energies of Hydration.
in The journal of physical chemistry. B
Ding W
(2015)
Effects of Lipid Composition on Bilayer Membranes Quantified by All-Atom Molecular Dynamics.
in The journal of physical chemistry. B
Chudyk EI
(2013)
Nonempirical energetic analysis of reactivity and covalent inhibition of fatty acid amide hydrolase.
in The journal of physical chemistry. B
Ranaghan KE
(2017)
Ab Initio QM/MM Modeling of the Rate-Limiting Proton Transfer Step in the Deamination of Tryptamine by Aromatic Amine Dehydrogenase.
in The journal of physical chemistry. B
Hsu PC
(2016)
Molecular Dynamics Simulations Predict the Pathways via Which Pristine Fullerenes Penetrate Bacterial Membranes.
in The journal of physical chemistry. B
King B
(2023)
Tautomerisation Mechanisms in the Adenine-Thymine Nucleobase Pair during DNA Strand Separation.
in The journal of physical chemistry. B
Domanski J
(2017)
Convergence and Sampling in Determining Free Energy Landscapes for Membrane Protein Association.
in The journal of physical chemistry. B
Koldsø H
(2016)
Membrane Compartmentalization Reducing the Mobility of Lipids and Proteins within a Model Plasma Membrane.
in The journal of physical chemistry. B
Amos STA
(2021)
Membrane Interactions of a-Synuclein Revealed by Multiscale Molecular Dynamics Simulations, Markov State Models, and NMR.
in The journal of physical chemistry. B
Brown PM
(2016)
Kainate receptor pore-forming and auxiliary subunits regulate channel block by a novel mechanism.
in The Journal of physiology
Hamdan L
(2015)
Deviation from the anti-Markovnikov rule: a computational study of the regio- and stereoselectivity of diene hydroboration reactions
in Theoretical Chemistry Accounts
Parkhurst JM
(2024)
Computational models of amorphous ice for accurate simulation of cryo-EM images of biological samples.
in Ultramicroscopy
Huggins D
(2018)
Biomolecular simulations: From dynamics and mechanisms to computational assays of biological activity
in WIREs Computational Molecular Science
Lester Hedges
(2019)
BioSimSpace: An interoperable Python framework for biomolecular simulation
in Zenodo
Lester Hedges
(2019)
BioSimSpace: An interoperable Python framework for biomolecular simulation
in Zenodo
Von Glehn Patrick
(2015)
Modelling the reactivity of glutamate mutase and heme dioxygenase enzymes
Mulholland A
(2020)
Catalytic Mechanism of the Colistin Resistance Protein MCR-1
Twidale Rebecca M.
(2021)
Modelling the reactivity of zinc metalloenzymes and the SARS-CoV-2 main protease
Chudyk Ewa Iwona
(2013)
Calculating free energy profiles for enzyme catalysed reactions
Limb Michael
(2015)
Modelling catalysis in hen egg-white lysozyme
Steventon Jack
(2020)
Directed evolution of artificial oxidoreductases
Haldar S
(2021)
Ligand-induced unfolding mechanism of an RNA G-quadruplex
Van Der Kamp M
(2017)
Dynamical origins of heat capacity changes in enzyme catalysed reactions
Ranaghan K
(2016)
Simulating Enzyme Reactivity - Computational Methods in Enzyme Catalysis
Bunzel H
(2022)
Photovoltaic enzymes by design and evolution
Jenkins Jonathan
(2019)
Computational design, construction, and characterisation of artificial peroxidases
Voice Angus
(2021)
Modelling the reactivity of cysteine targeting covalent inhibitors
J. Caceres-Delpiano
(2019)
Automated protein coarse-grained force field optimisation using free energy simulations
Dalkas G
(2019)
Handbook of Food Structure Development
Suardiaz R
(2020)
Catalytic Mechanism of the Colistin Resistance Protein MCR-1
| Description | There is tremendous future scope for biomolecular simulation to provide unprecedented insights into biomolecular systems. The level of detail afforded by these methods, along with their ability to rationalise experimental data and their predictive power are already enabling them to make significant contributions in a wide variety of areas that are crucial for healthcare, quality of life and the environment. The UK biomolecular simulation community has a strong international reputation, with world-leading efforts in in drug design and development, biocatalysis, bionano-technology, chemical biology and medicine. HECBioSim has already delivered outstanding research with impact in bionanotechology, drug design and AMR. But we have only just scratched the surface and there is currently huge room for expansion. Having access to the largest, most modern computing facilities is essential for this. We place special emphasis on reaching out to experimentalists and scientists working in industry in order to foster interactions between computational and experimental scientists, and academia and industry to encourage integrated multidisciplinary studies of key problems. Biomolecular simulation and modelling is an integral part of drug design and development. The pharmaceutical industry needs well-trained scientists in this area, as well as the development of new methods (e.g. for prediction of drug binding affinities, ligand selectivity and metabolism). Members of the consortium have a strong track record of collaboration with industry to deliver trained scientists and new methodologies. For example, PhD students trained by consortium members have recently taken up positions in UCB, Unilever, Oxford Nanoimaging and even Sky Broadcasting as software developer. Many of these academic-industry collaborations have been strengthened by work done through HECBioSim allocations. The Consortium will continue to welcome new members from across the whole community. We will continue to develop computational tools and training for both experts and non-experts using biomolecular simulation on HEC resources. We propose to develop new tools that will enable inter-conversion between biomolecular systems at different levels of resolution thereby allowing users to tackle more ambitious 'grand challenges' than are currently feasible. In summary HECBioSim fosters collaborations between computational and experimental scientists between scientists working in industry and academia in all disciplines within biomolecular simulation to maintain the UK as a world-leader in this field. Biomolecular simulation is increasingly central to understanding and designing biological molecules and their interactions. Detailed, physics-based simulation methods are demonstrating rapidly growing impact in areas as diverse as biocatalysis, drug delivery, biomaterials, biotechnology, and drug design. Simulations offer the potential of uniquely detailed, atomic-level insight into mechanisms, dynamics, and processes, as well as increasingly accurate predictions of molecular properties. Simulations can now be used as computational assays of biological activity, for example, in predictions of drug resistance. Methodological and algorithmic developments, combined with advances in computational hardware, are transforming the scope and range of calculations. Different types of methods are required for different types of problem. Accurate methods and extensive simulations promise quantitative comparison with experiments across biochemistry. Atomistic simulations can now access experimentally relevant timescales for large systems, leading to a fertile interplay of experiment and theory and offering unprecedented opportunities for validating and developing models. Coarse-grained methods allow studies on larger length- and timescales, and theoretical developments are bringing electronic structure calculations into new regimes. Multiscale methods are another key focus for development, combining different levels of theory to increase accuracy, aiming to connect chemical and molecular changes to macroscopic observables. Background HECBioSim, the UK HEC Biomolecular Simulation Consortium, was established in March 2013, and works closely with and complements CCP-BioSim (the UK Collaborative Computational Project for Biomolecular Simulation at the Life Sciences Interface). Most of the members of the Consortium are experienced users of high end computing. Biomolecular simulations are now making significant contributions to a wide variety of problems in drug design and development, biocatalysis, bio and nano-technology, chemical biology and medicine. The UK has a strong and growing community in this field, recognized by the establishment in 2011 by EPSRC of CCP-BioSim (ccpbiosim.ac.uk), , and its renewal in 2015. There is a clear, growing and demonstrable need for HEC in this field. Members of the Consortium have, e.g., served on the HECToR Resource Allocation Panel, including the current and previous Chairs of the RAP. The Consortium welcomes new members across the whole community. Since establishing the Consortium, several new members (FLG, DH, ER) have joined the Management Group. Many of the projects awarded ARCHER time under the Consortium do not involve CCP-BioSim or HECBioSim Management Group members, demonstrating the openness of HECBioSim and its support of the biomolecular simulation community in the UK. A number of other researchers have expressed interest in joining and it is our expectation that other researchers will join HECBioSim in future. We actively engage with structural and chemical biologists and industrial researchers. We foster interactions between computational, experimental and industrial scientists (see e.g. case studies; members of the Consortium have excellent links with many pharmaceutical, chemical and biotechnology companies). Details of HECBioSim are available via our webpages at: http://www.hecbiosim.ac.uk Management HECBioSim supports three different types of project allocation for time on ARCHER. Pump priming projects are those designed to assist a number of activities (e.g. testing of new codes) and typically fall in the <1MAU range. The standard project is probably the most common and is covered in the 1-15 MAU range. Grand challenge projects are typically projects that fall in the 15-50 MAU range, these are generally large collaborative projects that would involve collaboration on a national scale. Applications are made through the website www.hecbiosim.ac.uk and reviewed at one of a series of regular panel meetings. A list of successful HECtime allocations on ARCHER is available at http://www.hecbiosim.ac.uk/applications/successfulprojects (to-date 31 projects). We have welcomed several new groups into HECBioSim since our inception - we are open to new members, unlike some Consortia. All proposals are of course subject to scientific and technical review, but we have the philosophy of supporting the best science to deliver the highest impact, rather than focusing on supporting development of a couple of codes. An allocation panel (with changing membership) meets twice yearly to judge proposals and requests for AUs; projects are assessed competitively; any groups in the UK can apply. The HECBioSim website also provides forums for the biomolecular simulation community, a wiki hosting useful how-tos and user guides, and software downloads (currently FESetup and Longbow). To-date, the website has been accessed by over 10,000 unique IPs. Our lead software development project between Nottingham (Charlie Laughton and Gareth Shannon) and Daresbury (James Gebbie), we have developed a remote job submission tool, 'Longbow' (see below). The tool is designed to reproduce the look and feel of local MD packages, but to stage data and submit jobs to a large HPC resource such as ARCHER in a manner invisible to the user. An open beta version was released unrestricted to the community in March 2015 (http://www.hecbiosim.ac.uk/longbow and via PyPI https://pypi.python.org ) with ~100 downloads. Functionality includes native support for biosimulation packages AMBER, CHARMM, GROMACS, LAMMPS and NAMD, native support for jobs on ARCHER, native support for jobs running on PBS and LSF schedulers, and support for three different job types (single, ensembles and multiple jobs). The software is written both as an application for users and an API for developers. CCP-EM have integrated Longbow into their developmental GUI, and shortly FESetup will ship with native support for job submission using Longbow. We are currently in talks with ClusterVision with respect to them distributing Longbow to their user base as a user friendly way for novices to interact with their systems. Highlights for the Current Reporting Period No more than half a page detailing significant highlights for the period that are not captured elsewhere in the report. Here we highlight in particular as one example (others are listed in sections below), work of Charlie Laughton (Pharmacy, Nottingham) and Sarah Harris (Physics, Leeds): A new, highly accurate, force field for the simulation of DNA, developed and tested using ARCHER through HECBioSim (as part of a large international consortium): see recent paper in Nature Methods, Parmbsc1: a refined force field for DNA simulations I. Ivani et al. Nature Methods aop, (2015) | doi:10.1038/nmeth.3658. Also their work in R.N. Irobalieva et al. Nature Communications 6, Article number: 8440 doi:10.1038/ncomms944055 (Structural diversity of supercoiled DNA) By regulating access to the genetic code, DNA supercoiling strongly affects DNA metabolism. Despite its importance, however, much about supercoiled DNA (positively supercoiled DNA, in particular) remains unknown. Here we use electron cryo-tomography together with biochemical analyses to investigate structures of individual purified DNA minicircle topoisomers with defined degrees of supercoiling. Our results reveal that each topoisomer, negative or positive, adopts a unique and surprisingly wide distribution of three-dimensional conformations. Moreover, we uncover striking differences in how the topoisomers handle torsional stress. As negative supercoiling increases, bases are increasingly exposed. Beyond a sharp supercoiling threshold, we also detect exposed bases in positively supercoiled DNA. Molecular dynamics simulations independently confirm the conformational heterogeneity and provide atomistic insight into the flexibility of supercoiled DNA. Our integrated approach reveals the three-dimensional structures of DNA that are essential for its function. Mark Sansom (Biochemistry, Oxford) Large scale simulations of bacterial outer membranes have revealed how dynamic co-clustering of membrane proteins is mediated by protein-lipid-protein interactions. Working closely with experimentalists in Oxford and York we have shown how this helps to explain segregation of 'old' and 'new' membrane proteins during cell growth and division. This is of direct relevance to probing for possible new targets for antimicrobials. Rassam, P., Copeland, N.A., Birkholz, O., Tóth, C., Chavent, M., Duncan, A.L., Cross, S.J., Housden, N.G., Seger, U., Quinn, D.M., Garrod, T.J., Sansom, M.S.P. Piehler, J., Baumann, C.G., & Kleanthous, C. (2015) Supramolecular assemblies underpin turnover of outer membrane proteins in bacteria. Nature 523:333-336.This approach has since been extended to mammalian cell membranes, and the role of lipid in dynamic co-clustering has been explored. This is of direct relevance to understanding the mode of action of lipid-like drugs targeted at GPCRs: Koldsø, H., & Sansom, M.S.P. (2015) Organization and dynamics of receptor proteins in a plasma membrane. J. Amer. Chem. Soc. 137:14694-14704. Dr Gareth Shannon worked as a HECBioSim Postdoctoral Research Associate in Software Development for Biomolecular Simulation at the University of Nottingham. This 12-month contract spanned 05/01/2015 - 04/01/2016. Longbow is a remote molecular dynamics (MD) job submitter. It allows biomolecular simulation researchers to submit molecular dynamics jobs on remote resources such as High Performance Computers (HPCs) without leaving the familiarity of the Unix-based desktop environment. Longbow delivers and it certainly has the potential to redefine the manner in which HPCs are used. Longbow can be adapted to run any executable installed on an HPC. In this way, the number of users could reach a critical mass such that Longbow becomes a well-known tool internationally in computational science communities. Our case studies provide examples of industrial engagement and impact. Workshops and New Opportunities No more than half a page detailing upcoming workshops and meetings. Also include discussion of other areas which are potentially of interest to other HEC Consortia and opportunities for cross CCP /HEC working. An example of a recent workshop is: our HECBioSim Workshop : 'Going Large: tools to simplify running and analysing large-scale MD simulations on HPC resources', Wed 16 December 2015, Daresbury Laboratory, UK. This 1 day workshop dealt with Longbow, a Python tool created by HECBioSim consortium that allows use of molecular dynamics packages (AMBER, GROMACS, LAMMPS, NAMD) with ease from the comfort of the desktop, and pyPcazip, a flexible Python-based package for the analysis of large molecular dynamics trajectory data sets. We work closely with CCP-BioSim, for example in organizing training workshops and meetings. Examples include: Free Energy Calculation and Molecular Kinetics Workshop, April 20-22, 2015. Free energy workshop, 2nd edition, Southampton, Nov 25th 2014. How to set up a Protein Simulation, 3rd edition, Oxford, Sep 29th 2014. CCPBioSim training week, Sep 2014: Analysis of Biomolecular Simulation Data Tuesday 9th Sep, led by Charlie Laughton/Sarah Harris/Phil Fowler (course material) Python for biomodellers Wednesday 10th Sept, led by Christopher Woods (course material) Monte Carlo methods for biomodelling Thursday 11th Sep, led by Christopher Woods (course material) QM/MM methods Friday 12th Sep, led by Marc van der Kamp Multiscale Modelling Conference. A joint CCPBioSim/CCP5 conference on the theme of multiscale simulation was held in Manchester on 7-9th Jan 2014. Other Joint CCP events: The collaborative computational projects for biomolecular and condensed matter simulation, CCPBioSim and CCP5, are holding a second international conference on the theme of multiscale modelling in Manchester, following on from the first held in January 2014. The three-day event will bring together leading researchers from biological and materials chemistry to discuss topics of common interest across the spectrum of electronic structure, atomistic and mesoscopic scales and to address the current and future challenges posed by multiscale modelling. We are also organizing a joint meeting with CCPN on the interface of NMR and simulation, to be held in July 2016 (Julien Michel, Edinburgh, is leading on organization for CCP-BioSim). Issues and Problems Short discussion of any issues or problems that the HEC Consortium faces including issues with the ARCHER service, funding, management of allocation and staffing. This is also a good opportunity to highlight to the SLA committee any issues that the Consortium may have experienced with their SLA support. Details of SLA activities are given in the SLA report. Dr. James Gebbie provides support to HECBioSIm through the SLA. He has been very helpful in the construction of the HECBioSim webpages (hecbiosim.ac.uk). James also worked with Dr. Gareth Shannon on the development of Longbow (See above). Membership List existing members, highlighting any new members that have joined the consortium during the reporting period. There are currently 105 users of HECBioSim Archer time. We have 28 current projects and we are awaiting 5 new sign ups (from the December awards). World class and world leading scientific output: ARCHER should enable high quality and world-leading science to be delivered. This should generate high impact outputs and outcomes that increase the UK's position in world science. • For the reporting period please provide a bullet pointed list of key research findings and any linked publications. • For the reporting period please include a bullet pointed list of any relevant press announcements and other communications of significance to an international community. • Since ARCHER came on line, what are the top 5 scientific outcomes that have resulted from projects supported by the Consortium? This could be research that has been published in high impact journals, work that has been highly cited, or research that has had a significant impact on the consortium's community or strategic direction. Recent publications from HECBioSim work include (this is a selected sample from groups across the Consortium; some are highlighted and described in more detail below): Ding, W., M. Palaiokostas, W. Wang, M. Orsi. Effects of lipid composition on bilayer membranes quantified by all-atom molecular dynamics, J. Phys. Chem. B J. Phys. Chem. B, 119, 15263-15274 (2015) P. Dinis et al. X-ray crystallographic and EPR spectroscopic analysis of HydG, a maturase in [FeFe]-hydrogenase H-cluster assembly Proc. Natl. Acad. Sci. USA 112 1362-1367 (2015) N.A. Berglund et al. Open Archive Establishing the Structural Rules for Ligand Recognition, Signaling and Assembly in Innate Immune Receptors Biophys. J. 108, 98a http://dx.doi.org/10.1016/j.bpj.2014.11.562 H. Strahl et al. Membrane Recognition and Dynamics of the RNA Degradosome PLoS Genetics DOI: 10.1371/journal.pgen.1004961 (2015) N.A. Berglund Interaction of the Antimicrobial Peptide Polymyxin B1 with Both Membranes of E. coli: A Molecular Dynamics Study PLoS Computational Biology DOI: 10.1371/journal.pcbi.1004180 (2015) R.M.A. Manara et al. DNA sequencing with MspA: Molecular Dynamics simulations reveal free-energy differences between sequencing and non-sequencing mutants Scientific Reports 5, Article number: 12783 doi:10.1038/srep12783 (2015) A. Gray et al. In pursuit of an accurate spatial and temporal model of biomolecules at the atomistic level: a perspective on computer simulation Acta Cryst. D71, 162-172 doi:10.1107/S1399004714026777 (2015). J. M. A. Manara et al. Free-Energy Calculations Reveal the Subtle Differences in the Interactions of DNA Bases with a-Hemolysin J. Chem. Theory Comput., 2015, 11 (2), pp 810-816 DOI: 10.1021/ct501081h (2015) Comparison of Molecular Contours for Measuring Writhe in Atomistic Supercoiled DNA T. Sutthibutpong, S.A. Harris, and A. Noy Comparison of Molecular Contours for Measuring Writhe in Atomistic Supercoiled DNA J. Chem. Theory Comput. 11, 2768-2775 DOI: 10.1021/acs.jctc.5b00035 (2015) R.N. Irobalieva, Structural diversity of supercoiled DNA Nature Communications 6, Article number: 8440 doi:10.1038/ncomms9440 (2015) E. Rosta, W. Yang and G. Hummer, Calcium inhibition of Ribonuclease H1 two-metal ion catalysis" Journal of the American Chemical Society 136, pp 3137-3144 DOI: 10.1021/ja411408x (2014) A. Ganguy et al. Quantum Mechanical/Molecular Mechanical Free Energy Simulations of the Self-Cleavage Reaction in the Hepatitis Delta Virus Ribozyme. J. American Chemical Society, 136, 1483-1496 (2014). Arianna Fornili (School of Biological and Chemical Sciences, Queen Mary University of London) Molecular basis of regulation of cardiac myosin under normal conditions and in the presence of pathogenic mutations. The findings from this study will be presented at the 60th Annual Meeting of the Biophysical Society (27Feb - 2Mar 2016) in Los Angeles. An abstract of this work (A.Fornili, E. Rostkova, F. Fraternali, M. Pfuhl: "Effect of RLC-Nterminal tails on the structure and dynamics of cardiac myosin") will be published in a special number of the Biophysical Journal. A manuscript is currently under preparation. Francesco Gervasio (Chemistry, UCL) ARCHER time through HECBioSIm has been used to elucidate the mode of action of cancer-causing and drug-resistance causing mutations in an important class of signalling proteins (protein kinases). This kind of information is of great importance in the rational design of more effective anti-cancer drugs. [1] T. D. Bunney, S. Wan, N. Thiyagarajan, L. Sutto, S. V. Williams, P. Ashford, H. Koss, M. A. Knowles, F. L. Gervasio, P. V. Coveney, M. Katan EBioMedicine, 2, 194-204, 2015. [2] K Marino, L Sutto, F L Gervasio* The Effect of a Wide-spread Cancer-causing Mutation on the Inactive to Active Dynamics of the B-Raf Kinase J. Am. Chem. Soc. 137, 5280-5283, 2015 [3] S. Lovera, M. Morando, E. Pucheta-Martinez, J. Martinez-Torrecuadrada, G. Saladino, F. L. Gervasio* Towards a Molecular Understanding of the Link Between Imatinib Resistance and Kinase Conformational Dynamics Plos Comp Biol. 12, e1004578, 2015. Julien Michel (Chemistry, Edinburgh) Established the mechanisms by which a key cancer causing protein recognises small molecule drugs via a disordered protein region. The findings are helping drug designers target more effectively this protein to develop more efficacious drugs. Elucidation of Ligand-Dependent Modulation of Disorder-Order Transitions in the Oncoprotein MDM2 Bueren-Calabuig, J. A. ; Michel, J. PLoS Comput. Biol. , 11(6): e1004282, 2015 Mario Orsi (School of Engineering and Materials Science, Queen Mary University of London) Atomistic molecular dynamics simulations were performed on models for cell membranes. In particular, effects due to changes in the lamellar vs. nonlamellar lipid composition of membranes were quantified. A number of properties of mixed lipid membranes were characterized quantitatively for the first time, including the lateral pressure, electric field and dipole potential. This work has been published in a high quality peer-reviewed international journal [Wei Ding, Michail Palaiokostas, Wen Wang, and Mario Orsi, Effects of Lipid Composition on Bilayer Membranes Quantified by All-Atom Molecular Dynamics The Journal of Physical Chemistry B 2015 119 (49), 15263-15274, DOI: 10.1021/acs.jpcb.5b06604]. Molecular simulations were conducted to study permeation processes of small molecules through mixed lipid membranes. For the first time, it is shown that nonlamellar lipids reduce membrane permeation through a mechanism that can be related to a small number of fundamental physical properties. A manuscript on this research is in preparation. The research conducted was selected for oral presentations at the 2015 MGMS Young Modellers' Forum (The Old Naval College, Greenwich, London, 27/11/15) and at the 2015 Thomas Young Centre Student Day (Imperial College, London, 17/12/15), as well as for poster presentations at the 2016 Annual Biophysical Society meeting (Los Angeles, 27 Feb-2 Mar 2016). Mark Sansom (Biochemistry, Oxford) We have also used ARCHER as part of our ongoing programme of very large scale simulations of the dynamic properties of viral membrane envelopes in biomedically important enveloped viruses including influenza and dengue. (Reddy, T. & Sansom, M.S.P. (2015) The role of the membrane in the structure and biophysical robustness of the dengue virion envelope. http://dx.doi.org/10.1016/j.str.2015.12.011). These virus simulations were featured in local media following their presentation by Tyler Reddy at the 2014 US Biophysics meeting. Other recent successes of the use of ARCHER under HECBioSim (Sansom Group, Oxford) include a collaboration between computational and experimental groups (the latter using advanced microscopy imaging of bacterial membranes) to study role of nanoscale 'islands' of membrane proteins in bacterial cell division (see above). This work is continuing, and is of relevance to developing novel targets to help overcome antimicrobial resistance. It has also led to an increase in interest in large scale simulations of membranes from a number of structural biology and biophysics groups, including those of Carol Robinson (Chemistry, Oxford) and Liz Carpenter (SGC, Oxford), in particular using these methods to characterise the interactions of membrane proteins with their lipid bilayer environment Stansfeld, P.J., Goose, J.E., Caffrey, M., Carpenter, E.P., Parker, J.L., Newstead, N. & Sansom, M.S.P. (2015) MemProtMD: automated insertion of membrane protein structures into explicit lipid membranes. Structure (doi:10.1016/j.str.2015.05.006) Phil Biggin (Biochemistry, Oxford) Work from the Biggin group has made strong use of ARCHER through HECBioSim and has resulted in the following publications from the allocations from the Consortium over the past year: Kainate receptor pore-forming and auxiliary subunits regulate channel block by a novel mechanism. Brown PM, Aurousseau MR, Musgaard M, Biggin PC, Bowie D. J Physiol. 2015 Dec 18. doi: 10.1113/JP271690. [Epub ahead of print] Accurate calculation of the absolute free energy of binding for drug molecules, Aldeghi M, Heifetz A, Bodkin MJ, Knapp S, Biggin PC. Chem. Sci., 2016,7, 207-218 doi: 10.1039/C5SC02678D Distinct structural pathways coordinate the activation of AMPA receptor-auxiliary subunit complexes Dawe GB, Musgaard M, Aurousseau M, Nayeem N, Green T, Biggin PC, Bowie D. Neuron [in press] The role of an absolutely conserved tryptophan pair in the extracellular domain of Cys-loop receptors. Braun N, Lynagh T, Yu R, Biggin PC, Pless S. ACS Chem. Neurosci. [in press] Greater scientific productivity: As well as speed increases, the optimisation of codes for the ARCHER machine will enable problems to be solved in less time using fewer compute resources. • For the reporting period please provide a brief update on progress of software development activities associated with the consortium and the impact this has had on consortium members and the broader research community. Charlie Laughton (Pharmacy, Nottingham) Development and deployment of Longbow, a high-throughput remote job submission tool for the biomolecular simulation community, now being leveraged by other CCPs as well. Longbow makes at easy for biomolecular simulation jobs to be run on Archer as on a local desktop. Journal of Open Research Software 2016, DOI: http://dx.doi.org/10.5334/jors.95 Francesco Gervasio (Chemistry, UCL) Researchers from University College London, led by Francesco Gervasio in collaboration with the Structural Biology Computational Group of the Spanish National Cancer Research Centre (CNIO) headed by Alfonso Valencia have developed the first computational method based on evolutionary principles to predict protein dynamics, which explains the changes in the shape or dimensional structure that they experience in order to interact with other compounds or speed up chemical reactions. The study made possible by the supercomputing resources provided by Archer and PRACE constitutes a major step forward in the computational study of protein dynamics. [4] L. Sutto, S. Marsili, A. Valencia, F. L. Gervasio* From residue co-evolution to protein conformational ensembles and functional dynamics Proc Natl Acad Sci USA, 112 13567-13572, 2015 Press release: http://www.eurekalert.org/pub_releases/2015-10/cndi-ana102315.php Phil Biggin (Biochemistry, Oxford) Our recent publication on Accurate free energy predictions made use of the FESetup package (through the CCPBioSIM CCP). Increasing the UK's CSE skills base (including graduate and post doctorate training and support): This builds on the skills sets of trained people in HPC, both in terms of capacity and raising the overall skill level available to the sector. • For the reporting period please provide a bullet pointed list of training activities undertaken by the Consortium, providing information on the target audience and level of attendance. For example: Arianna Fornili (School of Biological and Chemical Sciences, Queen Mary University of London) A 1st year PhD student working on this project is currently being trained under my supervision in the use of HPC resources and in particular of ARCHER. Charlie Laughton (Pharmacy, Nottingham) "Going Large" workshop: Daresbury 16/12/15. Hands-on introduction to HECBioSim tools (Longbow and pyPcazip) developed to aid the running and analysis of large scale ensemble simulations. 16 attendees. Francesco Gervasio and Edina Rosta (Chemistry, UCL and Chemistry, KCL) E. Rosta (KCL) & F. Gervasio (UCL) organized a workshop on Free Energy Calculation and Molecular Kinetics in London April 20-22, 2015. The successful workshop was attended by more than 40 (mainly post-doctoral) academic and industrial researcher from all over Europe. Increased impact and collaboration with industry: ARCHER does not operate in isolation and the 'impact' of ARCHER's science is converted to economic growth through the interfaces with business and industry. In order to capture the impacts, which may be economic, social, environmental, scientific or political, various metrics may be utilised. • Please provide a brief update on any planned activities / collaborations / outcomes outlined in the original Pathways to Impact plan for the Consortium. • For the reporting period please provide information on any Consortium projects that have been performed in collaboration with industry, this should include details of the company involved, a statement on the impact that the work has / is making and, if relevant, details of any in kind or in cash contributions that have been associated with this work. • For the reporting period include a list of Consortium publications that have industrial co-authorship. • For the reporting period please provide details of the any other activities involving industrial participation e.g. activities involving any Industrial Advisory panels, attendance / participation in workshops and Consortium based activities. Arianna Fornili (School of Biological and Chemical Sciences, Queen Mary University of London) This project is done in collaboration with experimental (NMR and SAXS) partners at King's College London (Dr. Mark Pfuhl and Dr. Elena Rostkova), with the final aim of providing a complete molecular model of how muscle contraction is regulated in the heart. Francesco Gervasio (Chemistry, UCL) A new collaboration with UCB on developing new approaches to sample cryptic binding sites of pharmaceutical interest was started. UCB co-sponsored a BBSRC-CASE PhD studentships. The code development and its application to interesting targets was made possible by the access to Archer. Phil Biggin (Biochemistry, Oxford) The following has industrial partners as co-authors: Accurate calculation of the absolute free energy of binding for drug molecules, Aldeghi M, Heifetz A, Bodkin MJ, Knapp S, Biggin PC. Chem. Sci., 2016,7, 207-218 doi: 10.1039/C5SC02678D. The GLAS scoring module for gromacs has yet to be implemented but that would also constitute industrial activity. Strengthening of UK's international position: The impacts of ARCHER's science extend beyond national borders and most science is delivered through partnerships on a national or international level. • For the reporting period please provide a bullet pointed list of projects that have involved international collaboration. • For the reporting period please provide a list of consortium publications with international co-authorship. • For the reporting period please detail any other international activities that the Consortium might be involved in (workshops, EU projects etc.). Alessandro Pandini (Computer Science, Brunel University London) The "Analysis of the allosteric communication in HIF-2a-ARNT heterodimer" has recently started (1st December 2015). It is aimed at the identification of the allosteric pathways in the HIF-2a-ARNT heterodimer. This can advance the discovery of therapeutic molecules and shed light on the mechanisms underlying disease mutations and post-translational modifications affecting the response to hypoxic stress in cells. In this early stages of the project, a promising collaboration has been explored with the group of Prof. Laura Bonati at the University of Milan-Bicocca. This collaboration will provide an avenue for scientific visits, for the training of a PhD student currently working in Prof. Bonati's group. Charlie Laughton (Pharmacy, Nottingham) • The "Ascona B-DNA Consortium" project to develop next-generation simulations of nucleic acids. Partners across Europe and in the USA and India. Publication: Nature Methods, 2016, 13(1), 55-+ • EU H2020 project "Multiscale genomics" (multiscalegenomics.eu): developing computational tools and infrastructures to support a multiscale genomics virtual research environment. • CECAM Extended Software Development Workshop (joint with NSF): Deployment and development of advanced sampling tools on HPC resources. Juelich, 11-24/10/15. 91 attendees from across Europe and the US. Francesco Gervasio (Chemistry, UCL) Both projects listed above as well as references 3 and 4 involved international collaborations with research groups at the Spanish National Cancer Research Centre, one of the most important cancer biology research centres in Europe. Phil Biggin (Biochemistry, Oxford) All of these have international collaboration and co-authorships: Kainate receptor pore-forming and auxiliary subunits regulate channel block by a novel mechanism. Brown PM, Aurousseau MR, Musgaard M, Biggin PC, Bowie D. J Physiol. 2015 Dec 18. doi: 10.1113/JP271690. [Epub ahead of print] Accurate calculation of the absolute free energy of binding for drug molecules, Aldeghi M, Heifetz A, Bodkin MJ, Knapp S, Biggin PC. Chem. Sci., 2016,7, 207-218 doi: 10.1039/C5SC02678D Distinct structural pathways coordinate the activation of AMPA receptor-auxiliary subunit complexes Dawe GB, Musgaard M, Aurousseau M, Nayeem N, Green T, Biggin PC, Bowie D. Neuron [in press] The role of an absolutely conserved tryptophan pair in the extracellular domain of Cys-loop receptors. Braun N, Lynagh T, Yu R, Biggin PC, Pless S. ACS Chem. Neurosci. [in press] Future Vision: How do you see the Consortium strategy evolving and changing in the future? In the next 5 years, what new science questions will members of your Consortium be seeking to address? Why are these important? We aim to expand the breadth of the work of the Consortium focusing on cutting-edge applications, and building collaborations with experiments and industry, to achieve maximum impact from ARCHER use. HECBioSim is now well established, supporting work of many groups across the UK in the growing field of biomolecular simulation. We benefit from an Advisory Group containing members from industry, as we as international biomolecular simulation experts and experimental scientists. The Advisory Board was expanded and refreshed for the renewal and consists of: Dr. Nicolas Foloppe (Vernalis plc, Chair); Dr. Colin Edge (GlaxoSmithKline); Dr. Mike King (UCB Pharmaceuticals); Dr. Mike Mazanetz (Evotec AG); Dr. Garrett Morris (Crysalin Ltd.); Dr. Gary Tresadern (Johnson and Johnson Pharmaceuticals); Dr. Richard Ward (AstraZeneca); Prof. Modesto Orozco (IRB, Barcelona); Prof. Tony Watts, (Oxford, NMR); Dr. Pete Bond (A*STAR Bioinformatics Institute Singapore). We aim to foster industrial collaborations and collaborations with experimentalists (e.g. joint workshops with CCPN, Institute of Physics (Sarah Harris, Leeds Physics); see e.g. case studies. A particular them for strategic development will be multiscale modelling, building on collaborations between several groups in the Consortium. We discussed Grand Challenges at our most recent Management Group meeting. In December 2015, and have have identified several to follow up as strategic priorities. We aim to tackle and support large-scale grand challenge applications in biomolecular science, in areas such as antimicrobial resistance, membrane dynamics, drug design and synthetic biology. One specific theme with potentially high impact in drug discovery is large -scale comparative investigation of allosteric regulation in different superfamilies of proteins (e.g. PAS domain containing proteins, tyrosine kinases, etc.). The major impact will be in the identification of novel selective therapeutic molecules with limited adverse side effects. As a Consortium, we intend to develop and apply novel computational approaches for the rational design of allosteric regulators of hitherto 'undruggable' targets. Many of the targets emerging from large-scale genetic screening are deemed undruggable due to the difficulty of designing drug-like modulators that bind to their catalytic sites. It is increasingly clear that these targets might be effectively targeted by designing drugs that bind to protein-protein interfaces and allosteric sites. To do that, however, new rational design strategies, based on an in-depth knowledge of protein dynamics and advanced modelling and new simulation techniques are required. Other challenging frontier areas include dynamics of motor proteins; prediction of the effects of pathogenic mutations on protein function. The accurate prediction of free energy of binding is still in its infancy and needs much further investigation. Finally, kinetics of biomolecular reactions will become the next big topic. It is clear that high end computing resource can provide the necessary power and capability to provide inroads into this vital area. This is important because it is becoming increasingly apparent that kinetics of drug binding is a key factor that the pharmaceutical sector should really be looking at in terms of a major dictator of potency. Background HECBioSim, the UK HEC Biomolecular Simulation Consortium, was established in March 2013, and works closely with and complements CCP-BioSim (the UK Collaborative Computational Project for Biomolecular Simulation at the Life Sciences Interface). Most of the members of the Consortium are experienced users of high end computing. Biomolecular simulations are now making significant contributions to a wide variety of problems in drug design and development, biocatalysis, bio and nano-technology, chemical biology and medicine. The UK has a strong and growing community in this field, recognized by the establishment in 2011 by the EPSRC of CCP-BioSim (ccpbiosim.ac.uk), and its renewal in 2015. There is a clear, growing and demonstrable need for HEC in this field. Members of the Consortium have, for example, served on the HECToR and ARCHER Resource Allocation Panel. The Consortium welcomes members across the whole biomolecular sciences community, and we are currently (and will remain) open to new members (unlike some consortia). Since establishing the Consortium, several new members (FLG, DH, ER) have joined the Management Group. Many of the projects awarded ARCHER time under the Consortium do not involve CCP-BioSim or HECBioSim Management Group members, demonstrating the openness of HECBioSim and its support of the biomolecular simulation community in the UK. A number of other researchers have joined and it is our expectation that other researchers will join HECBioSim in the future. We actively engage with structural and chemical biologists and industrial researchers. We foster interactions between computational, experimental and industrial scientists (see the example case studies; members of the Consortium have excellent links with many pharmaceutical, chemical and biotechnology companies). Details of HECBioSim are available via our webpages at: http://www.hecbiosim.ac.uk. Applications are made through the website http://www.hecbiosim.ac.uk and reviewed at one of the series of regular panel meetings. A list of successful HECtime allocations on ARCHER is available at:http://www.hecbiosim.ac.uk/applications/successfulprojects. All proposals are of course subject to scientific and technical review, but we have the philosophy of supporting the best science to deliver the highest impact, rather than focusing on supporting development of a couple of codes. An allocation panel (with changing membership) meets twice yearly to judge proposals and requests for AUs; projects are assessed competitively: any groups in the UK can apply. All submitted proposals receive constructive feedback from the allocation panel. The HECBioSim website also provides forums for the biomolecular simulation community, a wiki hosting useful how-tos and user guides, and software downloads (currently FESetup and Longbow). Our lead software development project between Nottingham (Charlie Laughton and Gareth Shannon) and Daresbury (James Gebbie), we have developed a remote job submission tool, 'Longbow' (see below). The tool is designed to reproduce the look and feel of local MD packages, but to stage data and submit jobs to a large HPC resource, such as ARCHER, in a manner invisible to the user. Workshops and New Opportunities Workshops are listed below and can be found on the HECBioSim Website We work closely with CCP-BioSim, for example in organizing training workshops and meetings. Our activities are outlined at www.hecbiosim.ac.uk Examples of forthcoming meetings include: Computational Molecular Science 2017 - on Sunday 19 March 2017 17th European Seminar on Computational Methods in Quantum Chemistry - on Tuesday 11 July 2017 Frontiers of Biomolecular Simulation Southampton, September 2017 Issues and Problems Details of SLA activities are given in the SLA report. Dr. James Gebbie provides support to HECBioSIm through the SLA. He has been very helpful in the construction of the HECBioSim webpages (hecbiosim.ac.uk). James also worked with Dr. Gareth Shannon on the development of Longbow (See above). In the past year, members of the Consortium faced some queuing problems; close to the end of the first allocation period in particular, there were long queuing times, which led to problems in completing jobs and using allocated time. Throughput has been a real problem in the past few months. Membership Please provide a full list of existing members and their institutions, highlighting any new members that have joined the consortium during the reporting period. If available please provide information on the number of distinct users that have accessed ARCHER via the Consortium during this reporting period. Below is a list of PIs with HECBioSim projects in the current reporting period: Agnes Noy University of York new to this reporting period Alessandro Pandini Brunel University London Arianna Fornili Queen Mary University of London Cait MacPhee University of Edinbrurgh new to this reporting period Charlie Laughton University of Nottingham Clare-Louise Towse University of Bradford new to this reporting period D Flemming Hansen University College London