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
Espejo-Román JM
(2022)
Selective Anticancer Therapy Based on a HA-CD44 Interaction Inhibitor Loaded on Polymeric Nanoparticles.
in Pharmaceutics
Catlow CR
(2020)
Science to enable the circular economy.
in Philosophical transactions. Series A, Mathematical, physical, and engineering sciences
Sampson C
(2019)
On the magnetosensitivity of lipid peroxidation: two- versus three-radical dynamics
in Physical Chemistry Chemical Physics
Brandani GB
(2017)
Adsorption of the natural protein surfactant Rsn-2 onto liquid interfaces.
in Physical chemistry chemical physics : PCCP
Nutho B
(2019)
The reaction mechanism of Zika virus NS2B/NS3 serine protease inhibition by dipeptidyl aldehyde: a QM/MM study.
in Physical chemistry chemical physics : PCCP
Heiblum Robles A
(2018)
Phase transitions in stigmergic territorial systems
in Physical Review E
Lonsdale R
(2014)
A multiscale approach to modelling drug metabolism by membrane-bound cytochrome P450 enzymes.
in PLoS computational biology
Hashem S
(2017)
Allosteric modulation of cardiac myosin dynamics by omecamtiv mecarbil
in PLOS Computational Biology
Wells S
(2015)
Structure and Function in Homodimeric Enzymes: Simulations of Cooperative and Independent Functional Motions
in PLOS ONE
Deeks HM
(2020)
Interactive molecular dynamics in virtual reality for accurate flexible protein-ligand docking.
in PloS one
Sartori GR
(2019)
Ligand-induced conformational selection predicts the selectivity of cysteine protease inhibitors.
in PloS one
Mulholland A
(2016)
Dispelling the effects of a sorceress in enzyme catalysis
in Proceedings of the National Academy of Sciences
Sharma V
(2017)
Insights into functions of the H channel of cytochrome c oxidase from atomistic molecular dynamics simulations.
in Proceedings of the National Academy of Sciences of the United States of America
Kwon H
(2020)
Visualizing the protons in a metalloenzyme electron proton transfer pathway.
in Proceedings of the National Academy of Sciences of the United States of America
Oláh J
(2011)
Understanding the determinants of selectivity in drug metabolism through modeling of dextromethorphan oxidation by cytochrome P450.
in Proceedings of the National Academy of Sciences of the United States of America
Hutchins GH
(2023)
An expandable, modular de novo protein platform for precision redox engineering.
in Proceedings of the National Academy of Sciences of the United States of America
Gervasoni S
(2022)
A multiscale approach to predict the binding mode of metallo beta-lactamase inhibitors.
in Proteins
Warman H
(2023)
How proton transfer impacts hachimoji DNA.
in RSC advances
Tooke CL
(2020)
Cyclic boronates as versatile scaffolds for KPC-2 ß-lactamase inhibition.
in RSC medicinal chemistry
Kamsri P
(2019)
In silico study directed towards identification of the key structural features of GyrB inhibitors targeting MTB DNA gyrase: HQSAR, CoMSIA and molecular dynamics simulations.
in SAR and QSAR in environmental research
Toelzer C
(2020)
Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein.
in Science (New York, N.Y.)
Parker JL
(2021)
Cryo-EM structure of PepT2 reveals structural basis for proton-coupled peptide and prodrug transport in mammals.
in Science advances
Corey R
(2021)
Identification and assessment of cardiolipin interactions with E. coli inner membrane proteins
in Science Advances
Yamamoto E
(2020)
Multiple lipid binding sites determine the affinity of PH domains for phosphoinositide-containing membranes.
in Science advances
O'Connor M
(2018)
Sampling molecular conformations and dynamics in a multiuser virtual reality framework
in Science Advances
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
Deeks HM
(2023)
Free energy along drug-protein binding pathways interactively sampled in virtual reality.
in Scientific reports
Miles BT
(2017)
Direct Evidence of Lack of Colocalisation of Fluorescently Labelled Gold Labels Used in Correlative Light Electron Microscopy.
in Scientific reports
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
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
Woods CJ
(2013)
Computational assay of H7N9 influenza neuraminidase reveals R292K mutation reduces drug binding affinity.
in Scientific reports
Morando MA
(2016)
Conformational Selection and Induced Fit Mechanisms in the Binding of an Anticancer Drug to the c-Src Kinase.
in Scientific reports
Karabencheva-Christova TG
(2017)
Mechanistic Insights into the Reaction of Chlorination of Tryptophan Catalyzed by Tryptophan 7-Halogenase.
in Scientific reports
Pucheta-Martínez E
(2016)
An Allosteric Cross-Talk Between the Activation Loop and the ATP Binding Site Regulates the Activation of Src Kinase.
in Scientific reports
Dunseath O
(2019)
Studies of Black Diamond as an antibacterial surface for Gram Negative bacteria: the interplay between chemical and mechanical bactericidal activity.
in Scientific reports
Palaiokostas M
(2018)
Effects of lipid composition on membrane permeation
in Soft Matter
Zurek J
(2004)
MM and QM/MM Modeling of Threonyl-tRNA Synthetase: Model Testing and Simulations
in Structural Chemistry
Samsudin F
(2016)
OmpA: A Flexible Clamp for Bacterial Cell Wall Attachment.
in Structure (London, England : 1993)
Trick JL
(2016)
Functional Annotation of Ion Channel Structures by Molecular Simulation.
in Structure (London, England : 1993)
Hedger G
(2019)
Cholesterol Interaction Sites on the Transmembrane Domain of the Hedgehog Signal Transducer and Class F G Protein-Coupled Receptor Smoothened.
in Structure (London, England : 1993)
Rao S
(2020)
Characterizing Membrane Association and Periplasmic Transfer of Bacterial Lipoproteins through Molecular Dynamics Simulations.
in Structure (London, England : 1993)
Oliveira ASF
(2019)
Identification of the Initial Steps in Signal Transduction in the a4ß2 Nicotinic Receptor: Insights from Equilibrium and Nonequilibrium Simulations.
in Structure (London, England : 1993)
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)
Song W
(2021)
Modulation of adenosine A2a receptor oligomerization by receptor activation and PIP2 interactions.
in Structure (London, England : 1993)
Oliveira ASF
(2021)
Dynamical nonequilibrium molecular dynamics reveals the structural basis for allostery and signal propagation in biomolecular systems.
in The European physical journal. B
Dommer A
(2023)
#COVIDisAirborne: AI-enabled multiscale computational microscopy of delta SARS-CoV-2 in a respiratory aerosol.
in The international journal of high performance computing applications
Phintha A
(2021)
Dissecting the low catalytic capability of flavin-dependent halogenases.
in The Journal of biological chemistry
Freeman SL
(2023)
Heme binding to the SARS-CoV-2 spike glycoprotein.
in The Journal of biological chemistry
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 |