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
Ranaghan KE
(2017)
Ab Initio QM/MM Modeling of the Rate-Limiting Proton Transfer Step in the Deamination of Tryptamine by Aromatic Amine Dehydrogenase.
in The journal of physical chemistry. B
Rao S
(2020)
Characterizing Membrane Association and Periplasmic Transfer of Bacterial Lipoproteins through Molecular Dynamics Simulations.
in Structure (London, England : 1993)
Raza S
(2019)
Visualizing protein-ligand binding with chemical energy-wise decomposition (CHEWD): application to ligand binding in the kallikrein-8 S1 Site.
in Journal of computer-aided molecular design
Reddy T
(2016)
Computational virology: From the inside out
in Biochimica et Biophysica Acta (BBA) - Biomembranes
Rego Campello H
(2018)
Unlocking Nicotinic Selectivity via Direct C?H Functionalization of (-)-Cytisine
in Chem
Ren Q
(2010)
Optimal control design of laser pulses for mode specific vibrational excitation in an enzyme-substrate complex
in Chemical Physics Letters
Rhys GG
(2018)
Maintaining and breaking symmetry in homomeric coiled-coil assemblies.
in Nature communications
Ridder L
(1999)
Combined quantum mechanical and molecular mechanical reaction pathway calculation for aromatic hydroxylation by p-hydroxybenzoate-3-hydroxylase.
in Journal of molecular graphics & modelling
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
Ross G
(2015)
Water Sites, Networks, And Free Energies with Grand Canonical Monte Carlo
in Journal of the American Chemical Society
Rowlands Heather Ann
(2009)
Modelling of the sugar processing enzymes chitinase B and Phosphomannomutase/ Phosphoglucomutase
RUNGROTMONGKOL T
(2011)
MECHANISTIC STUDY OF HIV-1 REVERSE TRANSCRIPTASE AT THE ACTIVE SITE BASED ON QM/MM METHOD
in Journal of Theoretical and Computational Chemistry
Sampson C
(2015)
A "Stepping Stone" Approach for Obtaining Quantum Free Energies of Hydration.
in The journal of physical chemistry. B
Sampson C
(2019)
On the magnetosensitivity of lipid peroxidation: two- versus three-radical dynamics
in Physical Chemistry Chemical Physics
Samsudin F
(2016)
OmpA: A Flexible Clamp for Bacterial Cell Wall Attachment.
in Structure (London, England : 1993)
Sartori GR
(2019)
Ligand-induced conformational selection predicts the selectivity of cysteine protease inhibitors.
in PloS one
Schiffrin B
(2016)
Skp is a multivalent chaperone of outer-membrane proteins.
in Nature structural & molecular biology
Scott AJ
(2021)
Constructing ion channels from water-soluble a-helical barrels.
in Nature chemistry
Shahane G
(2019)
Physical properties of model biological lipid bilayers: insights from all-atom molecular dynamics simulations.
in Journal of molecular modeling
Shahane G
(2019)
Interaction of Antimicrobial Lipopeptides with Bacterial Lipid Bilayers
in The Journal of Membrane Biology
Shannon RJ
(2021)
Exploring human-guided strategies for reaction network exploration: Interactive molecular dynamics in virtual reality as a tool for citizen scientists.
in The Journal of chemical 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
Shaw K
(2009)
Compatibility of Quantum Chemical Methods and Empirical (MM) Water Models in Quantum Mechanics/Molecular Mechanics Liquid Water Simulations
in The Journal of Physical Chemistry Letters
Shaw Katherine E.
(2010)
Testing QM/MM Methods Using Free Energy Simulations
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 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
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)
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)
Simcock PW
(2021)
Membrane Binding of Antimicrobial Peptides Is Modulated by Lipid Charge Modification.
in Journal of chemical theory and computation
Singh J
(2021)
Real-time super-resolution mapping of locally anisotropic grain orientations for ultrasonic non-destructive evaluation of crystalline material
in Neural Computing and Applications
Sirirak J
(2020)
Benchmarking quantum mechanical methods for calculating reaction energies of reactions catalyzed by enzymes
in PeerJ Physical Chemistry
Sirirak Jitnapa
(2011)
Modelling of fatty acid amide hydrolase and aristolochene synthase from Aspergillus terreus
Sjöström T
(2016)
Bactericidal nanospike surfaces via thermal oxidation of Ti alloy substrates
in Materials Letters
Sofia F Oliveira A
(2022)
The fatty acid site is coupled to functional motifs in the SARS-CoV-2 spike protein and modulates spike allosteric behaviour.
in Computational and structural biotechnology journal
Song W
(2021)
Modulation of adenosine A2a receptor oligomerization by receptor activation and PIP2 interactions.
in Structure (London, England : 1993)
Song W
(2019)
State-dependent Lipid Interactions with the A2a Receptor Revealed by MD Simulations Using In Vivo-Mimetic Membranes.
in Structure (London, England : 1993)
Song W
(2022)
PyLipID: A Python Package for Analysis of Protein-Lipid Interactions from Molecular Dynamics Simulations.
in Journal of chemical theory and computation
Steventon Jack
(2020)
Directed evolution of artificial oxidoreductases
Suardiaz R
(2020)
Catalytic Mechanism of the Colistin Resistance Protein MCR-1
Suardíaz R
(2016)
Understanding the Mechanism of the Hydrogen Abstraction from Arachidonic Acid Catalyzed by the Human Enzyme 15-Lipoxygenase-2. A Quantum Mechanics/Molecular Mechanics Free Energy Simulation.
in Journal of chemical theory and computation
Suardíaz R
(2021)
Catalytic mechanism of the colistin resistance protein MCR-1.
in Organic & biomolecular chemistry
Szefczyk B
(2007)
Quantum chemical analysis of reaction paths in chorismate mutase: Conformational effects and electrostatic stabilization
in International Journal of Quantum Chemistry
Szeto M
(2009)
QM/MM study on the mechanism of peptide hydrolysis by carboxypeptidase A
in Journal of Molecular Structure: THEOCHEM
Thomas F
(2018)
De Novo-Designed a-Helical Barrels as Receptors for Small Molecules.
in ACS synthetic biology
Thongdee P
(2022)
Virtual Screening Identifies Novel and Potent Inhibitors of Mycobacterium tuberculosis PknB with Antibacterial Activity.
in Journal of chemical information and modeling
Toelzer C
(2020)
Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein.
in Science (New York, N.Y.)
| 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 |