Annual Report for EPSRC High End Computing Consortia 2015/16

HEC Consortium

HECBioSim (The UK High-End Computing Consortium for Biomolecular Simulation)

Consortia Chair

Adrian Mulholland (School of Chemistry, University of Bristol)

Management Group

Background

HECBioSim, the UK HEC Biomolecular Simulation Consortium, was established in March 2013, and works closely with and complements CCP-BioSim (the UK Collaborative Computational Project for Biomolecular Simulation at the Life Sciences Interface). Most of the members of the Consortium are experienced users of high end computing. Biomolecular simulations are now making significant contributions to a wide variety of problems in drug design and development, biocatalysis, bio and nano-technology, chemical biology and medicine. The UK has a strong and growing community in this field, recognized by the establishment in 2011 by EPSRC of CCP-BioSim (ccpbiosim.ac.uk), and its renewal in 2015. There is a clear, growing and demonstrable need for HEC in this field. Members of the Consortium have, served on the HECToR Resource Allocation Panel, including the current and previous Chairs of the RAP.

The Consortium welcomes new members across the whole community. Since establishing the Consortium, several new members (FLG, DH, ER) have joined the Management Group. Many of the projects awarded ARCHER time under the Consortium do not involve CCP-BioSim or HECBioSim Management Group members, demonstrating the openness of HECBioSim and its support of the biomolecular simulation community in the UK. A number of other researchers have expressed interest in joining and it is our expectation that other researchers will join HECBioSim in future.

We actively engage with structural and chemical biologists and industrial researchers. We foster interactions between computational, experimental and industrial scientists (see e.g. case studies; members of the Consortium have excellent links with many pharmaceutical, chemical and biotechnology companies). Details of HECBioSim are available via our webpages at: http://www.hecbiosim.ac.uk.

Management

HECBioSim supports three different types of project allocation for time on ARCHER. Pump priming projects are those designed to assist a number of activities (e.g. testing of new codes) and typically fall in the <1MAU range. The standard project is probably the most common and is covered in the 1-15 MAU range. Grand challenge projects are typically projects that fall in the 15-50 MAU range, these are generally large collaborative projects that would involve collaboration on a national scale. Applications are made through the website www.hecbiosim.ac.uk and reviewed at one of a series of regular panel meetings.

A list of successful HECtime allocations on ARCHER is available at http://www.hecbiosim.ac.uk/applications/successfulprojects (to-date 31 projects).

We have welcomed several new groups into HECBioSim since our inception - we are open to new members, unlike some Consortia. All proposals are of course subject to scientific and technical review, but we have the philosophy of supporting the best science to deliver the highest impact, rather than focusing on supporting development of a couple of codes. An allocation panel (with changing membership) meets twice yearly to judge proposals and requests for AUs; projects are assessed competitively; any groups in the UK can apply.

The HECBioSim website also provides forums for the biomolecular simulation community, a wiki hosting useful how-tos and user guides, and software downloads (currently FESetup and Longbow). To-date, the website has been accessed by over 10,000 unique IPs. Our lead software development project between Nottingham (Charlie Laughton and Gareth Shannon) and Daresbury (James Gebbie), we have developed a remote job submission tool, ‘Longbow’ (see below). The tool is designed to reproduce the look and feel of local MD packages, but to stage data and submit jobs to a large HPC resource such as ARCHER in a manner invisible to the user. An open beta version was released unrestricted to the community in March 2015 (http://www.hecbiosim.ac.uk/longbow and via PyPI https://pypi.python.org ) with ~100 downloads. Functionality includes native support for biosimulation packages AMBER, CHARMM, GROMACS, LAMMPS and NAMD, native support for jobs on ARCHER, native support for jobs running on PBS and LSF schedulers, and support for three different job types (single, ensembles and multiple jobs). The software is written both as an application for users and an API for developers. CCP-EM have integrated Longbow into their developmental GUI, and shortly FESetup will ship with native support for job submission using Longbow. We are currently in talks with ClusterVision with respect to them distributing Longbow to their user base as a user friendly way for novices to interact with their systems.

