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
Haldar S
(2021)
Ligand-induced unfolding mechanism of an RNA G-quadruplex
Haldar S
(2018)
A Multiscale Simulation Approach to Modeling Drug-Protein Binding Kinetics.
in Journal of chemical theory and computation
Haldar S
(2022)
Mechanistic Insights into the Ligand-Induced Unfolding of an RNA G-Quadruplex.
in Journal of the American Chemical Society
Gupta K
(2022)
Structural insights in cell-type specific evolution of intra-host diversity by SARS-CoV-2.
in Nature communications
Grundmann M
(2016)
A Molecular Mechanism for Sequential Activation of a G Protein-Coupled Receptor.
in Cell chemical 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
Grant Ian M.
(2009)
Conformation and Catalysis in Lysozyme. A computational study
Glowacki DR
(2012)
Protein dynamics and enzyme catalysis: the ghost in the machine?
in Biochemical Society transactions
Gervasoni S
(2022)
A multiscale approach to predict the binding mode of metallo beta-lactamase inhibitors.
in Proteins
Gerrard W
(2020)
IMPRESSION - prediction of NMR parameters for 3-dimensional chemical structures using machine learning with near quantum chemical accuracy.
in Chemical science
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
Galdadas I
(2021)
Allosteric communication in class A ß-lactamases occurs via cooperative coupling of loop dynamics.
in eLife
Freeman SL
(2023)
Heme binding to the SARS-CoV-2 spike glycoprotein.
in The Journal of biological chemistry
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
Fan Betty
(2017)
Stage IV breast cancer is increased by omitting screening mammography
in ANNALS OF SURGICAL ONCOLOGY
Evans LE
(2019)
Exploitation of Antibiotic Resistance as a Novel Drug Target: Development of a ß-Lactamase-Activated Antibacterial Prodrug.
in Journal of medicinal chemistry
Espejo-Román JM
(2022)
Selective Anticancer Therapy Based on a HA-CD44 Interaction Inhibitor Loaded on Polymeric Nanoparticles.
in Pharmaceutics
Elcock A
(2002)
Combined Quantum and Molecular Mechanical Study of DNA Crosslinking by Nitrous Acid
in Journal of the American Chemical Society
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
Douglas-Gallardo OA
(2020)
Electronic structure benchmark calculations of CO2 fixing elementary chemical steps in RuBisCO using the projector-based embedding approach.
in Journal of computational chemistry
Douglas-Gallardo O
(2022)
Carbon Dioxide Fixation in RuBisCO Is Protonation-State-Dependent and Irreversible
in ACS Catalysis
Dommer A
(2021)
#COVIDisAirborne: AI-Enabled Multiscale Computational Microscopy of Delta SARS-CoV-2 in a Respiratory Aerosol.
in bioRxiv : the preprint server for biology
Dommer A
(2023)
#COVIDisAirborne: AI-enabled multiscale computational microscopy of delta SARS-CoV-2 in a respiratory aerosol.
in The international journal of high performance computing applications
Ding W
(2015)
Effects of Lipid Composition on Bilayer Membranes Quantified by All-Atom Molecular Dynamics.
in The journal of physical chemistry. B
Ding W
(2017)
Effects of High Pressure on Phospholipid Bilayers.
in The journal of physical chemistry. B
Deeks HM
(2023)
Free energy along drug-protein binding pathways interactively sampled in virtual reality.
in Scientific reports
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
Deeks HM
(2020)
Interactive molecular dynamics in virtual reality for accurate flexible protein-ligand docking.
in PloS one
De Simone A
(2019)
A computationally designed binding mode flip leads to a novel class of potent tri-vector cyclophilin inhibitors.
in Chemical science
Dawson WM
(2021)
Structural resolution of switchable states of a de novo peptide assembly.
in Nature communications
Daniels DE
(2023)
Human cellular model systems of ß-thalassemia enable in-depth analysis of disease phenotype.
in Nature communications
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
Crossley-Lewis J
(2023)
Interactive molecular dynamics in virtual reality for modelling materials and catalysts.
in Journal of molecular graphics & modelling
Corey R
(2021)
Identification and assessment of cardiolipin interactions with E. coli inner membrane proteins
in Science Advances
Claeyssens F
(2011)
Analysis of chorismate mutase catalysis by QM/MM modelling of enzyme-catalysed and uncatalysed reactions.
in Organic & biomolecular chemistry
Chudyk Ewa Iwona
(2013)
Calculating free energy profiles for enzyme catalysed reactions
Chudyk EI
(2022)
QM/MM Simulations Reveal the Determinants of Carbapenemase Activity in Class A ß-Lactamases.
in ACS infectious diseases
Chudyk E
(2013)
Nonempirical Energetic Analysis of Reactivity and Covalent Inhibition of Fatty Acid Amide Hydrolase
in The Journal of Physical Chemistry B
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
Chrestia JF
(2022)
A Functional Interaction Between Y674-R685 Region of the SARS-CoV-2 Spike Protein and the Human a7 Nicotinic Receptor.
in Molecular neurobiology
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 |