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
Mulholland AJ
(2023)
Science after Brexit: bright spots on the Horizon?
in EMBO reports
Mulholland AJ
(2020)
COVID19 - Computational Chemists Meet the Moment.
in Journal of chemical information and modeling
Mulholland, AJ
(2009)
Using high-performance computing to model enzyme-catalysed reactions
Musgaard M
(2016)
Steered Molecular Dynamics Simulations Predict Conformational Stability of Glutamate Receptors.
in Journal of chemical information and modeling
Naafs B
(2021)
Molecular dynamics simulations support the hypothesis that the brGDGT paleothermometer is based on homeoviscous adaptation
in Geochimica et Cosmochimica Acta
Nett N
(2021)
A robust and stereocomplementary panel of ene-reductase variants for gram-scale asymmetric hydrogenation
in Molecular Catalysis
Newport TD
(2019)
The MemProtMD database: a resource for membrane-embedded protein structures and their lipid interactions.
in Nucleic acids research
Noy A
(2017)
Interference between Triplex and Protein Binding to Distal Sites on Supercoiled DNA
in Biophysical Journal
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
Nutho B
(2019)
QM/MM Study on Cleavage Mechanism Catalyzed by Zika Virus NS2B/NS3 Serine Protease
in Biophysical Journal
Nutho B
(2019)
Quantum Mechanics/Molecular Mechanics (QM/MM) Calculations Support a Concerted Reaction Mechanism for the Zika Virus NS2B/NS3 Serine Protease with Its Substrate.
in The journal of physical chemistry. B
O'Connor M
(2018)
Sampling molecular conformations and dynamics in a multiuser virtual reality framework
in Science Advances
O'Connor MB
(2019)
Interactive molecular dynamics in virtual reality from quantum chemistry to drug binding: An open-source multi-person framework.
in The Journal of chemical physics
O'Hagan M
(2019)
A Photoresponsive Stiff-Stilbene Ligand Fuels the Reversible Unfolding of G-Quadruplex DNA
in Angewandte Chemie
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
O'Hagan MP
(2020)
Visible-light photoswitching of ligand binding mode suggests G-quadruplex DNA as a target for photopharmacology.
in Chemical communications (Cambridge, England)
O'Hagan MP
(2019)
A Photoresponsive Stiff-Stilbene Ligand Fuels the Reversible Unfolding of G-Quadruplex DNA.
in Angewandte Chemie (International ed. in English)
Oliveira A
(2019)
A General Mechanism for Signal Propagation in the Nicotinic Acetylcholine Receptor Family
in Journal of the American Chemical Society
Oliveira A
(2023)
Fluctuation Relations to Calculate Protein Redox Potentials from Molecular Dynamics Simulations
in Journal of Chemical Theory and Computation
Oliveira A. S. F.
(2019)
Nicotine-induced conformational changes in the a4ß2 nicotinic receptor
in EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS
Oliveira ASF
(2021)
A potential interaction between the SARS-CoV-2 spike protein and nicotinic acetylcholine receptors.
in Biophysical journal
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)
Oliveira ASF
(2023)
SARS-CoV-2 spike variants differ in their allosteric responses to linoleic acid.
in Journal of molecular cell biology
Oliveira ASF
(2020)
Simulations support the interaction of the SARS-CoV-2 spike protein with nicotinic acetylcholine receptors.
in bioRxiv : the preprint server for biology
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
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
Pakamwong B
(2022)
Identification of Potent DNA Gyrase Inhibitors Active against Mycobacterium tuberculosis.
in Journal of chemical information and modeling
Palaiokostas M
(2018)
Effects of lipid composition on membrane permeation
in Soft Matter
Paramo T
(2017)
Functional Validation of Heteromeric Kainate Receptor Models.
in Biophysical journal
Parker JL
(2021)
Cryo-EM structure of PepT2 reveals structural basis for proton-coupled peptide and prodrug transport in mammals.
in Science advances
Pasi M
(2014)
µABC: a systematic microsecond molecular dynamics study of tetranucleotide sequence effects in B-DNA.
in Nucleic acids research
Pennifold RC
(2017)
Correcting density-driven errors in projection-based embedding.
in The Journal of chemical physics
Pentikäinen U
(2009)
Lennard-Jones Parameters for B3LYP/CHARMM27 QM/MM Modeling of Nucleic Acid Bases
in Journal of Chemical Theory and Computation
Phintha A
(2021)
Dissecting the low catalytic capability of flavin-dependent halogenases.
in The Journal of biological chemistry
Pradon Juliette Jeanne Marie
(2010)
Molecular modelling studies of the relationship between structure and mechanism in (beta)-lactamases and related enzymes
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
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
Punkvang A
(2019)
Simulations of Shikimate Dehydrogenase from Mycobacterium tuberculosis in Complex with 3-Dehydroshikimate and NADPH Suggest Strategies for MtbSDH Inhibition.
in Journal of chemical information and modeling
Ranaghan K
(2010)
Investigations of enzyme-catalysed reactions with combined quantum mechanics/molecular mechanics (QM/MM) methods
in International Reviews in Physical Chemistry
Ranaghan K
(2016)
Simulating Enzyme Reactivity - Computational Methods in Enzyme Catalysis
RANAGHAN K
(2009)
Insights into enzyme catalysis from QM/MM modelling: transition state stabilization in chorismate mutase
in Molecular Physics
Ranaghan K
(2014)
A catalytic role for methionine revealed by a combination of computation and experiments on phosphite dehydrogenase
in Chem. Sci.
Ranaghan KE
(2019)
Projector-Based Embedding Eliminates Density Functional Dependence for QM/MM Calculations of Reactions in Enzymes and Solution.
in Journal of chemical information and modeling
Ranaghan KE
(2010)
Computer simulations of quantum tunnelling in enzyme-catalysed hydrogen transfer reactions.
in Interdisciplinary sciences, computational life sciences
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 |