new to this reporting period David Huggins Aston University Edina Rosta King's College London Francesco Gervasio University College London Ian Collinson University of Bristol new to this reporting period Irina Tikhonova Queen's University Belfast Jiayun Pang University of Greenwich Jonathan Doye University of Oxford Julien Michel University of Edinburgh Mario Orsi UWE Bristol Michele Vendruscolo University of Cambridge Michelle Sahai University of Roehampton Philip Biggin University of Oxford Richard Sessions University of Bristol Stephen Euston Heriot-Watt University Syma Khalid University of Southampton HECBioSIm has facilitated several industrial collaborations, as described in case studies submitted to EPSRC. See hecbiosim.ac.uk for further details. A recent bid for further EPSRC support of HECBioSim was successful (PI: Prof. Syma Khalid, Southampton University). EP/R029407/1 The UK High-End Computing Consortium for Biomolecular Simulation 2018-2022 HECBioSim, the UK HEC Biomolecular Simulation Consortium, was established in March 2013, and works closely with and complements CCP-BioSim (the UK Collaborative Computational Project for Biomolecular Simulation at the Life Sciences Interface). Most of the members of the Consortium are experienced users of high end computing. Biomolecular simulations are now making significant contributions to a wide variety of problems in drug design and development, biocatalysis, bio and nano-technology, chemical biology and medicine. The UK has a strong and growing community in this field, recognized by the establishment in 2011 by EPSRC of CCP-BioSim (ccpbiosim.ac.uk), , and its renewal in 2015. There is a clear, growing and demonstrable need for HEC in this field. Members of the Consortium have, e.g., served on the HECToR Resource Allocation Panel, including the current and previous Chairs of the RAP. The Consortium welcomes new members across the whole community. Since establishing the Consortium, several new members (FLG, DH, ER) have joined the Management Group. Many of the projects awarded ARCHER time under the Consortium do not involve CCP-BioSim or HECBioSim Management Group members, demonstrating the openness of HECBioSim and its support of the biomolecular simulation community in the UK. A number of other researchers have expressed interest in joining and it is our expectation that other researchers will join HECBioSim in future. We actively engage with structural and chemical biologists and industrial researchers. We foster interactions between computational, experimental and industrial scientists (see e.g. case studies; members of the Consortium have excellent links with many pharmaceutical, chemical and biotechnology companies). Details of HECBioSim are available via our webpages at: http://www.hecbiosim.ac.uk Management HECBioSim supports three different types of project allocation for time on ARCHER. Pump priming projects are those designed to assist a number of activities (e.g. testing of new codes) and typically fall in the <1MAU range. The standard project is probably the most common and is covered in the 1-15 MAU range. Grand challenge projects are typically projects that fall in the 15-50 MAU range, these are generally large collaborative projects that would involve collaboration on a national scale. Applications are made through the website www.hecbiosim.ac.uk and reviewed at one of a series of regular panel meetings. A list of successful HECtime allocations on ARCHER is available at http://www.hecbiosim.ac.uk/applications/successfulprojects (to-date 31 projects). We have welcomed several new groups into HECBioSim since our inception - we are open to new members, unlike some Consortia. All proposals are of course subject to scientific and technical review, but we have the philosophy of supporting the best science to deliver the highest impact, rather than focusing on supporting development of a couple of codes. An allocation panel (with changing membership) meets twice yearly to judge proposals and requests for AUs; projects are assessed competitively; any groups in the UK can apply. The HECBioSim website also provides forums for the biomolecular simulation community, a wiki hosting useful how-tos and user guides, and software downloads (currently FESetup and Longbow). To-date, the website has been accessed by over 10,000 unique IPs. Our lead software development project between Nottingham (Charlie Laughton and Gareth Shannon) and Daresbury (James Gebbie), we have developed a remote job submission tool, 'Longbow' (see below). The tool is designed to reproduce the look and feel of local MD packages, but to stage data and submit jobs to a large HPC resource such as ARCHER in a manner invisible to the user. An open beta version was released unrestricted to the community in March 2015 (http://www.hecbiosim.ac.uk/longbow and via PyPI https://pypi.python.org ) with ~100 downloads. Functionality includes native support for biosimulation packages AMBER, CHARMM, GROMACS, LAMMPS and NAMD, native support for jobs on ARCHER, native support for jobs running on PBS and LSF schedulers, and support for three different job types (single, ensembles and multiple jobs). The software is written both as an application for users and an API for developers. CCP-EM have integrated Longbow into their developmental GUI, and shortly FESetup will ship with native support for job submission using Longbow. We are currently in talks with ClusterVision with respect to them distributing Longbow to their user base as a user friendly way for novices to interact with their systems. Highlights for the Current Reporting Period No more than half a page detailing significant highlights for the period that are not captured elsewhere in the report. Here we highlight in particular as one example (others are listed in sections below), work of Charlie Laughton (Pharmacy, Nottingham) and Sarah Harris (Physics, Leeds): A new, highly accurate, force field for the simulation of DNA, developed and tested using ARCHER through HECBioSim (as part of a large international consortium): see recent paper in Nature Methods, Parmbsc1: a refined force field for DNA simulations I. Ivani et al. Nature Methods aop, (2015) | doi:10.1038/nmeth.3658. Also their work in R.N. Irobalieva et al. Nature Communications 6, Article number: 8440 doi:10.1038/ncomms944055 (Structural diversity of supercoiled DNA) By regulating access to the genetic code, DNA supercoiling strongly affects DNA metabolism. Despite its importance, however, much about supercoiled DNA (positively supercoiled DNA, in particular) remains unknown. Here we use electron cryo-tomography together with biochemical analyses to investigate structures of individual purified DNA minicircle topoisomers with defined degrees of supercoiling. Our results reveal that each topoisomer, negative or positive, adopts a unique and surprisingly wide distribution of three-dimensional conformations. Moreover, we uncover striking differences in how the topoisomers handle torsional stress. As negative supercoiling increases, bases are increasingly exposed. Beyond a sharp supercoiling threshold, we also detect exposed bases in positively supercoiled DNA. Molecular dynamics simulations independently confirm the conformational heterogeneity and provide atomistic insight into the flexibility of supercoiled DNA. Our integrated approach reveals the three-dimensional structures of DNA that are essential for its function. Mark Sansom (Biochemistry, Oxford) Large scale simulations of bacterial outer membranes have revealed how dynamic co-clustering of membrane proteins is mediated by protein-lipid-protein interactions. Working closely with experimentalists in Oxford and York we have shown how this helps to explain segregation of 'old' and 'new' membrane proteins during cell growth and division. This is of direct relevance to probing for possible new targets for antimicrobials. Rassam, P., Copeland, N.A., Birkholz, O., Tóth, C., Chavent, M., Duncan, A.L., Cross, S.J., Housden, N.G., Seger, U., Quinn, D.M., Garrod, T.J., Sansom, M.S.P. Piehler, J., Baumann, C.G., & Kleanthous, C. (2015) Supramolecular assemblies underpin turnover of outer membrane proteins in bacteria. Nature 523:333-336.This approach has since been extended to mammalian cell membranes, and the role of lipid in dynamic co-clustering has been explored. This is of direct relevance to understanding the mode of action of lipid-like drugs targeted at GPCRs: Koldsø, H., & Sansom, M.S.P. (2015) Organization and dynamics of receptor proteins in a plasma membrane. J. Amer. Chem. Soc. 137:14694-14704. Dr Gareth Shannon worked as a HECBioSim Postdoctoral Research Associate in Software Development for Biomolecular Simulation at the University of Nottingham. This 12-month contract spanned 05/01/2015 - 04/01/2016. Longbow is a remote molecular dynamics (MD) job submitter. It allows biomolecular simulation researchers to submit molecular dynamics jobs on remote resources such as High Performance Computers (HPCs) without leaving the familiarity of the Unix-based desktop environment. Longbow delivers and it certainly has the potential to redefine the manner in which HPCs are used. Longbow can be adapted to run any executable installed on an HPC. In this way, the number of users could reach a critical mass such that Longbow becomes a well-known tool internationally in computational science communities. Our case studies provide examples of industrial engagement and impact. Workshops and New Opportunities No more than half a page detailing upcoming workshops and meetings. Also include discussion of other areas which are potentially of interest to other HEC Consortia and opportunities for cross CCP /HEC working. An example of a recent workshop is: our HECBioSim Workshop : 'Going Large: tools to simplify running and analysing large-scale MD simulations on HPC resources', Wed 16 December 2015, Daresbury Laboratory, UK. This 1 day workshop dealt with Longbow, a Python tool created by HECBioSim consortium that allows use of molecular dynamics packages (AMBER, GROMACS, LAMMPS, NAMD) with ease from the comfort of the desktop, and pyPcazip, a flexible Python-based package for the analysis of large molecular dynamics trajectory data sets. We work closely with CCP-BioSim, for example in organizing training workshops and meetings. Examples include: Free Energy Calculation and Molecular Kinetics Workshop, April 20-22, 2015. Free energy workshop, 2nd edition, Southampton, Nov 25th 2014. How to set up a Protein Simulation, 3rd edition, Oxford, Sep 29th 2014. CCPBioSim training week, Sep 2014: Analysis of Biomolecular Simulation Data Tuesday 9th Sep, led by Charlie Laughton/Sarah Harris/Phil Fowler (course material) Python for biomodellers Wednesday 10th Sept, led by Christopher Woods (course material) Monte Carlo methods for biomodelling Thursday 11th Sep, led by Christopher Woods (course material) QM/MM methods Friday 12th Sep, led by Marc van der Kamp Multiscale Modelling Conference. A joint CCPBioSim/CCP5 conference on the theme of multiscale simulation was held in Manchester on 7-9th Jan 2014. Other Joint CCP events: The collaborative computational projects for biomolecular and condensed matter simulation, CCPBioSim and CCP5, are holding a second international conference on the theme of multiscale modelling in Manchester, following on from the first held in January 2014. The three-day event will bring together leading researchers from biological and materials chemistry to discuss topics of common interest across the spectrum of electronic structure, atomistic and mesoscopic scales and to address the current and future challenges posed by multiscale modelling. We are also organizing a joint meeting with CCPN on the interface of NMR and simulation, to be held in July 2016 (Julien Michel, Edinburgh, is leading on organization for CCP-BioSim). Issues and Problems Short discussion of any issues or problems that the HEC Consortium faces including issues with the ARCHER service, funding, management of allocation and staffing. This is also a good opportunity to highlight to the SLA committee any issues that the Consortium may have experienced with their SLA support. Details of SLA activities are given in the SLA report. Dr. James Gebbie provides support to HECBioSIm through the SLA. He has been very helpful in the construction of the HECBioSim webpages (hecbiosim.ac.uk). James also worked with Dr. Gareth Shannon on the development of Longbow (See above). Membership List existing members, highlighting any new members that have joined the consortium during the reporting period. There are currently 105 users of HECBioSim Archer time. We have 28 current projects and we are awaiting 5 new sign ups (from the December awards). World class and world leading scientific output: ARCHER should enable high quality and world-leading science to be delivered. This should generate high impact outputs and outcomes that increase the UK's position in world science. • For the reporting period please provide a bullet pointed list of key research findings and any linked publications. • For the reporting period please include a bullet pointed list of any relevant press announcements and other communications of significance to an international community. • Since ARCHER came on line, what are the top 5 scientific outcomes that have resulted from projects supported by the Consortium? This could be research that has been published in high impact journals, work that has been highly cited, or research that has had a significant impact on the consortium's community or strategic direction. Recent publications from HECBioSim work include (this is a selected sample from groups across the Consortium; some are highlighted and described in more detail below): Ding, W., M. Palaiokostas, W. Wang, M. Orsi. Effects of lipid composition on bilayer membranes quantified by all-atom molecular dynamics, J. Phys. Chem. B J. Phys. Chem. B, 119, 15263-15274 (2015) P. Dinis et al. X-ray crystallographic and EPR spectroscopic analysis of HydG, a maturase in [FeFe]-hydrogenase H-cluster assembly Proc. Natl. Acad. Sci. USA 112 1362-1367 (2015) N.A. Berglund et al. Open Archive Establishing the Structural Rules for Ligand Recognition, Signaling and Assembly in Innate Immune Receptors Biophys. J. 108, 98a http://dx.doi.org/10.1016/j.bpj.2014.11.562 H. Strahl et al. Membrane Recognition and Dynamics of the RNA Degradosome PLoS Genetics DOI: 10.1371/journal.pgen.1004961 (2015) N.A. Berglund Interaction of the Antimicrobial Peptide Polymyxin B1 with Both Membranes of E. coli: A Molecular Dynamics Study PLoS Computational Biology DOI: 10.1371/journal.pcbi.1004180 (2015) R.M.A. Manara et al. DNA sequencing with MspA: Molecular Dynamics simulations reveal free-energy differences between sequencing and non-sequencing mutants Scientific Reports 5, Article number: 12783 doi:10.1038/srep12783 (2015) A. Gray et al. In pursuit of an accurate spatial and temporal model of biomolecules at the atomistic level: a perspective on computer simulation Acta Cryst. D71, 162-172 doi:10.1107/S1399004714026777 (2015). J. M. A. Manara et al. Free-Energy Calculations Reveal the Subtle Differences in the Interactions of DNA Bases with a-Hemolysin J. Chem. Theory Comput., 2015, 11 (2), pp 810-816 DOI: 10.1021/ct501081h (2015) Comparison of Molecular Contours for Measuring Writhe in Atomistic Supercoiled DNA T. Sutthibutpong, S.A. Harris, and A. Noy Comparison of Molecular Contours for Measuring Writhe in Atomistic Supercoiled DNA J. Chem. Theory Comput. 11, 2768-2775 DOI: 10.1021/acs.jctc.5b00035 (2015) R.N. Irobalieva, Structural diversity of supercoiled DNA Nature Communications 6, Article number: 8440 doi:10.1038/ncomms9440 (2015) E. Rosta, W. Yang and G. Hummer, Calcium inhibition of Ribonuclease H1 two-metal ion catalysis" Journal of the American Chemical Society 136, pp 3137-3144 DOI: 10.1021/ja411408x (2014) A. Ganguy et al. Quantum Mechanical/Molecular Mechanical Free Energy Simulations of the Self-Cleavage Reaction in the Hepatitis Delta Virus Ribozyme. J. American Chemical Society, 136, 1483-1496 (2014). Arianna Fornili (School of Biological and Chemical Sciences, Queen Mary University of London) Molecular basis of regulation of cardiac myosin under normal conditions and in the presence of pathogenic mutations. The findings from this study will be presented at the 60th Annual Meeting of the Biophysical Society (27Feb - 2Mar 2016) in Los Angeles. An abstract of this work (A.Fornili, E. Rostkova, F. Fraternali, M. Pfuhl: "Effect of RLC-Nterminal tails on the structure and dynamics of cardiac myosin") will be published in a special number of the Biophysical Journal. A manuscript is currently under preparation. Francesco Gervasio (Chemistry, UCL) ARCHER time through HECBioSIm has been used to elucidate the mode of action of cancer-causing and drug-resistance causing mutations in an important class of signalling proteins (protein kinases). This kind of information is of great importance in the rational design of more effective anti-cancer drugs. [1] T. D. Bunney, S. Wan, N. Thiyagarajan, L. Sutto, S. V. Williams, P. Ashford, H. Koss, M. A. Knowles, F. L. Gervasio, P. V. Coveney, M. Katan EBioMedicine, 2, 194-204, 2015. [2] K Marino, L Sutto, F L Gervasio* The Effect of a Wide-spread Cancer-causing Mutation on the Inactive to Active Dynamics of the B-Raf Kinase J. Am. Chem. Soc. 137, 5280-5283, 2015 [3] S. Lovera, M. Morando, E. Pucheta-Martinez, J. Martinez-Torrecuadrada, G. Saladino, F. L. Gervasio* Towards a Molecular Understanding of the Link Between Imatinib Resistance and Kinase Conformational Dynamics Plos Comp Biol. 12, e1004578, 2015. Julien Michel (Chemistry, Edinburgh) Established the mechanisms by which a key cancer causing protein recognises small molecule drugs via a disordered protein region. The findings are helping drug designers target more effectively this protein to develop more efficacious drugs. Elucidation of Ligand-Dependent Modulation of Disorder-Order Transitions in the Oncoprotein MDM2 Bueren-Calabuig, J. A. ; Michel, J. PLoS Comput. Biol. , 11(6): e1004282, 2015 Mario Orsi (School of Engineering and Materials Science, Queen Mary University of London) Atomistic molecular dynamics simulations were performed on models for cell membranes. In particular, effects due to changes in the lamellar vs. nonlamellar lipid composition of membranes were quantified. A number of properties of mixed lipid membranes were characterized quantitatively for the first time, including the lateral pressure, electric field and dipole potential. This work has been published in a high quality peer-reviewed international journal [Wei Ding, Michail Palaiokostas, Wen Wang, and Mario Orsi, Effects of Lipid Composition on Bilayer Membranes Quantified by All-Atom Molecular Dynamics The Journal of Physical Chemistry B 2015 119 (49), 15263-15274, DOI: 10.1021/acs.jpcb.5b06604]. Molecular simulations were conducted to study permeation processes of small molecules through mixed lipid membranes. For the first time, it is shown that nonlamellar lipids reduce membrane permeation through a mechanism that can be related to a small number of fundamental physical properties. A manuscript on this research is in preparation. The research conducted was selected for oral presentations at the 2015 MGMS Young Modellers' Forum (The Old Naval College, Greenwich, London, 27/11/15) and at the 2015 Thomas Young Centre Student Day (Imperial College, London, 17/12/15), as well as for poster presentations at the 2016 Annual Biophysical Society meeting (Los Angeles, 27 Feb-2 Mar 2016). Mark Sansom (Biochemistry, Oxford) We have also used ARCHER as part of our ongoing programme of very large scale simulations of the dynamic properties of viral membrane envelopes in biomedically important enveloped viruses including influenza and dengue. (Reddy, T. & Sansom, M.S.P. (2015) The role of the membrane in the structure and biophysical robustness of the dengue virion envelope. http://dx.doi.org/10.1016/j.str.2015.12.011). These virus simulations were featured in local media following their presentation by Tyler Reddy at the 2014 US Biophysics meeting. Other recent successes of the use of ARCHER under HECBioSim (Sansom Group, Oxford) include a collaboration between computational and experimental groups (the latter using advanced microscopy imaging of bacterial membranes) to study role of nanoscale 'islands' of membrane proteins in bacterial cell division (see above). This work is continuing, and is of relevance to developing novel targets to help overcome antimicrobial resistance. It has also led to an increase in interest in large scale simulations of membranes from a number of structural biology and biophysics groups, including those of Carol Robinson (Chemistry, Oxford) and Liz Carpenter (SGC, Oxford), in particular using these methods to characterise the interactions of membrane proteins with their lipid bilayer environment Stansfeld, P.J., Goose, J.E., Caffrey, M., Carpenter, E.P., Parker, J.L., Newstead, N. & Sansom, M.S.P. (2015) MemProtMD: automated insertion of membrane protein structures into explicit lipid membranes. Structure (doi:10.1016/j.str.2015.05.006) Phil Biggin (Biochemistry, Oxford) Work from the Biggin group has made strong use of ARCHER through HECBioSim and has resulted in the following publications from the allocations from the Consortium over the past year: Kainate receptor pore-forming and auxiliary subunits regulate channel block by a novel mechanism. Brown PM, Aurousseau MR, Musgaard M, Biggin PC, Bowie D. J Physiol. 2015 Dec 18. doi: 10.1113/JP271690. [Epub ahead of print] Accurate calculation of the absolute free energy of binding for drug molecules, Aldeghi M, Heifetz A, Bodkin MJ, Knapp S, Biggin PC. Chem. Sci., 2016,7, 207-218 doi: 10.1039/C5SC02678D Distinct structural pathways coordinate the activation of AMPA receptor-auxiliary subunit complexes Dawe GB, Musgaard M, Aurousseau M, Nayeem N, Green T, Biggin PC, Bowie D. Neuron [in press] The role of an absolutely conserved tryptophan pair in the extracellular domain of Cys-loop receptors. Braun N, Lynagh T, Yu R, Biggin PC, Pless S. ACS Chem. Neurosci. [in press] Greater scientific productivity: As well as speed increases, the optimisation of codes for the ARCHER machine will enable problems to be solved in less time using fewer compute resources. • For the reporting period please provide a brief update on progress of software development activities associated with the consortium and the impact this has had on consortium members and the broader research community. Charlie Laughton (Pharmacy, Nottingham) Development and deployment of Longbow, a high-throughput remote job submission tool for the biomolecular simulation community, now being leveraged by other CCPs as well. Longbow makes at easy for biomolecular simulation jobs to be run on Archer as on a local desktop. Journal of Open Research Software 2016, DOI: http://dx.doi.org/10.5334/jors.95 Francesco Gervasio (Chemistry, UCL) Researchers from University College London, led by Francesco Gervasio in collaboration with the Structural Biology Computational Group of the Spanish National Cancer Research Centre (CNIO) headed by Alfonso Valencia have developed the first computational method based on evolutionary principles to predict protein dynamics, which explains the changes in the shape or dimensional structure that they experience in order to interact with other compounds or speed up chemical reactions. The study made possible by the supercomputing resources provided by Archer and PRACE constitutes a major step forward in the computational study of protein dynamics. [4] L. Sutto, S. Marsili, A. Valencia, F. L. Gervasio* From residue co-evolution to protein conformational ensembles and functional dynamics Proc Natl Acad Sci USA, 112 13567-13572, 2015 Press release: http://www.eurekalert.org/pub_releases/2015-10/cndi-ana102315.php Phil Biggin (Biochemistry, Oxford) Our recent publication on Accurate free energy predictions made use of the FESetup package (through the CCPBioSIM CCP). Increasing the UK's CSE skills base (including graduate and post doctorate training and support): This builds on the skills sets of trained people in HPC, both in terms of capacity and raising the overall skill level available to the sector. • For the reporting period please provide a bullet pointed list of training activities undertaken by the Consortium, providing information on the target audience and level of attendance. For example: Arianna Fornili (School of Biological and Chemical Sciences, Queen Mary University of London) A 1st year PhD student working on this project is currently being trained under my supervision in the use of HPC resources and in particular of ARCHER. Charlie Laughton (Pharmacy, Nottingham) "Going Large" workshop: Daresbury 16/12/15. Hands-on introduction to HECBioSim tools (Longbow and pyPcazip) developed to aid the running and analysis of large scale ensemble simulations. 16 attendees. Francesco Gervasio and Edina Rosta (Chemistry, UCL and Chemistry, KCL) E. Rosta (KCL) & F. Gervasio (UCL) organized a workshop on Free Energy Calculation and Molecular Kinetics in London April 20-22, 2015. The successful workshop was attended by more than 40 (mainly post-doctoral) academic and industrial researcher from all over Europe. Increased impact and collaboration with industry: ARCHER does not operate in isolation and the 'impact' of ARCHER's science is converted to economic growth through the interfaces with business and industry. In order to capture the impacts, which may be economic, social, environmental, scientific or political, various metrics may be utilised. • Please provide a brief update on any planned activities / collaborations / outcomes outlined in the original Pathways to Impact plan for the Consortium. • For the reporting period please provide information on any Consortium projects that have been performed in collaboration with industry, this should include details of the company involved, a statement on the impact that the work has / is making and, if relevant, details of any in kind or in cash contributions that have been associated with this work. • For the reporting period include a list of Consortium publications that have industrial co-authorship. • For the reporting period please provide details of the any other activities involving industrial participation e.g. activities involving any Industrial Advisory panels, attendance / participation in workshops and Consortium based activities. Arianna Fornili (School of Biological and Chemical Sciences, Queen Mary University of London) This project is done in collaboration with experimental (NMR and SAXS) partners at King's College London (Dr. Mark Pfuhl and Dr. Elena Rostkova), with the final aim of providing a complete molecular model of how muscle contraction is regulated in the heart. Francesco Gervasio (Chemistry, UCL) A new collaboration with UCB on developing new approaches to sample cryptic binding sites of pharmaceutical interest was started. UCB co-sponsored a BBSRC-CASE PhD studentships. The code development and its application to interesting targets was made possible by the access to Archer. Phil Biggin (Biochemistry, Oxford) The following has industrial partners as co-authors: Accurate calculation of the absolute free energy of binding for drug molecules, Aldeghi M, Heifetz A, Bodkin MJ, Knapp S, Biggin PC. Chem. Sci., 2016,7, 207-218 doi: 10.1039/C5SC02678D. The GLAS scoring module for gromacs has yet to be implemented but that would also constitute industrial activity. Strengthening of UK's international position: The impacts of ARCHER's science extend beyond national borders and most science is delivered through partnerships on a national or international level. • For the reporting period please provide a bullet pointed list of projects that have involved international collaboration. • For the reporting period please provide a list of consortium publications with international co-authorship. • For the reporting period please detail any other international activities that the Consortium might be involved in (workshops, EU projects etc.). Alessandro Pandini (Computer Science, Brunel University London) The "Analysis of the allosteric communication in HIF-2a-ARNT heterodimer" has recently started (1st December 2015). It is aimed at the identification of the allosteric pathways in the HIF-2a-ARNT heterodimer. This can advance the discovery of therapeutic molecules and shed light on the mechanisms underlying disease mutations and post-translational modifications affecting the response to hypoxic stress in cells. In this early stages of the project, a promising collaboration has been explored with the group of Prof. Laura Bonati at the University of Milan-Bicocca. This collaboration will provide an avenue for scientific visits, for the training of a PhD student currently working in Prof. Bonati's group. Charlie Laughton (Pharmacy, Nottingham) • The "Ascona B-DNA Consortium" project to develop next-generation simulations of nucleic acids. Partners across Europe and in the USA and India. Publication: Nature Methods, 2016, 13(1), 55-+ • EU H2020 project "Multiscale genomics" (multiscalegenomics.eu): developing computational tools and infrastructures to support a multiscale genomics virtual research environment. • CECAM Extended Software Development Workshop (joint with NSF): Deployment and development of advanced sampling tools on HPC resources. Juelich, 11-24/10/15. 91 attendees from across Europe and the US. Francesco Gervasio (Chemistry, UCL) Both projects listed above as well as references 3 and 4 involved international collaborations with research groups at the Spanish National Cancer Research Centre, one of the most important cancer biology research centres in Europe. Phil Biggin (Biochemistry, Oxford) All of these have international collaboration and co-authorships: Kainate receptor pore-forming and auxiliary subunits regulate channel block by a novel mechanism. Brown PM, Aurousseau MR, Musgaard M, Biggin PC, Bowie D. J Physiol. 2015 Dec 18. doi: 10.1113/JP271690. [Epub ahead of print] Accurate calculation of the absolute free energy of binding for drug molecules, Aldeghi M, Heifetz A, Bodkin MJ, Knapp S, Biggin PC. Chem. Sci., 2016,7, 207-218 doi: 10.1039/C5SC02678D Distinct structural pathways coordinate the activation of AMPA receptor-auxiliary subunit complexes Dawe GB, Musgaard M, Aurousseau M, Nayeem N, Green T, Biggin PC, Bowie D. Neuron [in press] The role of an absolutely conserved tryptophan pair in the extracellular domain of Cys-loop receptors. Braun N, Lynagh T, Yu R, Biggin PC, Pless S. ACS Chem. Neurosci. [in press] Future Vision: How do you see the Consortium strategy evolving and changing in the future? In the next 5 years, what new science questions will members of your Consortium be seeking to address? Why are these important? We aim to expand the breadth of the work of the Consortium focusing on cutting-edge applications, and building collaborations with experiments and industry, to achieve maximum impact from ARCHER use. HECBioSim is now well established, supporting work of many groups across the UK in the growing field of biomolecular simulation. We benefit from an Advisory Group containing members from industry, as we as international biomolecular simulation experts and experimental scientists. The Advisory Board was expanded and refreshed for the renewal and consists of: Dr. Nicolas Foloppe (Vernalis plc, Chair); Dr. Colin Edge (GlaxoSmithKline); Dr. Mike King (UCB Pharmaceuticals); Dr. Mike Mazanetz (Evotec AG); Dr. Garrett Morris (Crysalin Ltd.); Dr. Gary Tresadern (Johnson and Johnson Pharmaceuticals); Dr. Richard Ward (AstraZeneca); Prof. Modesto Orozco (IRB, Barcelona); Prof. Tony Watts, (Oxford, NMR); Dr. Pete Bond (A*STAR Bioinformatics Institute Singapore). We aim to foster industrial collaborations and collaborations with experimentalists (e.g. joint workshops with CCPN, Institute of Physics (Sarah Harris, Leeds Physics); see e.g. case studies. A particular them for strategic development will be multiscale modelling, building on collaborations between several groups in the Consortium. We discussed Grand Challenges at our most recent Management Group meeting. In December 2015, and have have identified several to follow up as strategic priorities. We aim to tackle and support large-scale grand challenge applications in biomolecular science, in areas such as antimicrobial resistance, membrane dynamics, drug design and synthetic biology. One specific theme with potentially high impact in drug discovery is large -scale comparative investigation of allosteric regulation in different superfamilies of proteins (e.g. PAS domain containing proteins, tyrosine kinases, etc.). The major impact will be in the identification of novel selective therapeutic molecules with limited adverse side effects. As a Consortium, we intend to develop and apply novel computational approaches for the rational design of allosteric regulators of hitherto 'undruggable' targets. Many of the targets emerging from large-scale genetic screening are deemed undruggable due to the difficulty of designing drug-like modulators that bind to their catalytic sites. It is increasingly clear that these targets might be effectively targeted by designing drugs that bind to protein-protein interfaces and allosteric sites. To do that, however, new rational design strategies, based on an in-depth knowledge of protein dynamics and advanced modelling and new simulation techniques are required. Other challenging frontier areas include dynamics of motor proteins; prediction of the effects of pathogenic mutations on protein function. The accurate prediction of free energy of binding is still in its infancy and needs much further investigation. Finally, kinetics of biomolecular reactions will become the next big topic. It is clear that high end computing resource can provide the necessary power and capability to provide inroads into this vital area. This is important because it is becoming increasingly apparent that kinetics of drug binding is a key factor that the pharmaceutical sector should really be looking at in terms of a major dictator of potency. The mechanism of protein translocation across cell membranes Created: 07 April 2017 Last Updated: 07 April 2017 The essential process of protein secretion is achieved by the ubiquitous Sec machinery. In prokaryotes, the drive for translocation through the SecYEG channel comes primarily from ATP hydrolysis by the cytosolic motor-protein SecA. However, the mechanism through which ATP hydrolysis is coupled to directional movement through SecYEG is unclear. Through a combination of all-atom MD simulations and single molecule FRET and biochemical assays, it is shown that ATP binding by SecA causes opening of the SecY-channel at long range, while substrates at the SecY-channel entrance feed back to regulate nucleotide exchange in SecA. This two-way communication suggests a new 'Brownian ratchet' mechanism, whereby ATP binding and hydrolysis bias the direction of polypeptide diffusion. The model represents a solution to the problem of transporting inherently variable substrates such as polypeptides, and may underlie mechanisms of other motors that translocate proteins and nucleic acids. Engineering bacteriophages for treating antimicrobial resistance using all-atom models of entire viruses Created: 07 April 2017 Last Updated: 10 April 2017 The goal of this project was to study an atomistic model of the entire PCV2 virus using molecular dynamics simulation. The developed model has been used to understand how alterations to the structure of the virus enhance its potential antimicrobial resistance properties as phage therapy agents. Development of hybrid coarse-grain/atomistic simulation models and their application to membrane-bound proteins Created: 07 April 2017 Last Updated: 07 April 2017 The membrane environment is really important. It acts as a barrier to maintain the integrity of cells, and many important biological processes take place in the membrane, including the requirement of drugs to pass through to reach their binding sites. Computer modelling of membrane systems is therefore crucial to obtaining a full understanding. However, simulating all the atoms, while generally accurate, is expensive to perform owing to the large number of interaction sites. A common method to improve computational efficiency is to reduce the number of interaction sites by subsuming groups of atoms into larger beads. However, this simplification leads to a loss of accuracy. A solution to this problem is to keep part of the system at the atomistic level, and to use a hybrid coarse-grain/atomistic approach. In this project we have developed and tested just such an approach, using it to explore proteins in biological membranes, and how readily small molecules permeate, a critical component of the drug delivery process. Follow us on twitter! @hecbiosim HECBioSim acknowledges the funding support it receives from EPSRC through an SLA with STFC's Scientific Computing Department. HECBioSim, the UK HEC Biomolecular Simulation Consortium, was established in March 2013, and works closely with and complements CCP-BioSim (the UK Collaborative Computational Project for Biomolecular Simulation at the Life Sciences Interface). Most of the members of the Consortium are experienced users of high end computing. Biomolecular simulations are now making significant contributions to a wide variety of problems in drug design and development, biocatalysis, bio and nano-technology, chemical biology and medicine. The UK has a strong and growing community in this field, recognized by the establishment in 2011 by the EPSRC of CCP-BioSim (ccpbiosim.ac.uk), and its renewal in 2015. There is a clear, growing and demonstrable need for HEC in this field. Members of the Consortium have, for example, served on the HECToR and ARCHER Resource Allocation Panel. The Consortium welcomes members across the whole biomolecular sciences community, and we are currently (and will remain) open to new members (unlike some consortia). Since establishing the Consortium, several new members (FLG, DH, ER) have joined the Management Group. Many of the projects awarded ARCHER time under the Consortium do not involve CCP-BioSim or HECBioSim Management Group members, demonstrating the openness of HECBioSim and its support of the biomolecular simulation community in the UK. A number of other researchers have joined and it is our expectation that other researchers will join HECBioSim in the future. We actively engage with structural and chemical biologists and industrial researchers. We foster interactions between computational, experimental and industrial scientists (see the example case studies; members of the Consortium have excellent links with many pharmaceutical, chemical and biotechnology companies). Details of HECBioSim are available via our webpages at: http://www.hecbiosim.ac.uk Applications are made through the website http://www.hecbiosim.ac.uk and reviewed at one of the series of regular panel meetings. A list of successful HECtime allocations on ARCHER is available at:http://www.hecbiosim.ac.uk/applications/successfulprojects All proposals are of course subject to scientific and technical review, but we have the philosophy of supporting the best science to deliver the highest impact, rather than focusing on supporting development of a couple of codes. An allocation panel (with changing membership) meets twice yearly to judge proposals and requests for AUs; projects are assessed competitively: any groups in the UK can apply. All submitted proposals receive constructive feedback from the allocation panel. The HECBioSim website also provides forums for the biomolecular simulation community, a wiki hosting useful how-tos and user guides, and software downloads (currently FESetup and Longbow). Our lead software development project between Nottingham (Charlie Laughton and Gareth Shannon) and Daresbury (James Gebbie), we have developed a remote job submission tool, 'Longbow' (see below). The tool is designed to reproduce the look and feel of local MD packages, but to stage data and submit jobs to a large HPC resource, such as ARCHER, in a manner invisible to the user. Workshops and New Opportunities No more than half a page detailing upcoming workshops and meetings. Also include discussion of other areas which are potentially of interest to other HEC Consortia and opportunities for cross CCP /HEC working. Workshops are listed below and can be found on the HECBioSim Website We work closely with CCP-BioSim, for example in organizing training workshops and meetings. Our activities are outlined at www.hecbiosim.ac.uk Examples of forthcoming meetings include: Computational Molecular Science 2017 - on Sunday 19 March 2017 17th European Seminar on Computational Methods in Quantum Chemistry - on Tuesday 11 July 2017 Frontiers of Biomolecular Simulation Southampton, September 2016 Issues and Problems Short discussion of any issues or problems that the HEC Consortium faces including issues with the ARCHER service, funding, management of allocation and staffing. This is also a good opportunity to highlight to the SLA committee any issues that the Consortium may have experienced with their SLA support during the reporting period. Details of SLA activities are given in the SLA report. Dr. James Gebbie provides support to HECBioSIm through the SLA. He has been very helpful in the construction of the HECBioSim webpages (hecbiosim.ac.uk). James also worked with Dr. Gareth Shannon on the development of Longbow (See above). In the past year, members of the Consortium faced some queuing problems; close to the end of the first allocation period in particular, there were long queuing times, which led to problems in completing jobs and using allocated time. Throughput has been a real problem in the past few months. Membership Please provide a full list of existing members and their institutions, highlighting any new members that have joined the consortium during the reporting period. If available please provide information on the number of distinct users that have accessed ARCHER via the Consortium during this reporting period. Below is a list of PIs with HECBioSim projects in the current reporting period: Agnes Noy, University of York - new to this reporting period Alessandro Pandini, Brunel University London Arianna Fornili, Queen Mary University of London Cait MacPhee, University of Edinbrurgh - new to this reporting period Charlie Laughton, University of Nottingham Clare-Louise Towse, University of Bradford - new to this reporting period D Flemming Hansen, University College London - new to this reporting period David Huggins, Aston University Edina Rosta, King's College London Francesco Gervasio, University College London Ian Collinson, University of Bristol - new to this reporting period Irina Tikhonova, Queen's University Belfast Jiayun Pang, University of Greenwich Jonathan Doye, University of Oxford Julien Michel, University of Edinburgh Mario Orsi, UWE Bristol Michele Vendruscolo, University of Cambridge Michelle Sahai, University of Roehampton Philip Biggin, University of Oxford Richard Sessions, University of Bristol Stephen Euston, Heriot-Watt University Syma Khalid, University of Southampton PIs in HECBioSIm outside of current allocation period Peter Bond, University of Cambridge Richard Bryce, University of Manchester Juan Antonio Bueren-Calabuig, University of Edinburgh Christo Christov, Northumbria University Anna K Croft, University of Nottingham Jonathan Essex, University of Southampton Robert Glen, University of Cambridge Sarah A Harris, University of Leeds Jonathan Hirst, University of Nottingham Douglas Houston, University of Edinburgh Dmitry Nerukh, Aston University Andrei Pisliakov, University of Dundee Mark Sansom, University of Oxford Marieke Schor, University of Edinburgh Gareth Shannon, University of Nottingham Tatyana Karabencheva-Christova, Northumbria University There are currently 164 members of HECBioSim (i.e. users of HECBioSIm ARCHER time), included the above PIs. 20 new users have been added since January 2016. All publications can be found in ResearchFish, and have been added by individual researchers. A selection of illustrative highlights are provided below: Julien Michel (University of Edinburgh) New molecular simulation methods have enabled for the first time a complete description of the interactions of several drug-like small molecules with an intrinsically disordered region of the oncoprotein MDM2, as well as the effect of post-translational modifications on the dynamics of this protein. The results obtained suggest new medicinal chemistry strategies to achieve potent and selective inhibition of MDM2 for cancer therapies. Publication: Elucidation of Ligand-Dependent Modulation of Disorder-Order Transitions in the Oncoprotein MDM2 http://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1004282 Impact of Ser17 Phosphorylation on the Conformational Dynamics of the Oncoprotein MDM2 http://pubs.acs.org/doi/abs/10.1021/acs.biochem.6b00127 An outreach document is being prepared by EPCC to showcase a lab project on isoform selective inhibition that has benefited from both HECBioSim and EPCC ARCHER allocations. Syma Khalid (Chemistry, Southampton) Publication: OmpA: A Flexible Clamp for Bacterial Cell Wall Attachment Samsudin F, Ortiz-Suarez ML, Piggot TJ, Bond PJ, Khalid S (2016). "OmpA: a Flexible Clamp for Bacterial Cell Wall Attachment", Structure, 24(12):2227-2235 With Singapore National Center for Biotechnology. Sarah Harris (Physics, Leeds) In collaboration with the experimental biochemistry group lead by Radford at Leeds, Sarah Harris used ARCHER time to show how chaperones help outer membrane proteins to fold, see: Schiffrin B, Calabrese AN, Devine PWA, Harris SA, Ashcroft AE, Brockwell DJ, Radford SE "Skp is a multivalent chaperone of outer-membrane proteins" Nature Structural and Molecular Biology 23 786-793, 2016. DOI:10.1038/nsmb.3266 Michelle Sahai (Department of Life Sciences, Roehampton) Publication: Combined in vitro and in silico approaches to the assessment of stimulant properties of novel psychoactive substances - The case of the benzofuran 5-MAPB. Progress in Neuro-Psychopharmacology and Biological Psychiatry 75, Pages 1-9 (2017) https://www.ncbi.nlm.nih.gov/pubmed/27890676 Phil Biggin (Biochemistry, Oxford) Outputs that have used HECBioSim time: 1. Steered Molecular Dynamics Simulations Predict Conformational Stability of Glutamate Receptors. Musgaard M, Biggin PC. J Chem Inf Model. 