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
Hirvonen V
(2020)
Small Changes in Hydration Determine Cephalosporinase Activity of OXA-48 ß-Lactamases
in ACS Catalysis
Suardiaz R
(2024)
Solvent channels and proton transfer pathways in peroxidase catalysis
Larsen AH
(2022)
Specific interactions of peripheral membrane proteins with lipids: what can molecular simulations show us?
in Bioscience reports
Fan Betty
(2017)
Stage IV breast cancer is increased by omitting screening mammography
in ANNALS OF SURGICAL ONCOLOGY
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)
Aldeghi M
(2017)
Statistical Analysis on the Performance of Molecular Mechanics Poisson-Boltzmann Surface Area versus Absolute Binding Free Energy Calculations: Bromodomains as a Case Study
in Journal of Chemical Information and Modeling
Musgaard M
(2016)
Steered Molecular Dynamics Simulations Predict Conformational Stability of Glutamate Receptors.
in Journal of chemical information and modeling
Moore DS
(2018)
Steered molecular dynamics simulations reveal critical residues for (un)binding of substrates, inhibitors and a product to the malarial M1 aminopeptidase.
in PLoS computational biology
Van Den Berg B
(2016)
Structural basis for Mep2 ammonium transceptor activation by phosphorylation.
in Nature communications
Parker JL
(2021)
Structural basis of antifolate recognition and transport by PCFT.
in Nature
Karuppiah V
(2017)
Structural Basis of Catalysis in the Bacterial Monoterpene Synthases Linalool Synthase and 1,8-Cineole Synthase.
in ACS catalysis
Lodola A
(2010)
Structural Fluctuations in Enzyme-Catalyzed Reactions: Determinants of Reactivity in Fatty Acid Amide Hydrolase from Multivariate Statistical Analysis of Quantum Mechanics/Molecular Mechanics Paths
in Journal of Chemical Theory and Computation
Ainsley J
(2018)
Structural Insights from Molecular Dynamics Simulations of Tryptophan 7-Halogenase and Tryptophan 5-Halogenase.
in ACS omega
Gupta K
(2022)
Structural insights in cell-type specific evolution of intra-host diversity by SARS-CoV-2
in Nature Communications
Dawson WM
(2021)
Structural resolution of switchable states of a de novo peptide assembly.
in Nature communications
Wells SA
(2015)
Structure and Function in Homodimeric Enzymes: Simulations of Cooperative and Independent Functional Motions.
in PloS one
Coupland C
(2021)
Structure and Mechanism of Hedgehog Acyl Transferase
Coupland CE
(2021)
Structure, mechanism, and inhibition of Hedgehog acyltransferase.
in Molecular cell
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
Hazell G
(2018)
Studies of black silicon and black diamond as materials for antibacterial surfaces.
in Biomaterials science
Tooke Catherine L.
(2020)
Substrate and inhibitor interactions of class A ß-lactamases
Jenkins JMX
(2021)
Substrate promiscuity of a de novo designed peroxidase.
in Journal of inorganic biochemistry
Glowacki DR
(2012)
Taking Ockham's razor to enzyme dynamics and catalysis.
in Nature chemistry
Leferink NGH
(2020)
Taming the Reactivity of Monoterpene Synthases To Guide Regioselective Product Hydroxylation.
in Chembiochem : a European journal of chemical biology
Tooke C
(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
King B
(2023)
Tautomerisation Mechanisms in the Adenine-Thymine Nucleobase Pair during DNA Strand Separation.
in The journal of physical chemistry. B
Bennie S
(2019)
Teaching Enzyme Catalysis Using Interactive Molecular Dynamics in Virtual Reality
in Journal of Chemical Education
Arcus VL
(2020)
Temperature, Dynamics, and Enzyme-Catalyzed Reaction Rates.
in Annual review of biophysics
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
Shaw Katherine E.
(2010)
Testing QM/MM Methods Using Free Energy Simulations
Fonseca F
(2012)
The Basis for Carbapenem Hydrolysis by Class A ß-Lactamases: A Combined Investigation using Crystallography and Simulations
in Journal of the American Chemical Society
Balint-Kurti G
(1991)
The calculation of product quantum state distributions and partial cross-sections in time-dependent molecular collision and photodissociation theory
in Computer Physics Communications
Byrne MJ
(2016)
The Catalytic Mechanism of a Natural Diels-Alderase Revealed in Molecular Detail.
in Journal of the American Chemical Society
Matheson AB
(2017)
The development of phytosterol-lecithin mixed micelles and organogels.
in Food & function
Walters RK
(2022)
The emerging potential of interactive virtual reality in drug discovery.
in Expert opinion on drug discovery
Corey R
(2020)
The energetics of protein-lipid interactions as viewed by molecular simulations
in Biochemical Society Transactions
Sofia F Oliveira A
(2022)
The fatty acid site is coupled to functional motifs in the SARS-CoV-2 spike protein and modulates spike allosteric behaviour.
in Computational and structural biotechnology journal
Newport TD
(2019)
The MemProtMD database: a resource for membrane-embedded protein structures and their lipid interactions.
in Nucleic acids research
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
| 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 |