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 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
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)
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
(2014)
Rapid decomposition and visualisation of protein-ligand binding free energies by residue and by water.
in Faraday discussions
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
Woods CJ
(2013)
Computational assay of H7N9 influenza neuraminidase reveals R292K mutation reduces drug binding affinity.
in Scientific reports
Woods CJ
(2011)
A water-swap reaction coordinate for the calculation of absolute protein-ligand binding free energies.
in The Journal of chemical physics
Wells S
(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
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
Van Der Kamp MW
(2013)
Conformational change and ligand binding in the aristolochene synthase catalytic cycle.
in Biochemistry
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
(2018)
Dynamical origins of heat capacity changes in enzyme-catalysed reactions.
in Nature communications
Van Der Kamp M
(2009)
ChemInform Abstract: Computational Enzymology: Insight into Biological Catalyst from Modelling
in ChemInform
Van Der Kamp M
(2011)
"Lethal Synthesis" of Fluorocitrate by Citrate Synthase Explained through QM/MM Modeling
in Angewandte Chemie
Van Der Kamp M
(2013)
Combined Quantum Mechanics/Molecular Mechanics (QM/MM) Methods in Computational Enzymology
in Biochemistry
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
Trick JL
(2016)
Functional Annotation of Ion Channel Structures by Molecular Simulation.
in Structure (London, England : 1993)
Tooke CL
(2023)
Tautomer-Specific Deacylation and O-Loop Flexibility Explain the Carbapenem-Hydrolyzing Broad-Spectrum Activity of the KPC-2 ß-Lactamase.
in Journal of the American Chemical Society
Tooke CL
(2019)
Molecular Basis of Class A ß-Lactamase Inhibition by Relebactam.
in Antimicrobial agents and chemotherapy
Tooke CL
(2020)
Cyclic boronates as versatile scaffolds for KPC-2 ß-lactamase inhibition.
in RSC medicinal chemistry
Tooke Catherine L.
(2019)
Interactions of ß-lactamases with antibiotics and inhibitors
in JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
Tooke Catherine L.
(2020)
Substrate and inhibitor interactions of class A ß-lactamases
Tooke C
(2021)
Natural variants modify Klebsiella pneumoniae carbapenemase (KPC) acyl-enzyme conformational dynamics to extend antibiotic resistance
in Journal of Biological Chemistry
Toelzer C
(2020)
Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein.
in Science (New York, N.Y.)
Thongdee P
(2022)
Virtual Screening Identifies Novel and Potent Inhibitors of Mycobacterium tuberculosis PknB with Antibacterial Activity.
in Journal of chemical information and modeling
Thomas F
(2018)
De Novo-Designed a-Helical Barrels as Receptors for Small Molecules.
in ACS synthetic biology
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
Suardíaz R
(2016)
Understanding the Mechanism of the Hydrogen Abstraction from Arachidonic Acid Catalyzed by the Human Enzyme 15-Lipoxygenase-2. A Quantum Mechanics/Molecular Mechanics Free Energy Simulation.
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 | 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 |