CCP-BioSim: Biomolecular Simulation at the Life Sciences Interface

Lead Research Organisation: University of Bristol
Department Name: Chemistry

Abstract

"Everything that living things do can be understood in terms of the jigglings and wigglings of atoms" as Richard Feynman provocatively stated nearly fifty years ago. But how can we 'see' this wiggling and jiggling and understand how it drives biology? Increasingly, computer simulations of biological macromolecules are helping to meet this challenge. Experiments can provide detailed structures of biological macromolecules such as proteins, but it is hard to study directly how the structures of individual molecules change on short timescales as they function. Similarly it is not yet possible to study directly by experiment alone the molecular mechanisms of fast processes such as chemical reactions in enzymes or ion transport through membranes. Simulations based on fundamental physics offer the potential of filling-in these crucial 'gaps', modelling how proteins and other biomolecules move, fluctuate, interact, react and function.
Physics-based simulations 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. Simulations have already shown their worth in helping to analyse how enzymes catalyse biochemical reactions, and how proteins adopt their functional structures. They can help in the design of drugs and catalysts, and in understanding the molecular basis of disease. And 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, demonstrating the truth of Feynman's assertion.
Developing methods from chemical physics and computational science will open exciting new opportunities in biomolecular science, including in drug design and development, synthetic biology, biotechnology and biocatalysis. Much biomolecular simulation demands 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). We work to develop 'multiscale' modelling and simulation methods to tackle these large problems, in areas such as drug metabolism and transport.

Planned Impact

Biomolecular simulation and modelling is vital e.g. to the pharmaceutical industry, where it is an integral part of drug design and development (e.g. in structure-based drug design and predictions of drug metabolism). Pharma needs well-trained scientists in this area, and new methods (e.g. for prediction of drug binding affinities). CCP-BioSim contributes directly to both of these key requirements. Our activities also promote collaboration between simulation and experiment; biomolecular simulation is central to multidisciplinary research programmes. CCP-BioSim, and the computational tools it develops and contributes to, increase biological applications of high-end computing (HEC). As well as biosimulation specialists, a broad community of industrial and academic bioscientists investigating biomolecular structure and function will benefit from CCP-BioSim. Longer term, CCP-BioSim has the potential to contribute to improvements in health and quality of life. The 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. CCP-BioSim helps to train scientists able to work across the theory/experimental boundary. Impacts on health will come from the application of the methods fostered and disseminated by CCP-BioSim to drug design and discovery. CCP-BioSim will a) help to train new researchers b) develop and disseminate advanced computational methods and c) provide a forum to enhance industrial-academic research links (members of the management group have strong links with many pharmaceutical/biotech companies, e.g. AstraZeneca, Vernalis, Phaminox, GSK, Evotec, Pfizer, Sanofi, Astex, etc.). There is also broader impact of biomolecular simulation in areas such as drug delivery and synthetic biology. Finally, vast amounts of data are coming from genomics, proteomics, glycomics and structural biology. Developments in X-ray crystallography, high-throughput sequencing, protein production and crystallization, EM, SAXS, NMR and mass spectrometry, combined with modern data storage capacities have vastly increased the quantity of information available in structural biology, proteomics and genomics databases. Investment in understanding and interpretation in terms of biological function is vital to make use of this information. Biomolecular simulation is essential to enhance understanding and guide further experiments, especially as the quantity and complexity of biological data is immense and continues to grow. Improved understanding of biomolecular interactions and their consequences is not just of fundamental interest, but also benefits applied science. Progress in understanding biomacromolecules requires an integrated approach using a range of biophysical techniques, both experimental and computational. Biomolecular simulation will help to use these data to develop new drugs, catalysts and nanotechnology.

Publications

10 25 50
 
Description "Everything that living things do can be understood in terms of the jigglings and wigglings of atoms" as Richard Feynman provocatively stated nearly fifty years ago. But how can we 'see' this wiggling and jiggling and understand how it drives biology? Increasingly, computer simulations of biological macromolecules are helping to meet this challenge. Experiments can provide detailed structures of biological macromolecules such as proteins, but it is hard to study directly how the structures of individual molecules change on short timescales as they function. Similarly it is not yet possible to study directly by experiment alone the molecular mechanisms of fast processes such as chemical reactions in enzymes or ion transport through membranes. Simulations based on fundamental physics offer the potential of filling-in these crucial 'gaps', modelling how proteins and other biomolecules move, fluctuate, interact, react and function.

Physics-based simulations 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. Simulations have already shown their worth in helping to analyse how enzymes catalyse biochemical reactions, and how proteins adopt their functional structures. They can help in the design of drugs and catalysts, and in understanding the molecular basis of disease. And 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, demonstrating the truth of Feynman's assertion.

Developing methods from chemical physics and computational science will open exciting new opportunities in biomolecular science, including in drug design and development, synthetic biology, biotechnology and biocatalysis. Much biomolecular simulation demands 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). We work to develop 'multiscale' modelling and simulation methods to tackle these large problems, in areas such as drug metabolism and transport.
CCP-BioSim: Biomolecular Simulation at the Life Sciences Interface

Management Group:
Adrian Mulholland (AJM) (Chair) Professor of Chemistry, University of Bristol
Phil Biggin (PCB) Associate Professor of Computational Biochemistry, University of Oxford
Jonathan Essex (JWE) Professor of Chemistry, University of Southampton
Francesco Gervasio (FLG) Chair of Biomolecular Modelling, UCL; Thomas Young Centre
Sarah Harris (SAH) Lecturer in Biological Physics, School of Physics and Astronomy, University of Leeds and a member of the Astbury Centre for Structural Molecular Biology
Richard Henchman (RHH) Lecturer in the Manchester Interdisciplinary Biocentre and School of Chemistry at the University of Manchester
David Huggins (DH) MRC Fellow, Theory of Condensed Matter Group, University of Cambridge
Syma Khalid (SK) Associate Professor in Chemistry, University of Southampton
Charles Laughton (CAL) Associate Professor and Reader in Molecular Recognition in the School of Pharmacy, University of Nottingham
Julien Michel (JM) Royal Society University Research Fellow, University of Edinburgh
Edina Rosta (ER) Lecturer in Computational Chemistry, King's College London
Mark Sansom (MS) David Phillips Professor of Molecular Biophysics at the University of Oxford

Tom Keal (STFC)
Hannes Loeffler (HL) STFC Daresbury Laboratory (now Pfizer).


