Multiscale Ensemble Computing for Modelling Biological Catalysts
Lead Research Organisation:
University of Bristol
Department Name: Chemistry
Abstract
The goal of this project is to use the flexible HPC resource made available on HPCx to perform a detailed investigation of the mechanism of chemical reactions catalysed by the enzyme fatty acid amide hydrolase (FAAH), an important target for drug development. HPC resources are increasingly helping to illuminate and analyse the fundamental mechanisms of biological 'molecular machines'. An example is enzyme catalysis. Enzymes are very efficient natural catalysts. Understanding how they work is a vital first step to the goal of harnessing their power for industrial and pharmaceutical applications. For example, many drugs work by stopping enzymes from functioning.Atomically detailed computer models of enzyme-catalysed reactions provide an insight into the source of an enzyme's power. Due to the large size of biological molecules, simplified classical models of atomic interactions are used. These molecular mechanics (MM) models have been used successfully to understand the molecular dynamics of proteins. However, MM can provide only a low-quality model of a chemical reaction, as electrons are represented implicitly. The best quality chemical models are provided by quantum mechanics (QM). QM calculations are highly computationally expensive, so it would be challenging to solve a QM model of an entire enzyme system. One solution is to use multiscale methods that embed a QM representation of the reactive region of the enzyme within an MM model of the rest of the system. Multilevel simulations of biological systems scale poorly over the many processors available on an HPC resource. New multiscale modelling methods(4) that split a single calculation into an ensemble of loosely-coupled simulations, are therefore a promising new direction to utilize maximum computingpower. The aim is to make best use of the large numbers of processors by effectively coupling multiple individual simulations into a single supra-simulation. This method, applied on an HPC resource, promises to lead to a step change in the quality of the modelling of enzyme-catalysed reactions, and will provide new insights into these remarkable biological molecules.
Organisations
Publications
Morando MA
(2016)
Conformational Selection and Induced Fit Mechanisms in the Binding of an Anticancer Drug to the c-Src Kinase.
in Scientific reports
Reddy T
(2016)
Computational virology: From the inside out.
in Biochimica et biophysica acta
Grundmann M
(2016)
A Molecular Mechanism for Sequential Activation of a G Protein-Coupled Receptor
in Cell Chemical Biology
Samsudin F
(2016)
OmpA: A Flexible Clamp for Bacterial Cell Wall Attachment.
in Structure (London, England : 1993)
Musgaard M
(2016)
Steered Molecular Dynamics Simulations Predict Conformational Stability of Glutamate Receptors.
in Journal of chemical information and modeling
Pucheta-MartÃnez E
(2016)
An Allosteric Cross-Talk Between the Activation Loop and the ATP Binding Site Regulates the Activation of Src Kinase.
in Scientific reports
Trick JL
(2016)
Functional Annotation of Ion Channel Structures by Molecular Simulation.
in Structure (London, England : 1993)
Ranaghan K
(2016)
Simulating Enzyme Reactivity - Computational Methods in Enzyme Catalysis
Sjöström T
(2016)
Bactericidal nanospike surfaces via thermal oxidation of Ti alloy substrates
in Materials Letters
Mulholland AJ
(2016)
Dispelling the effects of a sorceress in enzyme catalysis.
in Proceedings of the National Academy of Sciences of the United States of America
Pucheta-Martinez E
(2016)
Changes in the folding landscape of the WW domain provide a molecular mechanism for an inherited genetic syndrome
in Scientific Reports
Matos GDR
(2017)
Approaches for calculating solvation free energies and enthalpies demonstrated with an update of the FreeSolv database.
in Journal of chemical and engineering data
Ranaghan KE
(2017)
Ab Initio QM/MM Modeling of the Rate-Limiting Proton Transfer Step in the Deamination of Tryptamine by Aromatic Amine Dehydrogenase.
in The journal of physical chemistry. B
Hinchliffe P
(2017)
Insights into the Mechanistic Basis of Plasmid-Mediated Colistin Resistance from Crystal Structures of the Catalytic Domain of MCR-1.
in Scientific reports
Noy A
(2017)
Interference between Triplex and Protein Binding to Distal Sites on Supercoiled DNA.
in Biophysical journal
Pennifold RC
(2017)
Correcting density-driven errors in projection-based embedding.
in The Journal of chemical physics
Beker W
(2017)
Rapid Estimation of Catalytic Efficiency by Cumulative Atomic Multipole Moments: Application to Ketosteroid Isomerase Mutants.
in Journal of chemical theory and computation
Ge Y
(2017)
Identification of the quinolinedione inhibitor binding site in Cdc25 phosphatase B through docking and molecular dynamics simulations.
in Journal of computer-aided molecular design
Domicevica L
(2017)
Multiscale molecular dynamics simulations of lipid interactions with P-glycoprotein in a complex membrane.
in Journal of molecular graphics & modelling
Matheson AB
(2017)
The development of phytosterol-lecithin mixed micelles and organogels.
in Food & function
Watkins DW
(2017)
Construction and in vivo assembly of a catalytically proficient and hyperthermostable de novo enzyme.
in Nature communications
Brandani GB
(2017)
Adsorption of the natural protein surfactant Rsn-2 onto liquid interfaces.
in Physical chemistry chemical physics : PCCP
| Description | BBSRC Tools and Techniques: Computational tools for enzyme engineering: bridging the gap between enzymologists and expert simulation |
| Amount | £146,027 (GBP) |
| Funding ID | BB/L018756/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 06/2014 |
| End | 01/2016 |
| Description | Biocatalysis and Biotransformation: A 5th Theme for the National Catalysis Hub |
| Amount | £3,053,639 (GBP) |
| Funding ID | EP/M013219/1 |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 01/2015 |
| End | 12/2019 |
| Title | Sire 2009.1 |
| Description | 2009.1 release of the Sire molecular simulation framework. Main enhancement was making the code portable to a wide range of architectures, e.g. including PowerPC/AIX (so that the code could run efficiently on HPCx) and enhancing the functionality of the QM/MM free energy code. |
| Type Of Technology | Software |
| Year Produced | 2009 |
| Open Source License? | Yes |
| Impact | Sire is used in several pharmaceutical companies for applications in drug design and development. This version of the code was used to run the simulations in "Compatibility of Quantum Chemical Methods and Empirical (MM) Water Models in Quantum Mechanics / Molecular Mechanics Liquid Water Simulations", J. Phys. Chem. Lett., doi:10.1021/jz900096p and "Combined Quantum Mechanics Molecular Mechanics (QM MM) Simulations for Protein Ligand Complexes: Free Energies of Binding of Water Molecules in Influenza Neuraminidase", J. Phys. Chem. B, 2014, Accepted 10.1021/jp506413j |
| URL | http://www.siremol.org/Sire/Home.html |