2016 Sep 26;56(9):1787-97. doi: 10.1021/acs.jcim.6b00297. 2. Kainate receptor pore-forming and auxiliary subunits regulate channel block by a novel mechanism. Brown PM, Aurousseau MR, Musgaard M, Biggin PC, Bowie D. J Physiol. 2016 Apr 1;594(7):1821-40. doi: 10.1113/JP271690. 3. Role of an Absolutely Conserved Tryptophan Pair in the Extracellular Domain of Cys-Loop Receptors. Braun N, Lynagh T, Yu R, Biggin PC, Pless SA. ACS Chem Neurosci. 2016 Mar 16;7(3):339-48. doi: 10.1021/acschemneuro.5b00298. 4. Distinct Structural Pathways Coordinate the Activation of AMPA Receptor-Auxiliary Subunit Complexes. Dawe GB, Musgaard M, Aurousseau MR, Nayeem N, Green T, Biggin PC, Bowie D. Neuron. 2016 Mar 16;89(6):1264-76. doi: 10.1016/j.neuron.2016.01.038. Covered by 7 news outlets: I. Health Canal (http://www.healthcanal.com/brain-nerves/70646-what-makes-the-brain-tick-so-fast.html) II. Health Medicine Network (http://healthmedicinet.com/i/scientists-reveal-how-the-brain-processes-information-with-lightning-speed/) III. News Medical (http://www.news-medical.net/news/20160227/Scientists-reveal-how-the-brain-processes-information-with-lightning-speed.aspx) IV. Wired (http://www.wired.co.uk/article/what-we-learned-about-the-brain-this-week-3) V. Alpha Galileo (http://www.alphagalileo.org/ViewItem.aspx?ItemId=161473&CultureCode=en) VI. Science Daily (https://www.sciencedaily.com/releases/2016/02/160225140254.htm) VII. Eureka Alert (https://www.eurekalert.org/pub_releases/2016-02/mu-wmt022516.php) Recommended by F1000 Prime: http://f1000.com/prime/726180600. 5. Accurate calculation of the absolute free energy of binding for drug molecules. Aldeghi M, Heifetz A, Bodkin MJ, Knapp S, Biggin PC. Chem Sci. 2016 Jan 14;7(1):207-218. Arianna Fornili (Biological and Chemical Sciences, Queen Mary University of London) Publication: Fornili, E. Rostkova, F. Fraternali, M. Pfuhl: Effect of RlC N-Terminal Tails on the Structure and Dynamics of Cardiac Myosin. Biophysical J. 110 (2016) 297A. More in preparation. Dmitry Nerukh (Engineering and Applied Science, Aston University) Important research findings: Distribution of ions inside a viral capsids influences the stability of the capsid Edina Rosta (Computational Chemistry, Kings College London) Highlighted publication: We have a joint experimental paper with the Vertessy group in JACS where we identified a novel arginine finger residue in dUTPase enzymes, and described the mechanism of action for this residue using crystallographic data, biochemical experiments, MD and QM/MM simulations thanks to HECBioSim. http://pubs.acs.org/doi/abs/10.1021/jacs.6b09012 Press release: Our joint paper with Jeremy Baumberg's group in Cambridge was published in Nature. http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/newssummary/news_13-6-2016-16-52-4 Our lead software development project between Nottingham (Charlie Laughton and Gareth Shannon) and Daresbury (James Gebbie), we have developed a remote job submission tool, 'Longbow' (see below). The tool is designed to reproduce the look and feel of local MD packages, but to stage data and submit jobs to a large HPC resource such as ARCHER in a manner invisible to the user. An open beta version was released unrestricted to the community in March 2015 (http://www.hecbiosim.ac.uk/longbow and via PyPI https://pypi.python.org ) with ~100 downloads. Functionality includes native support for biosimulation packages AMBER, CHARMM, GROMACS, LAMMPS and NAMD, native support for jobs on ARCHER, native support for jobs running on PBS and LSF schedulers, and support for three different job types (single, ensembles and multiple jobs). The software is written both as an application for users and an API for developers. CCP-EM have integrated Longbow into their developmental GUI, and shortly FESetup will ship with native support for job submission using Longbow. We are currently in talks with ClusterVision with respect to them distributing Longbow to their user base as a user friendly way for novices to interact with their systems. Longbow Longbow has been growing in popularity both amongst researchers within the biosimulation field and those in other fields. In this reporting period there have been five new releases of Longbow delivering a plethora of user requested features and bug fixes. Some of the key developments are summarised below: • Implemented a Recovery mode - Should the event happen that Longbow crashes or the system in which Longbow is controlling jobs from powers down. The user can now reconnect to the crashed session and carry on as if nothing happened. • Sub-Queuing - More and more system administrators are setting limits not just on the number of simulations that can run, but also on the number of jobs that can go into the queue. Longbow can now automatically detect this and implement its own queue feeding jobs into the system queue as slots open up. • Dis-connectible/Re-connectible Longbow sessions - A user can now launch Longbow to fire off all jobs and then disconnect, at a later date the user can re-establish the connection and download all results (no need for persistent connections anymore) • Ability to include scripts in the Longbow generated submit files. • Numerous stability, performance and bug fixes Longbow continues to be the submission engine that is used under the hood of the CCP-EM toolkit FLEX-EM. There are several other interesting projects that are making use of Longbow. A project by the energy efficient computing group (Hartree Center) are currently integrating Longbow with CK, a crowd sourced compilation optimisation tool aimed at finding efficient compilation configuration. A project by the Applications performance engineering group (Hartree Center) are currently integrating longbow into Melody, a runtime optimisation tool aimed at optimising runtime configuration of simulations. A project by the computational biology group (Hartree Center) an automated setup, launch and analysis platform for MD on protein-membrane simulations. Metrics Downloads (HECBioSim) 985 Downloads (PyPi) 3456 125 PhD and PDRAs have been trained and have used ARCHER through HECBioSim. In the past 6 months alone that has included: PhD students: Marc Dämgen, University of Oxford Laura Domicevica, University of Oxford Matteo Aldeghi, University of Oxford Shaima Hashem, Queen Mary University of London Ruth Dingle, University College London Lucas Siemons, University College London Elvira Tarasova, Aston University Vladimiras Oleinikovas, University College London Havva Yalinca, University College London Daniel Moore, Queen's University Belfast Aaron Maguire, Queen's University Belfast Maxime Tortora, University of Oxford Michail Palaiokostas, UWE Bristol Wei Ding, UWE Bristol Ganesh Shahane, UWE Bristol Pin-Chia Hsu, University of Southampton Damien Jefferies, University of Southampton PDRA: Maria Musgaard, University of Oxford Teresa Paramo, University of Oxford Marieke Schor, University of Edinbrurgh Antonia Mey, University of Edinbrurgh Ioanna Styliari, University of Nottingham Ivan Korotkin, Aston University Silvia Gomez Coca, King's College London Giorgio Saladino, University College London Federico Comitani, University College London Robin Corey, University of Bristol Jordi Juarez-Jimenez, University of Edinburgh Predrag Kukic, University of Cambridge Giulia Tomba, University of Cambridge Deborah Shoemark, University of Bristol Georgios Dalkas, Heriot-Watt University Robin Westacott, Heriot-Watt University Firdaus Samsudin, University of Southampton Agnes Noy, University of Leeds (now EPSRC fellow at York). Please see below details of the training week held in June 2016 at the University of Bristol. 170 delegates attending the training which ran over 5 days. There is course content available on the HECBioSim Workshop Page CCPBioSim Training Week - Day 5: QM/MM enzyme reaction modelling - on Friday 10 June 2016 CCPBioSim Training Week - Day 4: Monte Carlo Methods for Biomodelling - on Thursday 09 June 2016 CCPBioSim Training Week - Day 3: Python for Biomodellers and FESetup - on Wednesday 08 June 2016 CCPBioSim Training Week - Day 2: Running and analysing MD simulations - on Tuesday 07 June 2016 125 PhD and PDRAs have been trained and have used ARCHER through HECBioSim. In the past 6 months alone that has included: PhD students: Marc Dämgen, University of Oxford Laura Domicevica, University of Oxford Matteo Aldeghi, University of Oxford Shaima Hashem, Queen Mary University of London Ruth Dingle, University College London Lucas Siemons, University College London Elvira Tarasova, Aston University Vladimiras Oleinikovas, University College London Havva Yalinca, University College London Daniel Moore, Queen's University Belfast Aaron Maguire, Queen's University Belfast Maxime Tortora, University of Oxford Michail Palaiokostas, UWE Bristol Wei Ding, UWE Bristol Ganesh Shahane, UWE Bristol Pin-Chia Hsu, University of Southampton Damien Jefferies, University of Southampton PDRA: Maria Musgaard, University of Oxford Teresa Paramo, University of Oxford Marieke Schor, University of Edinbrurgh Antonia Mey, University of Edinbrurgh Ioanna Styliari, University of Nottingham Ivan Korotkin, Aston University Silvia Gomez Coca, King's College London Giorgio Saladino, University College London Federico Comitani, University College London Robin Corey, University of Bristol Jordi Juarez-Jimenez, University of Edinburgh Predrag Kukic, University of Cambridge Giulia Tomba, University of Cambridge Deborah Shoemark, University of Bristol Georgios Dalkas, Heriot-Watt University Robin Westacott, Heriot-Watt University Firdaus Samsudin, University of Southampton Agnes Noy, University of Leeds (now EPSRC fellow at York). Please see below details of the training week held in June 2016 at the University of Bristol. 170 delegates attending the training which ran over 5 days. There is course content available on the HECBioSim Workshop Page CCPBioSim Training Week - Day 5: QM/MM enzyme reaction modelling - on Friday 10 June 2016 CCPBioSim Training Week - Day 4: Monte Carlo Methods for Biomodelling - on Thursday 09 June 2016 CCPBioSim Training Week - Day 3: Python for Biomodellers and FESetup - on Wednesday 08 June 2016 CCPBioSim Training Week - Day 2: Running and analysing MD simulations - on Tuesday 07 June 2016 CCPBioSim Training Week - Day 1: Enlighten: Tools for enzyme-ligand modelling - on Monday 06 June 2016 Past Workshops and Conferences: AMOEBA advanced potential energies workshop - on Friday 09 December 2016 Intel Training Workshop (Parallel programming and optimisation for Intel architecture) - on Wednesday 30 November 2016 3rd Workshop on High-Throughput Molecular Dynamics (HTMD) 2016 - on Thursday 10 November 2016 Free Energy Calculation and Molecular Kinetics Workshop - on Tuesday 13 September 2016 Going Large: tools to simplify running and analysing large-scale MD simulations on HPC resources - HECBioSim - on Wednesday 16 December 2015 This 1 day workshop dealt with Longbow, a Python tool created by HECBioSim consortium that allows use of molecular dynamics packages (AMBER, GROMACS, LAMMPS, NAMD) with ease from the comfort of the desktop, and pyPcazip, a flexible Python-based package for the analysis of large molecular dynamics trajectory data sets. Richard Henchman ( Chemistry, Manchester) I lectured on the CCP5 Summer School in 2015 in Manchester and 2016 in Lancaster for the Advanced Topic Biomolecular Simulation drawing on CCPBiosim training materials. Sarah Harris (Physics, Leeds) Agnes Noy Agnes Noy was trained to use ARCHER independently which helped her to obtain an Early-career EPSRC fellowship. The fellowship grant follows the study of supercoiling DNA by modelling (further funding) and introduces a new member to the community (grant is EPSRC (EP/N027639/1)). Examples of industrial engagement through HECBioSim include: Syma Khalid (Computational Biophysics, Southampton) Collaboration with Siewert-Jan Marrink (Netherlands) and Wonpil Im(USA) - paper is being written at the moment - also we have developed and tested the following computational tool as part of this project: http://www.charmm-gui.org/?doc=input/membrane We have signed an NDA with a company developing antibiotics (Auspherix) based on work published in Samsudin et al, Structure, 2016. Examples of industrial engagement through HECBioSim include: Syma Khalid (Computational Biophysics, Southampton) Collaboration with Siewert-Jan Marrink (Netherlands) and Wonpil Im(USA) - paper is being written at the moment - also we have developed and tested the following computational tool as part of this project: http://www.charmm-gui.org/?doc=input/membrane We have signed an NDA with a company developing antibiotics (Auspherix) based on work published in Samsudin et al, Structure, 2016. The company provide us with experimental data and crucially the structures of their potential drug molecules, and we work out how they interact with the bacterial membrane. Press releases https://www.sciencedaily.com/releases/2016/11/161121094122.htm ARCHER time we got from HECBioSim was essential for this project. These are large simulations that are very computationally demanding. Julien Michel (Chemistry, Edinburgh) Industrial collaborations that have benefited from HECBioSim UCB was a project partner of EPSRC-funded research in the Michel lab on modelling binding of ligands to flexible proteins. HECBioSim supported the research via allocation of computing time on ARCHER. The work has been published. Impact of Ser17 phosphorylation on the conformational dynamics of the oncoprotein MDM2 Bueren-Calabuig, J. A. ; Michel, J. Biochemistry, 55 (17), 2500-2509, 2016 Elucidation of Ligand-Dependent Modulation of Disorder-Order Transitions in the Oncoprotein MDM2 Bueren-Calabuig, J. A. ; Michel, J. PLoS Comput. Biol. , 11(6): e1004282, 2015 International activities I represented HECBioSim at the MolSSI conceptualisation workshop in Houston (October 2016). Arianna Fornili (School of Biological and Chemical Sciences, Queen Mary University of London) This project is done in collaboration with experimental (NMR and SAXS) partners at King's College London (Dr. Mark Pfuhl and Dr. Elena Rostkova), with the final aim of providing a complete molecular model of how muscle contraction is regulated in the heart. Francesco Gervasio (Chemistry, UCL) A new collaboration with UCB on developing new approaches to sample cryptic binding sites of pharmaceutical interest was started. UCB co-sponsored a BBSRC-CASE PhD studentships. The code development and its application to interesting targets was made possible by the access to Archer. Phil Biggin (Biochemistry, Oxford) The following has industrial partners as co-authors: Accurate calculation of the absolute free energy of binding for drug molecules, Aldeghi M, Heifetz A, Bodkin MJ, Knapp S, Biggin PC. Chem. Sci., 2016,7, 207-218 doi: 10.1039/C5SC02678D. The GLAS scoring module for gromacs has yet to be implemented but that would also constitute industrial activity. Richard Henchman (Chemistry, Manchester) Industrial Collaboration I have one publication with an industrial co-author (Evotec), which Julien Michel is part of as well. Assessment of hydration thermodynamics at protein interfaces with grid cell theory, G. Gerogiokas, M. W. Y. Southey, M. P. Mazanetz, A. Heifetz, M. Bodkin, R. J. Law, R. H. Henchman and J. Michel, J. Phys. Chem. B, 2016, 120, 10442-10452. Examples of HECBioSim international engagement include: Michelle Sahai (Department of Life Sciences, Roehampton) Combined in vitro and in silico approaches to the assessment of stimulant properties of novel psychoactive substances - The case of the benzofuran 5-MAPB. Sahai MA, Davidson C, Khelashvili G, Barrese V, Dutta N, Weinstein H, Opacka-Juffry J. Prog Neuropsychopharmacol Biol Psychiatry. (2016) 75:1-9. doi: 10.1016/j.pnpbp.2016.11.004. co-authors affiliations include: Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University (WCMC), New York, NY, 10065, USA and HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute of Computational Biomedicine, Weill Cornell Medical College of Cornell University, New York, NY, 10065, USA. Author contribution: CD, MAS, HW and JOJ were responsible for the study concept and design. CD and VB collected and interpreted the voltammetry data. JOJ and ND conducted the ligand binding experiments and ND analysed the data. MAS (ARCHER user) and GK performed the molecular modelling studies and interpreted the findings. CD, MAS, GK and JOJ drafted the manuscript. All authors critically reviewed the content and approved the final version for publication. Dmitry Nerukh (Engineering and Applied Science, Aston University) Collaborations: • Prof. Makoto Taiji group (K-computer, MDGRAPE), Laboratory for Computational Molecular Design, Computational Biology Research Core, RIKEN Quantitative Biology Center (QBiC), Kobe, Japan • Prof. Reza Khayat group, City College of New York, United States • Prof. Artyom Yurov group, Immanuel Kant Baltic Federal University, Russian Federation • Prof. Nikolay Mchedlov-Petrosyan group, V.N. Karazin Kharkiv National University, Ukraine • Prof. Natalya Vaysfeld group, Odessa I.I.Mechnikov National University, Ukraine International activities: • International Workshop - Engineering bacteriophages for treating antimicrobial resistance using computational models. Dec. 2016, Aston University, UK Dmitry Nerukh group at Aston University collaborates with the group of Prof. Makoto Taiji (the deputy director of RIKEN Quantitative Biology Institute). Prof. Taiji group is the author and implementer of the fastest machine in the world for molecular dynamics simulations, MDGRAPE, as well as part of the team designing the K-computer and working on it (several times the fastest computer in the world). We are currently preparing a joint manuscript for publication where the results obtained on ARCHER will be used alongside with the results obtained on MDGRAPE-4. Julien Michel (Chemistry, Edinburgh) Free Energy Reproducibility Project Free energy reproducibility project between the Michel, Mobley, Roux groups and STFC. This makes use of FESetup which is CCPBioSim, but calculations have been executed on various HPC platforms, Hannes can clarify whether any of the systems used is within the remit of HECBioSim. Sarah Harris (Physics, Leeds), Charlie Laughton (Pharmacy, Nottingham) and Agnes Noy (Physics, York) In an international collaboration with the Institute for Research in Biomedicine in Barcelona, Noy, Harris and Laughton used ARCHER time obtained through the HecBioSim consortium to perform multiple 100ns molecular dynamics (MD) simulations of DNA minicircles containing ~100 base pairs as part of the validation suite for the new BSC1 nucleic acid forcefield, see: Ivani I., Dans P. D., Noy A., Perez A., Faustino I., Hospital A., Walther J., Andrio P., Goni R., Portella G., Battistini F.,Gelpi J. L. Gonzalez C., Vendruscolo M., Laughton C. A., Harris S. A. Case D. A. & Orozco M. "Parmbsc1: a refined force field for DNA simulations" Nat. Methods 13, 55, 2015, doi:10.1038/nmeth.3658 Jon Essex (Chemistry, Southampton) Development and testing of hybrid coarse-grain/atomistic model of membrane systems. ARCHER and the consortium were instrumental in providing the computing time necessary to complete this work. The work was performed by a research fellow in my group, who has subsequently taken up an academic post in Sweden, where he is continuing to develop this methodology. Publication: All-atom/coarse-grained hybrid predictions of distributioncoefficients in SAMPL5 Samuel Genheden1, Jonathan W. Essex, J Comput Aided Mol Des (2016) 30:969-976 DOI 10.1007/s10822-016-9926-z IP and other industrial engagement, or translation, which has benefited from HECBioSim international collaborations Collaboration Dr Samuel Genheden, University of Gothenburg - see above International activities (e.g. workshops) that have benefited from HECBioSim The work performed with Sam resulted in an successful eCSE application for development work on the LAMMPS software. This is an international simulation package run out of Sandia labs in the US. Through this eCSE application we were able to update the rotational integrator and improve the load balancing for our hybrid simulation methodology. These developments have been incorporated in the latest release versions of the code. An ARCHER training webinar resulted from this work. Training activities see above - ARCHER training webinar on our developments within LAMMPS Software development see above - code modifications in LAMMPS which either have been, or will be, in the release version of the code Advantages you see of the consortium (e.g. could be ability to pursue project quickly; develop collaborations) resources to run the sort of large-scale calculations we need Michelle Sahai (Department of life Sciences, Roehampton) The publication I added on ResearchFish has international co-authors. Combined in vitro and in silico approaches to the assessment of stimulant properties of novel psychoactive substances - The case of the benzofuran 5-MAPB. Sahai MA, Davidson C, Khelashvili G, Barrese V, Dutta N, Weinstein H, Opacka-Juffry J. Prog Neuropsychopharmacol Biol Psychiatry. (2016) 75:1-9. doi: 10.1016/j.pnpbp.2016.11.004. co-authors affiliations include: Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University (WCMC), New York, NY, 10065, USA and HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute of Computational Biomedicine, Weill Cornell Medical College of Cornell University, New York, NY, 10065, USA. Author contribution: CD, MAS, HW and JOJ were responsible for the study concept and design. CD and VB collected and interpreted the voltammetry data. JOJ and ND conducted the ligand binding experiments and ND analysed the data. MAS (ARCHER user) and GK performed the molecular modelling studies and interpreted the findings. CD, MAS, GK and JOJ drafted the manuscript. All authors critically reviewed the content and approved the final version for publication. Edina Rosta (Computational Chemistry, Kings College London) International collaborations I have several international collaborators with joint computational/experimental projects. For their success the HECBioSim computer time was essential: • Prof. Beata Vertessy, Budapest Technical University, Hungary JACS 2016 138 (45), 15035-15045 • Profs. Walter Kolch, Vio Buchete and Boris Kholodenko, UCD, Ireland Angewandte 55 (3), 983-986, 2016 (this may have been reported previously) PLOS Computational Biology 12 (10), e1005051, 2016 J Phys Chem Letters 7 (14), 2676-2682, 2016 • Jose Maria Lluch, Angels Gonzalez, Autonomous University of Barcelona, Spain JCTC 12 (4), 2079-2090, 2016 Other international activities Free energy and molecular kinetics workshop with Frank Noe's group (Free University of Berlin) and Vio Buchete (UCD, Dublin). Maybe this should be for training activities? Following the workshop, Erasmus students apply to visit my group. Phil Biggin (Biochemistry, Oxford) 2 and 4 were with colleagues from McGill (Brown PM, Aurousseau MR and Bowie) and 3 was with colleagues from Denmark (Braun and Pless) 2. Kainate receptor pore-forming and auxiliary subunits regulate channel block by a novel mechanism. Brown PM, Aurousseau MR, Musgaard M, Biggin PC, Bowie D. J Physiol. 2016 Apr 1;594(7):1821-40. doi: 10.1113/JP271690. 3. Role of an Absolutely Conserved Tryptophan Pair in the Extracellular Domain of Cys-Loop Receptors. Braun N, Lynagh T, Yu R, Biggin PC, Pless SA. ACS Chem Neurosci. 2016 Mar 16;7(3):339-48. doi: 10.1021/acschemneuro.5b00298. 4. Distinct Structural Pathways Coordinate the Activation of AMPA Receptor-Auxiliary Subunit Complexes. Dawe GB, Musgaard M, Aurousseau MR, Nayeem N, Green T, Biggin PC, Bowie D. Neuron. 2016 Mar 16;89(6):1264-76. doi: 10.1016/j.neuron.2016.01.038. Richard Henchman I have an international collaboration with Professor Franke Grater at the University of Heidelberg on entropy theory for biomolecular systems. Syma Khalid (Chemistry, Southampton) Collaboration with Singapore National Center for Biotechnology. Contributions to CECAM workshops Professor Adrian Mullholland organised and chaired the Computational Chemistry, Gordon Research Conference, Girona, Spain 24th - 29th July 2016. The theme of the 2016 Computational Chemistry GRC was "Theory and Simulation Across Scales in Molecular Science". It focused on method development and state-of-the-art applications across computational molecular science, and encouraged cross-fertilization between areas. The conference was oversubscribed, with attendees from industry and academia. The meeting received a High-Performance Rating, and was commended for the assessment that 95% of conferees rated this meeting "above average" on all evaluation areas (science, discussion, management, atmosphere and suitability). We aim to expand the breadth of the work of the Consortium focusing on cutting-edge applications, and building collaborations with experiments and industry, to achieve maximum impact from ARCHER use. We discussed Grand Challenges at our most recent Management Group meeting. In December 2015, and have identified several to follow up as strategic priorities. We aim to tackle and support large-scale grand challenge applications in biomolecular science, in areas such as antimicrobial resistance, membrane dynamics, drug design and synthetic biology. One specific theme with potentially high impact in drug discovery is large -scale comparative investigation of allosteric regulation in different superfamilies of proteins (e.g. PAS domain containing proteins, tyrosine kinases, etc.). The major impact will be in the identification of novel selective therapeutic molecules with limited adverse side effects. As a Consortium, we intend to develop and apply novel computational approaches for the rational design of allosteric regulators of hitherto 'undruggable' targets. Many of the targets emerging from large-scale genetic screening are deemed undruggable due to the difficulty of designing drug-like modulators that bind to their catalytic sites. It is increasingly clear that these targets might be effectively targeted by designing drugs that bind to protein-protein interfaces and allosteric sites. To do that, however, new rational design strategies, based on an in-depth knowledge of protein dynamics and advanced modelling and new simulation techniques are required. Other challenging frontier areas include dynamics of motor proteins; prediction of the effects of pathogenic mutations on protein function. The accurate prediction of free energy of binding is still in its infancy and needs much further investigation. Finally, kinetics of biomolecular reactions will become the next big topic. It is clear that high end computing resource can provide the necessary power and capability to provide inroads into this vital area. This is important because it is becoming increasingly apparent that kinetics of drug binding is a key factor that the pharmaceutical sector should really be looking at in terms of a major dictator of potency. HECBioSim is now well established, supporting work of many groups across the UK in the growing field of biomolecular simulation. We benefit from an Advisory Group containing members from industry, as we as international biomolecular simulation experts and experimental scientists. The Advisory Board was expanded and refreshed for the renewal and consists of: Dr. Nicolas Foloppe (Vernalis plc, Chair); Dr. Colin Edge (GlaxoSmithKline); Dr. Mike King (UCB Pharmaceuticals); Dr. Mike Mazanetz (Evotec AG); Dr. Garrett Morris (Crysalin Ltd.); Dr. Gary Tresadern (Johnson and Johnson Pharmaceuticals); Dr. Richard Ward (AstraZeneca); Prof. Modesto Orozco (IRB, Barcelona); Prof. Tony Watts, (Oxford, NMR); Dr. Pete Bond (A*STAR Bioinformatics Institute Singapore). We aim to foster industrial collaborations and collaborations with experimentalists (e.g. joint workshops with CCPN, Institute of Physics (Sarah Harris, Leeds Physics); see e.g. case studies. A particular theme for strategic development will be multiscale modelling, building on collaborations between several groups in the Consortium and the other CCPs. This theme reflects the inclusive and forward looking philosophy of HecBioSim, which is a community open to new ideas, keen to develop new methods, and ultimately to use HEC to drive exciting new science. The Consortium model allows new collaborations to develop. The recent reduction in time allocated to HECBioSim has meant that we can support fewer projects. There is significantly more demand for computer time than we can accommodate through our current allocation. We intend to work with Tier 2 Centres to explore possibilities for applications, and e.g. to test emerging arc |
| Exploitation Route | HECBioSim, the UK HEC Biomolecular Simulation Consortium, was established in March 2013, and works closely with and complements CCP-BioSim (the UK Collaborative Computational Project for Biomolecular Simulation at the Life Sciences Interface). Most of the members of the Consortium are experienced users of high end computing. Biomolecular simulations are now making significant contributions to a wide variety of problems in drug design and development, biocatalysis, bio and nano-technology, chemical biology and medicine. The UK has a strong and growing community in this field, recognized by the establishment in 2011 by EPSRC of CCP-BioSim (ccpbiosim.ac.uk), , and its renewal in 2015. There is a clear, growing and demonstrable need for HEC in this field. Members of the Consortium have, e.g., served on the HECToR Resource Allocation Panel, including the current and previous Chairs of the RAP. The Consortium welcomes new members across the whole community. Since establishing the Consortium, several new members (FLG, DH, ER) have joined the Management Group. Many of the projects awarded ARCHER time under the Consortium do not involve CCP-BioSim or HECBioSim Management Group members, demonstrating the openness of HECBioSim and its support of the biomolecular simulation community in the UK. A number of other researchers have expressed interest in joining and it is our expectation that other researchers will join HECBioSim in future. We actively engage with structural and chemical biologists and industrial researchers. We foster interactions between computational, experimental and industrial scientists (see e.g. case studies; members of the Consortium have excellent links with many pharmaceutical, chemical and biotechnology companies). Details of HECBioSim are available via our webpages at: http://www.hecbiosim.ac.uk Management HECBioSim supports three different types of project allocation for time on ARCHER. Pump priming projects are those designed to assist a number of activities (e.g. testing of new codes) and typically fall in the <1MAU range. The standard project is probably the most common and is covered in the 1-15 MAU range. Grand challenge projects are typically projects that fall in the 15-50 MAU range, these are generally large collaborative projects that would involve collaboration on a national scale. Applications are made through the website www.hecbiosim.ac.uk and reviewed at one of a series of regular panel meetings. A list of successful HECtime allocations on ARCHER is available at http://www.hecbiosim.ac.uk/applications/successfulprojects (to-date 31 projects). We have welcomed several new groups into HECBioSim since our inception - we are open to new members, unlike some Consortia. All proposals are of course subject to scientific and technical review, but we have the philosophy of supporting the best science to deliver the highest impact, rather than focusing on supporting development of a couple of codes. An allocation panel (with changing membership) meets twice yearly to judge proposals and requests for AUs; projects are assessed competitively; any groups in the UK can apply. The HECBioSim website also provides forums for the biomolecular simulation community, a wiki hosting useful how-tos and user guides, and software downloads (currently FESetup and Longbow). To-date, the website has been accessed by over 10,000 unique IPs. Our lead software development project between Nottingham (Charlie Laughton and Gareth Shannon) and Daresbury (James Gebbie), we have developed a remote job submission tool, 'Longbow' (see below). The tool is designed to reproduce the look and feel of local MD packages, but to stage data and submit jobs to a large HPC resource such as ARCHER in a manner invisible to the user. An open beta version was released unrestricted to the community in March 2015 (http://www.hecbiosim.ac.uk/longbow and via PyPI https://pypi.python.org ) with ~100 downloads. Functionality includes native support for biosimulation packages AMBER, CHARMM, GROMACS, LAMMPS and NAMD, native support for jobs on ARCHER, native support for jobs running on PBS and LSF schedulers, and support for three different job types (single, ensembles and multiple jobs). The software is written both as an application for users and an API for developers. CCP-EM have integrated Longbow into their developmental GUI, and shortly FESetup will ship with native support for job submission using Longbow. We are currently in talks with ClusterVision with respect to them distributing Longbow to their user base as a user friendly way for novices to interact with their systems. Highlights for the Current Reporting Period No more than half a page detailing significant highlights for the period that are not captured elsewhere in the report. Here we highlight in particular as one example (others are listed in sections below), work of Charlie Laughton (Pharmacy, Nottingham) and Sarah Harris (Physics, Leeds): A new, highly accurate, force field for the simulation of DNA, developed and tested using ARCHER through HECBioSim (as part of a large international consortium): see recent paper in Nature Methods, Parmbsc1: a refined force field for DNA simulations I. Ivani et al. Nature Methods aop, (2015) | doi:10.1038/nmeth.3658. Also their work in R.N. Irobalieva et al. Nature Communications 6, Article number: 8440 doi:10.1038/ncomms944055 (Structural diversity of supercoiled DNA) By regulating access to the genetic code, DNA supercoiling strongly affects DNA metabolism. Despite its importance, however, much about supercoiled DNA (positively supercoiled DNA, in particular) remains unknown. Here we use electron cryo-tomography together with biochemical analyses to investigate structures of individual purified DNA minicircle topoisomers with defined degrees of supercoiling. Our results reveal that each topoisomer, negative or positive, adopts a unique and surprisingly wide distribution of three-dimensional conformations. Moreover, we uncover striking differences in how the topoisomers handle torsional stress. As negative supercoiling increases, bases are increasingly exposed. Beyond a sharp supercoiling threshold, we also detect exposed bases in positively supercoiled DNA. Molecular dynamics simulations independently confirm the conformational heterogeneity and provide atomistic insight into the flexibility of supercoiled DNA. Our integrated approach reveals the three-dimensional structures of DNA that are essential for its function. Mark Sansom (Biochemistry, Oxford) Large scale simulations of bacterial outer membranes have revealed how dynamic co-clustering of membrane proteins is mediated by protein-lipid-protein interactions. Working closely with experimentalists in Oxford and York we have shown how this helps to explain segregation of 'old' and 'new' membrane proteins during cell growth and division. This is of direct relevance to probing for possible new targets for antimicrobials. Rassam, P., Copeland, N.A., Birkholz, O., Tóth, C., Chavent, M., Duncan, A.L., Cross, S.J., Housden, N.G., Seger, U., Quinn, D.M., Garrod, T.J., Sansom, M.S.P. Piehler, J., Baumann, C.G., & Kleanthous, C. (2015) Supramolecular assemblies underpin turnover of outer membrane proteins in bacteria. Nature 523:333-336.This approach has since been extended to mammalian cell membranes, and the role of lipid in dynamic co-clustering has been explored. This is of direct relevance to understanding the mode of action of lipid-like drugs targeted at GPCRs: Koldsø, H., & Sansom, M.S.P. (2015) Organization and dynamics of receptor proteins in a plasma membrane. J. Amer. Chem. Soc. 137:14694-14704. Dr Gareth Shannon worked as a HECBioSim Postdoctoral Research Associate in Software Development for Biomolecular Simulation at the University of Nottingham. This 12-month contract spanned 05/01/2015 - 04/01/2016. Longbow is a remote molecular dynamics (MD) job submitter. It allows biomolecular simulation researchers to submit molecular dynamics jobs on remote resources such as High Performance Computers (HPCs) without leaving the familiarity of the Unix-based desktop environment. Longbow delivers and it certainly has the potential to redefine the manner in which HPCs are used. Longbow can be adapted to run any executable installed on an HPC. In this way, the number of users could reach a critical mass such that Longbow becomes a well-known tool internationally in computational science communities. Our case studies provide examples of industrial engagement and impact. Workshops and New Opportunities No more than half a page detailing upcoming workshops and meetings. Also include discussion of other areas which are potentially of interest to other HEC Consortia and opportunities for cross CCP /HEC working. An example of a recent workshop is: our HECBioSim Workshop : 'Going Large: tools to simplify running and analysing large-scale MD simulations on HPC resources', Wed 16 December 2015, Daresbury Laboratory, UK. This 1 day workshop dealt with Longbow, a Python tool created by HECBioSim consortium that allows use of molecular dynamics packages (AMBER, GROMACS, LAMMPS, NAMD) with ease from the comfort of the desktop, and pyPcazip, a flexible Python-based package for the analysis of large molecular dynamics trajectory data sets. We work closely with CCP-BioSim, for example in organizing training workshops and meetings. Examples include: Free Energy Calculation and Molecular Kinetics Workshop, April 20-22, 2015. Free energy workshop, 2nd edition, Southampton, Nov 25th 2014. How to set up a Protein Simulation, 3rd edition, Oxford, Sep 29th 2014. CCPBioSim training week, Sep 2014: Analysis of Biomolecular Simulation Data Tuesday 9th Sep, led by Charlie Laughton/Sarah Harris/Phil Fowler (course material) Python for biomodellers Wednesday 10th Sept, led by Christopher Woods (course material) Monte Carlo methods for biomodelling Thursday 11th Sep, led by Christopher Woods (course material) QM/MM methods Friday 12th Sep, led by Marc van der Kamp Multiscale Modelling Conference. A joint CCPBioSim/CCP5 conference on the theme of multiscale simulation was held in Manchester on 7-9th Jan 2014. Other Joint CCP events: The collaborative computational projects for biomolecular and condensed matter simulation, CCPBioSim and CCP5, are holding a second international conference on the theme of multiscale modelling in Manchester, following on from the first held in January 2014. The three-day event will bring together leading researchers from biological and materials chemistry to discuss topics of common interest across the spectrum of electronic structure, atomistic and mesoscopic scales and to address the current and future challenges posed by multiscale modelling. We are also organizing a joint meeting with CCPN on the interface of NMR and simulation, to be held in July 2016 (Julien Michel, Edinburgh, is leading on organization for CCP-BioSim). Issues and Problems Short discussion of any issues or problems that the HEC Consortium faces including issues with the ARCHER service, funding, management of allocation and staffing. This is also a good opportunity to highlight to the SLA committee any issues that the Consortium may have experienced with their SLA support. Details of SLA activities are given in the SLA report. Dr. James Gebbie provides support to HECBioSIm through the SLA. He has been very helpful in the construction of the HECBioSim webpages (hecbiosim.ac.uk). James also worked with Dr. Gareth Shannon on the development of Longbow (See above). Membership List existing members, highlighting any new members that have joined the consortium during the reporting period. There are currently 105 users of HECBioSim Archer time. We have 28 current projects and we are awaiting 5 new sign ups (from the December awards). World class and world leading scientific output: ARCHER should enable high quality and world-leading science to be delivered. This should generate high impact outputs and outcomes that increase the UK's position in world science. • For the reporting period please provide a bullet pointed list of key research findings and any linked publications. • For the reporting period please include a bullet pointed list of any relevant press announcements and other communications of significance to an international community. • Since ARCHER came on line, what are the top 5 scientific outcomes that have resulted from projects supported by the Consortium? This could be research that has been published in high impact journals, work that has been highly cited, or research that has had a significant impact on the consortium's community or strategic direction. Recent publications from HECBioSim work include (this is a selected sample from groups across the Consortium; some are highlighted and described in more detail below): Ding, W., M. Palaiokostas, W. Wang, M. Orsi. Effects of lipid composition on bilayer membranes quantified by all-atom molecular dynamics, J. Phys. Chem. B J. Phys. Chem. B, 119, 15263-15274 (2015) P. Dinis et al. X-ray crystallographic and EPR spectroscopic analysis of HydG, a maturase in [FeFe]-hydrogenase H-cluster assembly Proc. Natl. Acad. Sci. USA 112 1362-1367 (2015) N.A. Berglund et al. Open Archive Establishing the Structural Rules for Ligand Recognition, Signaling and Assembly in Innate Immune Receptors Biophys. J. 108, 98a http://dx.doi.org/10.1016/j.bpj.2014.11.562 H. Strahl et al. Membrane Recognition and Dynamics of the RNA Degradosome PLoS Genetics DOI: 10.1371/journal.pgen.1004961 (2015) N.A. Berglund Interaction of the Antimicrobial Peptide Polymyxin B1 with Both Membranes of E. coli: A Molecular Dynamics Study PLoS Computational Biology DOI: 10.1371/journal.pcbi.1004180 (2015) R.M.A. Manara et al. DNA sequencing with MspA: Molecular Dynamics simulations reveal free-energy differences between sequencing and non-sequencing mutants Scientific Reports 5, Article number: 12783 doi:10.1038/srep12783 (2015) A. Gray et al. In pursuit of an accurate spatial and temporal model of biomolecules at the atomistic level: a perspective on computer simulation Acta Cryst. D71, 162-172 doi:10.1107/S1399004714026777 (2015). J. M. A. Manara et al. Free-Energy Calculations Reveal the Subtle Differences in the Interactions of DNA Bases with a-Hemolysin J. Chem. Theory Comput., 2015, 11 (2), pp 810-816 DOI: 10.1021/ct501081h (2015) Comparison of Molecular Contours for Measuring Writhe in Atomistic Supercoiled DNA T. Sutthibutpong, S.A. Harris, and A. Noy Comparison of Molecular Contours for Measuring Writhe in Atomistic Supercoiled DNA J. Chem. Theory Comput. 