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
Noy A
(2017)
Interference between Triplex and Protein Binding to Distal Sites on Supercoiled DNA
in Biophysical Journal
Van Der Kamp M
(2017)
Dynamical origins of heat capacity changes in enzyme catalysed reactions
Matheson AB
(2017)
The development of phytosterol-lecithin mixed micelles and organogels.
in Food & function
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
Ding W
(2017)
Effects of High Pressure on Phospholipid Bilayers.
in The journal of physical chemistry. B
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
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
Brandani GB
(2017)
Adsorption of the natural protein surfactant Rsn-2 onto liquid interfaces.
in Physical chemistry chemical physics : PCCP
Hashem S
(2017)
Allosteric modulation of cardiac myosin dynamics by omecamtiv mecarbil
in PLOS Computational Biology
Heiblum Robles A
(2018)
Phase transitions in stigmergic territorial systems
in Physical Review E
Thomas F
(2018)
De Novo-Designed a-Helical Barrels as Receptors for Small Molecules.
in ACS synthetic biology
Rego Campello H
(2018)
Unlocking Nicotinic Selectivity via Direct C?H Functionalization of (-)-Cytisine
in Chem
Matheson A
(2018)
Phytosterol-based edible oleogels: A novel way of replacing saturated fat in food.
in Nutrition bulletin
Amaro RE
(2018)
Multiscale Methods in Drug Design Bridge Chemical and Biological Complexity in the Search for Cures.
in Nature reviews. Chemistry
Kattnig D
(2018)
Molecular dynamics simulations disclose early stages of the photo-activation of cryptochrome 4
in New Journal of Physics
Ainsley J
(2018)
Structural Insights from Molecular Dynamics Simulations of Tryptophan 7-Halogenase and Tryptophan 5-Halogenase.
in ACS omega
Huggins D
(2018)
Biomolecular simulations: From dynamics and mechanisms to computational assays of biological activity
in WIREs Computational Molecular Science
Rhys GG
(2018)
Maintaining and breaking symmetry in homomeric coiled-coil assemblies.
in Nature communications
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
Ainsley J
(2018)
Combined Quantum Mechanics and Molecular Mechanics Studies of Enzymatic Reaction Mechanisms.
in Advances in protein chemistry and structural biology
Haldar S
(2018)
A Multiscale Simulation Approach to Modeling Drug-Protein Binding Kinetics.
in Journal of chemical theory and computation
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
Hazell G
(2018)
Studies of black silicon and black diamond as materials for antibacterial surfaces.
in Biomaterials science
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 |