Highlights for the Current Reporting Period

Here we highlight in particular as one example (others are listed in sections below), work of Charlie Laughton (Pharmacy, Nottingham) and Sarah Harris (Physics, Leeds): A new, highly accurate, force field for the simulation of DNA, developed and tested using ARCHER through HECBioSim (as part of a large international consortium): see recent paper in Nature Methods, Parmbsc1: a refined force field for DNA simulations I. Ivani et al. Nature Methods aop, (2015) | doi:10.1038/nmeth.3658. Also their work in R.N. Irobalieva et al. Nature Communications 6, Article number: 8440 doi:10.1038/ncomms944055 (Structural diversity of supercoiled DNA) By regulating access to the genetic code, DNA supercoiling strongly affects DNA metabolism. Despite its importance, however, much about supercoiled DNA (positively supercoiled DNA, in particular) remains unknown. Here we use electron cryo-tomography together with biochemical analyses to investigate structures of individual purified DNA minicircle topoisomers with defined degrees of supercoiling. Our results reveal that each topoisomer, negative or positive, adopts a unique and surprisingly wide distribution of three-dimensional conformations. Moreover, we uncover striking differences in how the topoisomers handle torsional stress. As negative supercoiling increases, bases are increasingly exposed. Beyond a sharp supercoiling threshold, we also detect exposed bases in positively supercoiled DNA. Molecular dynamics simulations independently confirm the conformational heterogeneity and provide atomistic insight into the flexibility of supercoiled DNA. Our integrated approach reveals the three-dimensional structures of DNA that are essential for its function.

Mark Sansom (Biochemistry, Oxford) - Large scale simulations of bacterial outer membranes have revealed how dynamic co-clustering of membrane proteins is mediated by protein-lipid-protein interactions. Working closely with experimentalists in Oxford and York we have shown how this helps to explain segregation of ‘old’ and ‘new’ membrane proteins during cell growth and division. This is of direct relevance to probing for possible new targets for antimicrobials. Rassam, P., Copeland, N.A., Birkholz, O., Tóth, C., Chavent, M., Duncan, A.L., Cross, S.J., Housden, N.G., Seger, U., Quinn, D.M., Garrod, T.J., Sansom, M.S.P. Piehler, J., Baumann, C.G., & Kleanthous, C. (2015) Supramolecular assemblies underpin turnover of outer membrane proteins in bacteria. Nature 523:333–336.This approach has since been extended to mammalian cell membranes, and the role of lipid in dynamic co-clustering has been explored. This is of direct relevance to understanding the mode of action of lipid-like drugs targeted at GPCRs: Koldsø, H., & Sansom, M.S.P. (2015) Organization and dynamics of receptor proteins in a plasma membrane. J. Amer. Chem. Soc. 137:14694-14704.

Dr Gareth Shannon worked as a HECBioSim Postdoctoral Research Associate in Software Development for Biomolecular Simulation at the University of Nottingham. This 12-month contract spanned 05/01/2015 – 04/01/2016. Longbow is a remote molecular dynamics (MD) job submitter. It allows biomolecular simulation researchers to submit molecular dynamics jobs on remote resources such as High Performance Computers (HPCs) without leaving the familiarity of the Unix-based desktop environment. Longbow delivers and it certainly has the potential to redefine the manner in which HPCs are used. Longbow can be adapted to run any executable installed on an HPC. In this way, the number of users could reach a critical mass such that Longbow becomes a well-known tool internationally in computational science communities.

Our case studies provide examples of industrial engagement and impact.

Workshops and New Opportunities

An example of a recent workshop is: our HECBioSim Workshop : ‘Going Large: tools to simplify running and analysing large-scale MD simulations on HPC resources’, Wed 16 December 2015, Daresbury Laboratory, UK. This 1 day workshop dealt with Longbow, a Python tool created by HECBioSim consortium that allows use of molecular dynamics packages (AMBER, GROMACS, LAMMPS, NAMD) with ease from the comfort of the desktop, and pyPcazip, a flexible Python-based package for the analysis of large molecular dynamics trajectory data sets.

We work closely with CCP-BioSim, for example in organizing training workshops and meetings. Examples include:

Free Energy Calculation and Molecular Kinetics Workshop, April 20-22, 2015.
Free energy workshop, 2nd edition, Southampton, Nov 25th 2014.
How to set up a Protein Simulation, 3rd edition, Oxford, Sep 29th 2014.
CCPBioSim training week, Sep 2014:

Analysis of Biomolecular Simulation Data - Tuesday 9th Sep, led by Charlie Laughton/Sarah Harris/Phil Fowler
Python for biomodellers - Wednesday 10th Sept, led by Christopher Woods
Monte Carlo methods for biomodelling - Thursday 11th Sep, led by Christopher Woods
QM/MM methods - Friday 12th Sep, led by Marc van der Kamp

Multiscale Modelling Conference. A joint CCPBioSim/CCP5 conference on the theme of multiscale simulation was held in Manchester on 7–9th Jan 2014.