11, 2768-2775 DOI: 10.1021/acs.jctc.5b00035 (2015) R.N. Irobalieva, Structural diversity of supercoiled DNA Nature Communications 6, Article number: 8440 doi:10.1038/ncomms9440 (2015) E. Rosta, W. Yang and G. Hummer, Calcium inhibition of Ribonuclease H1 two-metal ion catalysis" Journal of the American Chemical Society 136, pp 3137-3144 DOI: 10.1021/ja411408x (2014) A. Ganguy et al. Quantum Mechanical/Molecular Mechanical Free Energy Simulations of the Self-Cleavage Reaction in the Hepatitis Delta Virus Ribozyme. J. American Chemical Society, 136, 1483-1496 (2014). Arianna Fornili (School of Biological and Chemical Sciences, Queen Mary University of London) Molecular basis of regulation of cardiac myosin under normal conditions and in the presence of pathogenic mutations. The findings from this study will be presented at the 60th Annual Meeting of the Biophysical Society (27Feb - 2Mar 2016) in Los Angeles. An abstract of this work (A.Fornili, E. Rostkova, F. Fraternali, M. Pfuhl: "Effect of RLC-Nterminal tails on the structure and dynamics of cardiac myosin") will be published in a special number of the Biophysical Journal. A manuscript is currently under preparation. Francesco Gervasio (Chemistry, UCL) ARCHER time through HECBioSIm has been used to elucidate the mode of action of cancer-causing and drug-resistance causing mutations in an important class of signalling proteins (protein kinases). This kind of information is of great importance in the rational design of more effective anti-cancer drugs. [1] T. D. Bunney, S. Wan, N. Thiyagarajan, L. Sutto, S. V. Williams, P. Ashford, H. Koss, M. A. Knowles, F. L. Gervasio, P. V. Coveney, M. Katan EBioMedicine, 2, 194-204, 2015. [2] K Marino, L Sutto, F L Gervasio* The Effect of a Wide-spread Cancer-causing Mutation on the Inactive to Active Dynamics of the B-Raf Kinase J. Am. Chem. Soc. 137, 5280-5283, 2015 [3] S. Lovera, M. Morando, E. Pucheta-Martinez, J. Martinez-Torrecuadrada, G. Saladino, F. L. Gervasio* Towards a Molecular Understanding of the Link Between Imatinib Resistance and Kinase Conformational Dynamics Plos Comp Biol. 12, e1004578, 2015. Julien Michel (Chemistry, Edinburgh) Established the mechanisms by which a key cancer causing protein recognises small molecule drugs via a disordered protein region. The findings are helping drug designers target more effectively this protein to develop more efficacious drugs. Elucidation of Ligand-Dependent Modulation of Disorder-Order Transitions in the Oncoprotein MDM2 Bueren-Calabuig, J. A. ; Michel, J. PLoS Comput. Biol. , 11(6): e1004282, 2015 Mario Orsi (School of Engineering and Materials Science, Queen Mary University of London) Atomistic molecular dynamics simulations were performed on models for cell membranes. In particular, effects due to changes in the lamellar vs. nonlamellar lipid composition of membranes were quantified. A number of properties of mixed lipid membranes were characterized quantitatively for the first time, including the lateral pressure, electric field and dipole potential. This work has been published in a high quality peer-reviewed international journal [Wei Ding, Michail Palaiokostas, Wen Wang, and Mario Orsi, Effects of Lipid Composition on Bilayer Membranes Quantified by All-Atom Molecular Dynamics The Journal of Physical Chemistry B 2015 119 (49), 15263-15274, DOI: 10.1021/acs.jpcb.5b06604]. Molecular simulations were conducted to study permeation processes of small molecules through mixed lipid membranes. For the first time, it is shown that nonlamellar lipids reduce membrane permeation through a mechanism that can be related to a small number of fundamental physical properties. A manuscript on this research is in preparation. The research conducted was selected for oral presentations at the 2015 MGMS Young Modellers' Forum (The Old Naval College, Greenwich, London, 27/11/15) and at the 2015 Thomas Young Centre Student Day (Imperial College, London, 17/12/15), as well as for poster presentations at the 2016 Annual Biophysical Society meeting (Los Angeles, 27 Feb-2 Mar 2016). Mark Sansom (Biochemistry, Oxford) We have also used ARCHER as part of our ongoing programme of very large scale simulations of the dynamic properties of viral membrane envelopes in biomedically important enveloped viruses including influenza and dengue. (Reddy, T. & Sansom, M.S.P. (2015) The role of the membrane in the structure and biophysical robustness of the dengue virion envelope. http://dx.doi.org/10.1016/j.str.2015.12.011). These virus simulations were featured in local media following their presentation by Tyler Reddy at the 2014 US Biophysics meeting. Other recent successes of the use of ARCHER under HECBioSim (Sansom Group, Oxford) include a collaboration between computational and experimental groups (the latter using advanced microscopy imaging of bacterial membranes) to study role of nanoscale 'islands' of membrane proteins in bacterial cell division (see above). This work is continuing, and is of relevance to developing novel targets to help overcome antimicrobial resistance. It has also led to an increase in interest in large scale simulations of membranes from a number of structural biology and biophysics groups, including those of Carol Robinson (Chemistry, Oxford) and Liz Carpenter (SGC, Oxford), in particular using these methods to characterise the interactions of membrane proteins with their lipid bilayer environment Stansfeld, P.J., Goose, J.E., Caffrey, M., Carpenter, E.P., Parker, J.L., Newstead, N. & Sansom, M.S.P. (2015) MemProtMD: automated insertion of membrane protein structures into explicit lipid membranes. Structure (doi:10.1016/j.str.2015.05.006) Phil Biggin (Biochemistry, Oxford) Work from the Biggin group has made strong use of ARCHER through HECBioSim and has resulted in the following publications from the allocations from the Consortium over the past year: Kainate receptor pore-forming and auxiliary subunits regulate channel block by a novel mechanism. Brown PM, Aurousseau MR, Musgaard M, Biggin PC, Bowie D. J Physiol. 2015 Dec 18. doi: 10.1113/JP271690. [Epub ahead of print] Accurate calculation of the absolute free energy of binding for drug molecules, Aldeghi M, Heifetz A, Bodkin MJ, Knapp S, Biggin PC. Chem. Sci., 2016,7, 207-218 doi: 10.1039/C5SC02678D Distinct structural pathways coordinate the activation of AMPA receptor-auxiliary subunit complexes Dawe GB, Musgaard M, Aurousseau M, Nayeem N, Green T, Biggin PC, Bowie D. Neuron [in press] The role of an absolutely conserved tryptophan pair in the extracellular domain of Cys-loop receptors. Braun N, Lynagh T, Yu R, Biggin PC, Pless S. ACS Chem. Neurosci. [in press] Greater scientific productivity: As well as speed increases, the optimisation of codes for the ARCHER machine will enable problems to be solved in less time using fewer compute resources. • For the reporting period please provide a brief update on progress of software development activities associated with the consortium and the impact this has had on consortium members and the broader research community. Charlie Laughton (Pharmacy, Nottingham) Development and deployment of Longbow, a high-throughput remote job submission tool for the biomolecular simulation community, now being leveraged by other CCPs as well. Longbow makes at easy for biomolecular simulation jobs to be run on Archer as on a local desktop. Journal of Open Research Software 2016, DOI: http://dx.doi.org/10.5334/jors.95 Francesco Gervasio (Chemistry, UCL) Researchers from University College London, led by Francesco Gervasio in collaboration with the Structural Biology Computational Group of the Spanish National Cancer Research Centre (CNIO) headed by Alfonso Valencia have developed the first computational method based on evolutionary principles to predict protein dynamics, which explains the changes in the shape or dimensional structure that they experience in order to interact with other compounds or speed up chemical reactions. The study made possible by the supercomputing resources provided by Archer and PRACE constitutes a major step forward in the computational study of protein dynamics. [4] L. Sutto, S. Marsili, A. Valencia, F. L. Gervasio* From residue co-evolution to protein conformational ensembles and functional dynamics Proc Natl Acad Sci USA, 112 13567-13572, 2015 Press release: http://www.eurekalert.org/pub_releases/2015-10/cndi-ana102315.php Phil Biggin (Biochemistry, Oxford) Our recent publication on Accurate free energy predictions made use of the FESetup package (through the CCPBioSIM CCP). Increasing the UK's CSE skills base (including graduate and post doctorate training and support): This builds on the skills sets of trained people in HPC, both in terms of capacity and raising the overall skill level available to the sector. • For the reporting period please provide a bullet pointed list of training activities undertaken by the Consortium, providing information on the target audience and level of attendance. For example: Arianna Fornili (School of Biological and Chemical Sciences, Queen Mary University of London) A 1st year PhD student working on this project is currently being trained under my supervision in the use of HPC resources and in particular of ARCHER. Charlie Laughton (Pharmacy, Nottingham) "Going Large" workshop: Daresbury 16/12/15. Hands-on introduction to HECBioSim tools (Longbow and pyPcazip) developed to aid the running and analysis of large scale ensemble simulations. 16 attendees. Francesco Gervasio and Edina Rosta (Chemistry, UCL and Chemistry, KCL) E. Rosta (KCL) & F. Gervasio (UCL) organized a workshop on Free Energy Calculation and Molecular Kinetics in London April 20-22, 2015. The successful workshop was attended by more than 40 (mainly post-doctoral) academic and industrial researcher from all over Europe. Increased impact and collaboration with industry: ARCHER does not operate in isolation and the 'impact' of ARCHER's science is converted to economic growth through the interfaces with business and industry. In order to capture the impacts, which may be economic, social, environmental, scientific or political, various metrics may be utilised. • Please provide a brief update on any planned activities / collaborations / outcomes outlined in the original Pathways to Impact plan for the Consortium. • For the reporting period please provide information on any Consortium projects that have been performed in collaboration with industry, this should include details of the company involved, a statement on the impact that the work has / is making and, if relevant, details of any in kind or in cash contributions that have been associated with this work. • For the reporting period include a list of Consortium publications that have industrial co-authorship. • For the reporting period please provide details of the any other activities involving industrial participation e.g. activities involving any Industrial Advisory panels, attendance / participation in workshops and Consortium based activities. Arianna Fornili (School of Biological and Chemical Sciences, Queen Mary University of London) This project is done in collaboration with experimental (NMR and SAXS) partners at King's College London (Dr. Mark Pfuhl and Dr. Elena Rostkova), with the final aim of providing a complete molecular model of how muscle contraction is regulated in the heart. Francesco Gervasio (Chemistry, UCL) A new collaboration with UCB on developing new approaches to sample cryptic binding sites of pharmaceutical interest was started. UCB co-sponsored a BBSRC-CASE PhD studentships. The code development and its application to interesting targets was made possible by the access to Archer. Phil Biggin (Biochemistry, Oxford) The following has industrial partners as co-authors: Accurate calculation of the absolute free energy of binding for drug molecules, Aldeghi M, Heifetz A, Bodkin MJ, Knapp S, Biggin PC. Chem. Sci., 2016,7, 207-218 doi: 10.1039/C5SC02678D. The GLAS scoring module for gromacs has yet to be implemented but that would also constitute industrial activity. Strengthening of UK's international position: The impacts of ARCHER's science extend beyond national borders and most science is delivered through partnerships on a national or international level. • For the reporting period please provide a bullet pointed list of projects that have involved international collaboration. • For the reporting period please provide a list of consortium publications with international co-authorship. • For the reporting period please detail any other international activities that the Consortium might be involved in (workshops, EU projects etc.). Alessandro Pandini (Computer Science, Brunel University London) The "Analysis of the allosteric communication in HIF-2a-ARNT heterodimer" has recently started (1st December 2015). It is aimed at the identification of the allosteric pathways in the HIF-2a-ARNT heterodimer. This can advance the discovery of therapeutic molecules and shed light on the mechanisms underlying disease mutations and post-translational modifications affecting the response to hypoxic stress in cells. In this early stages of the project, a promising collaboration has been explored with the group of Prof. Laura Bonati at the University of Milan-Bicocca. This collaboration will provide an avenue for scientific visits, for the training of a PhD student currently working in Prof. Bonati's group. Charlie Laughton (Pharmacy, Nottingham) • The "Ascona B-DNA Consortium" project to develop next-generation simulations of nucleic acids. Partners across Europe and in the USA and India. Publication: Nature Methods, 2016, 13(1), 55-+ • EU H2020 project "Multiscale genomics" (multiscalegenomics.eu): developing computational tools and infrastructures to support a multiscale genomics virtual research environment. • CECAM Extended Software Development Workshop (joint with NSF): Deployment and development of advanced sampling tools on HPC resources. Juelich, 11-24/10/15. 91 attendees from across Europe and the US. Francesco Gervasio (Chemistry, UCL) Both projects listed above as well as references 3 and 4 involved international collaborations with research groups at the Spanish National Cancer Research Centre, one of the most important cancer biology research centres in Europe. Phil Biggin (Biochemistry, Oxford) All of these have international collaboration and co-authorships: Kainate receptor pore-forming and auxiliary subunits regulate channel block by a novel mechanism. Brown PM, Aurousseau MR, Musgaard M, Biggin PC, Bowie D. J Physiol. 2015 Dec 18. doi: 10.1113/JP271690. [Epub ahead of print] Accurate calculation of the absolute free energy of binding for drug molecules, Aldeghi M, Heifetz A, Bodkin MJ, Knapp S, Biggin PC. Chem. Sci., 2016,7, 207-218 doi: 10.1039/C5SC02678D Distinct structural pathways coordinate the activation of AMPA receptor-auxiliary subunit complexes Dawe GB, Musgaard M, Aurousseau M, Nayeem N, Green T, Biggin PC, Bowie D. Neuron [in press] The role of an absolutely conserved tryptophan pair in the extracellular domain of Cys-loop receptors. Braun N, Lynagh T, Yu R, Biggin PC, Pless S. ACS Chem. Neurosci. [in press] Future Vision: How do you see the Consortium strategy evolving and changing in the future? In the next 5 years, what new science questions will members of your Consortium be seeking to address? Why are these important? We aim to expand the breadth of the work of the Consortium focusing on cutting-edge applications, and building collaborations with experiments and industry, to achieve maximum impact from ARCHER use. HECBioSim is now well established, supporting work of many groups across the UK in the growing field of biomolecular simulation. We benefit from an Advisory Group containing members from industry, as we as international biomolecular simulation experts and experimental scientists. The Advisory Board was expanded and refreshed for the renewal and consists of: Dr. Nicolas Foloppe (Vernalis plc, Chair); Dr. Colin Edge (GlaxoSmithKline); Dr. Mike King (UCB Pharmaceuticals); Dr. Mike Mazanetz (Evotec AG); Dr. Garrett Morris (Crysalin Ltd.); Dr. Gary Tresadern (Johnson and Johnson Pharmaceuticals); Dr. Richard Ward (AstraZeneca); Prof. Modesto Orozco (IRB, Barcelona); Prof. Tony Watts, (Oxford, NMR); Dr. Pete Bond (A*STAR Bioinformatics Institute Singapore). We aim to foster industrial collaborations and collaborations with experimentalists (e.g. joint workshops with CCPN, Institute of Physics (Sarah Harris, Leeds Physics); see e.g. case studies. A particular them for strategic development will be multiscale modelling, building on collaborations between several groups in the Consortium. We discussed Grand Challenges at our most recent Management Group meeting. In December 2015, and have have identified several to follow up as strategic priorities. We aim to tackle and support large-scale grand challenge applications in biomolecular science, in areas such as antimicrobial resistance, membrane dynamics, drug design and synthetic biology. One specific theme with potentially high impact in drug discovery is large -scale comparative investigation of allosteric regulation in different superfamilies of proteins (e.g. PAS domain containing proteins, tyrosine kinases, etc.). The major impact will be in the identification of novel selective therapeutic molecules with limited adverse side effects. As a Consortium, we intend to develop and apply novel computational approaches for the rational design of allosteric regulators of hitherto 'undruggable' targets. Many of the targets emerging from large-scale genetic screening are deemed undruggable due to the difficulty of designing drug-like modulators that bind to their catalytic sites. It is increasingly clear that these targets might be effectively targeted by designing drugs that bind to protein-protein interfaces and allosteric sites. To do that, however, new rational design strategies, based on an in-depth knowledge of protein dynamics and advanced modelling and new simulation techniques are required. Other challenging frontier areas include dynamics of motor proteins; prediction of the effects of pathogenic mutations on protein function. The accurate prediction of free energy of binding is still in its infancy and needs much further investigation. Finally, kinetics of biomolecular reactions will become the next big topic. It is clear that high end computing resource can provide the necessary power and capability to provide inroads into this vital area. This is important because it is becoming increasingly apparent that kinetics of drug binding is a key factor that the pharmaceutical sector should really be looking at in terms of a major dictator of potency. Background HECBioSim, the UK HEC Biomolecular Simulation Consortium, was established in March 2013, and works closely with and complements CCP-BioSim (the UK Collaborative Computational Project for Biomolecular Simulation at the Life Sciences Interface). Most of the members of the Consortium are experienced users of high end computing. Biomolecular simulations are now making significant contributions to a wide variety of problems in drug design and development, biocatalysis, bio and nano-technology, chemical biology and medicine. The UK has a strong and growing community in this field, recognized by the establishment in 2011 by the EPSRC of CCP-BioSim (ccpbiosim.ac.uk), and its renewal in 2015. There is a clear, growing and demonstrable need for HEC in this field. Members of the Consortium have, for example, served on the HECToR and ARCHER Resource Allocation Panel. The Consortium welcomes members across the whole biomolecular sciences community, and we are currently (and will remain) open to new members (unlike some consortia). Since establishing the Consortium, several new members (FLG, DH, ER) have joined the Management Group. Many of the projects awarded ARCHER time under the Consortium do not involve CCP-BioSim or HECBioSim Management Group members, demonstrating the openness of HECBioSim and its support of the biomolecular simulation community in the UK. A number of other researchers have joined and it is our expectation that other researchers will join HECBioSim in the future. We actively engage with structural and chemical biologists and industrial researchers. We foster interactions between computational, experimental and industrial scientists (see the example case studies; members of the Consortium have excellent links with many pharmaceutical, chemical and biotechnology companies). Details of HECBioSim are available via our webpages at: http://www.hecbiosim.ac.uk. Applications are made through the website http://www.hecbiosim.ac.uk and reviewed at one of the series of regular panel meetings. A list of successful HECtime allocations on ARCHER is available at:http://www.hecbiosim.ac.uk/applications/successfulprojects. All proposals are of course subject to scientific and technical review, but we have the philosophy of supporting the best science to deliver the highest impact, rather than focusing on supporting development of a couple of codes. An allocation panel (with changing membership) meets twice yearly to judge proposals and requests for AUs; projects are assessed competitively: any groups in the UK can apply. All submitted proposals receive constructive feedback from the allocation panel. The HECBioSim website also provides forums for the biomolecular simulation community, a wiki hosting useful how-tos and user guides, and software downloads (currently FESetup and Longbow). Our lead software development project between Nottingham (Charlie Laughton and Gareth Shannon) and Daresbury (James Gebbie), we have developed a remote job submission tool, 'Longbow' (see below). The tool is designed to reproduce the look and feel of local MD packages, but to stage data and submit jobs to a large HPC resource, such as ARCHER, in a manner invisible to the user. Workshops and New Opportunities Workshops are listed below and can be found on the HECBioSim Website We work closely with CCP-BioSim, for example in organizing training workshops and meetings. Our activities are outlined at www.hecbiosim.ac.uk Examples of forthcoming meetings include: Computational Molecular Science 2017 - on Sunday 19 March 2017 17th European Seminar on Computational Methods in Quantum Chemistry - on Tuesday 11 July 2017 Frontiers of Biomolecular Simulation Southampton, September 2017 Issues and Problems Details of SLA activities are given in the SLA report. Dr. James Gebbie provides support to HECBioSIm through the SLA. He has been very helpful in the construction of the HECBioSim webpages (hecbiosim.ac.uk). James also worked with Dr. Gareth Shannon on the development of Longbow (See above). In the past year, members of the Consortium faced some queuing problems; close to the end of the first allocation period in particular, there were long queuing times, which led to problems in completing jobs and using allocated time. Throughput has been a real problem in the past few months. Membership Please provide a full list of existing members and their institutions, highlighting any new members that have joined the consortium during the reporting period. If available please provide information on the number of distinct users that have accessed ARCHER via the Consortium during this reporting period. Below is a list of PIs with HECBioSim projects in the current reporting period: Agnes Noy University of York new to this reporting period Alessandro Pandini Brunel University London Arianna Fornili Queen Mary University of London Cait MacPhee University of Edinbrurgh new to this reporting period Charlie Laughton University of Nottingham Clare-Louise Towse University of Bradford new to this reporting period D Flemming Hansen University College London new to this reporting period David Huggins Aston University Edina Rosta King's College London Francesco Gervasio University College London Ian Collinson University of Bristol new to this reporting period Irina Tikhonova Queen's University Belfast Jiayun Pang University of Greenwich Jonathan Doye University of Oxford Julien Michel University of Edinburgh Mario Orsi UWE Bristol Michele Vendruscolo University of Cambridge Michelle Sahai University of Roehampton Philip Biggin University of Oxford Richard Sessions University of Bristol Stephen Euston Heriot-Watt University Syma Khalid University of Southampton Evidence is emerging that vitamin D - and possibly vitamins K and A - might help combat COVID-19. A new study from the University of Bristol published in the journal of the German Chemical Society Angewandte Chemie has shown how they - and other antiviral drugs - might work. The research indicates that these dietary supplements and compounds could bind to the viral spike protein and so might reduce SARS-CoV-2 infectivity. In contrast, cholesterol may increase infectivity, which could explain why having high cholesterol is considered a risk factor for serious disease. Recently, Bristol researchers showed that linoleic acid binds to a specific site in the viral spike protein, and that by doing so, it locks the spike into a closed, less infective form. Now, a research team has used computational methods to search for other compounds that might have the same effect, as potential treatments. They hope to prevent human cells becoming infected by preventing the viral spike protein from opening enough to interact with a human protein (ACE2). New anti-viral drugs can take years to design, develop and test, so the researchers looked through a library of approved drugs and vitamins to identify those which might bind to this recently discovered 'druggable pocket' inside the SARS-CoV-2 spike protein. The team first studied the effects of linoleic acid on the spike, using computational simulations to show that it stabilizes the closed form. Further simulations showed that dexamethasone - which is an effective treatment for COVID-19 - might also bind to this site and help reduce viral infectivity in addition to its effects on the human immune system. The team then conducted simulations to see which other compounds bind to the fatty acid site. This identified some drugs that have been found by experiments to be active against the virus, suggesting that this may be one mechanism by which they prevent viral replication such as, by locking the spike structure in the same way as linoleic acid. The findings suggested several drug candidates among available pharmaceuticals and dietary components, including some that have been found to slow SARS-CoV-2 reproduction in the laboratory. These have the potential to bind to the SARS-CoV-2 spike protein and may help to prevent cell entry. The simulations also predicted that the fat-soluble vitamins D, K and A bind to the spike in the same way making the spike less able to infect cells. Dr Deborah Shoemark, Senior Research Associate (Biomolecular Modelling) in the School of Biochemistry, who modelled the spike, explained: "Our findings help explain how some vitamins may play a more direct role in combatting COVID than their conventional support of the human immune system. "Obesity is a major risk factor for severe COVID. Vitamin D is fat soluble and tends to accumulate in fatty tissue. This can lower the amount of vitamin D available to obese individuals. Countries in which some of these vitamin deficiencies are more common have also suffered badly during the course of the pandemic. Our research suggests that some essential vitamins and fatty acids including linoleic acid may contribute to impeding the spike/ACE2 interaction. Deficiency in any one of them may make it easier for the virus to infect." Pre-existing high cholesterol levels have been associated with increased risk for severe COVID-19. Reports that the SARS-CoV-2 spike protein binds cholesterol led the team to investigate whether it could bind at the fatty acid binding site. Their simulations indicate that it could bind, but that it may have a destabilising effect on the spike's locked conformation, and favour the open, more infective conformation. Dr Shoemark continued: "We know that the use of cholesterol lowering statins reduces the risk of developing severe COVID and shortens recovery time in less severe cases. Whether cholesterol de-stabilises the "benign", closed conformation or not, our results suggest that by directly interacting with the spike, the virus could sequester cholesterol to achieve the local concentrations required to facilitate cell entry and this may also account for the observed loss of circulating cholesterol post infection." Professor Adrian Mulholland, of Bristol's School of Chemistry, added: "Our simulations show how some molecules binding at the linoleic acid site affect the spike's dynamics and lock it closed. They also show that drugs and vitamins active against the virus may work in the same way. Targeting this site may be a route to new anti-viral drugs. A next step would be to look at effects of dietary supplements and test viral replication in cells." Alison Derbenwick Miller, Vice President, Oracle for Research, said: "It's incredibly exciting that researchers are gaining new insights into how SARS-CoV-2 interacts with human cells, which ultimately will lead to new ways to fight COVID-19. We are delighted that Oracle's high-performance cloud infrastructure is helping to advance this kind of world-changing research. Growing a globally-connected community of cloud-powered researchers is exactly what Oracle for Research is designed to do." The team included experts from Bristol UNCOVER Group, including Bristol's Schools of Chemistry, Biochemistry, Cellular and Molecular Medicine, and Max Planck Bristol Centre for Minimal Biology, and BrisSynBio, using Bristol's high performance computers and the UK supercomputer, ARCHER, as well as Oracle cloud computing. The study was supported by grants from the EPSRC and the BBSRC. Paper 'Molecular simulations suggest vitamins, retinoids and steroids as ligands binding the free fatty acid pocket of SARS-CoV-2 spike protein' by Deborah Karen Shoemark, Charlotte K. Colenso, Christine Toelzer, Kapil Gupta, Richard B. Sessions, Andrew D. Davidson, Imre Berger, Christiane Schaffitzel, James Spencer and Adrian J. Mulholland in Angewandte Chemie International Edition: doi.org/10.1002/anie.20201563 |
| Sectors | Chemicals Digital/Communication/Information Technologies (including Software) Education Healthcare Manufacturing including Industrial Biotechology Pharmaceuticals and Medical Biotechnology |
| URL | http://www.hecbiosim.ac.uk |
| Description | Research data and policy |
| Geographic Reach | National |
| Policy Influence Type | Contribution to new or improved professional practice |
| URL | https://www.chemistryworld.com/news/ukri-finds-itself-in-hot-water-too-over-researchfish-cyberbullyi... |
| Description | UKRI research data capture approaches |
| Geographic Reach | National |
| Policy Influence Type | Contribution to new or improved professional practice |
| URL | https://www.researchprofessionalnews.com/rr-news-uk-research-councils-2023-1-researchfish-tweets-aga... |
| Description | AMR Global Development Award 2017 |
| Amount | £88,000 (GBP) |
| Funding ID | MR/R014922/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2017 |
| End | 03/2018 |
| Description | An in silico structure-based approach to map the druggable allosteric space of membrane receptors |
| Amount | £310,098 (GBP) |
| Funding ID | BB/R007101/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 08/2018 |
| End | 01/2023 |
| Description | AstraZeneca CASE studentship |
| Amount | £29,500 (GBP) |
| Organisation | AstraZeneca |
| Sector | Private |
| Country | United Kingdom |
| Start | 03/2017 |
| End | 02/2021 |
| Description | BBSRC Tools and Techniques: Computational tools for enzyme engineering: bridging the gap between enzymologists and expert simulation |
| Amount | £146,027 (GBP) |
| Funding ID | BB/L018756/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 06/2014 |
| End | 01/2016 |
| Description | BBSRC sLoLa: Innovative Routes to Monoterpene Hydrocarbons and Their High Value Derivatives |
| Amount | £3,038,984 (GBP) |
| Funding ID | BB/M000354/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2010 |
| End | 09/2019 |
| Description | BEORHN: Bacterial Enzymatic Oxidation of Reactive Hydroxylamine in Nitrification via Combined Structural Biology and Molecular Simulation |
| Amount | £181,398 (GBP) |
| Funding ID | BB/V016768/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 01/2022 |
| End | 12/2024 |
| Description | BI - XChem |
| Amount | £248,000 (GBP) |
| Organisation | Boehringer Ingelheim |
| Sector | Private |
| Country | Germany |
| Start | 01/2019 |
| End | 12/2020 |
| Description | BioNet - Dynamical Redesign of Biomolecular Networks |
| Amount | £1,184,999 (GBP) |
| Funding ID | 757850 |
| Organisation | European Commission |
| Sector | Public |
| Country | European Union (EU) |
| Start | 02/2018 |
| End | 01/2023 |
| Description | Biocatalysis and Biotransformation: A 5th Theme for the National Catalysis Hub |
| Amount | £3,053,639 (GBP) |
| Funding ID | EP/M013219/1 |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 01/2015 |
| End | 12/2019 |
| Description | BristolBridge has contributed to the University of Bristol being the UK's largest recipient of RCUK AMR cross-council funding awards both in number (7) and value (£5.268M). 6 related AMR grants awarded with BristolBridge PIs/Co-Is include MRC-led AMR. |
| Amount | £5,268,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2016 |
| End | 09/2019 |
| Description | CCP-BioSim: Biomolecular Simulation at the Life Sciences Interface |
| Amount | £235,706 (GBP) |
| Funding ID | EP/M022609/1 |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 06/2015 |
| End | 04/2021 |
| Description | CCP-BioSim: Biomolecular simulation at the life sciences interface |
| Amount | £287,541 (GBP) |
| Funding ID | EP/J010588/1 |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2011 |
| End | 09/2015 |
| Description | CCPBioSim: Biomolecular Simulation at the Life Science Interface |
| Amount | £345,687 (FKP) |
| Funding ID | EP/T026308/1 |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 11/2020 |
| End | 10/2025 |
| Description | Carbapenem Antibiotic Resistance in Enterobacteriaceae: Understanding Interactions of KPC Carbapenemases with Substrates and Inhibitors |
| Amount | £668,396 (GBP) |
| Funding ID | MR/T016035/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 01/2020 |
| End | 01/2023 |
| Description | Combining quantum and classical methods to study bacterial membrane enzymes |
| Amount | £126,931 (GBP) |
| Organisation | The Leverhulme Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 06/2018 |
| End | 07/2021 |
| Description | Confidence in Concept 'Developing a mobile device for rapid antimicrobial resistance detection in primary care' |
| Amount | £74,685 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 05/2017 |
| End | 05/2018 |
| Description | Diet and Health Research Industry Club |
| Amount | £398,037 (GBP) |
| Funding ID | BB/M027449/1 and BB/M027597/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2015 |
| End | 05/2018 |
| Description | EPSRC |
| Amount | £188,950 (GBP) |
| Funding ID | E/EP/G007705/1 |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2013 |
| End | 03/2014 |
| Description | EPSRC Flagship Software |
| Amount | £523,963 (GBP) |
| Funding ID | EP/P022138/1 |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 05/2017 |
| End | 11/2019 |
| Description | EPSRC Project Grant |
| Amount | £293,994 (GBP) |
| Funding ID | EP/P011993/1 |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 04/2017 |
| End | 04/2020 |
| Description | Industrial PhD studentship |
| Amount | £30,000 (GBP) |
| Organisation | Heptares Therapeutics Ltd |
| Sector | Private |
| Country | United Kingdom |
| Start | 03/2017 |
| End | 02/2020 |
| Description | Inquire: Software for real-time analysis of binding |
| Amount | £105,748 (GBP) |
| Funding ID | BB/K016601/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 08/2013 |
| End | 09/2014 |
| Description | John Fell Fund |
| Amount | £86,614 (GBP) |
| Organisation | University of Oxford |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 08/2016 |
| End | 12/2018 |
| Description | MPLS NIF FUND |
| Amount | £8,420 (GBP) |
| Organisation | University of Oxford |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 02/2017 |
| Description | Nicotinic Ligand Development to Target Smoking Cessation and Gain a Molecular Level Understanding of Partial Agonism |
| Amount | £724,553 (GBP) |
| Funding ID | EP/N024117/1 |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 05/2016 |
| End | 11/2019 |
| Description | Oracle for Research Cloud Fellowship |
| Amount | $100,000 (USD) |
| Organisation | Oracle Corporation |
| Sector | Private |
| Country | United States |
| Start | 02/2023 |
| End | 12/2023 |
| Description | PREDACTED Predictive computational models for Enzyme Dynamics, Antimicrobial resistance, Catalysis and Thermoadaptation for Evolution and Desig |
| Amount | € 2,482,332 (EUR) |
| Funding ID | 101021207 |
| Organisation | European Research Council (ERC) |
| Sector | Public |
| Country | Belgium |
| Start | 09/2021 |
| End | 09/2026 |
| Description | Synthetic Biology Research Centre. BrisSynBio: Bristol Centre for Synthetic Biology |
| Amount | £13,528,180 (GBP) |
| Funding ID | BB/L01386X/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 06/2014 |
| End | 07/2019 |
| Description | The UK High-End Computing Consortium for Biomolecular Simulation |
| Amount | £321,432 (GBP) |
| Funding ID | EP/R029407/1 |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 02/2019 |
| End | 10/2021 |
| Description | Understanding gating kinetics in Cys-loop receptors |
| Amount | £345,655 (GBP) |
| Funding ID | BB/S001247/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 11/2018 |
| End | 10/2022 |
| Description | https://gtr.ukri.org/person/2A2990B1-E1E1-4888-8848-7C256C3A3B43 |
| Amount | £20,009,000 (GBP) |
| Funding ID | https://gtr.ukri.org/person/2A2990B1-E1E1-4888-8848-7C256C3A3B43 |
| Organisation | United Kingdom Research and Innovation |
| Sector | Public |
| Country | United Kingdom |
| Start | 01/2006 |
| End | 02/2033 |
| Title | An expandable, modular de novo protein platform for precision redox engineering |
| Description | Pioneering study signals new era of environment-friendly programmable bioelectronics Image shows the design of a protein nanowire, with the green arrow indicating electron flow. Ross Anderson Image shows structural analysis of the protein-based wire, comparing the model of the designed protein (shown in red) with the experimentally determined structure (in grey). Ross Anderson Press release issued: 25 July 2023 Researchers have created a unique microscopic toolkit of 'green' tuneable electrical components, paving the way for a new generation of bioelectronic devices and sensors. The University of Bristol-led study, published today in The Proceedings of the National Academy of Sciences (PNAS), demonstrates how to make conductive, biodegradable wires from designed proteins. These could be compatible with conventional electronic components made from copper or iron, as well as the biological machinery responsible for generating energy in all living organisms. The miniscule wires are the size of transistors on silicon chips or one thousandth of the breadth of the finest human hair. They are made completely of natural amino acids and heme molecules, found in proteins such as hemoglobin, which transports oxygen in red blood cells. Harmless bacteria were used for their manufacture, eliminating the need for potentially complex and environmentally damaging procedures commonly used in the production of synthetic molecules. Lead author Ross Anderson, Professor of Biological Chemistry at the University of Bristol, said: "While our designs take inspiration from the protein-based electronic circuits necessary for all life on Earth, they are free from much of the complexity and instability that can prevent the exploitation of their natural equivalents on our own terms. We can also build these minute electronic components to order, specifying their properties in a way that is not possible with natural proteins." Leading experts in biomolecular engineering and simulation worked together to produce this unique new method of designing tailor-made proteins with tuneable electronic properties. The multidisciplinary team used advanced computational tools to design simple building blocks that could be combined into longer, wire-like protein chains for conducting electrons. They were able to visualise the structures of these wires using protein X-ray crystallography and electron cryo-microscopy (cryo-EM), techniques which allow structures to be viewed in the finest detail. Pushing the technical boundaries of cryo-EM, images of the smallest individual protein ever studied were obtained with this technique. Ultimately, these nanoscale designer wires have the potential to be used in a wide range of applications, including biosensors for the diagnosis of diseases and detection of environmental pollutants. It is also hoped this invention will form the foundation of new electrical circuits for creating tailor-made catalysts for green industrial biotechnology and artificial photosynthetic proteins for capturing solar energy. The breakthrough was possible thanks to a £4.9 million grant from the Biotechnology and Biological Science Research Council (BBSRC), the UK's largest bioscience funder, which resulted in a five-year project entitled 'The Circuits of Life' involving the Universities of Bristol, Portsmouth, East Anglia, and University College London (UCL). The team harnessed their expertise in protein design, electron transfer, biomolecular simulation, structural biology and spectroscopy, gaining insight into how electrons flow through natural biological molecules, a fundamental process which underpins cellular respiration and photosynthesis. Further advances are expected as the project, which began last year, progresses, presenting significant opportunities to help meet the transition to net zero and more sustainable industrial processes. Co-author Adrian Mulholland, Professor of Chemistry at the University of Bristol, said: "These proteins show how protein design is increasingly delivering practically useful tools. They offer exciting possibilities as components for engineering biology and also are great systems for investigating the fundamental mechanisms of biological electron transfer." Paper 'An expandable, modular de novo protein platform for precision redox engineering' by George H. Hutchins, Claire E.M. Noble, Adrian Bunzel et al published in PNAS |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2023 |
| Provided To Others? | Yes |
| Impact | Pioneering study signals new era of environment-friendly programmable bioelectronics Image shows the design of a protein nanowire, with the green arrow indicating electron flow. Ross Anderson Image shows structural analysis of the protein-based wire, comparing the model of the designed protein (shown in red) with the experimentally determined structure (in grey). Ross Anderson Press release issued: 25 July 2023 Researchers have created a unique microscopic toolkit of 'green' tuneable electrical components, paving the way for a new generation of bioelectronic devices and sensors. The University of Bristol-led study, published today in The Proceedings of the National Academy of Sciences (PNAS), demonstrates how to make conductive, biodegradable wires from designed proteins. These could be compatible with conventional electronic components made from copper or iron, as well as the biological machinery responsible for generating energy in all living organisms. The miniscule wires are the size of transistors on silicon chips or one thousandth of the breadth of the finest human hair. They are made completely of natural amino acids and heme molecules, found in proteins such as hemoglobin, which transports oxygen in red blood cells. Harmless bacteria were used for their manufacture, eliminating the need for potentially complex and environmentally damaging procedures commonly used in the production of synthetic molecules. Lead author Ross Anderson, Professor of Biological Chemistry at the University of Bristol, said: "While our designs take inspiration from the protein-based electronic circuits necessary for all life on Earth, they are free from much of the complexity and instability that can prevent the exploitation of their natural equivalents on our own terms. We can also build these minute electronic components to order, specifying their properties in a way that is not possible with natural proteins." Leading experts in biomolecular engineering and simulation worked together to produce this unique new method of designing tailor-made proteins with tuneable electronic properties. The multidisciplinary team used advanced computational tools to design simple building blocks that could be combined into longer, wire-like protein chains for conducting electrons. They were able to visualise the structures of these wires using protein X-ray crystallography and electron cryo-microscopy (cryo-EM), techniques which allow structures to be viewed in the finest detail. Pushing the technical boundaries of cryo-EM, images of the smallest individual protein ever studied were obtained with this technique. Ultimately, these nanoscale designer wires have the potential to be used in a wide range of applications, including biosensors for the diagnosis of diseases and detection of environmental pollutants. It is also hoped this invention will form the foundation of new electrical circuits for creating tailor-made catalysts for green industrial biotechnology and artificial photosynthetic proteins for capturing solar energy. The breakthrough was possible thanks to a £4.9 million grant from the Biotechnology and Biological Science Research Council (BBSRC), the UK's largest bioscience funder, which resulted in a five-year project entitled 'The Circuits of Life' involving the Universities of Bristol, Portsmouth, East Anglia, and University College London (UCL). The team harnessed their expertise in protein design, electron transfer, biomolecular simulation, structural biology and spectroscopy, gaining insight into how electrons flow through natural biological molecules, a fundamental process which underpins cellular respiration and photosynthesis. Further advances are expected as the project, which began last year, progresses, presenting significant opportunities to help meet the transition to net zero and more sustainable industrial processes. Co-author Adrian Mulholland, Professor of Chemistry at the University of Bristol, said: "These proteins show how protein design is increasingly delivering practically useful tools. They offer exciting possibilities as components for engineering biology and also are great systems for investigating the fundamental mechanisms of biological electron transfer." Paper 'An expandable, modular de novo protein platform for precision redox engineering' by George H. Hutchins, Claire E.M. Noble, Adrian Bunzel et al published in PNAS |
| URL | https://www.bristol.ac.uk/news/2023/july/protein-nanowires.html |
| Title | Annual report to EPSRC; details below |
