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
Deeks HM
(2020)
Interactive molecular dynamics in virtual reality for accurate flexible protein-ligand docking.
in PloS one
Deeks HM
(2020)
Interactive Molecular Dynamics in Virtual Reality Is an Effective Tool for Flexible Substrate and Inhibitor Docking to the SARS-CoV-2 Main Protease.
in Journal of chemical information and modeling
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
Catlow CR
(2020)
Science to enable the circular economy.
in Philosophical transactions. Series A, Mathematical, physical, and engineering sciences
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
Mulholland A
(2020)
Catalytic Mechanism of the Colistin Resistance Protein MCR-1
Mulholland A
(2020)
Letter to the Editor.
in Journal of paediatrics and child health
Mulholland AJ
(2020)
COVID19 - Computational Chemists Meet the Moment.
in Journal of chemical information and modeling
Steventon Jack
(2020)
Directed evolution of artificial oxidoreductases
Minguez Teresa
(2020)
Novel determinants of agonist selectivity in nicotinic ACh receptors
in BRITISH JOURNAL OF PHARMACOLOGY
Tooke Catherine L.
(2020)
Substrate and inhibitor interactions of class A ß-lactamases
Arcus VL
(2020)
Temperature, Dynamics, and Enzyme-Catalyzed Reaction Rates.
in Annual review of biophysics
Gerrard W
(2020)
IMPRESSION - prediction of NMR parameters for 3-dimensional chemical structures using machine learning with near quantum chemical accuracy.
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)
Sirirak J
(2020)
Benchmarking quantum mechanical methods for calculating reaction energies of reactions catalyzed by enzymes
in PeerJ Physical Chemistry
Wang L
(2020)
Mixing and matching genes of marine and terrestrial origin in the biosynthesis of the mupirocin antibiotics.
in Chemical science
Rao S
(2020)
Characterizing Membrane Association and Periplasmic Transfer of Bacterial Lipoproteins through Molecular Dynamics Simulations.
in Structure (London, England : 1993)
Ingram M
(2020)
Determination of Bubble Size Distribution Using Ultrasound Array Imaging.
in IEEE transactions on ultrasonics, ferroelectrics, and frequency control
Von Kügelgen A
(2020)
In Situ Structure of an Intact Lipopolysaccharide-Bound Bacterial Surface Layer.
in Cell
Amaro RE
(2020)
A Community Letter Regarding Sharing Biomolecular Simulation Data for COVID-19.
in Journal of chemical information and modeling
Leferink NGH
(2020)
Taming the Reactivity of Monoterpene Synthases To Guide Regioselective Product Hydroxylation.
in Chembiochem : a European journal of chemical 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
Yamamoto E
(2020)
Multiple lipid binding sites determine the affinity of PH domains for phosphoinositide-containing membranes.
in Science advances
Amaro RE
(2020)
Biomolecular Simulations in the Time of COVID19, and After.
in Computing in science & engineering
Arcus VL
(2020)
Enzyme evolution and the temperature dependence of enzyme catalysis.
in Current opinion in structural biology
Suardiaz R
(2020)
Catalytic Mechanism of the Colistin Resistance Protein MCR-1
Tooke CL
(2020)
Cyclic boronates as versatile scaffolds for KPC-2 ß-lactamase inhibition.
in RSC medicinal chemistry
Jagger BR
(2020)
Multiscale simulation approaches to modeling drug-protein binding.
in Current opinion in structural biology
Kamsri P
(2020)
Discovery of New and Potent InhA Inhibitors as Antituberculosis Agents: Structure-Based Virtual Screening Validated by Biological Assays and X-ray Crystallography.
in Journal of chemical information and modeling
Hirvonen V
(2020)
Small Changes in Hydration Determine Cephalosporinase Activity of OXA-48 ß-Lactamases
in ACS Catalysis
Lythell E
(2020)
Resistance to the "last resort" antibiotic colistin: a single-zinc mechanism for phosphointermediate formation in MCR enzymes.
in Chemical communications (Cambridge, England)
Zinovjev K
(2020)
Enlighten2: molecular dynamics simulations of protein-ligand systems made accessible.
in Bioinformatics (Oxford, England)
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
Song W
(2021)
Modulation of adenosine A2a receptor oligomerization by receptor activation and PIP2 interactions.
in Structure (London, England : 1993)
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 |