Other Joint CCP events: The collaborative computational projects for biomolecular and condensed matter simulation, CCPBioSim and CCP5, are holding a second international conference on the theme of multiscale modelling in Manchester, following on from the first held in January 2014. The three-day event will bring together leading researchers from biological and materials chemistry to discuss topics of common interest across the spectrum of electronic structure, atomistic and mesoscopic scales and to address the current and future challenges posed by multiscale modelling.

We are also organizing a joint meeting with CCPN on the interface of NMR and simulation, to be held in July 2016 (Julien Michel, Edinburgh, is leading on organization for CCP-BioSim).

Issues and Problems

Details of SLA activities are given in the SLA report. Dr. James Gebbie provides support to HECBioSIm through the SLA. He has been very helpful in the construction of the HECBioSim webpages (hecbiosim.ac.uk). James also worked with Dr. Gareth Shannon on the development of Longbow (See above).

Membership

There are currently 105 users of HECBioSim Archer time. We have 28 current projects and we are awaiting 5 new sign ups (from the December awards).

Recent publications from HECBioSim work include (this is a selected sample from groups across the Consortium; some are highlighted and described in more detail below):

Ding, W., M. Palaiokostas, W. Wang, M. Orsi. Effects of lipid composition on bilayer membranes quantified by all-atom molecular dynamics, J. Phys. Chem. B J. Phys. Chem. B, 119, 15263–15274 (2015)
P. Dinis et al. X-ray crystallographic and EPR spectroscopic analysis of HydG, a maturase in [FeFe]-hydrogenase H-cluster assembly Proc. Natl. Acad. Sci. USA 112 1362-1367 (2015)
N.A. Berglund et al. Open Archive Establishing the Structural Rules for Ligand Recognition, Signaling and Assembly in Innate Immune Receptors Biophys. J. 108, 98a http://dx.doi.org/10.1016/j.bpj.2014.11.562
H. Strahl et al. Membrane Recognition and Dynamics of the RNA Degradosome PLoS Genetics DOI: 10.1371/journal.pgen.1004961 (2015)
N.A. Berglund Interaction of the Antimicrobial Peptide Polymyxin B1 with Both Membranes of E. coli: A Molecular Dynamics Study PLoS Computational Biology DOI: 10.1371/journal.pcbi.1004180 (2015)
R.M.A. Manara et al. DNA sequencing with MspA: Molecular Dynamics simulations reveal free-energy differences between sequencing and non-sequencing mutants Scientific Reports 5, Article number: 12783 doi:10.1038/srep12783 (2015)
A. Gray et al. In pursuit of an accurate spatial and temporal model of biomolecules at the atomistic level: a perspective on computer simulation Acta Cryst. D71, 162-172 doi:10.1107/S1399004714026777 (2015).
J. M. A. Manara et al. Free-Energy Calculations Reveal the Subtle Differences in the Interactions of DNA Bases with α-Hemolysin J. Chem. Theory Comput., 2015, 11 (2), pp 810–816 DOI: 10.1021/ct501081h (2015)
Comparison of Molecular Contours for Measuring Writhe in Atomistic Supercoiled DNA
T. Sutthibutpong, S.A. Harris, and A. Noy Comparison of Molecular Contours for Measuring Writhe in Atomistic Supercoiled DNA J. Chem. Theory Comput. 11, 2768–2775 DOI: 10.1021/acs.jctc.5b00035 (2015)
R.N. Irobalieva, Structural diversity of supercoiled DNA Nature Communications 6, Article number: 8440 doi:10.1038/ncomms9440 (2015)
E. Rosta, W. Yang and G. Hummer, Calcium inhibition of Ribonuclease H1 two-metal ion catalysis" Journal of the American Chemical Society 136, pp 3137–3144 DOI: 10.1021/ja411408x (2014)
A. Ganguy et al. Quantum Mechanical/Molecular Mechanical Free Energy Simulations of the Self-Cleavage Reaction in the Hepatitis Delta Virus Ribozyme. J. American Chemical Society, 136, 1483-1496 (2014).

Arianna Fornili (School of Biological and Chemical Sciences, Queen Mary University of London)

Molecular basis of regulation of cardiac myosin under normal conditions and in the presence of pathogenic mutations. The findings from this study will be presented at the 60th Annual Meeting of the Biophysical Society (27Feb - 2Mar 2016) in Los Angeles. An abstract of this work (A.Fornili, E. Rostkova, F. Fraternali, M. Pfuhl: “Effect of RLC-Nterminal tails on the structure and dynamics of cardiac myosin”) will be published in a special number of the Biophysical Journal. A manuscript is currently under preparation.