| Description | HECBioSim, the UK HEC Biomolecular Simulation Consortium, was established in March 2013, and works closely with and complements CCP-BioSim (the UK Collaborative Computational Project for Biomolecular Simulation at the Life Sciences Interface). Most of the members of the Consortium are experienced users of high end computing. Biomolecular simulations are now making significant contributions to a wide variety of problems in drug design and development, biocatalysis, bio and nano-technology, chemical biology and medicine. The UK has a strong and growing community in this field, recognized by the establishment in 2011 by the EPSRC of CCP-BioSim (ccpbiosim.ac.uk), and its renewal in 2015. There is a clear, growing and demonstrable need for HEC in this field. Members of the Consortium have, for example, served on the HECToR and ARCHER Resource Allocation Panel. The Consortium welcomes members across the whole biomolecular sciences community, and we are currently (and will remain) open to new members (unlike some consortia). Since establishing the Consortium, several new members (FLG, DH, ER) have joined the Management Group. Many of the projects awarded ARCHER time under the Consortium do not involve CCP-BioSim or HECBioSim Management Group members, demonstrating the openness of HECBioSim and its support of the biomolecular simulation community in the UK. A number of other researchers have joined and it is our expectation that other researchers will join HECBioSim in the future. We actively engage with structural and chemical biologists and industrial researchers. We foster interactions between computational, experimental and industrial scientists (see the example case studies; members of the Consortium have excellent links with many pharmaceutical, chemical and biotechnology companies). Details of HECBioSim are available via our webpages at: http://www.hecbiosim.ac.uk Applications are made through the website http://www.hecbiosim.ac.uk and reviewed at one of the series of regular panel meetings. A list of successful HECtime allocations on ARCHER is available at:http://www.hecbiosim.ac.uk/applications/successfulprojects All proposals are of course subject to scientific and technical review, but we have the philosophy of supporting the best science to deliver the highest impact, rather than focusing on supporting development of a couple of codes. An allocation panel (with changing membership) meets twice yearly to judge proposals and requests for AUs; projects are assessed competitively: any groups in the UK can apply. All submitted proposals receive constructive feedback from the allocation panel. The HECBioSim website also provides forums for the biomolecular simulation community, a wiki hosting useful how-tos and user guides, and software downloads (currently FESetup and Longbow). Our lead software development project between Nottingham (Charlie Laughton and Gareth Shannon) and Daresbury (James Gebbie), we have developed a remote job submission tool, 'Longbow' (see below). The tool is designed to reproduce the look and feel of local MD packages, but to stage data and submit jobs to a large HPC resource, such as ARCHER, in a manner invisible to the user. Workshops and New Opportunities No more than half a page detailing upcoming workshops and meetings. Also include discussion of other areas which are potentially of interest to other HEC Consortia and opportunities for cross CCP /HEC working. Workshops are listed below and can be found on the HECBioSim Website We work closely with CCP-BioSim, for example in organizing training workshops and meetings. Our activities are outlined at www.hecbiosim.ac.uk Examples of forthcoming meetings include: Computational Molecular Science 2017 - on Sunday 19 March 2017 17th European Seminar on Computational Methods in Quantum Chemistry - on Tuesday 11 July 2017 Frontiers of Biomolecular Simulation Southampton, September 2016 Issues and Problems Short discussion of any issues or problems that the HEC Consortium faces including issues with the ARCHER service, funding, management of allocation and staffing. This is also a good opportunity to highlight to the SLA committee any issues that the Consortium may have experienced with their SLA support during the reporting period. Details of SLA activities are given in the SLA report. Dr. James Gebbie provides support to HECBioSIm through the SLA. He has been very helpful in the construction of the HECBioSim webpages (hecbiosim.ac.uk). James also worked with Dr. Gareth Shannon on the development of Longbow (See above). In the past year, members of the Consortium faced some queuing problems; close to the end of the first allocation period in particular, there were long queuing times, which led to problems in completing jobs and using allocated time. Throughput has been a real problem in the past few months. Membership Please provide a full list of existing members and their institutions, highlighting any new members that have joined the consortium during the reporting period. If available please provide information on the number of distinct users that have accessed ARCHER via the Consortium during this reporting period. Below is a list of PIs with HECBioSim projects in the current reporting period: Agnes Noy, University of York - new to this reporting period Alessandro Pandini, Brunel University London Arianna Fornili, Queen Mary University of London Cait MacPhee, University of Edinbrurgh - new to this reporting period Charlie Laughton, University of Nottingham Clare-Louise Towse, University of Bradford - new to this reporting period D Flemming Hansen, University College London - new to this reporting period David Huggins, Aston University Edina Rosta, King's College London Francesco Gervasio, University College London Ian Collinson, University of Bristol - new to this reporting period Irina Tikhonova, Queen's University Belfast Jiayun Pang, University of Greenwich Jonathan Doye, University of Oxford Julien Michel, University of Edinburgh Mario Orsi, UWE Bristol Michele Vendruscolo, University of Cambridge Michelle Sahai, University of Roehampton Philip Biggin, University of Oxford Richard Sessions, University of Bristol Stephen Euston, Heriot-Watt University Syma Khalid, University of Southampton PIs in HECBioSIm outside of current allocation period Peter Bond, University of Cambridge Richard Bryce, University of Manchester Juan Antonio Bueren-Calabuig, University of Edinburgh Christo Christov, Northumbria University Anna K Croft, University of Nottingham Jonathan Essex, University of Southampton Robert Glen, University of Cambridge Sarah A Harris, University of Leeds Jonathan Hirst, University of Nottingham Douglas Houston, University of Edinburgh Dmitry Nerukh, Aston University Andrei Pisliakov, University of Dundee Mark Sansom, University of Oxford Marieke Schor, University of Edinburgh Gareth Shannon, University of Nottingham Tatyana Karabencheva-Christova, Northumbria University There are currently 164 members of HECBioSim (i.e. users of HECBioSIm ARCHER time), included the above PIs. 20 new users have been added since January 2016. World class and world leading scientific output: ARCHER should enable high quality and world-leading science to be delivered. This should generate high impact outputs and outcomes that increase the UK's position in world science. • If all the publications relating to the work of the Consortium for this reporting period have been added to ResearchFish / will be added to ResearchFish by the end of the ResearchFish reporting exercise, please indicate this below. • If submission of a full list of publications to the Consortium record/s in ResearchFish has not been possible for this reporting period please provide a list of publications that have resulted from work performed on ARCHER by the Consortium during this reporting period (this can be included as a separate attachment). • For the reporting period please provide a bullet pointed list of key / important research findings that has resulted from work performed on ARCHER by the Consortium. Please reference any related publications. • For the reporting period please include a bullet pointed list of any relevant press announcements and other communications of significance to an international community. All publications can be found in ResearchFish, and have been added by individual researchers. A selection of illustrative highlights are provided below: Julien Michel (University of Edinburgh) New molecular simulation methods have enabled for the first time a complete description of the interactions of several drug-like small molecules with an intrinsically disordered region of the oncoprotein MDM2, as well as the effect of post-translational modifications on the dynamics of this protein. The results obtained suggest new medicinal chemistry strategies to achieve potent and selective inhibition of MDM2 for cancer therapies. Publication: Elucidation of Ligand-Dependent Modulation of Disorder-Order Transitions in the Oncoprotein MDM2 http://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1004282 Impact of Ser17 Phosphorylation on the Conformational Dynamics of the Oncoprotein MDM2 http://pubs.acs.org/doi/abs/10.1021/acs.biochem.6b00127 An outreach document is being prepared by EPCC to showcase a lab project on isoform selective inhibition that has benefited from both HECBioSim and EPCC ARCHER allocations. Syma Khalid (Chemistry, Southampton) Publication: OmpA: A Flexible Clamp for Bacterial Cell Wall Attachment Samsudin F, Ortiz-Suarez ML, Piggot TJ, Bond PJ, Khalid S (2016). "OmpA: a Flexible Clamp for Bacterial Cell Wall Attachment", Structure, 24(12):2227-2235 With Singapore National Center for Biotechnology. Sarah Harris (Physics, Leeds) In collaboration with the experimental biochemistry group lead by Radford at Leeds, Sarah Harris used ARCHER time to show how chaperones help outer membrane proteins to fold, see: Schiffrin B, Calabrese AN, Devine PWA, Harris SA, Ashcroft AE, Brockwell DJ, Radford SE "Skp is a multivalent chaperone of outer-membrane proteins" Nature Structural and Molecular Biology 23 786-793, 2016. DOI:10.1038/nsmb.3266 Michelle Sahai (Department of Life Sciences, Roehampton) Publication: Combined in vitro and in silico approaches to the assessment of stimulant properties of novel psychoactive substances - The case of the benzofuran 5-MAPB. Progress in Neuro-Psychopharmacology and Biological Psychiatry 75, Pages 1-9 (2017) https://www.ncbi.nlm.nih.gov/pubmed/27890676 Phil Biggin (Biochemistry, Oxford) Outputs that have used HECBioSim time: 1. Steered Molecular Dynamics Simulations Predict Conformational Stability of Glutamate Receptors. Musgaard M, Biggin PC. J Chem Inf Model. 2016 Sep 26;56(9):1787-97. doi: 10.1021/acs.jcim.6b00297. 2. Kainate receptor pore-forming and auxiliary subunits regulate channel block by a novel mechanism. Brown PM, Aurousseau MR, Musgaard M, Biggin PC, Bowie D. J Physiol. 2016 Apr 1;594(7):1821-40. doi: 10.1113/JP271690. 3. Role of an Absolutely Conserved Tryptophan Pair in the Extracellular Domain of Cys-Loop Receptors. Braun N, Lynagh T, Yu R, Biggin PC, Pless SA. ACS Chem Neurosci. 2016 Mar 16;7(3):339-48. doi: 10.1021/acschemneuro.5b00298. 4. Distinct Structural Pathways Coordinate the Activation of AMPA Receptor-Auxiliary Subunit Complexes. Dawe GB, Musgaard M, Aurousseau MR, Nayeem N, Green T, Biggin PC, Bowie D. Neuron. 2016 Mar 16;89(6):1264-76. doi: 10.1016/j.neuron.2016.01.038. Covered by 7 news outlets: I. Health Canal (http://www.healthcanal.com/brain-nerves/70646-what-makes-the-brain-tick-so-fast.html) II. Health Medicine Network (http://healthmedicinet.com/i/scientists-reveal-how-the-brain-processes-information-with-lightning-speed/) III. News Medical (http://www.news-medical.net/news/20160227/Scientists-reveal-how-the-brain-processes-information-with-lightning-speed.aspx) IV. Wired (http://www.wired.co.uk/article/what-we-learned-about-the-brain-this-week-3) V. Alpha Galileo (http://www.alphagalileo.org/ViewItem.aspx?ItemId=161473&CultureCode=en) VI. Science Daily (https://www.sciencedaily.com/releases/2016/02/160225140254.htm) VII. Eureka Alert (https://www.eurekalert.org/pub_releases/2016-02/mu-wmt022516.php) Recommended by F1000 Prime: http://f1000.com/prime/726180600. 5. Accurate calculation of the absolute free energy of binding for drug molecules. Aldeghi M, Heifetz A, Bodkin MJ, Knapp S, Biggin PC. Chem Sci. 2016 Jan 14;7(1):207-218. Arianna Fornili (Biological and Chemical Sciences, Queen Mary University of London) Publication: Fornili, E. Rostkova, F. Fraternali, M. Pfuhl: Effect of RlC N-Terminal Tails on the Structure and Dynamics of Cardiac Myosin. Biophysical J. 110 (2016) 297A. More in preparation. Dmitry Nerukh (Engineering and Applied Science, Aston University) Important research findings: Distribution of ions inside a viral capsids influences the stability of the capsid Edina Rosta (Computational Chemistry, Kings College London) Highlighted publication: We have a joint experimental paper with the Vertessy group in JACS where we identified a novel arginine finger residue in dUTPase enzymes, and described the mechanism of action for this residue using crystallographic data, biochemical experiments, MD and QM/MM simulations thanks to HECBioSim. http://pubs.acs.org/doi/abs/10.1021/jacs.6b09012 Press release: Our joint paper with Jeremy Baumberg's group in Cambridge was published in Nature. http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/newssummary/news_13-6-2016-16-52-4 Greater scientific productivity: As well as speed increases, the optimisation of codes for the ARCHER machine will enable problems to be solved in less time using fewer compute resources. • For the reporting period please provide a brief update on the progress of software development activities associated with the Consortium and the impact this has had on Consortium members and the broader research community. Our lead software development project between Nottingham (Charlie Laughton and Gareth Shannon) and Daresbury (James Gebbie), we have developed a remote job submission tool, 'Longbow' (see below). The tool is designed to reproduce the look and feel of local MD packages, but to stage data and submit jobs to a large HPC resource such as ARCHER in a manner invisible to the user. An open beta version was released unrestricted to the community in March 2015 (http://www.hecbiosim.ac.uk/longbow and via PyPI https://pypi.python.org ) with ~100 downloads. Functionality includes native support for biosimulation packages AMBER, CHARMM, GROMACS, LAMMPS and NAMD, native support for jobs on ARCHER, native support for jobs running on PBS and LSF schedulers, and support for three different job types (single, ensembles and multiple jobs). The software is written both as an application for users and an API for developers. CCP-EM have integrated Longbow into their developmental GUI, and shortly FESetup will ship with native support for job submission using Longbow. We are currently in talks with ClusterVision with respect to them distributing Longbow to their user base as a user friendly way for novices to interact with their systems. Longbow Longbow has been growing in popularity both amongst researchers within the biosimulation field and those in other fields. In this reporting period there have been five new releases of Longbow delivering a plethora of user requested features and bug fixes. Some of the key developments are summarised below: • Implemented a Recovery mode - Should the event happen that Longbow crashes or the system in which Longbow is controlling jobs from powers down. The user can now reconnect to the crashed session and carry on as if nothing happened. • Sub-Queuing - More and more system administrators are setting limits not just on the number of simulations that can run, but also on the number of jobs that can go into the queue. Longbow can now automatically detect this and implement its own queue feeding jobs into the system queue as slots open up. • Dis-connectible/Re-connectible Longbow sessions - A user can now launch Longbow to fire off all jobs and then disconnect, at a later date the user can re-establish the connection and download all results (no need for persistent connections anymore) • Ability to include scripts in the Longbow generated submit files. • Numerous stability, performance and bug fixes Longbow continues to be the submission engine that is used under the hood of the CCP-EM toolkit FLEX-EM. There are several other interesting projects that are making use of Longbow. A project by the energy efficient computing group (Hartree Center) are currently integrating Longbow with CK, a crowd sourced compilation optimisation tool aimed at finding efficient compilation configuration. A project by the Applications performance engineering group (Hartree Center) are currently integrating longbow into Melody, a runtime optimisation tool aimed at optimising runtime configuration of simulations. A project by the computational biology group (Hartree Center) an automated setup, launch and analysis platform for MD on protein-membrane simulations. Metrics Downloads (HECBioSim) 985 Downloads (PyPi) 3456 Increasing the UK's CSE skills base (including graduate and post doctorate training and support): This builds on the skills sets of trained people in HPC, both in terms of capacity and raising the overall skill level available to the sector. • For the reporting period please provide information on the number of PhDs and Post-Docs that have been trained in the use of ARCHER as a result of work relating to the Consortium. • For the reporting period please provide a bullet pointed list of training activities undertaken by the Consortium, providing information on the target audience and level of attendance. 125 PhD and PDRAs have been trained and have used ARCHER through HECBioSim. In the past 6 months alone that has included: PhD students: Marc Dämgen, University of Oxford Laura Domicevica, University of Oxford Matteo Aldeghi, University of Oxford Shaima Hashem, Queen Mary University of London Ruth Dingle, University College London Lucas Siemons, University College London Elvira Tarasova, Aston University Vladimiras Oleinikovas, University College London Havva Yalinca, University College London Daniel Moore, Queen's University Belfast Aaron Maguire, Queen's University Belfast Maxime Tortora, University of Oxford Michail Palaiokostas, UWE Bristol Wei Ding, UWE Bristol Ganesh Shahane, UWE Bristol Pin-Chia Hsu, University of Southampton Damien Jefferies, University of Southampton PDRA: Maria Musgaard, University of Oxford Teresa Paramo, University of Oxford Marieke Schor, University of Edinbrurgh Antonia Mey, University of Edinbrurgh Ioanna Styliari, University of Nottingham Ivan Korotkin, Aston University Silvia Gomez Coca, King's College London Giorgio Saladino, University College London Federico Comitani, University College London Robin Corey, University of Bristol Jordi Juarez-Jimenez, University of Edinburgh Predrag Kukic, University of Cambridge Giulia Tomba, University of Cambridge Deborah Shoemark, University of Bristol Georgios Dalkas, Heriot-Watt University Robin Westacott, Heriot-Watt University Firdaus Samsudin, University of Southampton Agnes Noy, University of Leeds (now EPSRC fellow at York). Please see below details of the training week held in June 2016 at the University of Bristol. 170 delegates attending the training which ran over 5 days. There is course content available on the HECBioSim Workshop Page CCPBioSim Training Week - Day 5: QM/MM enzyme reaction modelling - on Friday 10 June 2016 CCPBioSim Training Week - Day 4: Monte Carlo Methods for Biomodelling - on Thursday 09 June 2016 CCPBioSim Training Week - Day 3: Python for Biomodellers and FESetup - on Wednesday 08 June 2016 CCPBioSim Training Week - Day 2: Running and analysing MD simulations - on Tuesday 07 June 2016 CCPBioSim Training Week - Day 1: Enlighten: Tools for enzyme-ligand modelling - on Monday 06 June 2016 Past Workshops and Conferences: AMOEBA advanced potential energies workshop - on Friday 09 December 2016 Intel Training Workshop (Parallel programming and optimisation for Intel architecture) - on Wednesday 30 November 2016 3rd Workshop on High-Throughput Molecular Dynamics (HTMD) 2016 - on Thursday 10 November 2016 Free Energy Calculation and Molecular Kinetics Workshop - on Tuesday 13 September 2016 Going Large: tools to simplify running and analysing large-scale MD simulations on HPC resources - HECBioSim - on Wednesday 16 December 2015 This 1 day workshop dealt with Longbow, a Python tool created by HECBioSim consortium that allows use of molecular dynamics packages (AMBER, GROMACS, LAMMPS, NAMD) with ease from the comfort of the desktop, and pyPcazip, a flexible Python-based package for the analysis of large molecular dynamics trajectory data sets. Richard Henchman ( Chemistry, Manchester) I lectured on the CCP5 Summer School in 2015 in Manchester and 2016 in Lancaster for the Advanced Topic Biomolecular Simulation drawing on CCPBiosim training materials. Sarah Harris (Physics, Leeds) Agnes Noy Agnes Noy was trained to use ARCHER independently which helped her to obtain an Early-career EPSRC fellowship. The fellowship grant follows the study of supercoiling DNA by modelling (further funding) and introduces a new member to the community (grant is EPSRC (EP/N027639/1)). Increased impact and collaboration with industry: ARCHER does not operate in isolation and the 'impact' of ARCHER's science is converted to economic growth through the interfaces with business and industry. In order to capture the impacts, which may be economic, social, environmental, scientific or political, various metrics may be utilised. • For the reporting period please provide where possible information on Consortium projects that have been performed in collaboration with industry, this should include: o Details of the companies involved. o Information on the part ARCHER and the Consortium played. o A statement on the impact that the work has / is making. o If relevant, details of any in kind or cash contributions that have been associated with this work. • For the reporting period include a list of Consortium publications that have industrial co-authorship. • For the reporting period please provide details of the any other activities involving industrial participation e.g. activities involving any Industrial Advisory panels, attendance / participation in workshops and Consortium based activities. Examples of industrial engagement through HECBioSim include: Syma Khalid (Computational Biophysics, Southampton) Collaboration with Siewert-Jan Marrink (Netherlands) and Wonpil Im(USA) - paper is being written at the moment - also we have developed and tested the following computational tool as part of this project: http://www.charmm-gui.org/?doc=input/membrane We have signed an NDA with a company developing antibiotics (Auspherix) based on work published in Samsudin et al, Structure, 2016. The company provide us with experimental data and crucially the structures of their potential drug molecules, and we work out how they interact with the bacterial membrane. Press releases https://www.sciencedaily.com/releases/2016/11/161121094122.htm ARCHER time we got from HECBioSim was essential for this project. These are large simulations that are very computationally demanding. Julien Michel (Chemistry, Edinburgh) Industrial collaborations that have benefited from HECBioSim UCB was a project partner of EPSRC-funded research in the Michel lab on modelling binding of ligands to flexible proteins. HECBioSim supported the research via allocation of computing time on ARCHER. The work has been published. Impact of Ser17 phosphorylation on the conformational dynamics of the oncoprotein MDM2 Bueren-Calabuig, J. A. ; Michel, J. Biochemistry, 55 (17), 2500-2509, 2016 Elucidation of Ligand-Dependent Modulation of Disorder-Order Transitions in the Oncoprotein MDM2 Bueren-Calabuig, J. A. ; Michel, J. PLoS Comput. Biol. , 11(6): e1004282, 2015 International activities I represented HECBioSim at the MolSSI conceptualisation workshop in Houston (October 2016). Arianna Fornili (School of Biological and Chemical Sciences, Queen Mary University of London) This project is done in collaboration with experimental (NMR and SAXS) partners at King's College London (Dr. Mark Pfuhl and Dr. Elena Rostkova), with the final aim of providing a complete molecular model of how muscle contraction is regulated in the heart. Francesco Gervasio (Chemistry, UCL) A new collaboration with UCB on developing new approaches to sample cryptic binding sites of pharmaceutical interest was started. UCB co-sponsored a BBSRC-CASE PhD studentships. The code development and its application to interesting targets was made possible by the access to Archer. Phil Biggin (Biochemistry, Oxford) The following has industrial partners as co-authors: Accurate calculation of the absolute free energy of binding for drug molecules, Aldeghi M, Heifetz A, Bodkin MJ, Knapp S, Biggin PC. Chem. Sci., 2016,7, 207-218 doi: 10.1039/C5SC02678D. The GLAS scoring module for gromacs has yet to be implemented but that would also constitute industrial activity. Richard Henchman (Chemistry, Manchester) Industrial Collaboration I have one publication with an industrial co-author (Evotec), which Julien Michel is part of as well. Assessment of hydration thermodynamics at protein interfaces with grid cell theory, G. Gerogiokas, M. W. Y. Southey, M. P. Mazanetz, A. Heifetz, M. Bodkin, R. J. Law, R. H. Henchman and J. Michel, J. Phys. Chem. B, 2016, 120, 10442-10452. Strengthening of UK's international position: The impacts of ARCHER's science extend beyond national borders and most science is delivered through partnerships on a national or international level. • For the reporting period please provide a bullet pointed list of projects that have involved international collaboration. For each example please provide a brief summary of the part that ARCHER and the Consortium have played. • For the reporting period please provide a list of consortium publications with international co-authorship. • For the reporting period please detail any other international activities that the Consortium might be involved in (workshops, EU projects etc.). Examples of HECBioSim international engagement include: Michelle Sahai (Department of Life Sciences, Roehampton) Combined in vitro and in silico approaches to the assessment of stimulant properties of novel psychoactive substances - The case of the benzofuran 5-MAPB. Sahai MA, Davidson C, Khelashvili G, Barrese V, Dutta N, Weinstein H, Opacka-Juffry J. Prog Neuropsychopharmacol Biol Psychiatry. (2016) 75:1-9. doi: 10.1016/j.pnpbp.2016.11.004. co-authors affiliations include: Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University (WCMC), New York, NY, 10065, USA and HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute of Computational Biomedicine, Weill Cornell Medical College of Cornell University, New York, NY, 10065, USA. Author contribution: CD, MAS, HW and JOJ were responsible for the study concept and design. CD and VB collected and interpreted the voltammetry data. JOJ and ND conducted the ligand binding experiments and ND analysed the data. MAS (ARCHER user) and GK performed the molecular modelling studies and interpreted the findings. CD, MAS, GK and JOJ drafted the manuscript. All authors critically reviewed the content and approved the final version for publication. Dmitry Nerukh (Engineering and Applied Science, Aston University) Collaborations: • Prof. Makoto Taiji group (K-computer, MDGRAPE), Laboratory for Computational Molecular Design, Computational Biology Research Core, RIKEN Quantitative Biology Center (QBiC), Kobe, Japan • Prof. Reza Khayat group, City College of New York, United States • Prof. Artyom Yurov group, Immanuel Kant Baltic Federal University, Russian Federation • Prof. Nikolay Mchedlov-Petrosyan group, V.N. Karazin Kharkiv National University, Ukraine • Prof. Natalya Vaysfeld group, Odessa I.I.Mechnikov National University, Ukraine International activities: • International Workshop - Engineering bacteriophages for treating antimicrobial resistance using computational models. Dec. 2016, Aston University, UK Dmitry Nerukh group at Aston University collaborates with the group of Prof. Makoto Taiji (the deputy director of RIKEN Quantitative Biology Institute). Prof. Taiji group is the author and implementer of the fastest machine in the world for molecular dynamics simulations, MDGRAPE, as well as part of the team designing the K-computer and working on it (several times the fastest computer in the world). We are currently preparing a joint manuscript for publication where the results obtained on ARCHER will be used alongside with the results obtained on MDGRAPE-4. Julien Michel (Chemistry, Edinburgh) Free Energy Reproducibility Project Free energy reproducibility project between the Michel, Mobley, Roux groups and STFC. This makes use of FESetup which is CCPBioSim, but calculations have been executed on various HPC platforms, Hannes can clarify whether any of the systems used is within the remit of HECBioSim. Sarah Harris (Physics, Leeds), Charlie Laughton (Pharmacy, Nottingham) and Agnes Noy (Physics, York) In an international collaboration with the Institute for Research in Biomedicine in Barcelona, Noy, Harris and Laughton used ARCHER time obtained through the HecBioSim consortium to perform multiple 100ns molecular dynamics (MD) simulations of DNA minicircles containing ~100 base pairs as part of the validation suite for the new BSC1 nucleic acid forcefield, see: Ivani I., Dans P. D., Noy A., Perez A., Faustino I., Hospital A., Walther J., Andrio P., Goni R., Portella G., Battistini F.,Gelpi J. L. Gonzalez C., Vendruscolo M., Laughton C. A., Harris S. A. Case D. A. & Orozco M. "Parmbsc1: a refined force field for DNA simulations" Nat. Methods 13, 55, 2015, doi:10.1038/nmeth.3658 Jon Essex (Chemistry, Southampton) Development and testing of hybrid coarse-grain/atomistic model of membrane systems. ARCHER and the consortium were instrumental in providing the computing time necessary to complete this work. The work was performed by a research fellow in my group, who has subsequently taken up an academic post in Sweden, where he is continuing to develop this methodology. Publication: All-atom/coarse-grained hybrid predictions of distributioncoefficients in SAMPL5 Samuel Genheden1, Jonathan W. Essex, J Comput Aided Mol Des (2016) 30:969-976 DOI 10.1007/s10822-016-9926-z IP and other industrial engagement, or translation, which has benefited from HECBioSim international collaborations Collaboration Dr Samuel Genheden, University of Gothenburg - see above International activities (e.g. workshops) that have benefited from HECBioSim The work performed with Sam resulted in an successful eCSE application for development work on the LAMMPS software. This is an international simulation package run out of Sandia labs in the US. Through this eCSE application we were able to update the rotational integrator and improve the load balancing for our hybrid simulation methodology. These developments have been incorporated in the latest release versions of the code. An ARCHER training webinar resulted from this work. Training activities see above - ARCHER training webinar on our developments within LAMMPS Software development see above - code modifications in LAMMPS which either have been, or will be, in the release version of the code Advantages you see of the consortium (e.g. could be ability to pursue project quickly; develop collaborations) resources to run the sort of large-scale calculations we need Michelle Sahai (Department of life Sciences, Roehampton) The publication I added on ResearchFish has international co-authors. Combined in vitro and in silico approaches to the assessment of stimulant properties of novel psychoactive substances - The case of the benzofuran 5-MAPB. Sahai MA, Davidson C, Khelashvili G, Barrese V, Dutta N, Weinstein H, Opacka-Juffry J. Prog Neuropsychopharmacol Biol Psychiatry. (2016) 75:1-9. doi: 10.1016/j.pnpbp.2016.11.004. co-authors affiliations include: Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University (WCMC), New York, NY, 10065, USA and HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute of Computational Biomedicine, Weill Cornell Medical College of Cornell University, New York, NY, 10065, USA. Author contribution: CD, MAS, HW and JOJ were responsible for the study concept and design. CD and VB collected and interpreted the voltammetry data. JOJ and ND conducted the ligand binding experiments and ND analysed the data. MAS (ARCHER user) and GK performed the molecular modelling studies and interpreted the findings. CD, MAS, GK and JOJ drafted the manuscript. All authors critically reviewed the content and approved the final version for publication. Edina Rosta (Computational Chemistry, Kings College London) International collaborations I have several international collaborators with joint computational/experimental projects. For their success the HECBioSim computer time was essential: • Prof. Beata Vertessy, Budapest Technical University, Hungary JACS 2016 138 (45), 15035-15045 • Profs. Walter Kolch, Vio Buchete and Boris Kholodenko, UCD, Ireland Angewandte 55 (3), 983-986, 2016 (this may have been reported previously) PLOS Computational Biology 12 (10), e1005051, 2016 J Phys Chem Letters 7 (14), 2676-2682, 2016 • Jose Maria Lluch, Angels Gonzalez, Autonomous University of Barcelona, Spain JCTC 12 (4), 2079-2090, 2016 Other international activities Free energy and molecular kinetics workshop with Frank Noe's group (Free University of Berlin) and Vio Buchete (UCD, Dublin). Maybe this should be for training activities? Following the workshop, Erasmus students apply to visit my group. Phil Biggin (Biochemistry, Oxford) 2 and 4 were with colleagues from McGill (Brown PM, Aurousseau MR and Bowie) and 3 was with colleagues from Denmark (Braun and Pless) 2. Kainate receptor pore-forming and auxiliary subunits regulate channel block by a novel mechanism. Brown PM, Aurousseau MR, Musgaard M, Biggin PC, Bowie D. J Physiol. 2016 Apr 1;594(7):1821-40. doi: 10.1113/JP271690. 3. Role of an Absolutely Conserved Tryptophan Pair in the Extracellular Domain of Cys-Loop Receptors. Braun N, Lynagh T, Yu R, Biggin PC, Pless SA. ACS Chem Neurosci. 2016 Mar 16;7(3):339-48. doi: 10.1021/acschemneuro.5b00298. 4. Distinct Structural Pathways Coordinate the Activation of AMPA Receptor-Auxiliary Subunit Complexes. Dawe GB, Musgaard M, Aurousseau MR, Nayeem N, Green T, Biggin PC, Bowie D. Neuron. 2016 Mar 16;89(6):1264-76. doi: 10.1016/j.neuron.2016.01.038. Richard Henchman I have an international collaboration with Professor Franke Grater at the University of Heidelberg on entropy theory for biomolecular systems. Syma Khalid (Chemistry, Southampton) Collaboration with Singapore National Center for Biotechnology. Contributions to CECAM workshops Other Highlights for the Current Reporting Period: Please provide details of any other significant highlights from the reporting period that are not captured elsewhere in the report. Professor Adrian Mullholland organised and chaired the Computational Chemistry, Gordon Research Conference, Girona, Spain 24th - 29th July 2016. The theme of the 2016 Computational Chemistry GRC was "Theory and Simulation Across Scales in Molecular Science". It focused on method development and state-of-the-art applications across computational molecular science, and encouraged cross-fertilization between areas. The conference was oversubscribed, with attendees from industry and academia. The meeting received a High-Performance Rating, and was commended for the assessment that 95% of conferees rated this meeting "above average" on all evaluation areas (science, discussion, management, atmosphere and suitability). HEC Consortia Model: Over the coming months EPSRC will be looking at the future of the HEC Consortia model and potential future funding. We would like to use this opportunity to ask the Consortia Chairs for input: • What are the key benefits that your community have experienced through the existence of the HEC Consortia? • What elements of the financial support provided by the HEC Consortium's grant have worked well and what could be improved in the future? We aim to expand the breadth of the work of the Consortium focusing on cutting-edge applications, and building collaborations with experiments and industry, to achieve maximum impact from ARCHER use. We discussed Grand Challenges at our most recent Management Group meeting. In December 2015, and have identified several to follow up as strategic priorities. We aim to tackle and support large-scale grand challenge applications in biomolecular science, in areas such as antimicrobial resistance, membrane dynamics, drug design and synthetic biology. One specific theme with potentially high impact in drug discovery is large -scale comparative investigation of allosteric regulation in different superfamilies of proteins (e.g. PAS domain containing proteins, tyrosine kinases, etc.). The major impact will be in the identification of novel selective therapeutic molecules with limited adverse side effects. As a Consortium, we intend to develop and apply novel computational approaches for the rational design of allosteric regulators of hitherto 'undruggable' targets. Many of the targets emerging from large-scale genetic screening are deemed undruggable due to the difficulty of designing drug-like modulators that bind to their catalytic sites. It is increasingly clear that these targets might be effectively targeted by designing drugs that bind to protein-protein interfaces and allosteric sites. To do that, however, new rational design strategies, based on an in-depth knowledge of protein dynamics and advanced modelling and new simulation techniques are required. Other challenging frontier areas include dynamics of motor proteins; prediction of the effects of pathogenic mutations on protein function. The accurate prediction of free energy of binding is still in its infancy and needs much further investigation. Finally, kinetics of biomolecular reactions will become the next big topic. It is clear that high end computing resource can provide the necessary power and capability to provide inroads into this vital area. This is important because it is becoming increasingly apparent that kinetics of drug binding is a key factor that the pharmaceutical sector should really be looking at in terms of a major dictator of potency. HECBioSim is now well established, supporting work of many groups across the UK in the growing field of biomolecular simulation. We benefit from an Advisory Group containing members from industry, as we as international biomolecular simulation experts and experimental scientists. The Advisory Board was expanded and refreshed for the renewal and consists of: Dr. Nicolas Foloppe (Vernalis plc, Chair); Dr. Colin Edge (GlaxoSmithKline); Dr. Mike King (UCB Pharmaceuticals); Dr. Mike Mazanetz (Evotec AG); Dr. Garrett Morris (Crysalin Ltd.); Dr. Gary Tresadern (Johnson and Johnson Pharmaceuticals); Dr. Richard Ward (AstraZeneca); Prof. Modesto Orozco (IRB, Barcelona); Prof. Tony Watts, (Oxford, NMR); Dr. Pete Bond (A*STAR Bioinformatics Institute Singapore). We aim to foster industrial collaborations and collaborations with experimentalists (e.g. joint workshops with CCPN, Institute of Physics (Sarah Harris, Leeds Physics); see e.g. case studies. A particular theme for strategic development will be multiscale modelling, building on collaborations between several groups in the Consortium and the other CCPs. This theme reflects the inclusive and forward looking philosophy of HecBioSim, which is a community open to new ideas, keen to develop new methods, and ultimately to use HEC to drive exciting new science. The Consortium model allows new collaborations to develop. The recent reduction in time allocated to HECBioSim has meant that we can support fewer projects. There is significantly more demand for computer time than we can accommodate through our current allocation. We intend to work with Tier 2 Centres to explore possibilities for applications, and e.g. to test emerging architectures for biomolecular simulation. Edina Rosta (Computational Chemistry, Kings College London) comments: "HECBioSim enables my group to perform biomolecular simulations at the high standards required for JACS, Angewandte, etc. Without this consortium I would not be able to perform the necessary calculations leading to publishable work in top journals as our local university resources are limited and the hpc systems are not well maintained". Regarding financial support: the administrative support provided via the consortium grant is essential to the functioning of HECBioSim. This role is currently undertaken by Simone Breckell who not only administers, allocates time to projects and arranges panel meetings but has also done a fantastic job collating the extensive information for this EPSRC report. |
| Type Of Material | Improvements to research infrastructure |
| Year Produced | 2017 |
| Provided To Others? | Yes |