CCP-BioSim was established in October 2011 with support from EPSRC to strengthen, promote and develop biomolecular simulation at the life sciences interface, an area that is increasingly contributing to biology, biocatalysis and important in drug design. Our recent networking and core support renewal application to EPSRC was successful. CCP-BioSim has now been renewed, with the new grant period starting on 1st July 2015. This will provide support for networking activities after March 2015, and core support for software development under the SLA. We plan networking, training and conferences, and industrial 'sandpits' and pilot projects. We will expand our international and industrial engagement, as recommended by the mid-term review. We will build on our previous widening participation activities, and continue to work with other CCPs in areas of joint interest such as multiscale modelling (e.g. with CCP5). We will also work with HECBioSim on developing HEC applications.

There is 1.25 FTE support provided under the SLA, of which 1.0 FTE is dedicated to software development and 0.25 to networking.
We have refreshed our Management Group, and expanded our Advisory Board, building further links with industry (particularly the pharmaceutical industry). The Advisory Board 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).
CCP-BioSim organizes training workshops and provides a framework for networking and collaboration. We also work to develop and apply advanced methods, and engage with international activities (e.g. NSF, CECAM, NIH, CSCS, FEBS, EMBO etc.). We welcome new members across the whole community. We actively engage with structural and chemical biologists and industrial researchers through collaboration, dissemination and application of software, and invitations to conferences and workshops. We have a particular focus on multiscale modelling. Software tools have been made available via CCP-Forge. Biomolecular simulations contribute to drug development (e.g. in structure-based drug design and predictions of metabolism), design of biomimetic catalysts, and in understanding the molecular bases of disease and drug resistance. Recent examples include simulations of biosensors and nanopores for DNA sequencing, and analysis of the causes of influenza resistance to Tamiflu. Advances in hardware and software now allow simulations on the microsecond (and even millisecond) timescale, enabling direct links with experiments. Simulations have proved crucial in analysing protein folding and mechanisms of biological catalysis. Developing methods from chemical physics and computational science will open new opportunities for new types and scales of application. A particular challenge is the integration of simulations of different types across length and timescales; multiscale modelling (e.g. of drug metabolism) is a CCP-BioSim theme.
Website ccpbiosim.ac.uk (we have also established a blog at ccpbiosim.tumblr.com)

Software development work by Hannes Loeffler (DL), Julien Michel (Edinburgh) and Christopher Woods (Bristol) has focused on extensions to the FESetup tool. To increase acceptability within the community, emphasis was put on support for alchemical free energy simulation in additional MD packages and support for easier standard MD simulation through abstract MD engines. The latter is expected to be also of interest to non-specialist and experimentalists as it takes some burden from setting up MD simulations. A paper on FESetup has recently been submitted to J Chem Inf Mod. FESetup v1.1 was released in Feb 2015 and included: support for AMBER free energy calculations with the pmemd program, to supplement the previous support for sander. GROMACS support has been finished with the help of Matteo Aldeghi (Phil Biggin group, Oxford) and David Mobley (UC Irvine, USA). DL_FIELD support finished, as well as direct support for DL_POLY (with input from Ilian Todorov and Chin Yong). FESetup provides parameterisation for ligands, and also a complete setup and equilibration procedure. Support for other AMBER force fields has been added, in particular the carbohydrate GLYCAM force field. Implementation of an abstract MD engine, so that various popular MD simulation software packages (currently AMBER, NAMD, GROMACS and DL_POLY) can be used in a transparent fashion without the need of control structures specific to the software. This is somewhat limited by the software not always providing fully equivalent features, and is currently used mainly for the "equilibration" step. Work has begun on setting up free energy calculations in NAMD with David Huggins (Cambridge)

A reproducibility study on free energy calculations has been started as a collaboration between Julien Michel (Edinburgh), Hannes Loeffler (DL), David Mobley and Benoit Roux (University of Chicago). This is a study to compare the codes AMBER, Sire, Gromacs and CHARMM and see if they can really produce comparable results. It is also about developing best practices in running this type of simulation and see how we can encode this in FESetup. It was included as a Hartree Centre project in Oct 2014. A study between Sushil Mishra (Masaryk University, Brno), Hannes Loeffler (DL) and Julien Michel (Edinburgh) has been carried out on the GLYCAM forcefield (manuscript recently submitted to J. Chem. Theory Comput.).

The 4th annual CCPBioSim conference was held in Leeds 7-9 January 2015 (91 registered, including 3 from industry). A training workshop on Free Energy Calculation and Molecular Kinetics was held at Kings College London, 20th-22nd April 2015, organised by Edina Rosta and Francesco Gervasio. The course proved extremely popular, with 55 students attending.

HL (and James Gebbie for HECBioSim, see below), will attend and present at the forthcoming NSCCS AMBER workshop week in London in July. SK and RH will teach biomolecular simulation at the CCP5 Summer School.

Other outputs include: A.Gray et al., "In pursuit of an accurate spatial and temporal model of biomolecules at the atomistic level: a perspective on computer simulation", Proceedings of the CCP4 Study Weekend, Acta Cryst., D71, 162 - 172 (2015). This paper arises from a talk given by Sarah Harris (Leeds, and member of the CCPBioSim management group) at the CCP4 Study Weekend on complementary methods in January 2014.
For the new grant period, the CCP-BioSim website will be refreshed in order to provide more interactivity. It will be modelled on the successful HECBioSim website. A series of movies is also being developed to highlight the work of CCPBioSim.