Francesco Gervasio (Chemistry, UCL)

ARCHER time through HECBioSIm has been used to elucidate the mode of action of cancer-causing and drug-resistance causing mutations in an important class of signalling proteins (protein kinases). This kind of information is of great importance in the rational design of more effective anti-cancer drugs.
[1] T. D. Bunney, S. Wan, N. Thiyagarajan, L. Sutto, S. V. Williams, P. Ashford, H. Koss, M. A. Knowles, F. L. Gervasio, P. V. Coveney, M. Katan EBioMedicine, 2, 194-204, 2015.
[2] K Marino, L Sutto, F L Gervasio* The Effect of a Wide-spread Cancer-causing Mutation on the Inactive to Active Dynamics of the B-Raf Kinase J. Am. Chem. Soc. 137, 5280–5283, 2015
[3] S. Lovera, M. Morando, E. Pucheta-Martinez, J. Martinez-Torrecuadrada, G. Saladino, F. L. Gervasio* Towards a Molecular Understanding of the Link Between Imatinib Resistance and Kinase Conformational Dynamics Plos Comp Biol. 12, e1004578, 2015.

Julien Michel (Chemistry, Edinburgh)

Established the mechanisms by which a key cancer causing protein recognises small molecule drugs via a disordered protein region. The findings are helping drug designers target more effectively this protein to develop more efficacious drugs. Elucidation of Ligand-Dependent Modulation of Disorder-Order Transitions in the Oncoprotein MDM2 Bueren-Calabuig, J. A. ; Michel, J. PLoS Comput. Biol. , 11(6): e1004282, 2015

Mario Orsi (School of Engineering and Materials Science, Queen Mary University of London)

Atomistic molecular dynamics simulations were performed on models for cell membranes. In particular, effects due to changes in the lamellar vs. nonlamellar lipid composition of membranes were quantified. A number of properties of mixed lipid membranes were characterized quantitatively for the first time, including the lateral pressure, electric field and dipole potential. This work has been published in a high quality peer-reviewed international journal [Wei Ding, Michail Palaiokostas, Wen Wang, and Mario Orsi, Effects of Lipid Composition on Bilayer Membranes Quantified by All-Atom Molecular Dynamics The Journal of Physical Chemistry B 2015 119 (49), 15263-15274, DOI: 10.1021/acs.jpcb.5b06604]. Molecular simulations were conducted to study permeation processes of small molecules through mixed lipid membranes. For the first time, it is shown that nonlamellar lipids reduce membrane permeation through a mechanism that can be related to a small number of fundamental physical properties. A manuscript on this research is in preparation. The research conducted was selected for oral presentations at the 2015 MGMS Young Modellers’ Forum (The Old Naval College, Greenwich, London, 27/11/15) and at the 2015 Thomas Young Centre Student Day (Imperial College, London, 17/12/15), as well as for poster presentations at the 2016 Annual Biophysical Society meeting (Los Angeles, 27 Feb-2 Mar 2016).

Mark Sansom (Biochemistry, Oxford)

We have also used ARCHER as part of our ongoing programme of very large scale simulations of the dynamic properties of viral membrane envelopes in biomedically important enveloped viruses including influenza and dengue. (Reddy, T. & Sansom, M.S.P. (2015) The role of the membrane in the structure and biophysical robustness of the dengue virion envelope. http://dx.doi.org/10.1016/j.str.2015.12.011). These virus simulations were featured in local media following their presentation by Tyler Reddy at the 2014 US Biophysics meeting. Other recent successes of the use of ARCHER under HECBioSim (Sansom Group, Oxford) include a collaboration between computational and experimental groups (the latter using advanced microscopy imaging of bacterial membranes) to study role of nanoscale ‘islands’ of membrane proteins in bacterial cell division (see above). This work is continuing, and is of relevance to developing novel targets to help overcome antimicrobial resistance. It has also led to an increase in interest in large scale simulations of membranes from a number of structural biology and biophysics groups, including those of Carol Robinson (Chemistry, Oxford) and Liz Carpenter (SGC, Oxford), in particular using these methods to characterise the interactions of membrane proteins with their lipid bilayer environment Stansfeld, P.J., Goose, J.E., Caffrey, M., Carpenter, E.P., Parker, J.L., Newstead, N. & Sansom, M.S.P. (2015) MemProtMD: automated insertion of membrane protein structures into explicit lipid membranes. Structure (doi:10.1016/j.str.2015.05.006)

