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
McGeagh JD
(2011)
Protein dynamics and enzyme catalysis: insights from simulations.
in Biochimica et biophysica acta
Glowacki DR
(2012)
Protein dynamics and enzyme catalysis: the ghost in the machine?
in Biochemical Society transactions
Wu Z
(2019)
Proton Control of Transitions in an Amino Acid Transporter.
in Biophysical journal
Song W
(2022)
PyLipID: A Python Package for Analysis of Protein-Lipid Interactions from Molecular Dynamics Simulations.
in Journal of chemical theory and computation
Hanpaibool C
(2023)
Pyrazolones Potentiate Colistin Activity against MCR-1-Producing Resistant Bacteria: Computational and Microbiological Study
in ACS Omega
Harvey J
(2006)
QM and QM/MM studies of selectivity in organic and bioorganic chemistry
in Journal of Physical Organic Chemistry
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
Karabencheva-Christova Tatyana Georgieva
(2009)
QM/MM modelling of mechanisms of flavin-containing enzymes
Lawan Narin
(2010)
QM/MM modelling of the reaction mechanism of chorismate synthase and mutase
Lawan N
(2022)
QM/MM Molecular Modeling Reveals Mechanism Insights into Flavin Peroxide Formation in Bacterial Luciferase.
in Journal of chemical information and modeling
Lence E
(2018)
QM/MM simulations identify the determinants of catalytic activity differences between type II dehydroquinase enzymes
in Organic & Biomolecular Chemistry
Chudyk EI
(2022)
QM/MM Simulations Reveal the Determinants of Carbapenemase Activity in Class A ß-Lactamases.
in ACS infectious diseases
Nutho B
(2019)
QM/MM Study on Cleavage Mechanism Catalyzed by Zika Virus NS2B/NS3 Serine Protease
in Biophysical Journal
Szeto M
(2009)
QM/MM study on the mechanism of peptide hydrolysis by carboxypeptidase A
in Journal of Molecular Structure: THEOCHEM
Szefczyk B
(2007)
Quantum chemical analysis of reaction paths in chorismate mutase: Conformational effects and electrostatic stabilization
in International Journal of Quantum Chemistry
Nutho B
(2019)
Quantum Mechanics/Molecular Mechanics (QM/MM) Calculations Support a Concerted Reaction Mechanism for the Zika Virus NS2B/NS3 Serine Protease with Its Substrate.
in The journal of physical chemistry. B
Jitonnom J
(2017)
Quantum Mechanics/Molecular Mechanics Simulations Identify the Ring-Opening Mechanism of Creatininase.
in Biochemistry
Limb MAL
(2019)
Quantum Mechanics/Molecular Mechanics Simulations Show Saccharide Distortion is Required for Reaction in Hen Egg-White Lysozyme.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Woods CJ
(2014)
Rapid decomposition and visualisation of protein-ligand binding free energies by residue and by water.
in Faraday discussions
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
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
Singh J
(2021)
Real-time super-resolution mapping of locally anisotropic grain orientations for ultrasonic non-destructive evaluation of crystalline material
in Neural Computing and Applications
Ansell TB
(2021)
Relative Affinities of Protein-Cholesterol Interactions from Equilibrium Molecular Dynamics Simulations.
in Journal of chemical theory and computation
Lythell E
(2020)
Resistance to the "last resort" antibiotic colistin: a single-zinc mechanism for phosphointermediate formation in MCR enzymes.
in Chemical communications (Cambridge, England)
Hindson S
(2021)
Rigidifying a De Novo Enzyme Increases Activity and Induces a Negative Activation Heat Capacity
in ACS Catalysis
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
O'Connor M
(2018)
Sampling molecular conformations and dynamics in a multiuser virtual reality framework
in Science Advances
Oliveira ASF
(2023)
SARS-CoV-2 spike variants differ in their allosteric responses to linoleic acid.
in Journal of molecular cell biology
Mulholland AJ
(2023)
Science after Brexit: bright spots on the Horizon?
in EMBO reports
Catlow CR
(2020)
Science to enable the circular economy.
in Philosophical transactions. Series A, Mathematical, physical, and engineering sciences
Espejo-Román JM
(2022)
Selective Anticancer Therapy Based on a HA-CD44 Interaction Inhibitor Loaded on Polymeric Nanoparticles.
in Pharmaceutics
Ranaghan K
(2016)
Simulating Enzyme Reactivity - Computational Methods in Enzyme Catalysis
Punkvang A
(2019)
Simulations of Shikimate Dehydrogenase from Mycobacterium tuberculosis in Complex with 3-Dehydroshikimate and NADPH Suggest Strategies for MtbSDH Inhibition.
in Journal of chemical information and modeling
Oliveira ASF
(2020)
Simulations support the interaction of the SARS-CoV-2 spike protein with nicotinic acetylcholine receptors.
in bioRxiv : the preprint server for biology
Schiffrin B
(2016)
Skp is a multivalent chaperone of outer-membrane proteins.
in Nature structural & molecular biology
Hirvonen V
(2020)
Small Changes in Hydration Determine Cephalosporinase Activity of OXA-48 ß-Lactamases
in ACS Catalysis
Larsen AH
(2022)
Specific interactions of peripheral membrane proteins with lipids: what can molecular simulations show us?
in Bioscience reports
Fan Betty
(2017)
Stage IV breast cancer is increased by omitting screening mammography
in ANNALS OF SURGICAL ONCOLOGY
Song W
(2019)
State-dependent Lipid Interactions with the A2a Receptor Revealed by MD Simulations Using In Vivo-Mimetic Membranes.
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
Van Den Berg B
(2016)
Structural basis for Mep2 ammonium transceptor activation by phosphorylation.
in Nature communications
Karuppiah V
(2017)
Structural Basis of Catalysis in the Bacterial Monoterpene Synthases Linalool Synthase and 1,8-Cineole Synthase.
in ACS catalysis
Lodola A
(2010)
Structural Fluctuations in Enzyme-Catalyzed Reactions: Determinants of Reactivity in Fatty Acid Amide Hydrolase from Multivariate Statistical Analysis of Quantum Mechanics/Molecular Mechanics Paths.
in Journal of chemical theory and computation
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 |