Industrial Engagement We have engaged with a number of industrial partners on short and longer-term projects. For example, JWE has developed and applied a range of phospholipid coarse-grain models including a more realistic incorporation of electrostatic interactions, for multiscale, dual-resolution simulations (collaboration with Massimo Noro, Unilever). In collaboration with Syngenta, JWE has developed Monte-Carlo based simulation methods for locating water molecules in protein-ligand binding sites, and estimating their binding affinities, and in collaboration with Vernalis, investigated the binding of ligands to kinase drug targets. identifying the role water can play in protein-ligand interactions. In collaboration with Heptares, free energy methods have been used to identify and score water molecules and their networks in structures of adenosine A2A antagonists. (WNP-MMSA). (J. Chem. Inf. Model. 53, 1700-1713 (2013)). AJM, with Pfizer and Vernalis, modelled cytochrome P450 drug metabolism with QM/MM methods (J Am Chem Soc. 135 8001 (2013). JMM and RHH have collaborated with Evotec using Sire/OpenMM software (developed with CCP-BioSim support, see e.g. http://ccpbiosim.ac.uk/node/15; Evaluation of Host/Guest Binding Thermodynamics of Model Cavities with Grid Cell Theory J. Chem. Theory Comput. in press; Prediction of Small Molecule Hydration Thermodynamics with Grid Cell Theory J. Chem. Theory Comput. 10, 35- 48, 2014 (featured on the cover of the journal). In collaboration with Sanofi, FLG used enhanced sampling MD to elucidate of the mode of action of SSR, the first allosteric inhibitor of fibroblast growth factor receptors; SSR (discovered in this research) has promise for anti-angiogenic cancer therapy (Cancer Cell, 23, 489, 2013). Elements of the multiscale modelling methods developed for biosimulation by CCP-BioSim have been adapted by the Laughton group for drug-polymer interactions in nanoparticle formulations, leading to the award of an EPSRC project grant to CAL with AstraZeneca (EP/L013835/1).

Flagship project We developed a multiscale modelling approach for modelling drug metabolism by cytochrome P450 enzymes, spanning coarse-grained and atomistic molecular dynamics simulations, and reaction modelling using QM/MM methods (AJM, MS, JWE). An essential aspect is the sharing of simulation data from different levels: we have developed scripts and procedures for conversion between the three different levels of simulation (available from ccpforge.cse.rl.ac.uk). We have applied this protocol to the most important human P450 in drug metabolism, CYP3A4, constructed and optimized a biologically realistic model of CYP3A4 in situ, simulated the dynamics of this complex, and modelled the oxidation of R-warfarin in the active site. Publications from the flagship project include: A multiscale approach to modelling drug metabolism by membrane-bound cytochrome P450 enzymes PLoS Comput Biol. 10:e1003714; Trends in predicted chemoselectivity of cytochrome P450 oxidation. J Mol Graph Model. 52 30 (2014); QM/MM modelling of drug-metabolizing enzymes. Curr. Top. Med. Chem. 14, 1339 (2014)

CCPBioSim Training Week 2018
The training week was 9-13 April in Bristol. There were sessions on Python for Biomolecular Modellers, Setting up and Running Molecular Dynamics Simulations, Tackling Protein Alchemistry, Alchemical Free Energy Simulation Analysis, ISAMBARD: A Python-based API for Biomolecular Structure Analysis and Parametric Design of Protein Structures, Introduction to BioSimSpace, Visualising Binding Free Energies Using Swap-based Methods, QM/MM Modelling of Enzyme Reactions, and Calculating Water Affinities in Protein Binding Sites with Grand Canonical Monte Carlo and ProtoMS. Each workshop had 20-30 attendees. The use of a cloud server with a kubernetes cluster and docker images provided a smooth experience for everyone.
The feedback form received 142 responses (each of the workshops had its own feedback). All of the workshops were reported as useful, with Introduction to BioSimSpace, Python, QM/MM, and Visualising Binding using Swap-Based Methods getting the most useful scores. Most attendees reported that they would regularly apply the knowledge they learned in their work and the demonstrators were very helpful.

"Awesome workshop" - attended the Isambard workshop

"The demonstrators were really helpful and patient, which meant that I was able to learn some really good key concepts." - attended the Python for Biomolecular Modellers workshop

"Very good introduction for beginners or people with limited experience on MD pitfalls, but a few tips for advanced users as well I suspect." - attended the Setting up and Running Molecular Dynamics Simulations workshop

Software
BioSimSpace
A new software framework to create an interoperability layer around the many software packages that are already embedded within the biosimulation community. BioSimSpace will enable rapid development of workflows between these software packages that can then be used in conjunction with existing workflow software such as Knime, Pipeline Pilot, ExTASY etc. This project is currently in an early phase of development, more information can be found here.

FESetup
FESetup1.2.1
A tool to automate setup for alchemical relative free energy simulations with Molecular Dynamics and Monte Carlo, and a tool for general simulation setup like equilibration.
Citation: A detailed description has been published in DOI: 10.1021/acs.jcim.5b00368. Please cite this when you use FESetup.

Other Software:
ProtoMS - a complete protein Monte Carlo free energy simulation package.

Sire - a complete python/C++ molecular simulation framework, particularly focussed around Monte Carlo, QM/MM and free energy methods.

PCAZIP - a toolkit for compression and analysis of molecular dynamics trajectories.

COCO - a tool to enrich an ensemble of structures, obtained e.g. from NMR.

Handy Routines for Ptraj/Cpptraj - additional analysis methods for ptraj and cpptraj.
Exploitation Route Biomolecular simulation is a vibrant and growing area, making increasingly significant contributions to structural and systems biology. Physics-based simulations 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. 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 design and development, biotechnology and biocatalysis. Much biomolecular simulation demands HPC 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).
Sectors Chemicals,Education,Pharmaceuticals and Medical Biotechnology

