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
Fonseca F
(2012)
The basis for carbapenem hydrolysis by class A ß-lactamases: a combined investigation using crystallography and simulations.
in Journal of the American Chemical Society
Lonsdale R
(2012)
ChemInform Abstract: A Practical Guide to Modelling Enzyme-Catalyzed Reactions
in ChemInform
Mulholland A
(2012)
Enzyme dynamics and catalysis in the mechanism of DNA polymerase
in Theoretical Chemistry Accounts
Jitonnom J
(2012)
Insights into conformational changes of procarboxypeptidase A and B from simulations: a plausible explanation for different intrinsic activity
in Theoretical Chemistry Accounts
Lonsdale R
(2012)
Determinants of reactivity and selectivity in soluble epoxide hydrolase from quantum mechanics/molecular mechanics modeling.
in Biochemistry
Glowacki DR
(2012)
Protein dynamics and enzyme catalysis: the ghost in the machine?
in Biochemical Society transactions
Lonsdale R
(2012)
Effects of Dispersion in Density Functional Based Quantum Mechanical/Molecular Mechanical Calculations on Cytochrome P450 Catalyzed Reactions.
in Journal of chemical theory and computation
Mujika JI
(2012)
Mechanism of C-terminal intein cleavage in protein splicing from QM/MM molecular dynamics simulations.
in Organic & biomolecular chemistry
Lonsdale R
(2012)
A practical guide to modelling enzyme-catalysed reactions.
in Chemical Society reviews
Mujika J
(2012)
Encyclopedia of Inorganic and Bioinorganic Chemistry
Van Der Kamp M
(2013)
Combined Quantum Mechanics/Molecular Mechanics (QM/MM) Methods in Computational Enzymology
in Biochemistry
Chudyk E
(2013)
Nonempirical Energetic Analysis of Reactivity and Covalent Inhibition of Fatty Acid Amide Hydrolase
in The Journal of Physical Chemistry B
Woods CJ
(2013)
Computational assay of H7N9 influenza neuraminidase reveals R292K mutation reduces drug binding affinity.
in Scientific reports
Christov C
(2013)
Conformational Effects on the pro - S Hydrogen Abstraction Reaction in Cyclooxygenase-1: An Integrated QM/MM and MD Study
in Biophysical Journal
Van Der Kamp MW
(2013)
Conformational change and ligand binding in the aristolochene synthase catalytic cycle.
in Biochemistry
Lodola A
(2013)
Computational enzymology.
in Methods in molecular biology (Clifton, N.J.)
Chudyk Ewa Iwona
(2013)
Calculating free energy profiles for enzyme catalysed reactions
Chavent M
(2014)
Methodologies for the analysis of instantaneous lipid diffusion in MD simulations of large membrane systems.
in Faraday discussions
Mlýnský V
(2014)
Comparison of ab Initio, DFT, and Semiempirical QM/MM Approaches for Description of Catalytic Mechanism of Hairpin Ribozyme.
in Journal of chemical theory and computation
Ranaghan K
(2014)
A catalytic role for methionine revealed by a combination of computation and experiments on phosphite dehydrogenase
in Chem. Sci.
Lonsdale R
(2014)
A multiscale approach to modelling drug metabolism by membrane-bound cytochrome P450 enzymes.
in PLoS computational biology
Jitonnom J
(2014)
QM/MM free-energy simulations of reaction in Serratia marcescens Chitinase B reveal the protonation state of Asp142 and the critical role of Tyr214.
in The journal of physical chemistry. B
Daniels AD
(2014)
Reaction mechanism of N-acetylneuraminic acid lyase revealed by a combination of crystallography, QM/MM simulation, and mutagenesis.
in ACS chemical biology
Pasi M
(2014)
µABC: a systematic microsecond molecular dynamics study of tetranucleotide sequence effects in B-DNA.
in Nucleic acids research
Woods CJ
(2014)
Rapid decomposition and visualisation of protein-ligand binding free energies by residue and by water.
in Faraday discussions
Román-Meléndez GD
(2014)
Role of active site residues in promoting cobalt-carbon bond homolysis in adenosylcobalamin-dependent mutases revealed through experiment and computation.
in Biochemistry
Lever G
(2014)
Large-Scale Density Functional Theory Transition State Searching in Enzymes.
in The journal of physical chemistry letters
Lawan N
(2014)
Comparison of DFT and ab initio QM/MM methods for modelling reaction in chorismate synthase
in Chemical Physics Letters
Jefferys E
(2014)
NRas slows the rate at which a model lipid bilayer phase separates.
in Faraday discussions
Wells S
(2015)
Structure and Function in Homodimeric Enzymes: Simulations of Cooperative and Independent Functional Motions
in PLOS ONE
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
Jambrina P
(2015)
Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation
in Angewandte Chemie
Ding W
(2015)
Effects of Lipid Composition on Bilayer Membranes Quantified by All-Atom Molecular Dynamics.
in The journal of physical chemistry. B
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
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
Von Glehn Patrick
(2015)
Modelling the reactivity of glutamate mutase and heme dioxygenase enzymes
Ross G
(2015)
Water Sites, Networks, And Free Energies with Grand Canonical Monte Carlo
in Journal of the American Chemical Society
Sampson C
(2015)
A "Stepping Stone" Approach for Obtaining Quantum Free Energies of Hydration.
in The journal of physical chemistry. B
Limb Michael
(2015)
Modelling catalysis in hen egg-white lysozyme
Maingi V
(2015)
Gating-like Motions and Wall Porosity in a DNA Nanopore Scaffold Revealed by Molecular Simulations.
in ACS nano
Loeffler HH
(2015)
FESetup: Automating Setup for Alchemical Free Energy Simulations.
in Journal of chemical information and modeling
Althorpe SC
(2016)
Non-adiabatic reactions: general discussion.
in Faraday discussions
Mulholland A
(2016)
Dispelling the effects of a sorceress in enzyme catalysis
in Proceedings of the National Academy of Sciences
Van Den Berg B
(2016)
Structural basis for Mep2 ammonium transceptor activation by phosphorylation.
in Nature communications
Suardíaz R
(2016)
Understanding the Mechanism of the Hydrogen Abstraction from Arachidonic Acid Catalyzed by the Human Enzyme 15-Lipoxygenase-2. A Quantum Mechanics/Molecular Mechanics Free Energy Simulation.
in Journal of chemical theory and computation
Reddy T
(2016)
Computational virology: From the inside out
in Biochimica et Biophysica Acta (BBA) - Biomembranes
May PW
(2016)
Diamond-coated 'black silicon' as a promising material for high-surface-area electrochemical electrodes and antibacterial surfaces.
in Journal of materials chemistry. B
Angulo G
(2016)
New methods: general discussion.
in Faraday discussions
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 |