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
Shoemark D
(2021)
Frontispiece: Molecular Simulations suggest Vitamins, Retinoids and Steroids as Ligands of the Free Fatty Acid Pocket of the SARS-CoV-2 Spike Protein
in Angewandte Chemie International Edition
Fan Betty
(2017)
Stage IV breast cancer is increased by omitting screening mammography
in ANNALS OF SURGICAL ONCOLOGY
Arcus VL
(2020)
Temperature, Dynamics, and Enzyme-Catalyzed Reaction Rates.
in Annual review of biophysics
Buzas D
(2023)
In vitro generated antibodies guide thermostable ADDomer nanoparticle design for nasal vaccination and passive immunization against SARS-CoV-2
in Antibody Therapeutics
Tooke CL
(2019)
Molecular Basis of Class A ß-Lactamase Inhibition by Relebactam.
in Antimicrobial agents and chemotherapy
Lodola A
(2009)
Insights into the mechanism and inhibition of fatty acid amide hydrolase from quantum mechanics/molecular mechanics (QM/MM) modelling.
in Biochemical Society transactions
Glowacki DR
(2012)
Protein dynamics and enzyme catalysis: the ghost in the machine?
in Biochemical Society transactions
Van Der Kamp MW
(2013)
Conformational change and ligand binding in the aristolochene synthase catalytic cycle.
in Biochemistry
Jitonnom J
(2017)
Quantum Mechanics/Molecular Mechanics Simulations Identify the Ring-Opening Mechanism of Creatininase.
in Biochemistry
Román-Meléndez GD
(2014)
Role of active site residues in promoting cobalt-carbon bond homolysis in adenosylcobalamin-dependent mutases revealed through experiment and computation.
in Biochemistry
Bueren-Calabuig JA
(2016)
Impact of Ser17 Phosphorylation on the Conformational Dynamics of the Oncoprotein MDM2.
in Biochemistry
Messiha HL
(2018)
Biocatalytic Routes to Lactone Monomers for Polymer Production.
in Biochemistry
Arcus VL
(2016)
On the Temperature Dependence of Enzyme-Catalyzed Rates.
in Biochemistry
Van Der Kamp M
(2013)
Combined Quantum Mechanics/Molecular Mechanics (QM/MM) Methods in Computational Enzymology
in Biochemistry
Lonsdale R
(2012)
Determinants of reactivity and selectivity in soluble epoxide hydrolase from quantum mechanics/molecular mechanics modeling.
in Biochemistry
McGeagh JD
(2011)
Protein dynamics and enzyme catalysis: insights from simulations.
in Biochimica et biophysica acta
Reddy T
(2016)
Computational virology: From the inside out
in Biochimica et Biophysica Acta (BBA) - Biomembranes
Zinovjev K
(2020)
Enlighten2: molecular dynamics simulations of protein-ligand systems made accessible.
in Bioinformatics (Oxford, England)
Hazell G
(2018)
Studies of black silicon and black diamond as materials for antibacterial surfaces.
in Biomaterials science
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
Christov C
(2013)
Conformational Effects on the pro - S Hydrogen Abstraction Reaction in Cyclooxygenase-1: An Integrated QM/MM and MD Study
in Biophysical Journal
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 |