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
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
Mulholland Adrian J.
(2009)
PHYS 47-Biomolecular simulations of enzymatic reactions
in ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY
Lear A
(2023)
Comment on: "Computer Simulations Reveal an Entirely Entropic Activation Barrier for the Chemical Step in a Designer Enzyme"
in ACS Catalysis
Hindson S
(2021)
Rigidifying a De Novo Enzyme Increases Activity and Induces a Negative Activation Heat Capacity
in ACS Catalysis
Douglas-Gallardo O
(2022)
Carbon Dioxide Fixation in RuBisCO Is Protonation-State-Dependent and Irreversible
in ACS Catalysis
Karuppiah V
(2017)
Structural Basis of Catalysis in the Bacterial Monoterpene Synthases Linalool Synthase and 1,8-Cineole Synthase.
in ACS catalysis
Martí S
(2022)
Impact of Warhead Modulations on the Covalent Inhibition of SARS-CoV-2 Mpro Explored by QM/MM Simulations.
in ACS catalysis
Hirvonen VHA
(2022)
Multiscale Simulations Identify Origins of Differential Carbapenem Hydrolysis by the OXA-48 ß-Lactamase.
in ACS catalysis
Leferink NGH
(2019)
Experiment and Simulation Reveal How Mutations in Functional Plasticity Regions Guide Plant Monoterpene Synthase Product Outcome.
in ACS catalysis
Hirvonen V
(2020)
Small Changes in Hydration Determine Cephalosporinase Activity of OXA-48 ß-Lactamases
in ACS Catalysis
Daniels AD
(2014)
Reaction mechanism of N-acetylneuraminic acid lyase revealed by a combination of crystallography, QM/MM simulation, and mutagenesis.
in ACS chemical biology
Chudyk EI
(2022)
QM/MM Simulations Reveal the Determinants of Carbapenemase Activity in Class A ß-Lactamases.
in ACS infectious diseases
Maingi V
(2015)
Gating-like Motions and Wall Porosity in a DNA Nanopore Scaffold Revealed by Molecular Simulations.
in ACS nano
Ainsley J
(2018)
Structural Insights from Molecular Dynamics Simulations of Tryptophan 7-Halogenase and Tryptophan 5-Halogenase.
in ACS omega
Hanpaibool C
(2023)
Pyrazolones Potentiate Colistin Activity against MCR-1-Producing Resistant Bacteria: Computational and Microbiological Study
in ACS Omega
Thomas F
(2018)
De Novo-Designed a-Helical Barrels as Receptors for Small Molecules.
in ACS synthetic biology
Gray A
(2015)
In pursuit of an accurate spatial and temporal model of biomolecules at the atomistic level: a perspective on computer simulation.
in Acta crystallographica. Section D, Biological crystallography
Ainsley J
(2018)
Combined Quantum Mechanics and Molecular Mechanics Studies of Enzymatic Reaction Mechanisms.
in Advances in protein chemistry and structural biology
O'Hagan M
(2019)
A Photoresponsive Stiff-Stilbene Ligand Fuels the Reversible Unfolding of G-Quadruplex DNA
in Angewandte Chemie
Van Der Kamp M
(2011)
"Lethal Synthesis" of Fluorocitrate by Citrate Synthase Explained through QM/MM Modeling
in Angewandte Chemie
Jambrina P
(2015)
Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation
in Angewandte Chemie
Shoemark D
(2021)
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
Shoemark DK
(2021)
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 ed. in English)
O'Hagan MP
(2019)
A Photoresponsive Stiff-Stilbene Ligand Fuels the Reversible Unfolding of G-Quadruplex DNA.
in Angewandte Chemie (International ed. in English)
Shoemark DK
(2021)
Frontispiz: 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 (Weinheim an der Bergstrasse, Germany)
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 |