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
Çinaroglu SS
(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
Çinaroglu S
(2023)
Computed Protein-Protein Enthalpy Signatures as a Tool for Identifying Conformation Sampling Problems
in Journal of Chemical Information and Modeling
Zurek J
(2004)
MM and QM/MM Modeling of Threonyl-tRNA Synthetase: Model Testing and Simulations
in Structural Chemistry
Zinovjev K
(2020)
Enlighten2: molecular dynamics simulations of protein-ligand systems made accessible.
in Bioinformatics (Oxford, England)
Zhang X
(2018)
Multiscale analysis of enantioselectivity in enzyme-catalysed 'lethal synthesis' using projector-based embedding.
in Royal Society open science
Yang Z
(2021)
Multiscale Workflow for Modeling Ligand Complexes of Zinc Metalloproteins.
in Journal of chemical information and modeling
Yamamoto E
(2020)
Multiple lipid binding sites determine the affinity of PH domains for phosphoinositide-containing membranes.
in Science advances
Wu Z
(2019)
Proton Control of Transitions in an Amino Acid Transporter.
in Biophysical journal
Woods CJ
(2011)
A water-swap reaction coordinate for the calculation of absolute protein-ligand binding free energies.
in The Journal of chemical physics
Woods CJ
(2014)
Rapid decomposition and visualisation of protein-ligand binding free energies by residue and by water.
in Faraday discussions
Woods CJ
(2013)
Computational assay of H7N9 influenza neuraminidase reveals R292K mutation reduces drug binding affinity.
in Scientific reports
Woods CJ
(2024)
Sire: An interoperability engine for prototyping algorithms and exchanging information between molecular simulation programs.
in The Journal of chemical physics
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
Woods CJ
(2009)
Multicore Parallelization of Kohn-Sham Theory.
in Journal of chemical theory and computation
Winokan M
(2023)
Multiscale simulations reveal the role of PcrA helicase in protecting against spontaneous point mutations in DNA.
in Scientific reports
Wells SA
(2015)
Structure and Function in Homodimeric Enzymes: Simulations of Cooperative and Independent Functional Motions.
in PloS one
Watkins DW
(2017)
Construction and in vivo assembly of a catalytically proficient and hyperthermostable de novo enzyme.
in Nature communications
Warman H
(2023)
How proton transfer impacts hachimoji DNA.
in RSC advances
Wang L
(2020)
Mixing and matching genes of marine and terrestrial origin in the biosynthesis of the mupirocin antibiotics.
in Chemical science
Walters RK
(2022)
The emerging potential of interactive virtual reality in drug discovery.
in Expert opinion on drug discovery
Walker EJ
(2024)
Cooperative Conformational Transitions Underpin the Activation Heat Capacity in the Temperature Dependence of Enzyme Catalysis.
in ACS catalysis
Von Kügelgen A
(2024)
Membraneless channels sieve cations in ammonia-oxidizing marine archaea
in Nature
Von Kügelgen A
(2020)
In Situ Structure of an Intact Lipopolysaccharide-Bound Bacterial Surface Layer.
in Cell
Von Glehn Patrick
(2015)
Modelling the reactivity of glutamate mutase and heme dioxygenase enzymes
Voice AT
(2021)
Mechanism of covalent binding of ibrutinib to Bruton's tyrosine kinase revealed by QM/MM calculations.
in Chemical science
Voice Angus
(2021)
Modelling the reactivity of cysteine targeting covalent inhibitors
Voice A
(2019)
Limitations of Ligand-Only Approaches for Predicting the Reactivity of Covalent Inhibitors.
in Journal of chemical information and modeling
Vinas Teresa Minguez
(2021)
A Conserved Arginine with Non-Conserved Function is a Key Determinant of Agonist Selectivity in Alpha7 Nicotinic Acetylcholine Receptors
in BIOPHYSICAL JOURNAL
Vickery ON
(2021)
CG2AT2: an Enhanced Fragment-Based Approach for Serial Multi-scale Molecular Dynamics Simulations.
in Journal of chemical theory and computation
Van Der Kamp MW
(2018)
Dynamical origins of heat capacity changes in enzyme-catalysed reactions.
in Nature communications
Van Der Kamp MW
(2010)
Testing high-level QM/MM methods for modeling enzyme reactions: acetyl-CoA deprotonation in citrate synthase.
in The journal of physical chemistry. B
Van Der Kamp MW
(2013)
Combined quantum mechanics/molecular mechanics (QM/MM) methods in computational enzymology.
in Biochemistry
Van Der Kamp MW
(2011)
"Lethal synthesis" of fluorocitrate by citrate synthase explained through QM/MM modeling.
in Angewandte Chemie (International ed. in English)
Van Der Kamp MW
(2013)
Conformational change and ligand binding in the aristolochene synthase catalytic cycle.
in Biochemistry
Van Der Kamp M
(2011)
"Lethal Synthesis" of Fluorocitrate by Citrate Synthase Explained through QM/MM Modeling
in Angewandte Chemie
Van Der Kamp M
(2009)
ChemInform Abstract: Computational Enzymology: Insight into Biological Catalyst from Modelling
in ChemInform
Van Der Kamp M
(2017)
Dynamical origins of heat capacity changes in enzyme catalysed reactions
Van Den Berg B
(2016)
Structural basis for Mep2 ammonium transceptor activation by phosphorylation.
in Nature communications
Twidale RM
(2021)
Crystallography and QM/MM Simulations Identify Preferential Binding of Hydrolyzed Carbapenem and Penem Antibiotics to the L1 Metallo-ß-Lactamase in the Imine Form.
in Journal of chemical information and modeling
Twidale Rebecca M.
(2021)
Modelling the reactivity of zinc metalloenzymes and the SARS-CoV-2 main protease
Trujillo P
(2024)
Insight from atomistic molecular dynamics simulations into the supramolecular assembly of the aldo-keto reductase from Trypanosoma cruzi.
in Journal of molecular modeling
Trick JL
(2016)
Functional Annotation of Ion Channel Structures by Molecular Simulation.
in Structure (London, England : 1993)
| 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 |