Phil Biggin (Biochemistry, Oxford)

Work from the Biggin group has made strong use of ARCHER through HECBioSim and has resulted in the following publications from the allocations from the Consortium over the past year: Kainate receptor pore-forming and auxiliary subunits regulate channel block by a novel mechanism. Brown PM, Aurousseau MR, Musgaard M, Biggin PC, Bowie D. J Physiol. 2015 Dec 18. doi: 10.1113/JP271690. [Epub ahead of print]
Accurate calculation of the absolute free energy of binding for drug molecules, Aldeghi M, Heifetz A, Bodkin MJ, Knapp S, Biggin PC. Chem. Sci., 2016,7, 207-218 doi: 10.1039/C5SC02678D
Distinct structural pathways coordinate the activation of AMPA receptor-auxiliary subunit complexes Dawe GB, Musgaard M, Aurousseau M, Nayeem N, Green T, Biggin PC, Bowie D. Neuron [in press]
The role of an absolutely conserved tryptophan pair in the extracellular domain of Cys-loop receptors. Braun N, Lynagh T, Yu R, Biggin PC, Pless S. ACS Chem. Neurosci. [in press]

Charlie Laughton (Pharmacy, Nottingham)

Development and deployment of Longbow, a high-throughput remote job submission tool for the biomolecular simulation community, now being leveraged by other CCPs as well. Longbow makes at easy for biomolecular simulation jobs to be run on Archer as on a local desktop. Journal of Open Research Software 2016, DOI: http://dx.doi.org/10.5334/jors.95

Francesco Gervasio (Chemistry, UCL)

Researchers from University College London, led by Francesco Gervasio in collaboration with the Structural Biology Computational Group of the Spanish National Cancer Research Centre (CNIO) headed by Alfonso Valencia have developed the first computational method based on evolutionary principles to predict protein dynamics, which explains the changes in the shape or dimensional structure that they experience in order to interact with other compounds or speed up chemical reactions. The study made possible by the supercomputing resources provided by Archer and PRACE constitutes a major step forward in the computational study of protein dynamics.

[4] L. Sutto, S. Marsili, A. Valencia, F. L. Gervasio* From residue co-evolution to protein conformational ensembles and functional dynamics Proc Natl Acad Sci USA, 112 13567–13572, 2015
Press release: http://www.eurekalert.org/pub_releases/2015-10/cndi-ana102315.php

Phil Biggin (Biochemistry, Oxford)

Our recent publication on Accurate free energy predictions made use of the FESetup package (through the CCPBioSIM CCP).

Arianna Fornili (School of Biological and Chemical Sciences, Queen Mary University of London)

A 1st year PhD student working on this project is currently being trained under my supervision in the use of HPC resources and in particular of ARCHER.

Charlie Laughton (Pharmacy, Nottingham)

“Going Large” workshop: Daresbury 16/12/15. Hands-on introduction to HECBioSim tools (Longbow and pyPcazip) developed to aid the running and analysis of large scale ensemble simulations. 16 attendees.

Francesco Gervasio and Edina Rosta (Chemistry, UCL and Chemistry, KCL)

E. Rosta (KCL) & F. Gervasio (UCL) organized a workshop on Free Energy Calculation and Molecular Kinetics in London April 20-22, 2015. The successful workshop was attended by more than 40 (mainly post-doctoral) academic and industrial researcher from all over Europe.

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.

Alessandro Pandini (Computer Science, Brunel University London)

The “Analysis of the allosteric communication in HIF-2α–ARNT heterodimer” has recently started (1st December 2015). It is aimed at the identification of the allosteric pathways in the HIF-2α–ARNT heterodimer. This can advance the discovery of therapeutic molecules and shed light on the mechanisms underlying disease mutations and post-translational modifications affecting the response to hypoxic stress in cells. In this early stages of the project, a promising collaboration has been explored with the group of Prof. Laura Bonati at the University of Milan-Bicocca. This collaboration will provide an avenue for scientific visits, for the training of a PhD student currently working in Prof. Bonati’s group.