| Impact | HECBioSim, the UK HEC Biomolecular Simulation Consortium, was established in March 2013, and works closely with and complements CCP-BioSim (the UK Collaborative Computational Project for Biomolecular Simulation at the Life Sciences Interface). Most of the members of the Consortium are experienced users of high end computing. Biomolecular simulations are now making significant contributions to a wide variety of problems in drug design and development, biocatalysis, bio and nano-technology, chemical biology and medicine. The UK has a strong and growing community in this field, recognized by the establishment in 2011 by the EPSRC of CCP-BioSim (ccpbiosim.ac.uk), and its renewal in 2015. There is a clear, growing and demonstrable need for HEC in this field. Members of the Consortium have, for example, served on the HECToR and ARCHER Resource Allocation Panel. The Consortium welcomes members across the whole biomolecular sciences community, and we are currently (and will remain) open to new members (unlike some consortia). Since establishing the Consortium, several new members (FLG, DH, ER) have joined the Management Group. Many of the projects awarded ARCHER time under the Consortium do not involve CCP-BioSim or HECBioSim Management Group members, demonstrating the openness of HECBioSim and its support of the biomolecular simulation community in the UK. A number of other researchers have joined and it is our expectation that other researchers will join HECBioSim in the future. We actively engage with structural and chemical biologists and industrial researchers. We foster interactions between computational, experimental and industrial scientists (see the example case studies; members of the Consortium have excellent links with many pharmaceutical, chemical and biotechnology companies). Details of HECBioSim are available via our webpages at: http://www.hecbiosim.ac.uk Applications are made through the website http://www.hecbiosim.ac.uk and reviewed at one of the series of regular panel meetings. A list of successful HECtime allocations on ARCHER is available at:http://www.hecbiosim.ac.uk/applications/successfulprojects All proposals are of course subject to scientific and technical review, but we have the philosophy of supporting the best science to deliver the highest impact, rather than focusing on supporting development of a couple of codes. An allocation panel (with changing membership) meets twice yearly to judge proposals and requests for AUs; projects are assessed competitively: any groups in the UK can apply. All submitted proposals receive constructive feedback from the allocation panel. The HECBioSim website also provides forums for the biomolecular simulation community, a wiki hosting useful how-tos and user guides, and software downloads (currently FESetup and Longbow). Our lead software development project between Nottingham (Charlie Laughton and Gareth Shannon) and Daresbury (James Gebbie), we have developed a remote job submission tool, 'Longbow' (see below). The tool is designed to reproduce the look and feel of local MD packages, but to stage data and submit jobs to a large HPC resource, such as ARCHER, in a manner invisible to the user. Workshops and New Opportunities No more than half a page detailing upcoming workshops and meetings. Also include discussion of other areas which are potentially of interest to other HEC Consortia and opportunities for cross CCP /HEC working. Workshops are listed below and can be found on the HECBioSim Website We work closely with CCP-BioSim, for example in organizing training workshops and meetings. Our activities are outlined at www.hecbiosim.ac.uk Examples of forthcoming meetings include: Computational Molecular Science 2017 - on Sunday 19 March 2017 17th European Seminar on Computational Methods in Quantum Chemistry - on Tuesday 11 July 2017 Frontiers of Biomolecular Simulation Southampton, September 2016 Issues and Problems Short discussion of any issues or problems that the HEC Consortium faces including issues with the ARCHER service, funding, management of allocation and staffing. This is also a good opportunity to highlight to the SLA committee any issues that the Consortium may have experienced with their SLA support during the reporting period. Details of SLA activities are given in the SLA report. Dr. James Gebbie provides support to HECBioSIm through the SLA. He has been very helpful in the construction of the HECBioSim webpages (hecbiosim.ac.uk). James also worked with Dr. Gareth Shannon on the development of Longbow (See above). In the past year, members of the Consortium faced some queuing problems; close to the end of the first allocation period in particular, there were long queuing times, which led to problems in completing jobs and using allocated time. Throughput has been a real problem in the past few months. Membership Please provide a full list of existing members and their institutions, highlighting any new members that have joined the consortium during the reporting period. If available please provide information on the number of distinct users that have accessed ARCHER via the Consortium during this reporting period. Below is a list of PIs with HECBioSim projects in the current reporting period: Agnes Noy, University of York - new to this reporting period Alessandro Pandini, Brunel University London Arianna Fornili, Queen Mary University of London Cait MacPhee, University of Edinbrurgh - new to this reporting period Charlie Laughton, University of Nottingham Clare-Louise Towse, University of Bradford - new to this reporting period D Flemming Hansen, University College London - new to this reporting period David Huggins, Aston University Edina Rosta, King's College London Francesco Gervasio, University College London Ian Collinson, University of Bristol - new to this reporting period Irina Tikhonova, Queen's University Belfast Jiayun Pang, University of Greenwich Jonathan Doye, University of Oxford Julien Michel, University of Edinburgh Mario Orsi, UWE Bristol Michele Vendruscolo, University of Cambridge Michelle Sahai, University of Roehampton Philip Biggin, University of Oxford Richard Sessions, University of Bristol Stephen Euston, Heriot-Watt University Syma Khalid, University of Southampton PIs in HECBioSIm outside of current allocation period Peter Bond, University of Cambridge Richard Bryce, University of Manchester Juan Antonio Bueren-Calabuig, University of Edinburgh Christo Christov, Northumbria University Anna K Croft, University of Nottingham Jonathan Essex, University of Southampton Robert Glen, University of Cambridge Sarah A Harris, University of Leeds Jonathan Hirst, University of Nottingham Douglas Houston, University of Edinburgh Dmitry Nerukh, Aston University Andrei Pisliakov, University of Dundee Mark Sansom, University of Oxford Marieke Schor, University of Edinburgh Gareth Shannon, University of Nottingham Tatyana Karabencheva-Christova, Northumbria University There are currently 164 members of HECBioSim (i.e. users of HECBioSIm ARCHER time), included the above PIs. 20 new users have been added since January 2016. World class and world leading scientific output: ARCHER should enable high quality and world-leading science to be delivered. This should generate high impact outputs and outcomes that increase the UK's position in world science. • If all the publications relating to the work of the Consortium for this reporting period have been added to ResearchFish / will be added to ResearchFish by the end of the ResearchFish reporting exercise, please indicate this below. • If submission of a full list of publications to the Consortium record/s in ResearchFish has not been possible for this reporting period please provide a list of publications that have resulted from work performed on ARCHER by the Consortium during this reporting period (this can be included as a separate attachment). • For the reporting period please provide a bullet pointed list of key / important research findings that has resulted from work performed on ARCHER by the Consortium. Please reference any related publications. • For the reporting period please include a bullet pointed list of any relevant press announcements and other communications of significance to an international community. All publications can be found in ResearchFish, and have been added by individual researchers. A selection of illustrative highlights are provided below: Julien Michel (University of Edinburgh) New molecular simulation methods have enabled for the first time a complete description of the interactions of several drug-like small molecules with an intrinsically disordered region of the oncoprotein MDM2, as well as the effect of post-translational modifications on the dynamics of this protein. The results obtained suggest new medicinal chemistry strategies to achieve potent and selective inhibition of MDM2 for cancer therapies. Publication: Elucidation of Ligand-Dependent Modulation of Disorder-Order Transitions in the Oncoprotein MDM2 http://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1004282 Impact of Ser17 Phosphorylation on the Conformational Dynamics of the Oncoprotein MDM2 http://pubs.acs.org/doi/abs/10.1021/acs.biochem.6b00127 An outreach document is being prepared by EPCC to showcase a lab project on isoform selective inhibition that has benefited from both HECBioSim and EPCC ARCHER allocations. Syma Khalid (Chemistry, Southampton) Publication: OmpA: A Flexible Clamp for Bacterial Cell Wall Attachment Samsudin F, Ortiz-Suarez ML, Piggot TJ, Bond PJ, Khalid S (2016). "OmpA: a Flexible Clamp for Bacterial Cell Wall Attachment", Structure, 24(12):2227-2235 With Singapore National Center for Biotechnology. Sarah Harris (Physics, Leeds) In collaboration with the experimental biochemistry group lead by Radford at Leeds, Sarah Harris used ARCHER time to show how chaperones help outer membrane proteins to fold, see: Schiffrin B, Calabrese AN, Devine PWA, Harris SA, Ashcroft AE, Brockwell DJ, Radford SE "Skp is a multivalent chaperone of outer-membrane proteins" Nature Structural and Molecular Biology 23 786-793, 2016. DOI:10.1038/nsmb.3266 Michelle Sahai (Department of Life Sciences, Roehampton) Publication: Combined in vitro and in silico approaches to the assessment of stimulant properties of novel psychoactive substances - The case of the benzofuran 5-MAPB. Progress in Neuro-Psychopharmacology and Biological Psychiatry 75, Pages 1-9 (2017) https://www.ncbi.nlm.nih.gov/pubmed/27890676 Phil Biggin (Biochemistry, Oxford) Outputs that have used HECBioSim time: 1. Steered Molecular Dynamics Simulations Predict Conformational Stability of Glutamate Receptors. Musgaard M, Biggin PC. J Chem Inf Model. 2016 Sep 26;56(9):1787-97. doi: 10.1021/acs.jcim.6b00297. 2. Kainate receptor pore-forming and auxiliary subunits regulate channel block by a novel mechanism. Brown PM, Aurousseau MR, Musgaard M, Biggin PC, Bowie D. J Physiol. 2016 Apr 1;594(7):1821-40. doi: 10.1113/JP271690. 3. Role of an Absolutely Conserved Tryptophan Pair in the Extracellular Domain of Cys-Loop Receptors. Braun N, Lynagh T, Yu R, Biggin PC, Pless SA. ACS Chem Neurosci. 2016 Mar 16;7(3):339-48. doi: 10.1021/acschemneuro.5b00298. 4. Distinct Structural Pathways Coordinate the Activation of AMPA Receptor-Auxiliary Subunit Complexes. Dawe GB, Musgaard M, Aurousseau MR, Nayeem N, Green T, Biggin PC, Bowie D. Neuron. 2016 Mar 16;89(6):1264-76. doi: 10.1016/j.neuron.2016.01.038. Covered by 7 news outlets: I. Health Canal (http://www.healthcanal.com/brain-nerves/70646-what-makes-the-brain-tick-so-fast.html) II. Health Medicine Network (http://healthmedicinet.com/i/scientists-reveal-how-the-brain-processes-information-with-lightning-speed/) III. News Medical (http://www.news-medical.net/news/20160227/Scientists-reveal-how-the-brain-processes-information-with-lightning-speed.aspx) IV. Wired (http://www.wired.co.uk/article/what-we-learned-about-the-brain-this-week-3) V. Alpha Galileo (http://www.alphagalileo.org/ViewItem.aspx?ItemId=161473&CultureCode=en) VI. Science Daily (https://www.sciencedaily.com/releases/2016/02/160225140254.htm) VII. Eureka Alert (https://www.eurekalert.org/pub_releases/2016-02/mu-wmt022516.php) Recommended by F1000 Prime: http://f1000.com/prime/726180600. 5. Accurate calculation of the absolute free energy of binding for drug molecules. Aldeghi M, Heifetz A, Bodkin MJ, Knapp S, Biggin PC. Chem Sci. 2016 Jan 14;7(1):207-218. Arianna Fornili (Biological and Chemical Sciences, Queen Mary University of London) Publication: Fornili, E. Rostkova, F. Fraternali, M. Pfuhl: Effect of RlC N-Terminal Tails on the Structure and Dynamics of Cardiac Myosin. Biophysical J. 110 (2016) 297A. More in preparation. Dmitry Nerukh (Engineering and Applied Science, Aston University) Important research findings: Distribution of ions inside a viral capsids influences the stability of the capsid Edina Rosta (Computational Chemistry, Kings College London) Highlighted publication: We have a joint experimental paper with the Vertessy group in JACS where we identified a novel arginine finger residue in dUTPase enzymes, and described the mechanism of action for this residue using crystallographic data, biochemical experiments, MD and QM/MM simulations thanks to HECBioSim. http://pubs.acs.org/doi/abs/10.1021/jacs.6b09012 Press release: Our joint paper with Jeremy Baumberg's group in Cambridge was published in Nature. http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/newssummary/news_13-6-2016-16-52-4 Greater scientific productivity: As well as speed increases, the optimisation of codes for the ARCHER machine will enable problems to be solved in less time using fewer compute resources. • For the reporting period please provide a brief update on the progress of software development activities associated with the Consortium and the impact this has had on Consortium members and the broader research community. Our lead software development project between Nottingham (Charlie Laughton and Gareth Shannon) and Daresbury (James Gebbie), we have developed a remote job submission tool, 'Longbow' (see below). The tool is designed to reproduce the look and feel of local MD packages, but to stage data and submit jobs to a large HPC resource such as ARCHER in a manner invisible to the user. An open beta version was released unrestricted to the community in March 2015 (http://www.hecbiosim.ac.uk/longbow and via PyPI https://pypi.python.org ) with ~100 downloads. Functionality includes native support for biosimulation packages AMBER, CHARMM, GROMACS, LAMMPS and NAMD, native support for jobs on ARCHER, native support for jobs running on PBS and LSF schedulers, and support for three different job types (single, ensembles and multiple jobs). The software is written both as an application for users and an API for developers. CCP-EM have integrated Longbow into their developmental GUI, and shortly FESetup will ship with native support for job submission using Longbow. We are currently in talks with ClusterVision with respect to them distributing Longbow to their user base as a user friendly way for novices to interact with their systems. Longbow Longbow has been growing in popularity both amongst researchers within the biosimulation field and those in other fields. In this reporting period there have been five new releases of Longbow delivering a plethora of user requested features and bug fixes. Some of the key developments are summarised below: • Implemented a Recovery mode - Should the event happen that Longbow crashes or the system in which Longbow is controlling jobs from powers down. The user can now reconnect to the crashed session and carry on as if nothing happened. • Sub-Queuing - More and more system administrators are setting limits not just on the number of simulations that can run, but also on the number of jobs that can go into the queue. Longbow can now automatically detect this and implement its own queue feeding jobs into the system queue as slots open up. • Dis-connectible/Re-connectible Longbow sessions - A user can now launch Longbow to fire off all jobs and then disconnect, at a later date the user can re-establish the connection and download all results (no need for persistent connections anymore) • Ability to include scripts in the Longbow generated submit files. • Numerous stability, performance and bug fixes Longbow continues to be the submission engine that is used under the hood of the CCP-EM toolkit FLEX-EM. There are several other interesting projects that are making use of Longbow. A project by the energy efficient computing group (Hartree Center) are currently integrating Longbow with CK, a crowd sourced compilation optimisation tool aimed at finding efficient compilation configuration. A project by the Applications performance engineering group (Hartree Center) are currently integrating longbow into Melody, a runtime optimisation tool aimed at optimising runtime configuration of simulations. A project by the computational biology group (Hartree Center) an automated setup, launch and analysis platform for MD on protein-membrane simulations. Metrics Downloads (HECBioSim) 985 Downloads (PyPi) 3456 Increasing the UK's CSE skills base (including graduate and post doctorate training and support): This builds on the skills sets of trained people in HPC, both in terms of capacity and raising the overall skill level available to the sector. • For the reporting period please provide information on the number of PhDs and Post-Docs that have been trained in the use of ARCHER as a result of work relating to the Consortium. • For the reporting period please provide a bullet pointed list of training activities undertaken by the Consortium, providing information on the target audience and level of attendance. 125 PhD and PDRAs have been trained and have used ARCHER through HECBioSim. In the past 6 months alone that has included: PhD students: Marc Dämgen, University of Oxford Laura Domicevica, University of Oxford Matteo Aldeghi, University of Oxford Shaima Hashem, Queen Mary University of London Ruth Dingle, University College London Lucas Siemons, University College London Elvira Tarasova, Aston University Vladimiras Oleinikovas, University College London Havva Yalinca, University College London Daniel Moore, Queen's University Belfast Aaron Maguire, Queen's University Belfast Maxime Tortora, University of Oxford Michail Palaiokostas, UWE Bristol Wei Ding, UWE Bristol Ganesh Shahane, UWE Bristol Pin-Chia Hsu, University of Southampton Damien Jefferies, University of Southampton PDRA: Maria Musgaard, University of Oxford Teresa Paramo, University of Oxford Marieke Schor, University of Edinbrurgh Antonia Mey, University of Edinbrurgh Ioanna Styliari, University of Nottingham Ivan Korotkin, Aston University Silvia Gomez Coca, King's College London Giorgio Saladino, University College London Federico Comitani, University College London Robin Corey, University of Bristol Jordi Juarez-Jimenez, University of Edinburgh Predrag Kukic, University of Cambridge Giulia Tomba, University of Cambridge Deborah Shoemark, University of Bristol Georgios Dalkas, Heriot-Watt University Robin Westacott, Heriot-Watt University Firdaus Samsudin, University of Southampton Agnes Noy, University of Leeds (now EPSRC fellow at York). Please see below details of the training week held in June 2016 at the University of Bristol. 170 delegates attending the training which ran over 5 days. There is course content available on the HECBioSim Workshop Page CCPBioSim Training Week - Day 5: QM/MM enzyme reaction modelling - on Friday 10 June 2016 CCPBioSim Training Week - Day 4: Monte Carlo Methods for Biomodelling - on Thursday 09 June 2016 CCPBioSim Training Week - Day 3: Python for Biomodellers and FESetup - on Wednesday 08 June 2016 CCPBioSim Training Week - Day 2: Running and analysing MD simulations - on Tuesday 07 June 2016 CCPBioSim Training Week - Day 1: Enlighten: Tools for enzyme-ligand modelling - on Monday 06 June 2016 Past Workshops and Conferences: AMOEBA advanced potential energies workshop - on Friday 09 December 2016 Intel Training Workshop (Parallel programming and optimisation for Intel architecture) - on Wednesday 30 November 2016 3rd Workshop on High-Throughput Molecular Dynamics (HTMD) 2016 - on Thursday 10 November 2016 Free Energy Calculation and Molecular Kinetics Workshop - on Tuesday 13 September 2016 Going Large: tools to simplify running and analysing large-scale MD simulations on HPC resources - HECBioSim - on Wednesday 16 December 2015 This 1 day workshop dealt with Longbow, a Python tool created by HECBioSim consortium that allows use of molecular dynamics packages (AMBER, GROMACS, LAMMPS, NAMD) with ease from the comfort of the desktop, and pyPcazip, a flexible Python-based package for the analysis of large molecular dynamics trajectory data sets. Richard Henchman ( Chemistry, Manchester) I lectured on the CCP5 Summer School in 2015 in Manchester and 2016 in Lancaster for the Advanced Topic Biomolecular Simulation drawing on CCPBiosim training materials. Sarah Harris (Physics, Leeds) Agnes Noy Agnes Noy was trained to use ARCHER independently which helped her to obtain an Early-career EPSRC fellowship. The fellowship grant follows the study of supercoiling DNA by modelling (further funding) and introduces a new member to the community (grant is EPSRC (EP/N027639/1)). Increased impact and collaboration with industry: ARCHER does not operate in isolation and the 'impact' of ARCHER's science is converted to economic growth through the interfaces with business and industry. In order to capture the impacts, which may be economic, social, environmental, scientific or political, various metrics may be utilised. • For the reporting period please provide where possible information on Consortium projects that have been performed in collaboration with industry, this should include: o Details of the companies involved. o Information on the part ARCHER and the Consortium played. o A statement on the impact that the work has / is making. o If relevant, details of any in kind or cash contributions that have been associated with this work. • For the reporting period include a list of Consortium publications that have industrial co-authorship. • For the reporting period please provide details of the any other activities involving industrial participation e.g. activities involving any Industrial Advisory panels, attendance / participation in workshops and Consortium based activities. Examples of industrial engagement through HECBioSim include: Syma Khalid (Computational Biophysics, Southampton) Collaboration with Siewert-Jan Marrink (Netherlands) and Wonpil Im(USA) - paper is being written at the moment - also we have developed and tested the following computational tool as part of this project: http://www.charmm-gui.org/?doc=input/membrane We have signed an NDA with a company developing antibiotics (Auspherix) based on work published in Samsudin et al, Structure, 2016. The company provide us with experimental data and crucially the structures of their potential drug molecules, and we work out how they interact with the bacterial membrane. Press releases https://www.sciencedaily.com/releases/2016/11/161121094122.htm ARCHER time we got from HECBioSim was essential for this project. These are large simulations that are very computationally demanding. Julien Michel (Chemistry, Edinburgh) Industrial collaborations that have benefited from HECBioSim UCB was a project partner of EPSRC-funded research in the Michel lab on modelling binding of ligands to flexible proteins. HECBioSim supported the research via allocation of computing time on ARCHER. The work has been published. Impact of Ser17 phosphorylation on the conformational dynamics of the oncoprotein MDM2 Bueren-Calabuig, J. A. ; Michel, J. Biochemistry, 55 (17), 2500-2509, 2016 Elucidation of Ligand-Dependent Modulation of Disorder-Order Transitions in the Oncoprotein MDM2 Bueren-Calabuig, J. A. ; Michel, J. PLoS Comput. Biol. , 11(6): e1004282, 2015 International activities I represented HECBioSim at the MolSSI conceptualisation workshop in Houston (October 2016). Arianna Fornili (School of Biological and Chemical Sciences, Queen Mary University of London) This project is done in collaboration with experimental (NMR and SAXS) partners at King's College London (Dr. Mark Pfuhl and Dr. Elena Rostkova), with the final aim of providing a complete molecular model of how muscle contraction is regulated in the heart. Francesco Gervasio (Chemistry, UCL) A new collaboration with UCB on developing new approaches to sample cryptic binding sites of pharmaceutical interest was started. UCB co-sponsored a BBSRC-CASE PhD studentships. The code development and its application to interesting targets was made possible by the access to Archer. Phil Biggin (Biochemistry, Oxford) The following has industrial partners as co-authors: Accurate calculation of the absolute free energy of binding for drug molecules, Aldeghi M, Heifetz A, Bodkin MJ, Knapp S, Biggin PC. Chem. Sci., 2016,7, 207-218 doi: 10.1039/C5SC02678D. The GLAS scoring module for gromacs has yet to be implemented but that would also constitute industrial activity. Richard Henchman (Chemistry, Manchester) Industrial Collaboration I have one publication with an industrial co-author (Evotec), which Julien Michel is part of as well. Assessment of hydration thermodynamics at protein interfaces with grid cell theory, G. Gerogiokas, M. W. Y. Southey, M. P. Mazanetz, A. Heifetz, M. Bodkin, R. J. Law, R. H. Henchman and J. Michel, J. Phys. Chem. B, 2016, 120, 10442-10452. Strengthening of UK's international position: The impacts of ARCHER's science extend beyond national borders and most science is delivered through partnerships on a national or international level. • For the reporting period please provide a bullet pointed list of projects that have involved international collaboration. For each example please provide a brief summary of the part that ARCHER and the Consortium have played. • For the reporting period please provide a list of consortium publications with international co-authorship. • For the reporting period please detail any other international activities that the Consortium might be involved in (workshops, EU projects etc.). Examples of HECBioSim international engagement include: Michelle Sahai (Department of Life Sciences, Roehampton) Combined in vitro and in silico approaches to the assessment of stimulant properties of novel psychoactive substances - The case of the benzofuran 5-MAPB. Sahai MA, Davidson C, Khelashvili G, Barrese V, Dutta N, Weinstein H, Opacka-Juffry J. Prog Neuropsychopharmacol Biol Psychiatry. (2016) 75:1-9. doi: 10.1016/j.pnpbp.2016.11.004. co-authors affiliations include: Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University (WCMC), New York, NY, 10065, USA and HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute of Computational Biomedicine, Weill Cornell Medical College of Cornell University, New York, NY, 10065, USA. Author contribution: CD, MAS, HW and JOJ were responsible for the study concept and design. CD and VB collected and interpreted the voltammetry data. JOJ and ND conducted the ligand binding experiments and ND analysed the data. MAS (ARCHER user) and GK performed the molecular modelling studies and interpreted the findings. CD, MAS, GK and JOJ drafted the manuscript. All authors critically reviewed the content and approved the final version for publication. Dmitry Nerukh (Engineering and Applied Science, Aston University) Collaborations: • Prof. Makoto Taiji group (K-computer, MDGRAPE), Laboratory for Computational Molecular Design, Computational Biology Research Core, RIKEN Quantitative Biology Center (QBiC), Kobe, Japan • Prof. Reza Khayat group, City College of New York, United States • Prof. Artyom Yurov group, Immanuel Kant Baltic Federal University, Russian Federation • Prof. Nikolay Mchedlov-Petrosyan group, V.N. Karazin Kharkiv National University, Ukraine • Prof. Natalya Vaysfeld group, Odessa I.I.Mechnikov National University, Ukraine International activities: • International Workshop - Engineering bacteriophages for treating antimicrobial resistance using computational models. Dec. 2016, Aston University, UK Dmitry Nerukh group at Aston University collaborates with the group of Prof. Makoto Taiji (the deputy director of RIKEN Quantitative Biology Institute). Prof. Taiji group is the author and implementer of the fastest machine in the world for molecular dynamics simulations, MDGRAPE, as well as part of the team designing the K-computer and working on it (several times the fastest computer in the world). We are currently preparing a joint manuscript for publication where the results obtained on ARCHER will be used alongside with the results obtained on MDGRAPE-4. Julien Michel (Chemistry, Edinburgh) Free Energy Reproducibility Project Free energy reproducibility project between the Michel, Mobley, Roux groups and STFC. This makes use of FESetup which is CCPBioSim, but calculations have been executed on various HPC platforms, Hannes can clarify whether any of the systems used is within the remit of HECBioSim. Sarah Harris (Physics, Leeds), Charlie Laughton (Pharmacy, Nottingham) and Agnes Noy (Physics, York) In an international collaboration with the Institute for Research in Biomedicine in Barcelona, Noy, Harris and Laughton used ARCHER time obtained through the HecBioSim consortium to perform multiple 100ns molecular dynamics (MD) simulations of DNA minicircles containing ~100 base pairs as part of the validation suite for the new BSC1 nucleic acid forcefield, see: Ivani I., Dans P. D., Noy A., Perez A., Faustino I., Hospital A., Walther J., Andrio P., Goni R., Portella G., Battistini F.,Gelpi J. L. Gonzalez C., Vendruscolo M., Laughton C. A., Harris S. A. Case D. A. & Orozco M. "Parmbsc1: a refined force field for DNA simulations" Nat. Methods 13, 55, 2015, doi:10.1038/nmeth.3658 Jon Essex (Chemistry, Southampton) Development and testing of hybrid coarse-grain/atomistic model of membrane systems. ARCHER and the consortium were instrumental in providing the computing time necessary to complete this work. The work was performed by a research fellow in my group, who has subsequently taken up an academic post in Sweden, where he is continuing to develop this methodology. Publication: All-atom/coarse-grained hybrid predictions of distributioncoefficients in SAMPL5 Samuel Genheden1, Jonathan W. Essex, J Comput Aided Mol Des (2016) 30:969-976 DOI 10.1007/s10822-016-9926-z IP and other industrial engagement, or translation, which has benefited from HECBioSim international collaborations Collaboration Dr Samuel Genheden, University of Gothenburg - see above International activities (e.g. workshops) that have benefited from HECBioSim The work performed with Sam resulted in an successful eCSE application for development work on the LAMMPS software. This is an international simulation package run out of Sandia labs in the US. Through this eCSE application we were able to update the rotational integrator and improve the load balancing for our hybrid simulation methodology. These developments have been incorporated in the latest release versions of the code. An ARCHER training webinar resulted from this work. Training activities see above - ARCHER training webinar on our developments within LAMMPS Software development see above - code modifications in LAMMPS which either have been, or will be, in the release version of the code Advantages you see of the consortium (e.g. could be ability to pursue project quickly; develop collaborations) resources to run the sort of large-scale calculations we need Michelle Sahai (Department of life Sciences, Roehampton) The publication I added on ResearchFish has international co-authors. Combined in vitro and in silico approaches to the assessment of stimulant properties of novel psychoactive substances - The case of the benzofuran 5-MAPB. Sahai MA, Davidson C, Khelashvili G, Barrese V, Dutta N, Weinstein H, Opacka-Juffry J. Prog Neuropsychopharmacol Biol Psychiatry. (2016) 75:1-9. doi: 10.1016/j.pnpbp.2016.11.004. co-authors affiliations include: Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University (WCMC), New York, NY, 10065, USA and HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute of Computational Biomedicine, Weill Cornell Medical College of Cornell University, New York, NY, 10065, USA. Author contribution: CD, MAS, HW and JOJ were responsible for the study concept and design. CD and VB collected and interpreted the voltammetry data. JOJ and ND conducted the ligand binding experiments and ND analysed the data. MAS (ARCHER user) and GK performed the molecular modelling studies and interpreted the findings. CD, MAS, GK and JOJ drafted the manuscript. All authors critically reviewed the content and approved the final version for publication. Edina Rosta (Computational Chemistry, Kings College London) International collaborations I have several international collaborators with joint computational/experimental projects. For their success the HECBioSim computer time was essential: • Prof. Beata Vertessy, Budapest Technical University, Hungary JACS 2016 138 (45), 15035-15045 • Profs. Walter Kolch, Vio Buchete and Boris Kholodenko, UCD, Ireland Angewandte 55 (3), 983-986, 2016 (this may have been reported previously) PLOS Computational Biology 12 (10), e1005051, 2016 J Phys Chem Letters 7 (14), 2676-2682, 2016 • Jose Maria Lluch, Angels Gonzalez, Autonomous University of Barcelona, Spain JCTC 12 (4), 2079-2090, 2016 Other international activities Free energy and molecular kinetics workshop with Frank Noe's group (Free University of Berlin) and Vio Buchete (UCD, Dublin). Maybe this should be for training activities? Following the workshop, Erasmus students apply to visit my group. Phil Biggin (Biochemistry, Oxford) 2 and 4 were with colleagues from McGill (Brown PM, Aurousseau MR and Bowie) and 3 was with colleagues from Denmark (Braun and Pless) 2. Kainate receptor pore-forming and auxiliary subunits regulate channel block by a novel mechanism. Brown PM, Aurousseau MR, Musgaard M, Biggin PC, Bowie D. J Physiol. 2016 Apr 1;594(7):1821-40. doi: 10.1113/JP271690. 3. Role of an Absolutely Conserved Tryptophan Pair in the Extracellular Domain of Cys-Loop Receptors. Braun N, Lynagh T, Yu R, Biggin PC, Pless SA. ACS Chem Neurosci. 2016 Mar 16;7(3):339-48. doi: 10.1021/acschemneuro.5b00298. 4. Distinct Structural Pathways Coordinate the Activation of AMPA Receptor-Auxiliary Subunit Complexes. Dawe GB, Musgaard M, Aurousseau MR, Nayeem N, Green T, Biggin PC, Bowie D. Neuron. 2016 Mar 16;89(6):1264-76. doi: 10.1016/j.neuron.2016.01.038. Richard Henchman I have an international collaboration with Professor Franke Grater at the University of Heidelberg on entropy theory for biomolecular systems. Syma Khalid (Chemistry, Southampton) Collaboration with Singapore National Center for Biotechnology. Contributions to CECAM workshops Other Highlights for the Current Reporting Period: Please provide details of any other significant highlights from the reporting period that are not captured elsewhere in the report. Professor Adrian Mullholland organised and chaired the Computational Chemistry, Gordon Research Conference, Girona, Spain 24th - 29th July 2016. The theme of the 2016 Computational Chemistry GRC was "Theory and Simulation Across Scales in Molecular Science". It focused on method development and state-of-the-art applications across computational molecular science, and encouraged cross-fertilization between areas. The conference was oversubscribed, with attendees from industry and academia. The meeting received a High-Performance Rating, and was commended for the assessment that 95% of conferees rated this meeting "above average" on all evaluation areas (science, discussion, management, atmosphere and suitability). HEC Consortia Model: Over the coming months EPSRC will be looking at the future of the HEC Consortia model and potential future funding. We would like to use this opportunity to ask the Consortia Chairs for input: • What are the key benefits that your community have experienced through the existence of the HEC Consortia? • What elements of the financial support provided by the HEC Consortium's grant have worked well and what could be improved in the future? We aim to expand the breadth of the work of the Consortium focusing on cutting-edge applications, and building collaborations with experiments and industry, to achieve maximum impact from ARCHER use. We discussed Grand Challenges at our most recent Management Group meeting. In December 2015, and have identified several to follow up as strategic priorities. We aim to tackle and support large-scale grand challenge applications in biomolecular science, in areas such as antimicrobial resistance, membrane dynamics, drug design and synthetic biology. One specific theme with potentially high impact in drug discovery is large -scale comparative investigation of allosteric regulation in different superfamilies of proteins (e.g. PAS domain containing proteins, tyrosine kinases, etc.). The major impact will be in the identification of novel selective therapeutic molecules with limited adverse side effects. As a Consortium, we intend to develop and apply novel computational approaches for the rational design of allosteric regulators of hitherto 'undruggable' targets. Many of the targets emerging from large-scale genetic screening are deemed undruggable due to the difficulty of designing drug-like modulators that bind to their catalytic sites. It is increasingly clear that these targets might be effectively targeted by designing drugs that bind to protein-protein interfaces and allosteric sites. To do that, however, new rational design strategies, based on an in-depth knowledge of protein dynamics and advanced modelling and new simulation techniques are required. Other challenging frontier areas include dynamics of motor proteins; prediction of the effects of pathogenic mutations on protein function. The accurate prediction of free energy of binding is still in its infancy and needs much further investigation. Finally, kinetics of biomolecular reactions will become the next big topic. It is clear that high end computing resource can provide the necessary power and capability to provide inroads into this vital area. This is important because it is becoming increasingly apparent that kinetics of drug binding is a key factor that the pharmaceutical sector should really be looking at in terms of a major dictator of potency. HECBioSim is now well established, supporting work of many groups across the UK in the growing field of biomolecular simulation. We benefit from an Advisory Group containing members from industry, as we as international biomolecular simulation experts and experimental scientists. The Advisory Board was expanded and refreshed for the renewal and consists of: Dr. Nicolas Foloppe (Vernalis plc, Chair); Dr. Colin Edge (GlaxoSmithKline); Dr. Mike King (UCB Pharmaceuticals); Dr. Mike Mazanetz (Evotec AG); Dr. Garrett Morris (Crysalin Ltd.); Dr. Gary Tresadern (Johnson and Johnson Pharmaceuticals); Dr. Richard Ward (AstraZeneca); Prof. Modesto Orozco (IRB, Barcelona); Prof. Tony Watts, (Oxford, NMR); Dr. Pete Bond (A*STAR Bioinformatics Institute Singapore). We aim to foster industrial collaborations and collaborations with experimentalists (e.g. joint workshops with CCPN, Institute of Physics (Sarah Harris, Leeds Physics); see e.g. case studies. A particular theme for strategic development will be multiscale modelling, building on collaborations between several groups in the Consortium and the other CCPs. This theme reflects the inclusive and forward looking philosophy of HecBioSim, which is a community open to new ideas, keen to develop new methods, and ultimately to use HEC to drive exciting new science. The Consortium model allows new collaborations to develop. The recent reduction in time allocated to HECBioSim has meant that we can support fewer projects. There is significantly more demand for computer time than we can accommodate through our current allocation. We intend to work with Tier 2 Centres to explore possibilities for applications, and e.g. to test emerging architectures for biomolecular simulation. Edina Rosta (Computational Chemistry, Kings College London) comments: "HECBioSim enables my group to perform biomolecular simulations at the high standards required for JACS, Angewandte, etc. Without this consortium I would not be able to perform the necessary calculations leading to publishable work in top journals as our local university resources are limited and the hpc systems are not well maintained". Regarding financial support: the administrative support provided via the consortium grant is essential to the functioning of HECBioSim. This role is currently undertaken by Simone Breckell who not only administers, allocates time to projects and arranges panel meetings but has also done a fantastic job collating the extensive information for this EPSRC report. |
| URL | http://www.hecbiosim.ac.uk |
| Title | A Dynamic and Responsive Host in Action: Light-Controlled Molecular Encapsulation - Part 2 |
| Description | MD.tar.gz and warehouse.tar.gz contain preliminary data and test calculations not explicitly mentioned in the publication. As we plan to include a link to this data in the final version of the article we prefer to keep restricted the access to this part of the data. See the related dataset linked to under REFERENCES, containing the geometries, energies, frequency, solvent, and PES scan calculations. 'A Dynamic and Responsive Host in Action Light-Controlled Molecular Encapsulation' https://doi.org/10.18742/RDM01-51 |
| Type Of Material | Database/Collection of data |
| Year Produced | 2022 |
| Provided To Others? | Yes |
| URL | https://kcl.figshare.com/articles/dataset/A_Dynamic_and_Responsive_Host_in_Action_Light-Controlled_M... |
| Title | A Dynamic and Responsive Host in Action: Light-Controlled Molecular Encapsulation - Part 2 |
| Description | MD.tar.gz and warehouse.tar.gz contain preliminary data and test calculations not explicitly mentioned in the publication. As we plan to include a link to this data in the final version of the article we prefer to keep restricted the access to this part of the data. See the related dataset linked to under REFERENCES, containing the geometries, energies, frequency, solvent, and PES scan calculations. 'A Dynamic and Responsive Host in Action Light-Controlled Molecular Encapsulation' https://doi.org/10.18742/RDM01-51 |
| Type Of Material | Database/Collection of data |
| Year Produced | 2022 |
| Provided To Others? | Yes |
| URL | https://kcl.figshare.com/articles/dataset/A_Dynamic_and_Responsive_Host_in_Action_Light-Controlled_M... |
| Title | CCDC 1497573: Experimental Crystal Structure Determination |
| Description | Related Article: Sean T. J. Ryan, Jesus del Barrio, Reynier Suardiaz, Daniel F. Ryan, Edina Rosta, Oren A. Scherman|2016|Angew.Chem.,Int.Ed.|55|16096|doi:10.1002/anie.201607693 |
| Type Of Material | Database/Collection of data |
| Year Produced | 2017 |
| Provided To Others? | Yes |
| URL | http://www.ccdc.cam.ac.uk/services/structure_request?id=doi:10.5517/ccdc.csd.cc1m8bt1&sid=DataCite |
| Title | Crystallography and QM/MM Simulations Identify Preferential Binding of Hydrolyzed Carbapenem and Penem Antibiotics to the L1 Metallo-beta-lactamase in the Imine Form |
| Description | MD trajectories, topologies, parameters and input files for the data presented in the paper Twidale et al. J Chem. Inf. Model. 2021. |
| Type Of Material | Database/Collection of data |
| Year Produced | 2021 |
| Provided To Others? | Yes |
| Impact | Widespread bacterial resistance to carbapenem antibiotics is an increasing global health concern. Resistance has emerged due to carbapenem-hydrolyzing enzymes, including metallo-ß-lactamases (MßLs), but despite their prevalence and clinical importance, MßL mechanisms are still not fully understood. Carbapenem hydrolysis by MßLs can yield alternative product tautomers with the potential to access different binding modes. Here, we show that a combined approach employing crystallography and quantum mechanics/molecular mechanics (QM/MM) simulations allow tautomer assignment in MßL:hydrolyzed antibiotic complexes. Molecular simulations also examine (meta)stable species of alternative protonation and tautomeric states, providing mechanistic insights into ß-lactam hydrolysis. We report the crystal structure of the hydrolyzed carbapenem ertapenem bound to the L1 MßL from Stenotrophomonas maltophilia and model alternative tautomeric and protonation states of both hydrolyzed ertapenem and faropenem (a related penem antibiotic), which display different binding modes with L1. We show how the structures of both complexed ß-lactams are best described as the (2S)-imine tautomer with the carboxylate formed after ß-lactam ring cleavage deprotonated. Simulations show that enamine tautomer complexes are significantly less stable (e.g., showing partial loss of interactions with the L1 binuclear zinc center) and not consistent with experimental data. Strong interactions of Tyr32 and one zinc ion (Zn1) with ertapenem prevent a C6 group rotation, explaining the different binding modes of the two ß-lactams. Our findings establish the relative stability of different hydrolyzed (carba)penem forms in the L1 active site and identify interactions important to stable complex formation, information that should assist inhibitor design for this important antibiotic resistance determinant. |
| URL | https://data.bris.ac.uk/data/dataset/13pu85dfaobij2rumzql5buyy2/ |
| Title | Evolution of dynamical networks enhances catalysis in a designer enzyme |
| Description | Data related to: "Evolution of dynamical networks enhances catalysis in a designer enzyme". H. Adrian Bunzel, J. L. Ross Anderson, Donald Hilvert, Vickery L. Arcus, Marc W. van der Kamp, Adrian J. Mulholland. Nature Chemistry 2021. MD Trajectories of a designed and evolved Kemp eliminase (1A53-2 and 1A53-2.5) in complex with a ground state (GS) or transition state (TS, TS2) model. The ligands are called GS1, TS1, and TS3 in the raw data. Cluster analysis of each trajectory, discriminating between an open (0) or closed (1) state for each frame. Pymol Sessions to reproduce Figures 1-3 of the paper. |
| Type Of Material | Database/Collection of data |
| Year Produced | 2021 |
| Provided To Others? | Yes |
| Impact | Activation heat capacity is emerging as a crucial factor in enzyme thermoadaptation, as shown by the non-Arrhenius behaviour of many natural enzymes. However, its physical origin and relationship to the evolution of catalytic activity remain uncertain. Here we show that directed evolution of a computationally designed Kemp eliminase reshapes protein dynamics, which gives rise to an activation heat capacity absent in the original design. These changes buttress transition-state stabilization. Extensive molecular dynamics simulations show that evolution results in the closure of solvent-exposed loops and a better packing of the active site. Remarkably, this gives rise to a correlated dynamical network that involves the transition state and large parts of the protein. This network tightens the transition-state ensemble, which induces a negative activation heat capacity and non-linearity in the activity-temperature dependence. Our results have implications for understanding enzyme evolution and suggest that selectively targeting the conformational dynamics of the transition-state ensemble by design and evolution will expedite the creation of novel enzymes. |
| URL | https://data.bris.ac.uk/data/dataset/l6hm9j11yil92bh9rvh27i7ge/ |
| Title | MemProtMD |
| Description | a datbase of all membrane protein structures and their interactions with lipids |
| Type Of Material | Database/Collection of data |
| Year Produced | 2015 |
| Provided To Others? | Yes |
| Impact | Considerable interest and uptake by membrane protein structural biologists in academia and industry (pharma). |
| URL | http://memprotmd.bioch.ox.ac.uk |
| Title | SWISH a new Hamiltonian Replica Exchange-based computational algorithm |
| Description | We developed a novel and effective computational approach to predict cryptic binding sites on targets of pharmaceutical interest. |
| Type Of Material | Computer model/algorithm |
| Year Produced | 2016 |
| Provided To Others? | Yes |
| Impact | The method has been described in an high-impact publication (JACS) and in a number of high-profile blogs in drug discovery. The PI has been invited by Pfizer and other pharmaceutical companies to give talks about the method. |
| Title | Simulation of Functional Motions in Enzymes |
| Description | Data related to: "Structure and function in homodimeric enzymes: simulations of cooperative and independent functional motions". Wells SA, Van der Kamp MW, Mulholland AJ. PLOS ONE, 2015. Results from two different simulation methods, normal-mode biased geometric simulations of flexible motion and conventional molecular dynamics, as applied to two different homodimeric enzymes, the DcpS scavanger decapping enzyme and citrate synthase. |
| Type Of Material | Database/Collection of data |
| Year Produced | 2015 |
| Provided To Others? | Yes |
| Impact | Large-scale conformational change is a common feature in the catalytic cycles of enzymes. Many enzymes function as homodimers with active sites that contain elements from both chains. Symmetric and anti-symmetric cooperative motions in homodimers can potentially lead to correlated active site opening and/or closure, likely to be important for ligand binding and release. Here, we examine such motions in two different domain-swapped homodimeric enzymes: the DcpS scavenger decapping enzyme and citrate synthase. We use and compare two types of all-atom simulations: conventional molecular dynamics simulations to identify physically meaningful conformational ensembles, and rapid geometric simulations of flexible motion, biased along normal mode directions, to identify relevant motions encoded in the protein structure. The results indicate that the opening/closure motions are intrinsic features of both unliganded enzymes. In DcpS, conformational change is dominated by an anti-symmetric cooperative motion, causing one active site to close as the other opens; however a symmetric motion is also significant. In CS, we identify that both symmetric (suggested by crystallography) and asymmetric motions are features of the protein structure, and as a result the behaviour in solution is largely non-cooperative. The agreement between two modelling approaches using very different levels of theory indicates that the behaviours are indeed intrinsic to the protein structures. Geometric simulations correctly identify and explore large amplitudes of motion, while molecular dynamics simulations indicate the ranges of motion that are energetically feasible. Together, the simulation approaches are able to reveal unexpected functionally relevant motions, and highlight differences between enzymes. |
| URL | http://data.bris.ac.uk/data/dataset/1klro7qjw27xi19qrcs1bb2nt6/ |
