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
Ainsley J
(2018)
Structural Insights from Molecular Dynamics Simulations of Tryptophan 7-Halogenase and Tryptophan 5-Halogenase.
in ACS omega
Ainsley J
(2018)
Combined Quantum Mechanics and Molecular Mechanics Studies of Enzymatic Reaction Mechanisms.
in Advances in protein chemistry and structural biology
Ali HS
(2019)
Entropy of Simulated Liquids Using Multiscale Cell Correlation.
in Entropy (Basel, Switzerland)
Althorpe SC
(2016)
Non-adiabatic reactions: general discussion.
in Faraday discussions
Amaro RE
(2020)
A Community Letter Regarding Sharing Biomolecular Simulation Data for COVID-19.
in Journal of chemical information and modeling
Amaro RE
(2018)
Multiscale Methods in Drug Design Bridge Chemical and Biological Complexity in the Search for Cures.
in Nature reviews. Chemistry
Amaro RE
(2020)
Biomolecular Simulations in the Time of COVID19, and After.
in Computing in science & engineering
Amos STA
(2021)
Membrane Interactions of a-Synuclein Revealed by Multiscale Molecular Dynamics Simulations, Markov State Models, and NMR.
in The journal of physical chemistry. B
Angulo G
(2016)
New methods: general discussion.
in Faraday discussions
Ansell TB
(2021)
Relative Affinities of Protein-Cholesterol Interactions from Equilibrium Molecular Dynamics Simulations.
in Journal of chemical theory and computation
Arcus VL
(2020)
Temperature, Dynamics, and Enzyme-Catalyzed Reaction Rates.
in Annual review of biophysics
Arcus VL
(2016)
On the Temperature Dependence of Enzyme-Catalyzed Rates.
in Biochemistry
Arcus VL
(2020)
Enzyme evolution and the temperature dependence of enzyme catalysis.
in Current opinion in structural biology
Ashraf S
(2021)
Exploration of the structural requirements of Aurora Kinase B inhibitors by a combined QSAR, modelling and molecular simulation approach.
in Scientific reports
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
Bennie S
(2019)
Teaching Enzyme Catalysis Using Interactive Molecular Dynamics in Virtual Reality
in Journal of Chemical Education
Bennie S
(2016)
A Projector-Embedding Approach for Multiscale Coupled-Cluster Calculations Applied to Citrate Synthase
in Journal of Chemical Theory and Computation
Brandani GB
(2017)
Adsorption of the natural protein surfactant Rsn-2 onto liquid interfaces.
in Physical chemistry chemical physics : PCCP
Bueren-Calabuig JA
(2016)
Impact of Ser17 Phosphorylation on the Conformational Dynamics of the Oncoprotein MDM2.
in Biochemistry
Bunzel H
(2022)
Photovoltaic enzymes by design and evolution
Bunzel HA
(2021)
Designing better enzymes: Insights from directed evolution.
in Current opinion in structural biology
Bunzel HA
(2019)
Emergence of a Negative Activation Heat Capacity during Evolution of a Designed Enzyme.
in Journal of the American Chemical Society
Bunzel HA
(2021)
Evolution of dynamical networks enhances catalysis in a designer enzyme.
in Nature chemistry
Calabrò G
(2016)
Elucidation of Nonadditive Effects in Protein-Ligand Binding Energies: Thrombin as a Case Study.
in The journal of physical chemistry. B
Caldwell TA
(2022)
Conformational dynamics of the membrane enzyme LspA upon antibiotic and substrate binding.
in Biophysical journal
Callegari D
(2018)
L718Q mutant EGFR escapes covalent inhibition by stabilizing a non-reactive conformation of the lung cancer drug osimertinib.
in Chemical science
Capoferri L
(2011)
Application of a SCC-DFTB QM/MM approach to the investigation of the catalytic mechanism of fatty acid amide hydrolase.
in Journal of molecular modeling
Catlow CR
(2020)
Science to enable the circular economy.
in Philosophical transactions. Series A, Mathematical, physical, and engineering sciences
Chan HTH
(2021)
Discovery of SARS-CoV-2 Mpro peptide inhibitors from modelling substrate and ligand binding.
in Chemical science
Chavent M
(2014)
Methodologies for the analysis of instantaneous lipid diffusion in MD simulations of large membrane systems.
in Faraday discussions
Chrestia JF
(2022)
A Functional Interaction Between Y674-R685 Region of the SARS-CoV-2 Spike Protein and the Human a7 Nicotinic Receptor.
in Molecular neurobiology
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
Chudyk E
(2013)
Nonempirical Energetic Analysis of Reactivity and Covalent Inhibition of Fatty Acid Amide Hydrolase
in The Journal of Physical Chemistry B
Chudyk EI
(2022)
QM/MM Simulations Reveal the Determinants of Carbapenemase Activity in Class A ß-Lactamases.
in ACS infectious diseases
Chudyk Ewa Iwona
(2013)
Calculating free energy profiles for enzyme catalysed reactions
Claeyssens F
(2011)
Analysis of chorismate mutase catalysis by QM/MM modelling of enzyme-catalysed and uncatalysed reactions.
in Organic & biomolecular chemistry
Corey R
(2021)
Identification and assessment of cardiolipin interactions with E. coli inner membrane proteins
in Science Advances
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
Dawson WM
(2021)
Structural resolution of switchable states of a de novo peptide assembly.
in Nature communications
De Simone A
(2019)
A computationally designed binding mode flip leads to a novel class of potent tri-vector cyclophilin inhibitors.
in Chemical science
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 |