URL http://www.ccpbiosim.ac.uk
 
Description See ccpbiosim.ac.uk "Everything that living things do can be understood in terms of the jigglings and wigglings of atoms" as Richard Feynman provocatively stated nearly fifty years ago. But how can we 'see' this wiggling and jiggling and understand how it drives biology? Increasingly, computer simulations of biological macromolecules are helping to meet this challenge. Experiments can provide detailed structures of biological macromolecules such as proteins, but it is hard to study directly how the structures of individual molecules change on short timescales as they function. Similarly it is not yet possible to study directly by experiment alone the molecular mechanisms of fast processes such as chemical reactions in enzymes or ion transport through membranes. Simulations based on fundamental physics offer the potential of filling-in these crucial 'gaps', modelling how proteins and other biomolecules move, fluctuate, interact, react and function. 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. Software developed: BioSimSpace A new software framework to create an interoperability layer around the many software packages that are already embedded within the biosimulation community. BioSimSpace will enable rapid development of workflows between these software packages that can then be used in conjunction with existing workflow software such as Knime, Pipeline Pilot, ExTASY etc. BioSimSpace is an interoperable Python framework for biomolecular simulation. With it you can: 1. Write robust and portable biomolecular workflow components that work on different hardware, with different software packages, and that can be run in different ways, e.g. command-line, Jupyter. 2. Interact with running molecular simulation processes in real-time. FESetup FESetup1.2.1 A tool to automate setup for alchemical relative free energy simulations with Molecular Dynamics and Monte Carlo, and a tool for general simulation setup like equilibration. Citation: A detailed description has been published in DOI: 10.1021/acs.jcim.5b00368. Please cite this when you use FESetup. Support: A mailing list for user support can be subscribed to here. License GNU/GPL Download 3,280 Other Software: ProtoMS - a complete protein Monte Carlo free energy simulation package. Sire - a complete python/C++ molecular simulation framework, particularly focussed around Monte Carlo, QM/MM and free energy methods. PCAZIP - a toolkit for compression and analysis of molecular dynamics trajectories. COCO - a tool to enrich an ensemble of structures, obtained e.g. from NMR. Handy Routines for Ptraj/Cpptraj - additional analysis methods for ptraj and cpptraj. Physics-based simulations 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. Simulations have already shown their worth in helping to analyse how enzymes catalyse biochemical reactions, and how proteins adopt their functional structures. They can help in the design of drugs and catalysts, and in understanding the molecular basis of disease. And 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, demonstrating the truth of Feynman's assertion. Developing methods from chemical physics and computational science will open exciting new opportunities in biomolecular science, including in drug design and development, synthetic biology, biotechnology and biocatalysis. Much biomolecular simulation demands 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). We work to develop 'multiscale' modelling and simulation methods to tackle these large problems, in areas such as drug metabolism and transport. CCP-BioSim: Biomolecular Simulation at the Life Sciences Interface Management Group: Adrian Mulholland (AJM) (Chair) Professor of Chemistry, University of Bristol Phil Biggin (PCB) Associate Professor of Computational Biochemistry, University of Oxford Jonathan Essex (JWE) Professor of Chemistry, University of Southampton Francesco Gervasio (FLG) Chair of Biomolecular Modelling, UCL; Thomas Young Centre Sarah Harris (SAH) Lecturer in Biological Physics, School of Physics and Astronomy, University of Leeds and a member of the Astbury Centre for Structural Molecular Biology Richard Henchman (RHH) Lecturer in the Manchester Interdisciplinary Biocentre and School of Chemistry at the University of Manchester David Huggins (DH) MRC Fellow, Theory of Condensed Matter Group, University of Cambridge Syma Khalid (SK) Associate Professor in Chemistry, University of Southampton Charles Laughton (CAL) Associate Professor and Reader in Molecular Recognition in the School of Pharmacy, University of Nottingham Julien Michel (JM) Royal Society University Research Fellow, University of Edinburgh Edina Rosta (ER) Lecturer in Computational Chemistry, King's College London Mark Sansom (MS) David Phillips Professor of Molecular Biophysics at the University of Oxford Martyn Winn (MW) Group leader in computational biology, STFC Daresbury Laboratory Hannes Loeffler (HL) STFC Daresbury Laboratory CCP-BioSim was established in October 2011 with support from EPSRC to strengthen, promote and develop biomolecular simulation at the life sciences interface, an area that is increasingly contributing to biology, biocatalysis and important in drug design. Our recent networking and core support renewal application to EPSRC was successful. CCP-BioSim has now been renewed, with the new grant period starting on 1st July 2015. This will provide support for networking activities after March 2015, and core support for software development under the SLA. We plan networking, training and conferences, and industrial 'sandpits' and pilot projects. We will expand our international and industrial engagement, as recommended by the mid-term review. We will build on our previous widening participation activities, and continue to work with other CCPs in areas of joint interest such as multiscale modelling (e.g. with CCP5). We will also work with HECBioSim on developing HEC applications. There is 1.25 FTE support provided under the SLA, of which 1.0 FTE is dedicated to software development and 0.25 to networking. We have refreshed our Management Group, and expanded our Advisory Board, building further links with industry (particularly the pharmaceutical industry). The Advisory Board 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). CCP-BioSim organizes training workshops and provides a framework for networking and collaboration. We also work to develop and apply advanced methods, and engage with international activities (e.g. NSF, CECAM, NIH, CSCS, FEBS, EMBO etc.). We welcome new members across the whole community. We actively engage with structural and chemical biologists and industrial researchers through collaboration, dissemination and application of software, and invitations to conferences and workshops. We have a particular focus on multiscale modelling. Software tools have been made available via CCP-Forge. Biomolecular simulations contribute to drug development (e.g. in structure-based drug design and predictions of metabolism), design of biomimetic catalysts, and in understanding the molecular bases of disease and drug resistance. Recent examples include simulations of biosensors and nanopores for DNA sequencing, and analysis of the causes of influenza resistance to Tamiflu. Advances in hardware and software now allow simulations on the microsecond (and even millisecond) timescale, enabling direct links with experiments. Simulations have proved crucial in analysing protein folding and mechanisms of biological catalysis. Developing methods from chemical physics and computational science will open new opportunities for new types and scales of application. A particular challenge is the integration of simulations of different types across length and timescales; multiscale modelling (e.g. of drug metabolism) is a CCP-BioSim