Charlie Laughton (Pharmacy, Nottingham)

The “Ascona B-DNA Consortium” project to develop next-generation simulations of nucleic acids. Partners across Europe and in the USA and India. Publication: Nature Methods, 2016, 13(1), 55-+
EU H2020 project “Multiscale genomics” (multiscalegenomics.eu): developing computational tools and infrastructures to support a multiscale genomics virtual research environment.
CECAM Extended Software Development Workshop (joint with NSF): Deployment and development of advanced sampling tools on HPC resources. Juelich, 11-24/10/15. 91 attendees from across Europe and the US.

Francesco Gervasio (Chemistry, UCL)

Both projects listed above as well as references 3 and 4 involved international collaborations with research groups at the Spanish National Cancer Research Centre, one of the most important cancer biology research centres in Europe.

Phil Biggin (Biochemistry, Oxford)

All of these have international collaboration and co-authorships:

Kainate receptor pore-forming and auxiliary subunits regulate channel block by a novel mechanism. Brown PM, Aurousseau MR, Musgaard M, Biggin PC, Bowie D. J Physiol. 2015 Dec 18. doi: 10.1113/JP271690. [Epub ahead of print]
Accurate calculation of the absolute free energy of binding for drug molecules, Aldeghi M, Heifetz A, Bodkin MJ, Knapp S, Biggin PC. Chem. Sci., 2016,7, 207-218 doi: 10.1039/C5SC02678D
Distinct structural pathways coordinate the activation of AMPA receptor-auxiliary subunit complexes Dawe GB, Musgaard M, Aurousseau M, Nayeem N, Green T, Biggin PC, Bowie D. Neuron [in press]
The role of an absolutely conserved tryptophan pair in the extracellular domain of Cys-loop receptors. Braun N, Lynagh T, Yu R, Biggin PC, Pless S. ACS Chem. Neurosci. [in press]

We aim to expand the breadth of the work of the Consortium focusing on cutting-edge applications, and building collaborations with experiments and industry, to achieve maximum impact from ARCHER use. HECBioSim is now well established, supporting work of many groups across the UK in the growing field of biomolecular simulation. We benefit from an Advisory Group containing members from industry, as we as international biomolecular simulation experts and experimental scientists. The Advisory Board was expanded and refreshed for the renewal and consists of: Dr. Nicolas Foloppe (Vernalis plc, Chair); Dr. Colin Edge (GlaxoSmithKline); Dr. Mike King (UCB Pharmaceuticals); Dr. Mike Mazanetz (Evotec AG); Dr. Garrett Morris (Crysalin Ltd.); Dr. Gary Tresadern (Johnson and Johnson Pharmaceuticals); Dr. Richard Ward (AstraZeneca); Prof. Modesto Orozco (IRB, Barcelona); Prof. Tony Watts, (Oxford, NMR); Dr. Pete Bond (A*STAR Bioinformatics Institute Singapore). We aim to foster industrial collaborations and collaborations with experimentalists (e.g. joint workshops with CCPN, Institute of Physics (Sarah Harris, Leeds Physics); see e.g. case studies. A particular them for strategic development will be multiscale modelling, building on collaborations between several groups in the Consortium. We discussed Grand Challenges at our most recent Management Group meeting. In December 2015, and have have identified several to follow up as strategic priorities. We aim to tackle and support large-scale grand challenge applications in biomolecular science, in areas such as antimicrobial resistance, membrane dynamics, drug design and synthetic biology.

One specific theme with potentially high impact in drug discovery is large -scale comparative investigation of allosteric regulation in different superfamilies of proteins (e.g. PAS domain containing proteins, tyrosine kinases, etc.). The major impact will be in the identification of novel selective therapeutic molecules with limited adverse side effects. As a Consortium, we intend to develop and apply novel computational approaches for the rational design of allosteric regulators of hitherto ‘undruggable’ targets. Many of the targets emerging from large-scale genetic screening are deemed undruggable due to the difficulty of designing drug-like modulators that bind to their catalytic sites. It is increasingly clear that these targets might be effectively targeted by designing drugs that bind to protein-protein interfaces and allosteric sites. To do that, however, new rational design strategies, based on an in-depth knowledge of protein dynamics and advanced modelling and new simulation techniques are required. Other challenging frontier areas include dynamics of motor proteins; prediction of the effects of pathogenic mutations on protein function. The accurate prediction of free energy of binding is still in its infancy and needs much further investigation. Finally, kinetics of biomolecular reactions will become the next big topic. It is clear that high end computing resource can provide the necessary power and capability to provide inroads into this vital area. This is important because it is becoming increasingly apparent that kinetics of drug binding is a key factor that the pharmaceutical sector should really be looking at in terms of a major dictator of potency.