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
Kamsri P
(2020)
Discovery of New and Potent InhA Inhibitors as Antituberculosis Agents: Structure-Based Virtual Screening Validated by Biological Assays and X-ray Crystallography.
in Journal of chemical information and modeling
Hanwarinroj C
(2022)
Discovery of novel and potent InhA inhibitors by an in silico screening and pharmacokinetic prediction
in Future Medicinal Chemistry
Chan HTH
(2021)
Discovery of SARS-CoV-2 Mpro peptide inhibitors from modelling substrate and ligand binding.
in Chemical science
Mulholland A
(2016)
Dispelling the effects of a sorceress in enzyme catalysis
in Proceedings of the National Academy of Sciences
Phintha A
(2021)
Dissecting the low catalytic capability of flavin-dependent halogenases.
in The Journal of biological chemistry
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
Van Der Kamp M
(2017)
Dynamical origins of heat capacity changes in enzyme catalysed reactions
Van Der Kamp MW
(2018)
Dynamical origins of heat capacity changes in enzyme-catalysed reactions.
in Nature communications
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
Ding W
(2017)
Effects of High Pressure on Phospholipid Bilayers.
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
Palaiokostas M
(2018)
Effects of lipid composition on membrane permeation
in Soft Matter
Douglas-Gallardo OA
(2020)
Electronic structure benchmark calculations of CO2 fixing elementary chemical steps in RuBisCO using the projector-based embedding approach.
in Journal of computational 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
Bunzel HA
(2019)
Emergence of a Negative Activation Heat Capacity during Evolution of a Designed Enzyme.
in Journal of the American Chemical Society
Mujika J
(2012)
Encyclopedia of Inorganic and Bioinorganic Chemistry
O'Hagan MP
(2020)
Enhanced sampling molecular dynamics simulations correctly predict the diverse activities of a series of stiff-stilbene G-quadruplex DNA ligands.
in Chemical science
Hanpaibool C
(2023)
Enhancement by pyrazolones of colistin efficacy against mcr-1-expressing E. coli: an in silico and in vitro investigation.
in Journal of computer-aided molecular design
Zinovjev K
(2020)
Enlighten2: molecular dynamics simulations of protein-ligand systems made accessible.
in Bioinformatics (Oxford, England)
Ali HS
(2019)
Entropy of Simulated Liquids Using Multiscale Cell Correlation.
in Entropy (Basel, Switzerland)
Mulholland A
(2012)
Enzyme dynamics and catalysis in the mechanism of DNA polymerase
in Theoretical Chemistry Accounts
Arcus VL
(2020)
Enzyme evolution and the temperature dependence of enzyme catalysis.
in Current opinion in structural biology
Çinaroglu S
(2021)
Evaluating the Performance of Water Models with Host-Guest Force Fields in Binding Enthalpy Calculations for Cucurbit[7]uril-Guest Systems
in The Journal of Physical Chemistry B
Bunzel H
(2021)
Evolution of dynamical networks enhances catalysis in a designer enzyme
in Nature Chemistry
Leferink NGH
(2019)
Experiment and Simulation Reveal How Mutations in Functional Plasticity Regions Guide Plant Monoterpene Synthase Product Outcome.
in ACS catalysis
Evans LE
(2019)
Exploitation of Antibiotic Resistance as a Novel Drug Target: Development of a ß-Lactamase-Activated Antibacterial Prodrug.
in Journal of medicinal chemistry
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
Shannon RJ
(2021)
Exploring human-guided strategies for reaction network exploration: Interactive molecular dynamics in virtual reality as a tool for citizen scientists.
in The Journal of chemical physics
Loeffler HH
(2015)
FESetup: Automating Setup for Alchemical Free Energy Simulations.
in Journal of chemical information and modeling
Oliveira A
(2023)
Fluctuation Relations to Calculate Protein Redox Potentials from Molecular Dynamics Simulations
in Journal of Chemical Theory and Computation
Deeks HM
(2023)
Free energy along drug-protein binding pathways interactively sampled in virtual reality.
in Scientific reports
Toelzer C
(2020)
Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein.
in Science (New York, N.Y.)
Shoemark D
(2021)
Frontispiece: Molecular Simulations suggest Vitamins, Retinoids and Steroids as Ligands of the Free Fatty Acid Pocket of the SARS-CoV-2 Spike Protein
in Angewandte Chemie International Edition
Shoemark DK
(2021)
Frontispiz: Molecular Simulations suggest Vitamins, Retinoids and Steroids as Ligands of the Free Fatty Acid Pocket of the SARS-CoV-2 Spike Protein.
in Angewandte Chemie (Weinheim an der Bergstrasse, Germany)
Trick JL
(2016)
Functional Annotation of Ion Channel Structures by Molecular Simulation.
in Structure (London, England : 1993)
Paramo T
(2017)
Functional Validation of Heteromeric Kainate Receptor Models.
in Biophysical journal
Maingi V
(2015)
Gating-like Motions and Wall Porosity in a DNA Nanopore Scaffold Revealed by Molecular Simulations.
in ACS nano
Lang EJM
(2022)
Generalized Born Implicit Solvent Models Do Not Reproduce Secondary Structures of De Novo Designed Glu/Lys Peptides.
in Journal of chemical theory and computation
Freeman SL
(2023)
Heme binding to the SARS-CoV-2 spike glycoprotein.
in The Journal of biological chemistry
Hermann JC
(2009)
High level QM/MM modeling of the formation of the tetrahedral intermediate in the acylation of wild type and K73A mutant TEM-1 class A beta-lactamase.
in The journal of physical chemistry. A
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
Warman H
(2023)
How proton transfer impacts hachimoji DNA.
in RSC advances
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 |