theme. Website ccpbiosim.ac.uk (we have also established a blog at ccpbiosim.tumblr.com) Software development work by Hannes Loeffler (DL), Julien Michel (Edinburgh) and Christopher Woods (Bristol) has focused on extensions to the FESetup tool. To increase acceptability within the community, emphasis was put on support for alchemical free energy simulation in additional MD packages and support for easier standard MD simulation through abstract MD engines. The latter is expected to be also of interest to non-specialist and experimentalists as it takes some burden from setting up MD simulations. A paper on FESetup has recently been submitted to J Chem Inf Mod. FESetup v1.1 was released in Feb 2015 and included: support for AMBER free energy calculations with the pmemd program, to supplement the previous support for sander. GROMACS support has been finished with the help of Matteo Aldeghi (Phil Biggin group, Oxford) and David Mobley (UC Irvine, USA). DL_FIELD support finished, as well as direct support for DL_POLY (with input from Ilian Todorov and Chin Yong). FESetup provides parameterisation for ligands, and also a complete setup and equilibration procedure. Support for other AMBER force fields has been added, in particular the carbohydrate GLYCAM force field. Implementation of an abstract MD engine, so that various popular MD simulation software packages (currently AMBER, NAMD, GROMACS and DL_POLY) can be used in a transparent fashion without the need of control structures specific to the software. This is somewhat limited by the software not always providing fully equivalent features, and is currently used mainly for the "equilibration" step. Work has begun on setting up free energy calculations in NAMD with David Huggins (Cambridge) A reproducibility study on free energy calculations has been started as a collaboration between Julien Michel (Edinburgh), Hannes Loeffler (DL), David Mobley and Benoit Roux (University of Chicago). This is a study to compare the codes AMBER, Sire, Gromacs and CHARMM and see if they can really produce comparable results. It is also about developing best practices in running this type of simulation and see how we can encode this in FESetup. It was included as a Hartree Centre project in Oct 2014. A study between Sushil Mishra (Masaryk University, Brno), Hannes Loeffler (DL) and Julien Michel (Edinburgh) has been carried out on the GLYCAM forcefield (manuscript recently submitted to J. Chem. Theory Comput.). The 4th annual CCPBioSim conference was held in Leeds 7-9 January 2015 (91 registered, including 3 from industry). A training workshop on Free Energy Calculation and Molecular Kinetics was held at Kings College London, 20th-22nd April 2015, organised by Edina Rosta and Francesco Gervasio. The course proved extremely popular, with 55 students attending. HL (and James Gebbie for HECBioSim, see below), will attend and present at the forthcoming NSCCS AMBER workshop week in London in July. SK and RH will teach biomolecular simulation at the CCP5 Summer School. Other outputs include: A.Gray et al., "In pursuit of an accurate spatial and temporal model of biomolecules at the atomistic level: a perspective on computer simulation", Proceedings of the CCP4 Study Weekend, Acta Cryst., D71, 162 - 172 (2015). This paper arises from a talk given by Sarah Harris (Leeds, and member of the CCPBioSim management group) at the CCP4 Study Weekend on complementary methods in January 2014. For the new grant period, the CCP-BioSim website will be refreshed in order to provide more interactivity. It will be modelled on the successful HECBioSim website. A series of movies is also being developed to highlight the work of CCPBioSim. Industrial Engagement We have engaged with a number of industrial partners on short and longer-term projects. For example, JWE has developed and applied a range of phospholipid coarse-grain models including a more realistic incorporation of electrostatic interactions, for multiscale, dual-resolution simulations (collaboration with Massimo Noro, Unilever). In collaboration with Syngenta, JWE has developed Monte-Carlo based simulation methods for locating water molecules in protein-ligand binding sites, and estimating their binding affinities, and in collaboration with Vernalis, investigated the binding of ligands to kinase drug targets. identifying the role water can play in protein-ligand interactions. In collaboration with Heptares, free energy methods have been used to identify and score water molecules and their networks in structures of adenosine A2A antagonists. (WNP-MMSA). (J. Chem. Inf. Model. 53, 1700-1713 (2013)). AJM, with Pfizer and Vernalis, modelled cytochrome P450 drug metabolism with QM/MM methods (J Am Chem Soc. 135 8001 (2013). JMM and RHH have collaborated with Evotec using Sire/OpenMM software (developed with CCP-BioSim support, see e.g. http://ccpbiosim.ac.uk/node/15; Evaluation of Host/Guest Binding Thermodynamics of Model Cavities with Grid Cell Theory J. Chem. Theory Comput. in press; Prediction of Small Molecule Hydration Thermodynamics with Grid Cell Theory J. Chem. Theory Comput. 10, 35- 48, 2014 (featured on the cover of the journal). In collaboration with Sanofi, FLG used enhanced sampling MD to elucidate of the mode of action of SSR, the first allosteric inhibitor of fibroblast growth factor receptors; SSR (discovered in this research) has promise for anti-angiogenic cancer therapy (Cancer Cell, 23, 489, 2013). Elements of the multiscale modelling methods developed for biosimulation by CCP-BioSim have been adapted by the Laughton group for drug-polymer interactions in nanoparticle formulations, leading to the award of an EPSRC project grant to CAL with AstraZeneca (EP/L013835/1). Flagship project We developed a multiscale modelling approach for modelling drug metabolism by cytochrome P450 enzymes, spanning coarse-grained and atomistic molecular dynamics simulations, and reaction modelling using QM/MM methods (AJM, MS, JWE). An essential aspect is the sharing of simulation data from different levels: we have developed scripts and procedures for conversion between the three different levels of simulation (available from ccpforge.cse.rl.ac.uk). We have applied this protocol to the most important human P450 in drug metabolism, CYP3A4, constructed and optimized a biologically realistic model of CYP3A4 in situ, simulated the dynamics of this complex, and modelled the oxidation of R-warfarin in the active site. Publications from the flagship project include: A multiscale approach to modelling drug metabolism by membrane-bound cytochrome P450 enzymes PLoS Comput Biol. 10:e1003714; Trends in predicted chemoselectivity of cytochrome P450 oxidation. J Mol Graph Model. 52 30 (2014); QM/MM modelling of drug-metabolizing enzymes. Curr. Top. Med. Chem. 14, 1339 (2014) Biomolecular simulations: From dynamics and mechanisms to computational assays of biological activity Overview DAVID J. HUGGINS, PHILIP C. BIGGIN, MARC A. DÄMGEN, JONATHAN W. ESSEX, SARAH A. HARRIS, RICHARD H. HENCHMAN, SYMA KHALID, ANTONIJA KUZMANIC, CHARLES A. LAUGHTON, JULIEN MICHEL, ADRIAN J. MULHOLLAND, EDINA ROSTA, MARK S. P. SANSOM, MARC W. VAN DER KAMP Published Online: Sep 27 2018 WIRES Computational Molecular Science DOI: 10.1002/wcms.1393 Abstract: 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. In this review, we outline biomolecular simulation methods and highlight examples of its application to investigate questions in biology.
First Year Of Impact 2015
Sector Chemicals,Education,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
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 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 Center for Future Health Fund
Amount £13,000 (GBP)
Organisation University of York 
Sector Academic/University
Country United Kingdom
Start 06/2018 
End 09/2019
 
