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
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 S
(2015)
Structure and Function in Homodimeric Enzymes: Simulations of Cooperative and Independent Functional Motions
in PLOS ONE
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
Leferink NGH
(2020)
Taming the Reactivity of Monoterpene Synthases To Guide Regioselective Product Hydroxylation.
in Chembiochem : a European journal of chemical biology
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
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
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
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
Meletiou A
(2019)
Tios: The Internet of Simulations. Turning Molecular Dynamics into a Data Streaming Web Application.
in Journal of chemical information and modeling
Malaisree Maturos
(2010)
Understanding of drug-target interactions and substrate binding to neuraminidase of influenza A virus subtypes H5N1 and H1N1-2009
in ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY
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
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
Lodola A
(2011)
Understanding the role of carbamate reactivity in fatty acid amide hydrolase inhibition by QM/MM mechanistic modelling.
in Chemical communications (Cambridge, England)
Rego Campello H
(2018)
Unlocking Nicotinic Selectivity via Direct C?H Functionalization of (-)-Cytisine
in Chem
Mulholland, AJ
(2009)
Using high-performance computing to model enzyme-catalysed reactions
Thongdee P
(2022)
Virtual Screening Identifies Novel and Potent Inhibitors of Mycobacterium tuberculosis PknB with Antibacterial Activity.
in Journal of chemical information and modeling
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)
Raza S
(2019)
Visualizing protein-ligand binding with chemical energy-wise decomposition (CHEWD): application to ligand binding in the kallikrein-8 S1 Site.
in Journal of computer-aided molecular design
Kwon H
(2020)
Visualizing the protons in a metalloenzyme electron proton transfer pathway.
in Proceedings of the National Academy of Sciences of the United States of America
Ross G
(2015)
Water Sites, Networks, And Free Energies with Grand Canonical Monte Carlo
in Journal of the American Chemical Society
Pasi M
(2014)
µABC: a systematic microsecond molecular dynamics study of tetranucleotide sequence effects in B-DNA.
in Nucleic acids research
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 |