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.

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

Publications

10 25 50

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Aldeghi M (2017) Predictions of Ligand Selectivity from Absolute Binding Free Energy Calculations. in Journal of the American Chemical Society

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Badaoui M (2018) Calculating Kinetic Rates and Membrane Permeability from Biased Simulations. in The journal of physical chemistry. B

 
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, physicsbased 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, atomiclevel 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. Coarsegrained 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
Exploitation Route Background
Single paragraph detailing what the HEC Consortium is/does.

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
Sectors Chemicals,Education,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

URL http://www.hecbiosim.ac.uk
 
Description 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.
First Year Of Impact 2013
Sector Chemicals,Digital/Communication/Information Technologies (including Software),Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology,Other
Impact Types Economic

 
Description Advisory Committee for the Austrian Funding Agency
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
 
Description Future of HPC
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
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 02/2018 
End 01/2021
 
Description AstraZeneca CASE studentship
Amount £29,500 (GBP)
Organisation AstraZeneca 
Sector Private
Country United Kingdom
Start 03/2017 
End 02/2021
 
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)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 02/2018 
End 01/2023
 
Description Combining quantum and classical methods to study bacterial membrane enzymes
Amount £126,931 (GBP)
Organisation The Leverhulme Trust 
Sector Academic/University
Country United Kingdom
Start 07/2018 
End 07/2021
 
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 10/2015 
End 05/2018
 
Description EPSRC Flagship Software
Amount £523,963 (GBP)
Funding ID EP/P022138/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 06/2017 
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 Academic/University
Country United Kingdom
Start 05/2017 
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 John Fell Fund
Amount £86,614 (GBP)
Organisation University of Oxford 
Sector Academic/University
Country United Kingdom
Start 09/2016 
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 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 Academic/University
Country United Kingdom
Start 11/2018 
End 10/2022
 
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 10/2021
 
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 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. 
 
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 with Beata Vertessy 
Organisation Budapest University of Technology and Economics
Department Department of Biotechnology and Food Sciences
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 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 Evotec AI 
Organisation Evotec (UK) Ltd
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 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 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 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 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 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 for members of the community to contribute their own software, documentation or guides so that the wider community can benefit from shared knowledge, this is a feature we hope to focus on in the near future. The portal itself has been constructed with different usage patterns and devices in mind, and to date works across all known smart phone, tablet and desktop type devices along with being cosmetically compatible with the 5 browsers at the top of the market share. 
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 repositories. 
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 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 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 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 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 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 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 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 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