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
Ranaghan K
(2014)
A catalytic role for methionine revealed by a combination of computation and experiments on phosphite dehydrogenase
in Chem. Sci.
Limb Michael
(2015)
Modelling catalysis in hen egg-white lysozyme
Sampson C
(2015)
A "Stepping Stone" Approach for Obtaining Quantum Free Energies of Hydration.
in The journal of physical chemistry. B
Ding W
(2015)
Effects of Lipid Composition on Bilayer Membranes Quantified by All-Atom Molecular Dynamics.
in The journal of physical chemistry. B
Kaiyawet N
(2015)
High-level QM/MM calculations support the concerted mechanism for Michael addition and covalent complex formation in thymidylate synthase.
in Journal of chemical theory and computation
Gray A
(2015)
In pursuit of an accurate spatial and temporal model of biomolecules at the atomistic level: a perspective on computer simulation.
in Acta crystallographica. Section D, Biological crystallography
Loeffler HH
(2015)
FESetup: Automating Setup for Alchemical Free Energy Simulations.
in Journal of chemical information and modeling
Woods CJ
(2015)
Combined quantum mechanics/molecular mechanics (QM/MM) simulations for protein-ligand complexes: free energies of binding of water molecules in influenza neuraminidase.
in The journal of physical chemistry. B
Jambrina P
(2015)
Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation
in Angewandte Chemie
Ross G
(2015)
Water Sites, Networks, And Free Energies with Grand Canonical Monte Carlo
in Journal of the American Chemical Society
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 | 07/2014 |
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 |