| Title | Supplementary data for: Tackling hysteresis in conformational sampling --- how to be forgetful with MEMENTO |
| Description | This is the supplementary data for our publication entitled: "Tackling hysteresis in conformational sampling --- how to be forgetful with MEMENTO". This version corresponds to the first revision of our paper in response to reviewer feedback. Abstract: <<< The structure of proteins has long been recognised to hold the key to understanding and engineering their function, and rapid advances in structural biology and protein structure prediction are now supplying researchers with an ever-increasing wealth of structural information. Most of the time, however, structures can only be determined in free energy minima, one at a time. While conformational flexibility may thus be inferred from static end-state structures, their interconversion mechanisms --- a central ambition of structural biology --- are often beyond the scope of direct experimentation. Given the dynamical nature of the processes in question, many studies have attempted to explore conformational transitions using molecular dynamics (MD). However, ensuring proper convergence and reversibility in the predicted transitions is extremely challenging. In particular, a commonly used technique to map out a path from a starting to a target conformation called steered MD (SMD) can suffer from starting-state dependence (hysteresis) when combined with techniques such as umbrella sampling (US) to compute the free energy profile of a transition. \\ Here, we study this problem in detail on conformational changes of increasing complexity. We also present a new, history-independent approach that we term "MEMENTO" (Morphing End states by Modelling Ensembles with iNdependent TOpologies) to generate paths that alleviate hysteresis in the construction of conformational free energy profiles. MEMENTO utilises template-based structure modelling to restore physically reasonable protein conformations based on coordinate interpolation (morphing) as an ensemble of plausible intermediates, from which a smooth path is picked. We compare SMD and MEMENTO on well-characterized test cases (the toy peptide deca-alanine and the enzyme adenylate kinase) before discussing its use in more complicated systems (the kinase P38a and the bacterial leucine transporter LeuT). Our work shows that for all but the simplest systems SMD paths should not in general be used to seed umbrella sampling or related techniques, unless the paths are validated by consistent results from biased runs in opposite directions. MEMENTO, on the other hand performs well as a flexible tool to generate intermediate structures for umbrella sampling. We also demonstrate that extended end-state sampling combined with MEMENTO can aid the discovery of collective variables on a case-by-case basis. >>> There are 4 folders in this dataset for the 4 simulation systems studied in the paper. Deca-alanine, ADK, P38a and LEUT. Each folder contains key coordinate files used to initialise MEMENTO and SMD runs, and data produced in the course of simulations (as labelled in the folders). In the simulation folders, 'raw_data' corresponds to the outputs produced by PLUMED during REUS or SMD, 'convergence' contains WHAM outputs taken at a certain percentage of the data included, and 'pointsfile' are the metadata files required by the Grossfield WHAM implementation. |
| Type Of Material | Database/Collection of data |
| Year Produced | 2023 |
| Provided To Others? | Yes |
| URL | https://zenodo.org/record/7567882 |
| Description | Catalysis Hub |
| Organisation | Research Complex at Harwell |
| Department | UK Catalysis Hub |
| Country | United Kingdom |
| Sector | Public |
| PI Contribution | Modelling and simulation of enzyme mechanisms for applications in biocatalysts via the Catalysis Hub |
| Collaborator Contribution | Modelling and simulation of enzyme mechanisms for applications in biocatalysts via the Catalysis Hub and training of Hub PDRAs. |
| Impact | Catalysis is a core area of contemporary science posing major fundamental and conceptual challenges, while being at the heart of the chemical industry - an immensely successful and important part of the overall UK economy (generating in excess of £50 billion per annum). UK catalytic science currently has a strong presence, but there is intense competition in both academic and industrial sectors, and a need for UK industrial activity to shift towards new innovative areas posing major challenges for the future. In light of these challenges the UK Catalysis Hub endeavours to become a leading institution, both nationally and internationally, in the field and acts to coordinate, promote and advance the UK catalysis research portfolio. With a strong emphasis on effective use of the world-leading facilities on the RAL campus. Structure The project has four mature themes and a fifth theme starting in 2015 , each with a lead investigator as PI - Catalysis by Design (Catlow); Energy (Hardacre); Environment (Hutchings); Chemical Transformations (Davidson) and the new Biocatalysis and Biotransformations (Nick Turner Manchester) - with the design theme based in the Harwell hub. Each theme is supported by £3 - 3.5M EPSRC funding over 5 years and within each theme there are typically six to eight sub-projects funded initially for 2 years, involving collaborative teams working at a variety of sites throughout the UK. Professor Hutchings acts as director of the whole national programme for the first three year period and chairs the management group, which is supported by a steering group and an industrial advisory panel. We note that engagement with industry is one of the key aims of the catalysis hub project. As well as hosting the design theme, the centre within the Research Complex at Harwell (RCaH) will coordinate the programme, be a base for national and international visitors and provide both training and outreach activities. |
| Start Year | 2015 |
| Description | Collaboration on Enzyme activation heat capacity (Chris Pudney, Vic Arcus etc.) |
| Organisation | University of Bath |
| Department | Department of Biology and Biochemistry |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Simulation studies and advice on simulation studies (conducted by research students) to 'translate' experimental data to specific structural/dynamic phenomena at the atomistic level (as uncovered through simulation). Detailed combined analysis of experimental and computational data. Co-supervision of postgraduate research students. |
| Collaborator Contribution | Performing experiments and analysis to further understand simulation data. (Co-)writing of publications. Dissemination of results. |
| Impact | Multidisciplinary - enzyme kinetics (Arcus, Pudney), spectroscopy studies of protein dynamics (Pudney); enzyme-substrate complex simulations (Van der Kamp). Multiple publications (see publications). Co-supervised PhD student thesis: https://purehost.bath.ac.uk/ws/portalfiles/portal/202462532/Rory_Crean_Thesis.pdf |
| Start Year | 2018 |
| Description | Collaboration on Enzyme activation heat capacity (Chris Pudney, Vic Arcus etc.) |
| Organisation | University of Waikato |
| Department | Faculty of Science and Engineering |
| Country | New Zealand |
| Sector | Academic/University |
| PI Contribution | Simulation studies and advice on simulation studies (conducted by research students) to 'translate' experimental data to specific structural/dynamic phenomena at the atomistic level (as uncovered through simulation). Detailed combined analysis of experimental and computational data. Co-supervision of postgraduate research students. |
| Collaborator Contribution | Performing experiments and analysis to further understand simulation data. (Co-)writing of publications. Dissemination of results. |
| Impact | Multidisciplinary - enzyme kinetics (Arcus, Pudney), spectroscopy studies of protein dynamics (Pudney); enzyme-substrate complex simulations (Van der Kamp). Multiple publications (see publications). Co-supervised PhD student thesis: https://purehost.bath.ac.uk/ws/portalfiles/portal/202462532/Rory_Crean_Thesis.pdf |
| Start Year | 2018 |
| Description | Collaboration with Beata Vertessy |
| Organisation | Budapest University of Technology and Economics |
| Department | Department of Biotechnology and Food Sciences |
| Country | Hungary |
| Sector | Academic/University |
| PI Contribution | We initiated a collaborative project to studey the role of conserved arginine residues in the dUTPase enzyme. We first performed a PDB-side structural analysis to compare arginine residues in NTP cleaving enzymes. Subsequently, we carried out QM/MM and MD calculations to establish the function of the key arginine finger residue in dUTPases. |
| Collaborator Contribution | In this collaboration the experimental group led by Beata Vertessy performed X-Ray crystallography experiments togeter with biochemical experiments to use this in our joint project. |
| Impact | Nagy et al, Journal of the American Chemical Society, 2016, DOI: 10.1021/jacs.6b09012 Multidisciplinary collaboration with experimental X-Ray crystallography and biochemistry group and our theoretical and computational biophysical chemistry group. |
| Start Year | 2014 |
| Description | Collaboration with Bristol university on predicting drug-target binding kinetics |
| Organisation | University of Bristol |
| Department | School of Chemistry |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We contributed our enhanced sampling simulation algorithms including TS-PPTIS. Our approach will be combined with Prof. Mulholland's QM/MM algorithms to accurately predict binding kinetics. |
| Collaborator Contribution | Prof. Mulholland's contributed his QMMM algorithms as well as Waterswap to the combined computational platform. |
| Impact | A combined computational platform to predict binding kinetics and model the transition state ensemble. |
| Start Year | 2015 |
| Description | Collaboration with Derick Rousseau |
| Organisation | Ryerson University |
| Country | Canada |
| Sector | Academic/University |
| PI Contribution | Coarse-grained molecular simulation of monoglyceride self-assembly at triglyceride-water and air-water interfaces. |
| Collaborator Contribution | Experimental studies on the molecular templating effect of monoglycerides on triglyceride crystallization at oil-water interfaces |
| Impact | A poster and oral presentation was given at Food Colloids 2016 held at Wageningen university the Netherlands. A manuscript has been submitted and is under review. |
| Start Year | 2016 |
| Description | Collaboration with Johnson and Johnson |
| Organisation | Johnson & Johnson |
| Department | Janssen-Cilag |
| Country | Global |
| Sector | Private |
| PI Contribution | We helped J & J implement a computational pipeline for cryptic binding pocket discovery and collaborated on looking for druggable cryptic binding pockets on targets such the IMPase. |
| Collaborator Contribution | Provided interesting drug targets and experimental data, including NMR fragment screening. |
| Impact | Found interesting cryptic pockets in IMPase |
| Start Year | 2020 |
| Description | Collaboration with Paul Clegg |
| Organisation | University of Edinburgh |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | This project was collaborative with UoE who provided experimental expertise to complement computer modelling at HWU. |
| Collaborator Contribution | Provided expertise in soft matter physics, atomic force microscopy, spectroscopy. |
| Impact | We have authored 5 papers (6th in preparation). These are listed under this award. |
| Start Year | 2016 |
| Description | Collaboration with Prof. Jose Maria Lluch's group |
| Organisation | Autonomous University of Barcelona (UAB) |
| Country | Spain |
| Sector | Academic/University |
| PI Contribution | We helped to carry out and analyse QM/MM MD simulations using umbrella sampling bias, and calculated the kinetics as well as the free energies of the catalytic reaction to obtain the Arrhenius prefactor. |
| Collaborator Contribution | Patricia Laura, a PhD student was awarded funding to visit my group and work in my lab. |
| Impact | Joint publication by Suardiaz et al, J. Chem. Theor. Comput. 2016, DOI: 10.1021/acs.jctc.5b01236. |
| Start Year | 2015 |
| Description | Collaboration with SANOFI and Evotec on the allosteric regulation of receptor Tyrosine kinases. |
| Organisation | Evotec |
| Country | Germany |
| Sector | Private |
| PI Contribution | In this successful partnership, we helped designing a new class of allosteric anticancer drugs by using our novel computational algorithms to sample rare events and predict binding kinetics. |
| Collaborator Contribution | The partners contributed to the success of the research by performing large scale ligand screening ad providing high resolution crystallographic structures and biophysical data on the ligand-target complex. |
| Impact | A novel allosteric inhibitor is in re-clinical development for cancer. |
| Start Year | 2015 |
| Description | Collaboration with SANOFI and Evotec on the allosteric regulation of receptor Tyrosine kinases. |
| Organisation | Sanofi |
| Department | Aventis |
| Country | France |
| Sector | Private |
| PI Contribution | In this successful partnership, we helped designing a new class of allosteric anticancer drugs by using our novel computational algorithms to sample rare events and predict binding kinetics. |
| Collaborator Contribution | The partners contributed to the success of the research by performing large scale ligand screening ad providing high resolution crystallographic structures and biophysical data on the ligand-target complex. |
| Impact | A novel allosteric inhibitor is in re-clinical development for cancer. |
| Start Year | 2015 |
| Description | Collaboration with the Nano-Optics to controlled Nano-Chemistry programme |
| Organisation | University of Cambridge |
| Department | Cavendish Laboratory |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Our team performs electronic structure calculations to validate and design experiments in our collaborator groups led by Profs. Oren Scherman and Jeremy Baumberg in Cambridge. |
| Collaborator Contribution | We have several joint publications already. |
| Impact | Chikkarady et al, Nature, 2016, DOI: 10.1038/nature17974 In collaboration with the nano-optics lab - led by Prof. Jeremy Baumberg. Del Barrio et al, J. Am. Chem. Soc., 2016, DOI: 10.1021/jacs.5b11642 Ryan et al, Angewandte, 2016, DOI: 10.1002/anie.201607693 McCune et al, Org. Biomol. Chem., 2017, DOI: 10.1039/c6ob02594c Synthetic chemistry and materials reseach on host-guest supramolecular chemistry - led by Prof. Oren Scherman. |
| Start Year | 2015 |
| Description | Collaboration with the Nano-Optics to controlled Nano-Chemistry programme |
| Organisation | University of Cambridge |
| Department | Department of Chemistry |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Our team performs electronic structure calculations to validate and design experiments in our collaborator groups led by Profs. Oren Scherman and Jeremy Baumberg in Cambridge. |
| Collaborator Contribution | We have several joint publications already. |
| Impact | Chikkarady et al, Nature, 2016, DOI: 10.1038/nature17974 In collaboration with the nano-optics lab - led by Prof. Jeremy Baumberg. Del Barrio et al, J. Am. Chem. Soc., 2016, DOI: 10.1021/jacs.5b11642 Ryan et al, Angewandte, 2016, DOI: 10.1002/anie.201607693 McCune et al, Org. Biomol. Chem., 2017, DOI: 10.1039/c6ob02594c Synthetic chemistry and materials reseach on host-guest supramolecular chemistry - led by Prof. Oren Scherman. |
| Start Year | 2015 |
| Description | Developing new computational approaches to inhibit "undruggable" targets. |
| Organisation | UCB Pharma |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | We shared with UCB early versions of a computational platform we are developing to target allosteric sites on otherwise "undruggable" targets, i.e. pharmaceutical targets that are difficult to target with traditional drug design approaches based on substrate competitive ligands. |
| Collaborator Contribution | UCB contributed to the project with high quality structural and biological data and is hiring a dedicated PDRA to work on the collaboration for 3 years. |
| Impact | The new tools have been used to design novel drugs. |
| Start Year | 2016 |
| Description | ERNEST - European Research Network on Signal Transduction (CA18133) / Member of ERNEST Management Committee and the organizer of the first ERNEST Conference |
| Organisation | European Cooperation in Science and Technology (COST) |
| Department | COST Action |
| Country | Belgium |
| Sector | Public |
| PI Contribution | We were honoured to host the inaugural meeting of the European Research Network on Signal Transduction (ERNEST) funded by COST (Cooperation in Science and Technology) Action at Queen's University Belfast on October 28-30, 2019. PI was a main organizer of the GPCR meeting in Belfast. 150 delegates from 31 countries have attended the meeting, which made our conference a truly international event. This meeting was entitled "GPCR Pharmacology: Activation, Signalling and Drug Design" and focused on recent advances in knowledge and technology in the field. PI has designed the scientific program of the conference and has taken care of sponsor and venue arrangements. PDRA has gave a oral presentation on this BBSRC research project. |
| Collaborator Contribution | ERNEST COST Network has provided funding to organize the event. |
| Impact | Scientific outcomes of the meeting included recent advancements in cryo-electron microscopy, which is currently revolutionizing the field; how artificial intelligence and big data could drive pharmacology; the development of a multi-dimensional map of GPCR signal transduction and an overview of the IUPHAR / BPS Guide to PHARMACOLOGY database. The meeting had great networking opportunities and cultural experiences. On the first evening, a Welcome Reception with Deputy Lord Mayor Councillor Peter McReynolds, took place at the Belfast City Hall. The welcoming lectures were given by Michael Livingstone, a local historian, and Dr Aidan Seeley from the British Pharmacological Society. On the second evening, the Conference Dinner with traditional Irish dancing and music took place at the Great Hall. The conference has got additional sponsors: Belfast City Hall, Visit Belfast, British Pharmacological Society, ACS Pharmacology and Translational Science, Boehringer Ingelheim, Sosei Heptares, Nanotemper Technologies and Crelux, WuXi AppTec Company. As a result of this meeting, PI is a contributor to the ERNEST signalling map group. |
| Start Year | 2019 |
| Description | Evotec AI |
| Organisation | Evotec (UK) Ltd |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | Studentship aimed at researching the use of MD in Artificial Intelligence. |
| Collaborator Contribution | None yet. |
| Impact | N/A yet. |
| Start Year | 2018 |
| Description | Immunocore |
| Organisation | Immunocore Ltd |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | Simulations of various T-cell receptor peptide-HLA complexes, including analysis and prediction of binding. |
| Collaborator Contribution | Providing structural and experimental data, discussing and interpreting results from simulations. |
| Impact | Several publications are accepted (Journal of Clinical Investigation), about to be submitted, or in progress. Immunocore supported an SWBio CASE studentship (candidate not selected for interview). Discussions for further/alternative support of (co-funded) studentships or postdocs have taken place. David Cole from Immunocore has given a seminar in Bristol. |
| Start Year | 2018 |
| Description | Industrial collaboration with EVOTEC |
| Organisation | Evotec |
| Country | Germany |
| Sector | Private |
| PI Contribution | We helped EVOTEC to rationalize the binding mode of a novel allosteric modulator of FGFR. By using our novel "SWISH" Hamiltonian Replica exchange algorithm, we predicted a previously unknown binding cavity in the D3 domain of FGFR3c, which was then validated by NMR spectroscopy. |
| Collaborator Contribution | Evotec provided a plethora of unpublished experimental data on the binding mode and on the biological effect of the new tool compound in cells. |
| Impact | The collaboration is multi-disciplinary involving Computational Chemistry, Chemical Biology, Structural Biology, Cellular Biology and Drug Discovery. A new manuscript is in preparation and will soon be submitted to a very prominent and high-impact journal. The PI (FLG) has been invited to a number of high-profile national international (ACS-meeting) conferences to discuss the results. |
| Start Year | 2016 |
| Description | MARISURF |
| Organisation | Marlow Foods |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | MARISURF is a 4.8Meuro H2020 project coordinated by HWU to identify, isolate and purify biosurfactants from marine bacteria. The production will then be scaled up to pilot scale and the surfactants tested by industrial end-users from various industry sectors including food, cosmetic and biomedical sectors. My research group is responsible for overall coordination of the project, and specifically for the screening of functional properties of the surfactants to ensure suitability in industrial applications. |
| Collaborator Contribution | Marlow Foods are a partner in MARISURF an EUH2020 project coordinated by HWU. They will test marine bacteria-derived surfactants in their Quorn food applications. |
| Impact | The collaboration is multi-disciplinary and involves the following scientific disciplines, Microbiology Chemistry Biochemistry Molecular Biology Process Engineering |
| Start Year | 2015 |
| Description | Organic synthesis of alternative gelator molecules |
| Organisation | Heriot-Watt University |
| Department | Department of Mathematics |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Shared information on olegelation. Invited collaborator to project meetings. Eventual joint publications. |
| Collaborator Contribution | The partner will synthesize a range of alternative olegelator molecules that are derivatives of gamma oryzanol that either have the ferullic acid side chain substituted for another group, or have a hydroxyl group substituted. The hydroxyl group is believed to be important in dimerization of the sterols prior to their subsequent self-association into tubules, and also stabilizes the tubules through cooperative H-bonding. The ferrulic acid group is believed to allow inter-tubule interaction (it sticks out from the surface of the tubule) via pi-pi stacking interactions, thus leading to gel formation. By creating and testing oleogelators where one or both of these groups has been substituted will allow us to understand the role they play in the self-association and gelation process. |
| Impact | Too early in project/collaboration. |
| Start Year | 2017 |
| Description | Participation of European Topology interdisciplinary Initiative (Eutopia) network |
| Organisation | European Cooperation in Science and Technology (COST) |
| Country | Belgium |
| Sector | Public |
| PI Contribution | Participation on the 2nd annual meeting |
| Collaborator Contribution | The network invited me to give a talk |
| Impact | I gave a talk to the 2nd annual meeting of the network It is a multidisciplinary network from mathematics to biology, physics and chemistry. |
| Start Year | 2019 |
| Description | Vertex - CFTR |
| Organisation | Vertex Pharmaceuticals |
| Country | United States |
| Sector | Private |
| PI Contribution | This is a studentship that will commence in 2019. |
| Collaborator Contribution | None yet., |
| Impact | N/A. |
| Start Year | 2019 |
| Description | collaboration with Dr.Chantal Valeriani |
| Organisation | Complutense University of Madrid |
| Country | Spain |
| Sector | Academic/University |
| PI Contribution | We have collaborated with Dr Valeriani and her team on the behaviour of different water models in simulations of aquaporins. We contributed expertise in water models and simulations of nanopores. This has resulted in a joint publication in J Chem Phys. |
| Collaborator Contribution | Dr. Valeriani's post doc Dr Miguel Angel Gonzalez visited Oxford for a few weeks and worked alongside Dr Lynch (the EPSRC postdoc on this project). We have continued the collaboration online and a paper has been published in J Chem Phys. |
| Impact | This has resulted in a joint publication in J Chem Phys. |
| Start Year | 2018 |
| Description | collaboration with Novartis |
| Organisation | Novartis |
| Department | Drug Discovery & Development |
| Country | United States |
| Sector | Private |
| PI Contribution | We have shared data and software/home-made code to derive kinetic rates from umbrella sampling simulations. We also developed methods to be used for calculating residence times frlom atomistic simulations. |
| Collaborator Contribution | Shared data with us of atomistic simulations for drug molecules crossing the membrane. |
| Impact | We have joint publications. |
| Start Year | 2018 |
| Description | collaboration with Walter Kolch |
| Organisation | University College Dublin |
| Country | Ireland |
| Sector | Academic/University |
| PI Contribution | Computational MD simulations to reveal structure and dynamics of RAF kinases. |
| Collaborator Contribution | Prof. Kolch's group carried out in vitro and in cell biochemical experiments to reveal RAF kinase activity and validate key mutations suggested by computational results. |
| Impact | Jambrina et al, Angewandte Chemie, 2016, DOI: 10.1002/anie.201509272 Sanchez-Sanz et al, PLOS Computational Biology, 2016, DOI: 10.1371/journal.pcbi.1005051 Interdisciplinary research with essential biochemical and biological experiments from the Kolch group (Systems Biology Ireland) and computational work from our group. |
| Start Year | 2012 |
| Title | Confidential |
| Description | Confidential |
| IP Reference | Confidential |
| Protection | Patent / Patent application |
| Year Protection Granted | 2024 |
| Licensed | Commercial In Confidence |
| Impact | Confidential |
| Title | Computational tool to predict allosteric sites in membrane proteins |
| Description | The jupyter notebook scripts to set up the mapping of allosteric sites in GPCRs used in the paper: Probe Confined Dynamic Mapping for GPCR Allosteric Site Prediction Ciancetta A., Gill A.K., Ding T., Karlov D.S., Chalhoub G., McCormick P.J. and Tikhonova I.G. ACS Central Science, 2021 in press https://doi.org/10.1021/acscentsci.1c00802 The automatic procedure of probe confined dynamic mapping is provided as jupyter notebooks (MIDAS_EC.ipynb, MIDAS_IC.ipynb, and MIDAS_LI.ipynb) available. The required input files are (i) pdb of a receptor (preoriented with OPM), membrane, and one copy of cosolvent/fragment structures and (ii) an input file containing the following information: a receptor, an orthosteric ligand (if applicable), cosolvent and membrane file names (1); an orthosteric ligand (if applicable), cosolvent, and lipid residue names (2); cosolvent/fragment molecular weight and desired water/probe m/m % (in the closed box) (3); and height of the water buffer region between the protein and the water/probe mixture box (4). |
| Type Of Technology | New/Improved Technique/Technology |
| Year Produced | 2021 |
| Open Source License? | Yes |
| Impact | The product has received press coverage and new research collaborations. https://www.qub.ac.uk/News/Allnews/Newcomputermodellingcouldboostdrugdiscovery.html |
| URL | https://github.com/irinat12/Probe-Confined-Dynamic-Mapping-Protocols-GPCRs_membrane_proteins |
| Title | FESetup |
| Description | FESetup FESetup is a tool to automate the setup of (relative) alchemical free energy simulations like thermodynamic integration (TI) and free energy perturbation (FEP) as well as post-processing methods like MM-PBSA and LIE. FESetup can also be used for general simulation setup ("equilibration") through an abstract MD engine. The latest releases are available from the project web page. |
| Type Of Technology | Software |
| Year Produced | 2017 |
| Impact | FESetup FESetup is a tool to automate the setup of (relative) alchemical free energy simulations like thermodynamic integration (TI) and free energy perturbation (FEP) as well as post-processing methods like MM-PBSA and LIE. FESetup can also be used for general simulation setup ("equilibration") through an abstract MD engine. The latest releases are available from the project web page. |
| Title | Grand - an OpenMM module for grand canonical Monte Carlo |
| Description | This software allows grand canonical Monte Carlo calculations to be performed in the OpenMM simulation environment |
| Type Of Technology | Software |
| Year Produced | 2020 |
| Open Source License? | Yes |
| Impact | None yet |
| Title | HECBioSim Web Portal |
| Description | The HECBioSim web portal provides a clean and simple way for us to interact with our community. It serves as a single place in which members of the bio-simulation community can get access to all of the things we offer; whether this be finding out about/applying for time on ARCHER, downloading our software tools, getting support with using HPC or our software, this web portal provides users with a single and consistent point of entry to what we have to offer. |
| Type Of Technology | Webtool/Application |
| Year Produced | 2016 |
| Impact | Based on usage patterns and user feedback, the HECBioSim pages were refreshed. More information was added to the ARCHER application guide and FAQs to assist new and non-traditional users of HPC traverse the jargon laden application process. The pages were simplified and redesigned to remain compatible with current technologies and trends in user expectations. Feedback provided by STFC impact managers was used to make the HECBioSim web portal more accessible to a wider audience. The biggest updates to this were related to cyber security, maintaining a feature rich website comes with its own set of risks. A security audit is performed regularly and this feeds directly into the code maintenance tasks to keep the portal secure. |
| URL | http://www.hecbiosim.ac.uk |
| Title | HECBioSim Web Portal |
| Description | The new web portal provides a clean and simple way for us to interact with our community. It serves as a single place in which members of the bio-simulation community can get access to all of the things we offer; whether this be finding out about/applying for time on ARCHER, downloading our software tools, getting support with using HPC or our software, this web portal provides users with a single and consistent point of entry to what we have to offer. Built into this portal are facilities fo |
| Type Of Technology | Webtool/Application |
| Year Produced | 2014 |
| Impact | The HECBioSim portal has been heavily utilised by a very broad spectrum of users. Since the website was installed in 2014 we have had just over 213,000 hits by 67,869 unique IP addresses. Users are making heavy use of the ARCHER application form, guidance material and the kAU calculator tool, suggesting that users are finding these tools helpful over the old word document by email application process. Other sections of the website seeing heavy use are the software download and the documentation |
| URL | http://www.hecbiosim.ac.uk |
| Title | HECBioSim kAU Calculator v1.0 |
| Description | The HECBioSim kAU calculator is a user friendly web application that provides a simple interface to the complex predictive scaling model derived from our benchmark studies of commonly used molecular dynamics codes on ARCHER. The basic premises of this tool are; To provide users of all abilities with real numbers of the notional costs of running molecular dynamics simulations on ARCHER with respect to information that is more familiar to the user such as number of atoms and simulation time etc. To provide a tool that the consortium can use to screen applications based on information given during the application process to assess the feasibility of a project achieving stated goals given the size of the resource request. This version of the software was the first public production release of the tool, it released with a smaller subset of the benchmarking data to start with (GROMACS and AMBER) so that the community could evaluate the accuracy of our model against their data. |
| Type Of Technology | Webtool/Application |
| Year Produced | 2015 |
| Impact | This tool has proved to be quite popular amongst the academic community, feedback from members of the community has been very positive for this tool with requests to expand to more codes being quite common. The tool has helped groups that do not have a traditional background in HPC to make sense of the often quite daunting application process for super computing time. Usage statistics from this tool suggest it has been utilised by 1,343 unique IP addresses globally and that users are likely to be making use of this tool for systems that are very similar to ARCHER. |
| URL | http://www.hecbiosim.ac.uk/applications/hectime-aucalculator |
| Title | HECBioSim kAU Calculator v1.1 |
| Description | The HECBioSim kAU calculator is a user friendly web application that provides a simple interface to the complex predictive scaling model derived from our benchmark studies of commonly used molecular dynamics codes on ARCHER. The basic premises of this tool are; To provide users of all abilities with real numbers of the notional costs of running molecular dynamics simulations on ARCHER with respect to information that is more familiar to the user such as number of atoms and simulation time etc. To provide a tool that the consortium can use to screen applications based on information given during the application process to assess the feasibility of a project achieving stated goals given the size of the resource request. Changes: This release focused on releasing the full data set (LAMMPS, NAMD and CHARMM). Cosmetic update to deal with browser changes (new edge browser). Security fixes. Small bug fixes. |
| Type Of Technology | Webtool/Application |
| Year Produced | 2015 |
| Impact | This tool has proved to be quite popular amongst the academic community, feedback from members of the community has been very positive for this tool with requests to expand to more codes being quite common. The tool has helped groups that do not have a traditional background in HPC to make sense of the often quite daunting application process for super computing time. Usage statistics from this tool suggest it has been utilised by 1,343 unique IP addresses globally and that users are likely to be making use of this tool for systems that are very similar to ARCHER. |
| URL | http://www.hecbiosim.ac.uk/applications/hectime-aucalculator |
| Title | HECBioSim kAU Calculator v1.2 |
| Description | The HECBioSim kAU calculator is a user friendly web application that provides a simple interface to the complex predictive scaling model derived from our benchmark studies of commonly used molecular dynamics codes on ARCHER. The basic premises of this tool are; To provide users of all abilities with real numbers of the notional costs of running molecular dynamics simulations on ARCHER with respect to information that is more familiar to the user such as number of atoms and simulation time etc. To provide a tool that the consortium can use to screen applications based on information given during the application process to assess the feasibility of a project achieving stated goals given the size of the resource request. |
| Type Of Technology | Webtool/Application |
| Year Produced | 2016 |
| Impact | This version release addressed problems that users of chrome and firefox browsers were having when trying to use the calculator. This version also patched a serious security vulnerability that would have allowed a malicious user to compromise the underlying server on which the HECBioSim portal is located. This tool has been heavily used by both users applying for time on ARCHER since its release, but also by the panel making the decisions on allocations. This tools has proved invaluable in getting better value out of the ARCHER time budget for the whole community. |
| URL | http://www.hecbiosim.ac.uk/applications/hectime-aucalculator |
| Title | Longbow 1.2.0 |
| Description | Longbow is a piece of software that acts as a job proxying tool for biomolecular simulations, Longbow reproduces the native look and feel of using popular molecular dynamics packages (AMBER, CHARMM, GROMACS, LAMMPS and NAMD), with the difference that when those packages are used through Longbow simulations can be run on High Performance Computing (HPC) resources such as ARCHER. Longbow handles jobs setup in terms of creating job submission scripts, automatically stages input files, launches and monitors jobs and stages back simulation results. The option is also there to persistently monitor and stage (realtime local syncing with remote simulation files) simulation files at a specified time interval. This is designed to have the jobs running on the HPC remote resource appear to the user as if the simulation has run on their local computer/cluster. Users do not have to concern themselves with writing submission files, nor do they have to worry about staging. Longbow provides a convenient interface for generating large ensembles of simulation jobs which in effect extends the packages it supports. |
| Type Of Technology | Software |
| Year Produced | 2016 |
| Open Source License? | Yes |
| Impact | Longbow has now been downloaded 1,266 times from the HECBioSim website and tens of thousands of times from the pypi directory (March 2017). It has a wide reaching user-base across the world, some of those users being at 24 UK institutions actively downloading new versions as they are released. This version was released to introduce new functionality in the form of restarts, this enabled users to be able to disconnect and reconnect thus eliminating the need to be always connected. Queue limits are now also automatically detected and Longbow can maintain its own local queues for jobs, allowing a much more powerful way to submit jobs to machines with extreme limitations. This release was really aimed at boosting the productivity gains realised by utilising Longbow. |
| URL | http://www.hecbiosim.ac.uk/longbow |
| Title | Longbow v1.0.0 |
| Description | Longbow is a piece of software that acts as a job proxying tool for biomolecular simulations, Longbow reproduces the native look and feel of using popular molecular dynamics packages (AMBER, CHARMM, GROMACS, LAMMPS and NAMD), with the difference that when those packages are used through Longbow simulations can be run on High Performance Computing (HPC) resources such as ARCHER. Longbow handles jobs setup in terms of creating job submission scripts, automatically stages input files, launches and monitors jobs and stages back simulation results. The option is also there to persistently monitor and stage (realtime local syncing with remote simulation files) simulation files at a specified time interval. This is designed to have the jobs running on the HPC remote resource appear to the user as if the simulation has run on their local computer/cluster. Users do not have to concern themselves with writing submission files, nor do they have to worry about staging. Longbow provides a convenient interface for generating large ensembles of simulation jobs which in effect extends the packages it supports. This version was the first public release of Longbow after an extended period of closed alpha and beta testing. |
| Type Of Technology | Software |
| Year Produced | 2015 |
| Open Source License? | Yes |
| Impact | Since the release of the first version of Longbow, there have been just over 400 verified unique downloads between the HECBioSim download repository and the Python PyPi index. The active user-base includes users from both academic (21 different institutions in the UK) and the industrial sector globally. Longbow has also been or is currently being incorporated into software pipelines of other groups/consortia, projects of notable progress include integrating with FLEX-EM a powerful tool developed by CCP-EM and FESetup developed by CCPBioSim. The Longbow project led to a collaboration with pharmaceutical company UCB into integration of Longbow into their workflow, this also led to a feasibility study into the construction of a similar tool for commercial cloud services such as Amazon EC2 or Microsoft Azure. |
| URL | http://www.hecbiosim.ac.uk/longbow |
| Title | Longbow v1.0.1 |
| Description | Longbow is a piece of software that acts as a job proxying tool for biomolecular simulations, Longbow reproduces the native look and feel of using popular molecular dynamics packages (AMBER, CHARMM, GROMACS, LAMMPS and NAMD), with the difference that when those packages are used through Longbow simulations can be run on High Performance Computing (HPC) resources such as ARCHER. Longbow handles jobs setup in terms of creating job submission scripts, automatically stages input files, launches and monitors jobs and stages back simulation results. The option is also there to persistently monitor and stage (realtime local syncing with remote simulation files) simulation files at a specified time interval. This is designed to have the jobs running on the HPC remote resource appear to the user as if the simulation has run on their local computer/cluster. Users do not have to concern themselves with writing submission files, nor do they have to worry about staging. Longbow provides a convenient interface for generating large ensembles of simulation jobs which in effect extends the packages it supports. Changes: 1. longbow commands now have a well defined format of: longbow [longbow arguments] executable [executableargs]. 2. The parameter hierarchy has changed such that now parameters provided on the Longbow command line will overrule the same parameters in configuration files. 3. The -stage longbow argument is no longer supported as Longbow will automatically detect additional input files. 4. The rsync --include and --exclude have been exposed so that users can mask out files they do not need. These are separated into upload and downloads by using the following parameters; upload-include, upload-exclude, download-include and download-exclude. Only the download variants are available to the user (upload variants are used internally within Longbow but developers can make use of them in the API). 5. For replicate jobs, the order in which Longbow will search for input files has changed such that it looks in the repX subdirectories before the current working directory. 6. The batch parameter has been renamed replicates. 7. The commandline parameter has been renamed executableargs. 8. The parameters replicates (formerly batch) and jobname can now be provided on the Longbow command line as longbow arguments. 9. jobname is an exception as it is the only parameter that cannot overrule the jobname provided in the job configuration file. 10. LongbowExamples is now downloaded to the current working directory rather than the home directory when downloaded using longbow -examples. Jobs now run on the remote resource in /remoteworkdir/jobnameXXXXX where XXXXX represents a random 5-digit number. This is to prevent jobs with the same jobname clashing on the remote resource. Bugs have been fixed such that jobs will run on remote resources that use the SGE_ARC2 scheduler. Four Gromacs executables are now supported: mdrun, mdrun_d, mdrun_mpi, mdrun_mpi_d The hosts configuration file and LongbowExamples will now be downloaded using curl for those who do not have wget. |
| Type Of Technology | Software |
| Year Produced | 2015 |
| Open Source License? | Yes |
| Impact | Since the release of the first version of Longbow, there have been just over 400 verified unique downloads between the HECBioSim download repository and the Python PyPi index. The active user-base includes users from both academic (21 different institutions in the UK) and the industrial sector globally. Longbow has also been or is currently being incorporated into software pipelines of other groups/consortia, projects of notable progress include integrating with FLEX-EM a powerful tool developed by CCP-EM and FESetup developed by CCPBioSim. The Longbow project led to a collaboration with pharmaceutical company UCB into integration of Longbow into their workflow, this also led to a feasibility study into the construction of a similar tool for commercial cloud services such as Amazon EC2 or Microsoft Azure. |
| URL | http://www.hecbiosim.ac.uk/longbow |
| Title | Longbow v1.1.0 |
| Description | Longbow is a piece of software that acts as a job proxying tool for biomolecular simulations, Longbow reproduces the native look and feel of using popular molecular dynamics packages (AMBER, CHARMM, GROMACS, LAMMPS and NAMD), with the difference that when those packages are used through Longbow simulations can be run on High Performance Computing (HPC) resources such as ARCHER. Longbow handles jobs setup in terms of creating job submission scripts, automatically stages input files, launches and monitors jobs and stages back simulation results. The option is also there to persistently monitor and stage (realtime local syncing with remote simulation files) simulation files at a specified time interval. This is designed to have the jobs running on the HPC remote resource appear to the user as if the simulation has run on their local computer/cluster. Users do not have to concern themselves with writing submission files, nor do they have to worry about staging. Longbow provides a convenient interface for generating large ensembles of simulation jobs which in effect extends the packages it supports. Changes: 1. Fix for overwritten rsync-includes (developers only). 2. Bad character length on PBS now has an error message to inform the user what went wrong. Job names longer than 15 chars would be rejected. 3. Jobs that failed in a multi job would bring down the whole lot due to a bad initialisation now fixed. 4. Command line Longbow is submitted with is now logged to the log file for debugging purposes. 5. Bug fix with a bad initialisation in job processing code. 6. New ini parsers that don't rely on python std lib parser, this means comments are no longer deleted. 7. The following methods; loadhosts(), loadjobs(), sortjobsconfigs(), sorthostsconfigs(), amendjobsconfigs() have been replaced with single method processconfigs() 8. Fix for critical failure when the remoteworkdir did not exist |