Description DTA PhD studentship
Amount £61,000 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 10/2017 
End 09/2020
 
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 PhD studentships for overseas
Amount £64,900 (GBP)
Funding ID 625750 / 472433 
Organisation National Council on Science and Technology (CONACYT) 
Sector Public
Country Mexico
Start 01/2018 
End 12/2020
 
Description RS Newton Fellowship
Amount £99,000 (GBP)
Funding ID NF171278 
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom
Start 03/2018 
End 02/2020
 
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 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 Improvements to research infrastructure 
Year Produced 2016 
Provided To Others? Yes  
Impact The method has been described in an high-impact publication (JACS) and in a number of high-profile blogs in drug discovery. The PI has been invited by Pfizer and other pharmaceutical companies to give talks about the method. 
 
Title 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 Dr. Alice Pyne and Prof. Bart Hoogenboom, UCL 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Leadership of the project and the PhD student for doing the work
Collaborator Contribution Training and access to the AFM equipment as well as exchange of ideas
Impact Experimental outputs, mainly AFM images on the molecules of interest
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. Anthony Maxwell, JIC, Norwich 
Organisation John Innes Centre
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Travel fund for a visit
Collaborator Contribution Expertise on microbial antibiotic development
Impact Consultancy on antibiotic development strategy
Start Year 2018
 
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 Prof. Lynn Zechiedrich, Baylor College of Medicine, and Twister Biotech, USA 
Organisation Baylor College of Medicine
Country United States 
Sector Hospitals 
PI Contribution Leading the project and providing the PhD students for doing simulations and experiments
Collaborator Contribution Synthesis of DNA minicircles
Impact As a result of this collaboration we have DNA minicircles for performing experiments
Start Year 2018
 
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 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 Modelling of enzyme catalysed reaction mechanisms relevant to pharmaceutical development 
Organisation Pfizer Ltd
Country United Kingdom 
Sector Private 
PI Contribution Confidential
Collaborator Contribution Confidential
Impact Confidential
Start Year 2011
 
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
 
Description water network analysis 
Organisation University of Oxford
Department Department of Biochemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution Training and insights related to our methods.
Collaborator Contribution Partners provided the data and and associated collaborators for us to use in our analysis.
Impact Paper reporting collaboration results published,
Start Year 2016
 
Title APPARATUS FOR AND METHOD OF PROCESSING BIOLOGICAL SAMPLES 
Description The present invention provides systems, devices, apparatuses and methods for automated bioprocessing. Examples of protocols and bioprocessing procedures suitable for the present invention include but are not limited to: immunoprecipitation, chromatin immunoprecipitation, recombinant protein isolation, nucleic acid separation and isolation, protein labeling, separation and isolation, cell separation and isolation, food safety analysis and automatic bead based separation. In some embodiments, the invention provides automated systems, automated devices, automated cartridges and automated methods of western blot processing. Other embodiments include automated systems, automated devices, automated cartridges and automated methods for separation, preparation and purification of nucleic acids, such as DNA or RNA or fragments thereof, including plasmid DNA, genomic DNA, bacterial DNA, viral DNA and any other DNA, and for automated systems, automated devices, automated cartridges and automated methods for processing, separation and purification of proteins, peptides and the like. 
IP Reference US2018111121 
Protection Patent application published
Year Protection Granted 2018
Licensed Yes
Impact the patent has been instrumental for the incorporation of the spin out company Vitamica Ltd
 
Title METHOD AND APPARATUS FOR BACTERIAL ANALYSIS 
Description An apparatus (10) comprising: a light source (12); to cast light toward a substrate (20) defining a bacteria binding volume to create an evanescent field (22), the bacteria binding volume being within the evanescent field; a detector (32, 34) arranged to receive light from the bacteria binding volume and output data (36, 37); and a processor (38) arranged to determine vibration of bacteria (26) within the bacteria binding volume in three-dimensions from the data. 
IP Reference WO2019025771 
Protection Patent application published
Year Protection Granted 2019
Licensed Yes
Impact The patent has being instrumental for the incorporation of the spin out company Vitamica Ltd.
 
Title METHOD FOR DETECTION OF INTESTINAL, AND BLOOD-BRAIN BARRIER PERMEABILITY AND TESTING MATERIALS THERETO 
Description METHOD FOR DETECTION OF INTESTINAL, AND BLOOD-BRAIN BARRIER PERMEABILITY AND TESTING MATERIALS THERETO Methods, assays, and apparatus are disclosed for testing of antigens associated with intestinal and/or blood-brain barrier permeability. For example, blood, saliva or other bodily fluid can be tested for binding (1) to a bacterial toxin (preferably a lipopolysaccharide), and (2) binding to tissue antigens selected from at least one of (a) a gut-related antigen and (b) a blood brain barrier-related antigen. Analysis of test results can be used to assist in detecting and diagnosing diseases associated with leaky gut syndrome (whether due to paracellular or transcellular pathways, and whether due to bacterial toxins or some other cause) and/or to diseases associated with excessive blood brain barrier permeability, which are contemplated herein to include both neuroinflammation and/or neuroautoimmunity conditions, and especially amyotrophic lateral sclerosis, Parkinsons disease, multiple sclerosis, Alzheimer's, or peripheral neuropathy, and major depression. 
IP Reference AU2016259430 
Protection Patent application published
Year Protection Granted 2016
Licensed Yes
Impact the patent has been instrumental for the incorporation of the spin out company Vitamica Ltd
 
Title BioSimSpace 
Description BioSimSpace is an interoperable Python framework for biomolecular simulation. It is the Flagship Software Development Project of CCP-BioSim. With it you can: -Write robust and portable biomolecular workflow components that work on different hardware, with different software packages, and that can be run in different ways, e.g. command-line, Jupyter. -Interact with running molecular simulation processes in real-time. BioSimSpace is a new software framework to create an interoperability layer around the many software packages that are already embedded within the biosimulation community. BioSimSpace will enable rapid development of workflows between these software packages that can then be used in conjunction with existing workflow software such as Knime, Pipeline Pilot, ExTASY etc. See: https://biosimspace.org 
Type Of Technology Software 
Year Produced 2018 
Open Source License? Yes  
Impact BioSimSpace has been used in several CCP-BioSim training workshops, and is now being applied in collaboration with industrialists and experimentalists. 
URL http://www.ccpbiosim.ac.uk
 
