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
Daniels DE
(2023)
Human cellular model systems of ß-thalassemia enable in-depth analysis of disease phenotype.
in Nature communications
Jitonnom Jitrayut
(2011)
Hybrid QM/MM study on the deglycosylation step of chitin hydrolysis catalysed by chitinase B from
Serratia marcescens
in MAEJO INTERNATIONAL JOURNAL OF SCIENCE AND TECHNOLOGY
Corey R
(2021)
Identification and assessment of cardiolipin interactions with E. coli inner membrane proteins
in Science Advances
Pakamwong B
(2022)
Identification of Potent DNA Gyrase Inhibitors Active against Mycobacterium tuberculosis.
in Journal of chemical information and modeling
Oliveira ASF
(2019)
Identification of the Initial Steps in Signal Transduction in the a4ß2 Nicotinic Receptor: Insights from Equilibrium and Nonequilibrium Simulations.
in Structure (London, England : 1993)
Ge Y
(2017)
Identification of the quinolinedione inhibitor binding site in Cdc25 phosphatase B through docking and molecular dynamics simulations.
in Journal of computer-aided molecular design
Bueren-Calabuig JA
(2016)
Impact of Ser17 Phosphorylation on the Conformational Dynamics of the Oncoprotein MDM2.
in Biochemistry
Martí S
(2022)
Impact of Warhead Modulations on the Covalent Inhibition of SARS-CoV-2 Mpro Explored by QM/MM Simulations.
in ACS catalysis
Gerrard W
(2020)
IMPRESSION - prediction of NMR parameters for 3-dimensional chemical structures using machine learning with near quantum chemical accuracy.
in Chemical science
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
Hanwarinroj C
(2022)
In silico design of novel quinazoline-based compounds as potential Mycobacterium tuberculosis PknB inhibitors through 2D and 3D-QSAR, molecular dynamics simulations combined with pharmacokinetic predictions.
in Journal of molecular graphics & modelling
Kamsri P
(2019)
In silico study directed towards identification of the key structural features of GyrB inhibitors targeting MTB DNA gyrase: HQSAR, CoMSIA and molecular dynamics simulations.
in SAR and QSAR in environmental research
Von Kügelgen A
(2020)
In Situ Structure of an Intact Lipopolysaccharide-Bound Bacterial Surface Layer.
in Cell
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
Lonsdale R
(2010)
Inclusion of Dispersion Effects Significantly Improves Accuracy of Calculated Reaction Barriers for Cytochrome P450 Catalyzed Reactions
in The Journal of Physical Chemistry Letters
Jitonnom J
(2012)
Insights into conformational changes of procarboxypeptidase A and B from simulations: a plausible explanation for different intrinsic activity
in Theoretical Chemistry Accounts
RANAGHAN K
(2009)
Insights into enzyme catalysis from QM/MM modelling: transition state stabilization in chorismate mutase
in Molecular Physics
Sharma V
(2017)
Insights into functions of the H channel of cytochrome c oxidase from atomistic molecular dynamics simulations.
in Proceedings of the National Academy of Sciences of the United States of America
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
Hinchliffe P
(2017)
Insights into the Mechanistic Basis of Plasmid-Mediated Colistin Resistance from Crystal Structures of the Catalytic Domain of MCR-1.
in Scientific reports
Shahane G
(2019)
Interaction of Antimicrobial Lipopeptides with Bacterial Lipid Bilayers
in The Journal of Membrane Biology
Tooke Catherine L.
(2019)
Interactions of ß-lactamases with antibiotics and inhibitors
in JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
Deeks HM
(2020)
Interactive molecular dynamics in virtual reality for accurate flexible protein-ligand docking.
in PloS one
Crossley-Lewis J
(2023)
Interactive molecular dynamics in virtual reality for modelling materials and catalysts.
in Journal of molecular graphics & modelling
O'Connor MB
(2019)
Interactive molecular dynamics in virtual reality from quantum chemistry to drug binding: An open-source multi-person framework.
in The Journal of chemical physics
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
Noy A
(2017)
Interference between Triplex and Protein Binding to Distal Sites on Supercoiled DNA
in Biophysical Journal
Ranaghan K
(2010)
Investigations of enzyme-catalysed reactions with combined quantum mechanics/molecular mechanics (QM/MM) methods
in International Reviews in Physical Chemistry
Hsu PC
(2017)
It Is Complicated: Curvature, Diffusion, and Lipid Sorting within the Two Membranes of Escherichia coli.
in The journal of physical chemistry letters
McGeagh J
(2010)
Kinetics and Dynamics - From Nano- to Bio-Scale
Callegari D
(2018)
L718Q mutant EGFR escapes covalent inhibition by stabilizing a non-reactive conformation of the lung cancer drug osimertinib.
in Chemical science
Lever G
(2014)
Large-Scale Density Functional Theory Transition State Searching in Enzymes.
in The journal of physical chemistry letters
Pentikäinen U
(2009)
Lennard-Jones Parameters for B3LYP/CHARMM27 QM/MM Modeling of Nucleic Acid Bases
in Journal of Chemical Theory and Computation
Mulholland A
(2020)
Letter to the Editor.
in Journal of paediatrics and child health
Sartori GR
(2019)
Ligand-induced conformational selection predicts the selectivity of cysteine protease inhibitors.
in PloS one
Haldar S
(2021)
Ligand-induced unfolding mechanism of an RNA G-quadruplex
Voice A
(2019)
Limitations of Ligand-Only Approaches for Predicting the Reactivity of Covalent Inhibitors.
in Journal of chemical information and modeling
Rhys GG
(2018)
Maintaining and breaking symmetry in homomeric coiled-coil assemblies.
in Nature communications
Mujika JI
(2012)
Mechanism of C-terminal intein cleavage in protein splicing from QM/MM molecular dynamics simulations.
in Organic & biomolecular chemistry
Voice AT
(2021)
Mechanism of covalent binding of ibrutinib to Bruton's tyrosine kinase revealed by QM/MM calculations.
in Chemical science
Haldar S
(2022)
Mechanistic Insights into the Ligand-Induced Unfolding of an RNA G-Quadruplex.
in Journal of the American Chemical Society
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 |