| Type Of Technology | Software |
| Year Produced | 2015 |
| Open Source License? | Yes |
| Impact | Since the release of the first version of Longbow, there have been just over 400 verified unique downloads between the HECBioSim download repository and the Python PyPi index. The active user-base includes users from both academic (21 different institutions in the UK) and the industrial sector globally. Longbow has also been or is currently being incorporated into software pipelines of other groups/consortia, projects of notable progress include integrating with FLEX-EM a powerful tool developed by CCP-EM and FESetup developed by CCPBioSim. The Longbow project led to a collaboration with pharmaceutical company UCB into integration of Longbow into their workflow, this also led to a feasibility study into the construction of a similar tool for commercial cloud services such as Amazon EC2 or Microsoft Azure. |
| URL | http://www.hecbiosim.ac.uk/longbow |
| Title | Longbow v1.1.1 |
| Description | Longbow is a piece of software that acts as a job proxying tool for biomolecular simulations, Longbow reproduces the native look and feel of using popular molecular dynamics packages (AMBER, CHARMM, GROMACS, LAMMPS and NAMD), with the difference that when those packages are used through Longbow simulations can be run on High Performance Computing (HPC) resources such as ARCHER. Longbow handles jobs setup in terms of creating job submission scripts, automatically stages input files, launches and monitors jobs and stages back simulation results. The option is also there to persistently monitor and stage (realtime local syncing with remote simulation files) simulation files at a specified time interval. This is designed to have the jobs running on the HPC remote resource appear to the user as if the simulation has run on their local computer/cluster. Users do not have to concern themselves with writing submission files, nor do they have to worry about staging. Longbow provides a convenient interface for generating large ensembles of simulation jobs which in effect extends the packages it supports. Changes: 1. Modifications to how Longbow accepts the help and version command line parameters, some people don't follow GNU standards and thus so that we can show them the help message/version we have allowed -v, -version, --version, -h, -help and --help 2. Longbow now creates missing repX directories if they are missing in cases where all input files are global. This would allow jobs that might use different random seeds on the same input files to be efficient on transfers. |
| Type Of Technology | Software |
| Year Produced | 2015 |
| Open Source License? | Yes |
| Impact | Since the release of the first version of Longbow, there have been just over 400 verified unique downloads between the HECBioSim download repository and the Python PyPi index. The active user-base includes users from both academic (21 different institutions in the UK) and the industrial sector globally. Longbow has also been or is currently being incorporated into software pipelines of other groups/consortia, projects of notable progress include integrating with FLEX-EM a powerful tool developed by CCP-EM and FESetup developed by CCPBioSim. The Longbow project led to a collaboration with pharmaceutical company UCB into integration of Longbow into their workflow, this also led to a feasibility study into the construction of a similar tool for commercial cloud services such as Amazon EC2 or Microsoft Azure. |
| URL | http://www.hecbiosim.ac.uk/longbow |
| Title | Longbow v1.1.3 |
| Description | Longbow is a piece of software that acts as a job proxying tool for biomolecular simulations, Longbow reproduces the native look and feel of using popular molecular dynamics packages (AMBER, CHARMM, GROMACS, LAMMPS and NAMD), with the difference that when those packages are used through Longbow simulations can be run on High Performance Computing (HPC) resources such as ARCHER. Longbow handles jobs setup in terms of creating job submission scripts, automatically stages input files, launches and monitors jobs and stages back simulation results. The option is also there to persistently monitor and stage (realtime local syncing with remote simulation files) simulation files at a specified time interval. This is designed to have the jobs running on the HPC remote resource appear to the user as if the simulation has run on their local computer/cluster. Users do not have to concern themselves with writing submission files, nor do they have to worry about staging. Longbow provides a convenient interface for generating large ensembles of simulation jobs which in effect extends the packages it supports. Changes: 1. Update to the supported command line arguments to support non and GNU standard options for help and version number. 2. Update to allow the creation of repX directories when they are missing (Stops gromacs etc from exiting with path not found error) 3. Fix for bugs in python 3, there were two issues, one a python name change and the second was due to garbled output coming from the linux shell environment. |
| Type Of Technology | Software |
| Year Produced | 2015 |
| Open Source License? | Yes |
| Impact | Since the release of the first version of Longbow, there have been just over 400 verified unique downloads between the HECBioSim download repository and the Python PyPi index. The active user-base includes users from both academic (21 different institutions in the UK) and the industrial sector globally. Longbow has also been or is currently being incorporated into software pipelines of other groups/consortia, projects of notable progress include integrating with FLEX-EM a powerful tool developed by CCP-EM and FESetup developed by CCPBioSim. The Longbow project led to a collaboration with pharmaceutical company UCB into integration of Longbow into their workflow, this also led to a feasibility study into the construction of a similar tool for commercial cloud services such as Amazon EC2 or Microsoft Azure. |
| URL | http://www.hecbiosim.ac.uk/longbow |
| Title | Longbow v1.1.4 |
| Description | Longbow is a piece of software that acts as a job proxying tool for biomolecular simulations, Longbow reproduces the native look and feel of using popular molecular dynamics packages (AMBER, CHARMM, GROMACS, LAMMPS and NAMD), with the difference that when those packages are used through Longbow simulations can be run on High Performance Computing (HPC) resources such as ARCHER. Longbow handles jobs setup in terms of creating job submission scripts, automatically stages input files, launches and monitors jobs and stages back simulation results. The option is also there to persistently monitor and stage (realtime local syncing with remote simulation files) simulation files at a specified time interval. This is designed to have the jobs running on the HPC remote resource appear to the user as if the simulation has run on their local computer/cluster. Users do not have to concern themselves with writing submission files, nor do they have to worry about staging. Longbow provides a convenient interface for generating large ensembles of simulation jobs which in effect extends the packages it supports. Changes: 1. Fix for issue #114 - The saveconfigs method would overwrite entries within the hosts config with potentially blank entries if it was triggered and parameters existed in such a state (perhaps via overrides). 2. Fix for issue #113 - There was a missing clause on one of the if statements that prevented parameters at the hosts level from overriding internal defaults. This has now been added in. |
| Type Of Technology | Software |
| Year Produced | 2015 |
| Open Source License? | Yes |
| Impact | Since the release of the first version of Longbow, there have been just over 400 verified unique downloads between the HECBioSim download repository and the Python PyPi index. The active user-base includes users from both academic (21 different institutions in the UK) and the industrial sector globally. Longbow has also been or is currently being incorporated into software pipelines of other groups/consortia, projects of notable progress include integrating with FLEX-EM a powerful tool developed by CCP-EM and FESetup developed by CCPBioSim. The Longbow project led to a collaboration with pharmaceutical company UCB into integration of Longbow into their workflow, this also led to a feasibility study into the construction of a similar tool for commercial cloud services such as Amazon EC2 or Microsoft Azure. |
| URL | http://www.hecbiosim.ac.uk/longbow |
| Title | Longbow v1.1.5 |
| Description | Longbow is a piece of software that acts as a job proxying tool for biomolecular simulations, Longbow reproduces the native look and feel of using popular molecular dynamics packages (AMBER, CHARMM, GROMACS, LAMMPS and NAMD), with the difference that when those packages are used through Longbow simulations can be run on High Performance Computing (HPC) resources such as ARCHER. Longbow handles jobs setup in terms of creating job submission scripts, automatically stages input files, launches and monitors jobs and stages back simulation results. The option is also there to persistently monitor and stage (realtime local syncing with remote simulation files) simulation files at a specified time interval. This is designed to have the jobs running on the HPC remote resource appear to the user as if the simulation has run on their local computer/cluster. Users do not have to concern themselves with writing submission files, nor do they have to worry about staging. Longbow provides a convenient interface for generating large ensembles of simulation jobs which in effect extends the packages it supports. Changes: Fix for issue #117 - Python 3 and pip bug: 1. Longbow would not install under python 3 using either pip or by running the setup script manually. This has now been fixed by using print statements of the format print("text"), this form will work in all versions of python. Fix for issue #116 - User reported annoyances: 1. Fix for user reported annoyance of installing the hosts.conf in secret, and also leaving the archive that is downloaded in $home. This has now been replaced with a warning during install, and also the file is created locally and not downloaded. 2. Removed padding from version numbers so v1.01.005 > v1.1.5 3. Changed the README.md from markdown format to reStructured text, so now the README is README.rst, this is to make Longbow more pip friendly whilst still being bitbucket and possibly github (in case in future we move). 4. setup.py modified to eliminate the python 3 issues, and also the long description is now the README.rst, this means that users will see something standard between the pip page and the bitbucket page, this will also tie in with new pages on the HECBioSim website which will push pip as the preferred way to install more prominently. 5. hosts.conf file has been removed from the development version since this is now created on install for new users using pip, this will be marked as deprecated on the website for a while so users on old versions can still get it. Documentation will need to be updated to reflect this change and provide the quickstart example that users can grab a copy of if they are doing a more manual install. However pip will be the encouraged way to install. Issue #115 - Parameters in input files: Parameters specified within the configuration files had to be specified in a very strict format (param = value), users that omitted the spaces would find that Longbow would crash. The code has now been fixed to use regular expression to read in and parse for the equals sign, this can now handle cases where users specify cases such as: param1 = value1 param2 =value2 param3= value3 param4=value4 Minor edits: Added python version to logging added longbow version to logging moved version to the top of the longbow file added the paper citation to the logging and readme |
| Type Of Technology | Software |
| Year Produced | 2016 |
| Open Source License? | Yes |
| Impact | Since the release of the first version of Longbow, there have been just over 400 verified unique downloads between the HECBioSim download repository and the Python PyPi index. The active user-base includes users from both academic (21 different institutions in the UK) and the industrial sector globally. Longbow has also been or is currently being incorporated into software pipelines of other groups/consortia, projects of notable progress include integrating with FLEX-EM a powerful tool developed by CCP-EM and FESetup developed by CCPBioSim. The Longbow project led to a collaboration with pharmaceutical company UCB into integration of Longbow into their workflow, this also led to a feasibility study into the construction of a similar tool for commercial cloud services such as Amazon EC2 or Microsoft Azure. |
| URL | http://www.hecbiosim.ac.uk/longbow |
| Title | Longbow v1.2.1 |
| Description | Longbow is a piece of software that acts as a job proxying tool for biomolecular simulations, Longbow reproduces the native look and feel of using popular molecular dynamics packages (AMBER, CHARMM, GROMACS, LAMMPS and NAMD), with the difference that when those packages are used through Longbow simulations can be run on High Performance Computing (HPC) resources such as ARCHER. Longbow handles jobs setup in terms of creating job submission scripts, automatically stages input files, launches and monitors jobs and stages back simulation results. The option is also there to persistently monitor and stage (realtime local syncing with remote simulation files) simulation files at a specified time interval. This is designed to have the jobs running on the HPC remote resource appear to the user as if the simulation has run on their local computer/cluster. Users do not have to concern themselves with writing submission files, nor do they have to worry about staging. Longbow provides a convenient interface for generating large ensembles of simulation jobs which in effect extends the packages it supports. |
| Type Of Technology | Software |
| Year Produced | 2016 |
| Open Source License? | Yes |
| Impact | Longbow has now been downloaded 1,266 times from the HECBioSim website and tens of thousands of times from the pypi directory (March 2017). It has a wide reaching user-base across the world, some of those users being at 24 UK institutions actively downloading new versions as they are released. This version was released to address complexities that were introduced in the previous release surrounding the creation of restart files. A new intuitive naming regimen was implemented based on user feedback. |
| URL | http://www.hecbiosim.ac.uk/longbow |
| Title | Longbow v1.3.0 |
| Description | Longbow is a piece of software that acts as a job proxying tool for biomolecular simulations, Longbow reproduces the native look and feel of using popular molecular dynamics packages (AMBER, CHARMM, GROMACS, LAMMPS and NAMD), with the difference that when those packages are used through Longbow simulations can be run on High Performance Computing (HPC) resources such as ARCHER. Longbow handles jobs setup in terms of creating job submission scripts, automatically stages input files, launches and monitors jobs and stages back simulation results. The option is also there to persistently monitor and stage (realtime local syncing with remote simulation files) simulation files at a specified time interval. This is designed to have the jobs running on the HPC remote resource appear to the user as if the simulation has run on their local computer/cluster. Users do not have to concern themselves with writing submission files, nor do they have to worry about staging. Longbow provides a convenient interface for generating large ensembles of simulation jobs which in effect extends the packages it supports. |
| Type Of Technology | Software |
| Year Produced | 2016 |
| Open Source License? | Yes |
| Impact | Longbow has now been downloaded 1,266 times from the HECBioSim website and tens of thousands of times from the pypi directory (March 2017). It has a wide reaching user-base across the world, some of those users being at 24 UK institutions actively downloading new versions as they are released. This release focused on bug fixes but there was also a new feature. User feedback showed that naming conventions for commonly used molecular dynamics packages were changing, this was added to Longbow for out of the box support. Bugs in the recovery feature were fixed and some bugs with automatic file staging were fixed. A new fire and forget mode was introduced, so users could use Longbow in launcher mode and not have to use the monitoring features, they can then use the recovery feature to get access to their files in an automated way. |
| URL | http://www.hecbiosim.ac.uk/longbow |
| Title | Longbow v1.3.1 |
| Description | Longbow is a piece of software that acts as a job proxying tool for biomolecular simulations, Longbow reproduces the native look and feel of using popular molecular dynamics packages (AMBER, CHARMM, GROMACS, LAMMPS and NAMD), with the difference that when those packages are used through Longbow simulations can be run on High Performance Computing (HPC) resources such as ARCHER. Longbow handles jobs setup in terms of creating job submission scripts, automatically stages input files, launches and monitors jobs and stages back simulation results. The option is also there to persistently monitor and stage (realtime local syncing with remote simulation files) simulation files at a specified time interval. This is designed to have the jobs running on the HPC remote resource appear to the user as if the simulation has run on their local computer/cluster. Users do not have to concern themselves with writing submission files, nor do they have to worry about staging. Longbow provides a convenient interface for generating large ensembles of simulation jobs which in effect extends the packages it supports. |
| Type Of Technology | Software |
| Year Produced | 2016 |
| Open Source License? | Yes |
| Impact | Longbow has now been downloaded 1,266 times from the HECBioSim website and tens of thousands of times from the pypi directory (March 2017). It has a wide reaching user-base across the world, some of those users being at 24 UK institutions actively downloading new versions as they are released. This was another dual release fixing bugs and introducing new features. User reported bugs on machines running SGE with GPUs have been fixed. A problem with premature exiting and an error with some configuration files were fixed. A new feature was implemented allowing pre-launch scripts to be called server-side enabling quite powerful workflows or analysis tools to be used. |
| URL | http://www.hecbiosim.ac.uk/longbow |
| Title | Longbow v1.3.2 |
| Description | Longbow is a piece of software that acts as a job proxying tool for biomolecular simulations, Longbow reproduces the native look and feel of using popular molecular dynamics packages (AMBER, CHARMM, GROMACS, LAMMPS and NAMD), with the difference that when those packages are used through Longbow simulations can be run on High Performance Computing (HPC) resources such as ARCHER. Longbow handles jobs setup in terms of creating job submission scripts, automatically stages input files, launches and monitors jobs and stages back simulation results. The option is also there to persistently monitor and stage (realtime local syncing with remote simulation files) simulation files at a specified time interval. This is designed to have the jobs running on the HPC remote resource appear to the user as if the simulation has run on their local computer/cluster. Users do not have to concern themselves with writing submission files, nor do they have to worry about staging. Longbow provides a convenient interface for generating large ensembles of simulation jobs which in effect extends the packages it supports. |
| Type Of Technology | Software |
| Year Produced | 2016 |
| Open Source License? | Yes |
| Impact | Longbow has now been downloaded 1,266 times from the HECBioSim website and tens of thousands of times from the pypi directory (March 2017). It has a wide reaching user-base across the world, some of those users being at 24 UK institutions actively downloading new versions as they are released. This was mainly a bug fix release to address a number of user reported problems. |
| URL | http://www.hecbiosim.ac.uk/longbow |
| Title | Longbow v1.4 |
| Description | Longbow is a piece of software that acts as a job proxying tool for biomolecular simulations, Longbow reproduces the native look and feel of using popular molecular dynamics packages (AMBER, CHARMM, GROMACS, LAMMPS and NAMD), with the difference that when those packages are used through Longbow simulations can be run on High Performance Computing (HPC) resources such as ARCHER. Longbow handles jobs setup in terms of creating job submission scripts, automatically stages input files, launches and monitors jobs and stages back simulation results. The option is also there to persistently monitor and stage (realtime local syncing with remote simulation files) simulation files at a specified time interval. This is designed to have the jobs running on the HPC remote resource appear to the user as if the simulation has run on their local computer/cluster. Users do not have to concern themselves with writing submission files, nor do they have to worry about staging. Longbow provides a convenient interface for generating large ensembles of simulation jobs which in effect extends the packages it supports. |
| Type Of Technology | Software |
| Year Produced | 2017 |
| Open Source License? | Yes |
| Impact | Longbow has now been downloaded 1,266 times from the HECBioSim website and tens of thousands of times from the pypi directory (March 2017). It has a wide reaching user-base across the world, some of those users being at 24 UK institutions actively downloading new versions as they are released. This version was a major new release which focused on addressing a number of architectural problems, this required major refactoring of the code base. In this release a move to continuous integration by making use of cloud services such as Travis (Testing), Landscape (Quality) and Coveralls (Coverage) was performed, this required writing of more than 600 unit tests based on the code refactors done on this version. The shift towards continuous integration should help to improve the quality of the software, help make development more collaborative, and also increase sustainability. Several new features were introduced and numerous bugs found during automated testing were fixed. |
| URL | http://www.hecbiosim.ac.uk/longbow |
| Title | Longbow v1.5 |
| Description | Longbow is a piece of software that acts as a job proxying tool for biomolecular simulations, Longbow reproduces the native look and feel of using popular molecular dynamics packages (AMBER, CHARMM, GROMACS, LAMMPS and NAMD), with the difference that when those packages are used through Longbow simulations can be run on High Performance Computing (HPC) resources such as ARCHER. Longbow handles jobs setup in terms of creating job submission scripts, automatically stages input files, launches and monitors jobs and stages back simulation results. The option is also there to persistently monitor and stage (realtime local syncing with remote simulation files) simulation files at a specified time interval. This is designed to have the jobs running on the HPC remote resource appear to the user as if the simulation has run on their local computer/cluster. Users do not have to concern themselves with writing submission files, nor do they have to worry about staging. Longbow provides a convenient interface for generating large ensembles of simulation jobs which in effect extends the packages it supports. |
| Type Of Technology | Software |
| Year Produced | 2017 |
| Open Source License? | Yes |
| Impact | Longbow has now been downloaded 1,523 times from the HECBioSim website and tens of thousands of times from the pypi directory (July 2017). It has a wide reaching user-base across the world, some of those users being at 26 UK institutions actively downloading new versions as they are released. This version was a major new release which focused on addressing a number of architectural problems, this required major refactoring of the code base. This version fixed a number of community reported bugs and added user requested new functionality. Support for the latest python 3 version was added and the API restructured to simplify uptake in other projects. |
| URL | https://github.com/HECBioSim/Longbow/releases/tag/v1.5.0 |
| Title | Longbow v1.5.0 |
| Description | Longbow is an automated simulation submission and monitoring tool. Longbow is designed to reproduce the look and feel of using software on the users local computer with the difference that the heavy lifting is done by a supercomputer. Longbow will automatically generate the necessary submit files and handle all initial file transfer, monitor jobs, transfer files at configurable intervals and perform final file transfer and cleanup. Longbow can be used to launch one-off jobs, generate ensembles of similar jobs or even run many different jobs over many different supercomputers. Out of the box, Longbow is currently supporting the PBS/Torque, LSF, SGE, Slurm, SoGE schedulers and ships with application plugins for commonly used bio-molecular simulation softwares AMBER, CHARMM, GROMACS, LAMMPS, NAMD. Longbow is however highly configurable and will function normally with generic software without plugins, however plugins can easily be made to extend Longbow to fully support applications and schedulers that do not ship out of the box. Longbow is also available to developers of applications which require support for automating job submission. Longbow is available as a convenient and light-weight python API that can be integrated in a number of different way. |
| Type Of Technology | Software |
| Year Produced | 2018 |
| Open Source License? | Yes |
| Impact | Longbow has been downloaded by 6,211 times world wide by researchers doing biomolecular simulation. Longbow simplifies the transfer, preparation and submission of simulations across a wide range of HPC architectures. Users at the beginner end of the spectrum can quickly be up and running on any HPC resource within minutes without having to learn much about the process of doing it. Power users can leverage the power of Longbow in generating huge arrays of simulations and have it fire and bring back results across multiple machines that they have access to. It is a tool mainly aimed at taking the pain out of HPC by automating the time consuming tedious tasks associated with doing it at scale. |
| URL | http://www.hecbiosim.ac.uk/longbow |
| Title | Longbow v1.5.1 |
| Description | Longbow is an automated simulation submission and monitoring tool. Longbow is designed to reproduce the look and feel of using software on the users local computer with the difference that the heavy lifting is done by a supercomputer. Longbow will automatically generate the necessary submit files and handle all initial file transfer, monitor jobs, transfer files at configurable intervals and perform final file transfer and cleanup. Longbow can be used to launch one-off jobs, generate ensembles of similar jobs or even run many different jobs over many different supercomputers. Out of the box, Longbow is currently supporting the PBS/Torque, LSF, SGE, Slurm, SoGE schedulers and ships with application plugins for commonly used bio-molecular simulation softwares AMBER, CHARMM, GROMACS, LAMMPS, NAMD. Longbow is however highly configurable and will function normally with generic software without plugins, however plugins can easily be made to extend Longbow to fully support applications and schedulers that do not ship out of the box. Longbow is also available to developers of applications which require support for automating job submission. Longbow is available as a convenient and light-weight python API that can be integrated in a number of different way. |
| Type Of Technology | Software |
| Year Produced | 2019 |
| Open Source License? | Yes |
| Impact | Longbow has been downloaded by 7,542 times world wide by researchers doing biomolecular simulation. Longbow simplifies the transfer, preparation and submission of simulations across a wide range of HPC architectures. Users at the beginner end of the spectrum can quickly be up and running on any HPC resource within minutes without having to learn much about the process of doing it. Power users can leverage the power of Longbow in generating huge arrays of simulations and have it fire and bring back results across multiple machines that they have access to. It is a tool mainly aimed at taking the pain out of HPC by automating the time consuming tedious tasks associated with doing it at scale. |
| URL | http://www.hecbiosim.ac.uk/longbow |
| Title | Longbow v1.5.2 |
| Description | Longbow is an automated simulation submission and monitoring tool. Longbow is designed to reproduce the look and feel of using software on the users local computer with the difference that the heavy lifting is done by a supercomputer. Longbow will automatically generate the necessary submit files and handle all initial file transfer, monitor jobs, transfer files at configurable intervals and perform final file transfer and cleanup. Longbow can be used to launch one-off jobs, generate ensembles of similar jobs or even run many different jobs over many different supercomputers. Out of the box, Longbow is currently supporting the PBS/Torque, LSF, SGE, Slurm, SoGE schedulers and ships with application plugins for commonly used bio-molecular simulation softwares AMBER, CHARMM, GROMACS, LAMMPS, NAMD. Longbow is however highly configurable and will function normally with generic software without plugins, however plugins can easily be made to extend Longbow to fully support applications and schedulers that do not ship out of the box. Longbow is also available to developers of applications which require support for automating job submission. Longbow is available as a convenient and light-weight python API that can be integrated in a number of different way. |
| Type Of Technology | Software |
| Year Produced | 2019 |
| Open Source License? | Yes |
| Impact | Longbow has been downloaded by 8,695 times world wide by researchers doing biomolecular simulation. Longbow simplifies the transfer, preparation and submission of simulations across a wide range of HPC architectures. Users at the beginner end of the spectrum can quickly be up and running on any HPC resource within minutes without having to learn much about the process of doing it. Power users can leverage the power of Longbow in generating huge arrays of simulations and have it fire and bring back results across multiple machines that they have access to. It is a tool mainly aimed at taking the pain out of HPC by automating the time consuming tedious tasks associated with doing it at scale. |
| URL | https://www.hecbiosim.ac.uk/downloads |
| Title | OpenMMSLICER |
| Description | scientific software for sequential monte carlo simulations in openmm |
| Type Of Technology | Software |
| Year Produced | 2022 |
| Impact | This software has been further developed for simulated tempering and is being used for new research projects |
| URL | https://github.com/openmmslicer/openmmslicer |
| Title | ProtoCaller |
| Description | Software to automate the setup of free energy calculations |
| Type Of Technology | Software |
| Year Produced | 2020 |
| Open Source License? | Yes |
| Impact | non yet |
| URL | https://protocaller.readthedocs.io/en/latest/index.html |
| Title | Software - Crossflow |
| Description | Crossflow is a Python framework for writing computational workflows for execution on distributed computing facilities. |
| Type Of Technology | Software |
| Year Produced | 2020 |
| Open Source License? | Yes |
| Impact | The software is currently being evaluated by UCB for use in their drug discovery activities |
| URL | http://bitbucket.org/claughton/crossflow.git |
| Title | WaterDock |
| Description | A software to predict the location of water molecules in proteins. |
| Type Of Technology | Software |
| Year Produced | 2016 |
| Open Source License? | Yes |
| Impact | N/A |
| URL | https://github.com/bigginlab/WaterDock-2.0 |
| Description | 6th Molecular Microbiology Meeting |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | I attended this conference and I gave a talk with the purpose of engaging with microbiologists on multidisciplinary exchange of knowledge |
| Year(s) Of Engagement Activity | 2019 |
| URL | https://conferences.ncl.ac.uk/molmicro2019/ |
| Description | Advanced technology to support research, innovation and economic growth in the UK |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Policymakers/politicians |
| Results and Impact | Reform hosted a policy roundtable on the opportunities for advanced technology in the UK in May 2019, with the kind support of Hewlett Packard Enterprise. The session was introduced by Chris Skidmore MP, then Minister of State for Universities, Science, Research and Innovation, and Professor Mark Parsons, Director at the Edinburgh Parallel Computing Centre. The Minister stressed the importance of international collaboration in R&D, reaffirming the UK's ambition to strengthen and enrich existing partnerships, as well as to develop new global partnerships - as outlined in the then recently announced International Research & Innovation Strategy. The discussion also focused on the opportunities the upcoming Comprehensive Spending Review would offer to the science, research and innovation sectors, and on the need to build a strong case for. investment in emerging technologies - including quantum technology, performance computing (HPC) and robotics. During this meeting it was highlighted that High-performance computing is considered a game-changing technology, which will be fundamental to the UK's ability to maintain its global competitiveness in the science, research and innovation sectors. |
| Year(s) Of Engagement Activity | 2019 |
| URL | https://reform.uk/research/advanced-technology-support-research-innovation-and-economic-growth-uk |
| Description | Alchemistry in Boston 2018 - Bluck and Biggin |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | A poster was presented on free energy calculations and received useful feedback. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Astbury Conversation - Introduction to HECBioSim and Longbow vendor stall |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Professional Practitioners |
| Results and Impact | HECBioSim had an exhibitor stand with access to information leaflets, a laptop with demonstration software and one of our software engineering and performance experts manning the stand. The audience was generally experimental and practical life sciences with an interest in simulation. We focused on what HECBioSim did and what resources they could apply for through us, what advice was available and how to access it. Longbow demonstrations were quite popular as this enabled non-experts in computation to run powerful simulations without them having to master another discipline. We had a large number of follow-up queries for information, and some of the individuals later attended our other training events. |
| Year(s) Of Engagement Activity | 2018 |
| URL | https://eps.leeds.ac.uk/chemistry/news/article/147/the-astbury-conversation-16-17-april-2018 |
| Description | Banff International Research Station for Mathematical Innovation and Discovery: "The Topology of Nucleic Acids" |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Invited talk that has been made accessible online |
| Year(s) Of Engagement Activity | 2019 |
| URL | https://www.birs.ca/events/2019/5-day-workshops/19w5226 |
| Description | CCPBioSim Training Week - Day 2: Running and analysing MD simulations |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Postgraduate students |
| Results and Impact | As part of the second day of the CCPBioSim training week workshop, users new to molecular dynamics were given a hands on introduction to how to setup up basic simulations through to how to analyse the results. In the second session of this day, Longbow was introduced with the aim of demonstrating how to move from running a small number of simulations to farming out hundreds if not thousands of simulations in one go. Users were introduced to the concepts surrounding simulation automation before moving onto hands on demonstration of the technology. Afterwards discussions with a number of the delegates revealed that they found the tool very useful and were planning on utilising it within their research to increase productivity. When asked if they would spread the word to their colleagues, all said they intended to. |
| Year(s) Of Engagement Activity | 2016 |
| URL | http://www.ccpbiosim.ac.uk/training-week-day2 |
| Description | Conference paper at Physics in Food manufacturing event, Chipping Campden, January 2019. |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Professional Practitioners |
| Results and Impact | Workshop organised by the Institute of Physics food group. Allowed networking with physicists/physical chemists with similar intersts in food science. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Conference paper on Food Oleogels at EFFost conference November 2018 in Nantes France |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Discussion were held with industrial (and academic) scientists who were interested in the finding of the work.The computational approaches used were of particular interests to academics and this has fostered new interactions with potential academic collaborators. |
| Year(s) Of Engagement Activity | 2018 |
| Description | EUTOPIA-2: 2 nd meeting of the European Topology interdisciplinary Initiative |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Invited talk and enroll at this EU-funded COST network |
| Year(s) Of Engagement Activity | 2019 |
| URL | https://eutopiaam2019.wordpress.com |
| Description | Exhibitor Stand at CCP5 & CCPBioSim multiscale meeting |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Postgraduate students |
| Results and Impact | HECBioSim had an exhibitor stand at the conference where we ran had information leaflets available about what HECBioSim is and does. We ran software demonstrations, in particular Longbow and Xbow. We also engaged with students on HPC and gave advice about performance and HPC. |
| Year(s) Of Engagement Activity | 2018 |
| URL | https://www.ccpbiosim.ac.uk/events/past-conferences/eventdetail/106/-/3rd-conference-on-multiscale-m... |
| Description | HECBioSim: tools to simplify running and analysing large-scale MD simulations on HPC resources |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Postgraduate students |
| Results and Impact | This workshop was to introduce members of the bio-simulation community to tools that simplify the process of running and analysing MD simulations on a large scale. Users were introduced to consortia developed tools (Longbow pyPcazip and pyPcazipgui), users attempted hands on demonstrations of how to use such software and how to introduce them into their own workflows. Users had access to the national super computing service ARCHER for the duration of this workshop, so they had hands on experience with such resources for the first time in some cases. This workshop provided users direct exposure to the developers of the tools, which helped to open dialogue between users and developers and bring more ideas for new features. |
| Year(s) Of Engagement Activity | 2015 |
| URL | http://www.ccpbiosim.ac.uk/hecbio-goinglarge |
| Description | Headstart program at the University of York |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Undergraduate students |
| Results and Impact | Lecture "Introduction to Biophysics" to A-level physics students within the Work Experience Week and Headstart programs |
| Year(s) Of Engagement Activity | 2019 |
| URL | https://www.york.ac.uk/physics/public-and-schools/events/headstart-2019/ |
| Description | Istanbul December 2018 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | A talk on free energy. |
| Year(s) Of Engagement Activity | 2018 |
| Description | London Free Energy Meeting |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | I presented a talk on free energy calculations to specialised audience of practitioners including industry attendees. |
| Year(s) Of Engagement Activity | 2017 |
| Description | Markov modelling and free energy calculation workshop 2016 |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Postgraduate students |
| Results and Impact | About 50 participants attended the Markov modelling workshop we organised at King's College London, some of which were international scientists from India, Europe or the US. Several participants were from pharmaceutical companies, such as Novartis, GSK, and UCB Pharma. The workshop initiated further collaborations and research visits with both academic groups and pharma companies. |
| Year(s) Of Engagement Activity | 2016 |
| Description | Pint of Science |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | Outreach talk for general public about current research in genomes and how affects our lives. |
| Year(s) Of Engagement Activity | 2019 |
| URL | https://pintofscience.co.uk/ |
| Description | Pint of Science talk: Making movies of Bacterial membranes |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | I gave a talk in a pub to an audience consisting of members of the general public who had bought tickets to the event. The talk explained some of the science behind antimicrobial resistance followed by some details of my own work in terms of 'making movies' of the bacterial membranes so we can understand how they protect bacteria. I talked about how we have to understand the membranes in molecular detail if we are to design new drugs with the ability to permeate across these membranes. Audience members said they had a much better understanding of how they must not abuse antibiotics, after the talk. |
| Year(s) Of Engagement Activity | 2017 |
| URL | https://pintofscience.co.uk/event/architecture-with-atoms |
| Description | Queen's Computational Biology Club Symposium. Almudena Pino-Angeles |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Postgraduate students |
| Results and Impact | Poster: Tracing the allosteric binding pathways to the cell membrane-GPCR interface. Discussions with bioinformaticians and appreciation of the application of AI in GPCR research. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Seminar at University of Leeds |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Other audiences |
| Results and Impact | Seminar on edible oleogels at the University of Leeds to academic staff and students |
| Year(s) Of Engagement Activity | 2017 |
| Description | Sweden Keynote Presentation |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | I gave a keynote presentation on drug design to a specialist audience. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Talk give in Oxford to Shanghai Tech |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Policymakers/politicians |
| Results and Impact | A talk was given on free energy calculations as part of a discussion to investigate joint operations between the university and Shanghai Tech. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Talk in Dundee |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Postgraduate students |
| Results and Impact | A talk to 50-60 scientists from the Dundee area that provoked some interesting ideas and discussion. |
| Year(s) Of Engagement Activity | 2017 |
| Description | Training workshop |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Postgraduate students |
| Results and Impact | 12 early career researchers (mainly a mixture of PhD students and PDRAs) attended a 1-day workshop in Leeds organised by CCPBioSim/HECBioSim to learn how to use the computational workflows package "Crossflow" that was developed during this grant. The objective was to raise awareness of the software and promote its usage on the national supercomputing service ARCHER2. |
| Year(s) Of Engagement Activity | 2023 |
| Description | UKQSAR Sept 2018 Meeting - Bromodomains and Drug design |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | A talk on drug design given. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Vertex 2018 Talk |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Industry/Business |
| Results and Impact | An invited talk given to Vertex Pharmaceuticals. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Yale iGluR Poster Presentation |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Postgraduate students |
| Results and Impact | Poster presentation to about 130 scientists in the field of glutamate research |
| Year(s) Of Engagement Activity | 2017 |