Title CCP-BioSim software for biomolecular simulation 
Description BioSimSpace A new software framework to create an interoperability layer around the many software packages that are already embedded within the biosimulation community. BioSimSpace will enable rapid development of workflows between these software packages that can then be used in conjunction with existing workflow software such as Knime, Pipeline Pilot, ExTASY etc. This project is currently in an early phase of development, more information can be found here. 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. Other Software: ProtoMS - a complete protein Monte Carlo free energy simulation package. Sire - a complete python/C++ molecular simulation framework, particularly focussed around Monte Carlo, QM/MM and free energy methods. PCAZIP - a toolkit for compression and analysis of molecular dynamics trajectories. COCO - a tool to enrich an ensemble of structures, obtained e.g. from NMR. Handy Routines for Ptraj/Cpptraj - additional analysis methods for ptraj and cpptraj. 
Type Of Technology Software 
Year Produced 2016 
Open Source License? Yes  
Impact BioSimSpace A new software framework to create an interoperability layer around the many software packages that are already embedded within the biosimulation community. BioSimSpace will enable rapid development of workflows between these software packages that can then be used in conjunction with existing workflow software such as Knime, Pipeline Pilot, ExTASY etc. This project is currently in an early phase of development, more information can be found here. 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. Other Software: ProtoMS - a complete protein Monte Carlo free energy simulation package. Sire - a complete python/C++ molecular simulation framework, particularly focussed around Monte Carlo, QM/MM and free energy methods. PCAZIP - a toolkit for compression and analysis of molecular dynamics trajectories. COCO - a tool to enrich an ensemble of structures, obtained e.g. from NMR. Handy Routines for Ptraj/Cpptraj - additional analysis methods for ptraj and cpptraj. 
URL http://www.ccpbiosim.ac.uk
 
Title CCPBioSim Web Portal 
Description A new web portal was launched to replace the old CCPBioSim drupal based website. The new web portal was designed to bring the CCPBioSim web presence in-line with that of HECBioSim. The new portal focuses on providing a collaborative environment where members of the consortium management can create material together that has a consistent and quality look and feel to users, this includes event related materials for conferences and workshops. 
Type Of Technology Webtool/Application 
Year Produced 2016 
Impact Since the launch of the new portal in February 2016, the portal has had around 50,000 hits by 17,847 unique IP addresses indicating that the website has a quite broad reach within the UK bio-simulation community. 
URL http://www.ccpbiosim.ac.uk
 
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 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 Plug-in and scripts for enhanced-sampling molecular simulations. 
Description We developed a new interoperable plug-in compatible with PLUMED and many widely-used MD codes (such as GROMACS) to run our TS-PPTIS approach for binding kinetics. The tool can be used to predict ligand and folding binding kinetics. 
Type Of Technology Software 
Year Produced 2016 
Open Source License? Yes  
Impact The tool is able to accurately predict the binding kinetics of drugs to their biological targets, paving the avenue to the rational design of new molecules with fine-tuned biomedical effects. 
 
Title ProtoMS 3.2 
Description This software allows for the calculation of protein-ligand binding free energies. This most recent version incorporates our latest work on grand canonical Monte Carlo. 
Type Of Technology Software 
Year Produced 2015 
Open Source License? Yes  
Impact This software is being adopted by other academics and some industrial partners are also using it. 
URL http://www.essexgroup.soton.ac.uk/ProtoMS/
 
Title ProtoMS 3.3 
Description This software allows the user to perform protein-ligand binding free energy calculations using advanced Monte Carlo methods, including grand canonical Monte Carlo. 
Type Of Technology Software 
Year Produced 2017 
Open Source License? Yes  
Impact This software is currently being deployed to industrial collaborators. Its impact in this context will be assessed once these deployments are complete. 
URL http://www.essexgroup.soton.ac.uk/ProtoMS/index.html
 
Title Sire 2014.4 
Description 2014.4 release of Sire. Molecular simulation framework. Main enhancement was the inclusion of new code that accelerated key routines. 
Type Of Technology Software 
Year Produced 2014 
Open Source License? Yes  
Impact Sire is now in use in a number of pharmaceutical companies for applications in drug design and development 
URL http://www.siremol.org/Sire/Home.html
 
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
 
Company Name VITAMICA LIMITED 
Description Vitamica was established in early 2018 as a spin-out company from the University of Bristol. Taking optical technology from the School of Physics, the new company is beginning its journey towards commercialisation of a rapid and novel diagnostic method that has high potential for use in antimicrobial susceptibility testing. With a growing IP portfolio and an active approach to identifying opportunities in healthcare, veterinary and pharma sectors, Vitamica fully intends to make its mark as another successful company to originate from the University of Bristol. 
Year Established 2018 
Impact The company is working on the development of a rapid AMR diagnostic device that could be used in healthcare, veterinary and pharma sectors.
Website https://www.vitamica.co.uk
 
Description 19th International Union of Pure and Applied Biophysics (IUPAB) and 11th European Biophysical Societies Association (EBSA) Congress in Edinburgh 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Agnes Noy succeed to be selected for giving a talk on the most relevant international conference of the year on Biophysics.
Year(s) Of Engagement Activity 2017
URL http://www.iupab2017.org/home
 
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 Biocomputation workshop sponsored by the Physics-of-Life network in Durham 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Agnes Noy participated on the organization of this event in designing the program and selecting the speakers. The event was around the future and scope of biocomputation and how the ideas were articulated for future grants. A grant application was produced as a result of that workshop
Year(s) Of Engagement Activity 2017
URL http://www.physicsoflife.org.uk/biocomputation.html
 
Description Biomolecular Simulations Presentation, DLS, November 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Sarah Fegan gave a presentation on "Biomolecular Simulations" at the Simulations for Experimentalists and Industrialists training course at Diamond Light Source, 7 November 2018. This led to discussions about future research activities.
Year(s) Of Engagement Activity 2018
 
Description Bristol Chemshell training Feb 2019 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Tom Keal and You Lu gave a 2-day training course in the use of ChemShell for materials and biomolecular modelling to a group of 15 researchers at the University of Bristol
Year(s) Of Engagement Activity 2019
 
