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
Fan Betty
(2017)
Stage IV breast cancer is increased by omitting screening mammography
in ANNALS OF SURGICAL ONCOLOGY
Miles BT
(2017)
Direct Evidence of Lack of Colocalisation of Fluorescently Labelled Gold Labels Used in Correlative Light Electron Microscopy.
in Scientific reports
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
Hashem S
(2017)
Allosteric modulation of cardiac myosin dynamics by omecamtiv mecarbil.
in PLoS computational biology
Ding W
(2017)
Effects of High Pressure on Phospholipid Bilayers.
in The journal of physical chemistry. B
Graham JA
(2017)
PyCGTOOL: Automated Generation of Coarse-Grained Molecular Dynamics Models from Atomistic Trajectories.
in Journal of chemical information and modeling
Karuppiah V
(2017)
Structural Basis of Catalysis in the Bacterial Monoterpene Synthases Linalool Synthase and 1,8-Cineole Synthase.
in ACS catalysis
Piggot TJ
(2017)
On the Calculation of Acyl Chain Order Parameters from Lipid Simulations.
in Journal of chemical theory and computation
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
Karabencheva-Christova TG
(2017)
Mechanistic Insights into the Reaction of Chlorination of Tryptophan Catalyzed by Tryptophan 7-Halogenase.
in Scientific reports
Laverty D
(2017)
Crystal structures of a GABAA-receptor chimera reveal new endogenous neurosteroid-binding sites
in Nature Structural & Molecular Biology
Jitonnom J
(2017)
Quantum Mechanics/Molecular Mechanics Simulations Identify the Ring-Opening Mechanism of Creatininase.
in Biochemistry
Van Der Kamp M
(2017)
Dynamical origins of heat capacity changes in enzyme catalysed reactions
Jefferies D
(2017)
Through the Lipopolysaccharide Glass: A Potent Antimicrobial Peptide Induces Phase Changes in Membranes.
in Biochemistry
Paramo T
(2017)
Functional Validation of Heteromeric Kainate Receptor Models.
in Biophysical journal
Aldeghi M
(2017)
Statistical Analysis on the Performance of Molecular Mechanics Poisson-Boltzmann Surface Area versus Absolute Binding Free Energy Calculations: Bromodomains as a Case Study
in Journal of Chemical Information and Modeling
Thomas F
(2018)
De Novo-Designed a-Helical Barrels as Receptors for Small Molecules.
in ACS synthetic biology
Rhys GG
(2018)
Maintaining and breaking symmetry in homomeric coiled-coil assemblies.
in Nature communications
Van Der Kamp MW
(2018)
Dynamical origins of heat capacity changes in enzyme-catalysed reactions.
in Nature communications
Palaiokostas M
(2018)
Effects of lipid composition on membrane permeation.
in Soft matter
O'Connor M
(2018)
Sampling molecular conformations and dynamics in a multiuser virtual reality framework.
in Science advances
Amaro RE
(2018)
Multiscale Methods in Drug Design Bridge Chemical and Biological Complexity in the Search for Cures.
in Nature reviews. Chemistry
Loeffler HH
(2018)
Reproducibility of Free Energy Calculations across Different Molecular Simulation Software Packages.
in Journal of chemical theory and computation
Hazell G
(2018)
Studies of black silicon and black diamond as materials for antibacterial surfaces.
in Biomaterials science
Callegari D
(2018)
L718Q mutant EGFR escapes covalent inhibition by stabilizing a non-reactive conformation of the lung cancer drug osimertinib.
in Chemical science
Kattnig D
(2018)
Molecular dynamics simulations disclose early stages of the photo-activation of cryptochrome 4
in New Journal of Physics
Heiblum Robles A
(2018)
Phase transitions in stigmergic territorial systems
in Physical Review E
Rego Campello H
(2018)
Unlocking Nicotinic Selectivity via Direct C?H Functionalization of (-)-Cytisine
in Chem
Haldar S
(2018)
A Multiscale Simulation Approach to Modeling Drug-Protein Binding Kinetics.
in Journal of chemical theory and computation
Ainsley J
(2018)
Combined Quantum Mechanics and Molecular Mechanics Studies of Enzymatic Reaction Mechanisms.
in Advances in protein chemistry and structural biology
Hashem S
(2018)
Allosteric Modulation of Cardiac Myosin Dynamics by Omecamtiv Mecarbil
in Biophysical Journal
Acevedo-Rocha C
(2018)
P450-Catalyzed Regio- and Diastereoselective Steroid Hydroxylation: Efficient Directed Evolution Enabled by Mutability Landscaping
in ACS Catalysis
Moore DS
(2018)
Steered molecular dynamics simulations reveal critical residues for (un)binding of substrates, inhibitors and a product to the malarial M1 aminopeptidase.
in PLoS computational biology
Huggins D
(2018)
Biomolecular simulations: From dynamics and mechanisms to computational assays of biological activity
in WIREs Computational Molecular Science
Messiha HL
(2018)
Biocatalytic Routes to Lactone Monomers for Polymer Production.
in Biochemistry
Lence E
(2018)
QM/MM simulations identify the determinants of catalytic activity differences between type II dehydroquinase enzymes.
in Organic & biomolecular chemistry
Rinaldi S
(2018)
Understanding Complex Mechanisms of Enzyme Reactivity: The Case of Limonene-1,2-Epoxide Hydrolases
in ACS Catalysis
Liao Q
(2018)
Loop Motion in Triosephosphate Isomerase Is Not a Simple Open and Shut Case.
in Journal of the American Chemical Society
Ainsley J
(2018)
Structural Insights from Molecular Dynamics Simulations of Tryptophan 7-Halogenase and Tryptophan 5-Halogenase.
in ACS omega
Matheson A
(2018)
Phytosterol-based edible oleogels: A novel way of replacing saturated fat in food.
in Nutrition bulletin
Ranasinghe RT
(2018)
Detecting RNA base methylations in single cells by in situ hybridization.
in Nature communications
Motta S
(2018)
Ligand-induced perturbation of the HIF-2a:ARNT dimer dynamics.
in PLoS computational biology
Zhang X
(2018)
Multiscale analysis of enantioselectivity in enzyme-catalysed 'lethal synthesis' using projector-based embedding.
in Royal Society open science
Newport TD
(2019)
The MemProtMD database: a resource for membrane-embedded protein structures and their lipid interactions.
in Nucleic acids research
Wu Z
(2019)
Proton Control of Transitions in an Amino Acid Transporter.
in Biophysical journal
| 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 |