Description CCP5 Summer School, Advanced Lectures in Biomolecular Simulation 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Dr Richard Henchman and Dr Syma Khalid delivered lectures and workshops over three days on how to use simulations study biomolecular systems (setting them up, running them, analysing them). This drew on material given at other CCP-Biosim training events. About 25 student attended from the UK and Europe. The module delivered is one of three given in parallel. Preceding this was the five-day core part of the Summer School.
Year(s) Of Engagement Activity 2015
URL http://www.ccp5.ac.uk/events/summer_school_2015/
 
Description CCPBioSim Biomolecular QM/MM Modelling with ChemShell workshop, June 2018 
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 CCPBioSim held a training day on combined quantum mechanical/molecular mechanical (QM/MM) modelling of biomolecular systems at the University of St Andrews on 14 June 2018 as part of the ScotCHEM 2018 conference. In the morning session we discussed the principles of QM/MM modelling and introduced the ChemShell software package. ChemShell is a scriptable computational chemistry environment which provides a flexible way to link QM and MM codes together to perform QM/MM calculations. There was then an opportunity to learn the basics of ChemShell in the first practical. In the second lecture we described in more depth how QM/MM biomolecular calculations are set up and performed, using a cytochrome P450 system as a case study. The second practical explored modelling of enzymatic reactions with ChemShell on STFC's SCARF cluster.
Year(s) Of Engagement Activity 2018
URL https://www.scotchem.ac.uk/st-andrews-2018/
 
Description CCPBioSim Biomolecular QM/MM Modelling with ChemShell workshop, May 2017 
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 CCPBioSim held a training day on combined quantum mechanical/molecular mechanical (QM/MM) modelling of biomolecular systems at STFC Daresbury Laboratory on the 9th May 2017.In the morning session we discussed the principles of QM/MM modelling and introduced the ChemShell software package. ChemShell is a scriptable computational chemistry environment which provides a flexible way to link QM and MM codes together to perform QM/MM calculations. There was then an opportunity to learn the basics of ChemShell in the first practical. In the second lecture we described in more depth how QM/MM biomolecular calculations are set up and performed, using a cytochrome P450 system as a case study. The second practical explored modelling of enzymatic reactions with ChemShell on the Hartree Centre systems. In the final lecture we showcased recent ChemShell developments.
Year(s) Of Engagement Activity 2017
URL http://www.ccpbiosim.ac.uk/events/workshop-course-material/eventdetail/95/-/qm-mm-modelling-of-biomo...
 
Description CCPBioSim Training Week 2018 - QM/MM enzyme reaction modelling 
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 During the CCPBioSim training week in 2018, I led a training workshop to introduce non-specialists to the use of combined quantum mechanics/molecular mechanics (QM/MM) methods for modelling enzyme-catalysed reaction mechanisms. I developed new, open-source course material for this, available online. 25 people attended, and evaluated very positively (>60% would strongly recommend the workshop to colleagues, 100% found the workshop (very) useful). Excellent discussion afterwards with several attendees.
Year(s) Of Engagement Activity 2018
URL https://ccpbiosim.github.io/qmmm_workshop/
 
Description CECAM workshop "Computational biophysics on your desktop: is that possible?" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Invitation of PI grant, Agnes Noy, to give a talk on a CECAM workshop which is a series of scientific conferences
Year(s) Of Engagement Activity 2018
URL https://www.cecam.org/workshop-1534.html
 
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 Industry training workshops 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Training on our software ProtoMS was given to three industrial partners - GSK, AZ and UCB. This involved visits to the industrial sites, presentation of the theory underpinning the work, and the provision of training materials.
Year(s) Of Engagement Activity 2017
 
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 Joint CCP-BioSim CCP-EM workshop on Computation for cryo-EM 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact The first day of the workshop provided new users of the Fluctuating Finite Element analysis software (developed at Leeds). As this is the first time this software has been used by people outside of the group, we obtained very useful feedback on performance and usability. The software has been adopted by at least one other research team since the event. On the second day, we had the first (to our knowledge) community discussion of the role of computation in cryo-EM from a prestigious range of international speakers. The event was extremely well received, and we are planning a subsequent workshop for 2019.
Year(s) Of Engagement Activity 2017
 
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 Lorentz-Center workshop on DNA Damage and Repair in Leiden, Netherlands 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Agnes Noy was invited to give a talk and to participate as an expert panel on a dialogue about the subject with numerous questions and long discussions
Year(s) Of Engagement Activity 2017
URL http://www.lorentzcenter.nl/lc/web/2017/932/info.php3?wsid=932&venue=Oort
 
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 Multiscale Modelling Conference jointly between CCPBiosim and CCP5 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Conference of 100 people bringing together experts in the UK, Europe and USA in the area of multiscale modelling in a 2-day conference in Manchester in April 2016. There are about 30 talks and a poster session of about 40 posters. The conference ran previously in January 2014 with a similar size and format.
Year(s) Of Engagement Activity 2014,2016
URL http://www.ccpbiosim.ac.uk/multiscale2016/eventdetail/55/-/2nd-conference-on-multiscale-modelling-of...
 
Description Multiscale modelling presentation, DLS, November 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Tom Keal gave a presentation on "Multiscale modelling of biomolecules and materials" at the Simulations for Experimentalists and Industrialists training course at Diamond Light Source, 7 November 2018
Year(s) Of Engagement Activity 2018
 
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 at Bristol Scientific Club 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other audiences
Results and Impact I gave a presentation which covered the use of holographic tweezers to control 3D-printed micro tools as a 3D optical AFM. The audience was from a wide science and engineering background and I believe the talk was received with enthusiasm. One result was that I was invited to join this prestigious club.
Year(s) Of Engagement Activity 2017
 
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 Talk on "Why is life so complicated, can my computer help"? at Edinburgh science festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Talk at Edinburgh science festival explaining how supercomputing helps us to understand molecular biology.
Year(s) Of Engagement Activity 2017
 
Description Talk on "Why supercomputing is like Christmas" for the Wanstrow Christmas Lectures 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact I explain how supercomputers are used to help scientists at the annual Wanstrow Christmas Lectures, Wanstrow Village Hall, Somerset.
Year(s) Of Engagement Activity 2017
 
Description Training workshop on using TINKER with the AMOEBA force field 
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 We arranged a one-day training workshop on using the AMOEBA force field in the context of the TINKER molecular dynamics software.
Year(s) Of Engagement Activity 2016
URL https://sites.google.com/site/amoebaworkshop/
 
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