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
Woods CJ
(2009)
Multicore Parallelization of Kohn-Sham Theory.
in Journal of chemical theory and computation
Yamamoto E
(2020)
Multiple lipid binding sites determine the affinity of PH domains for phosphoinositide-containing membranes.
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
Jagger BR
(2020)
Multiscale simulation approaches to modeling drug-protein binding.
in Current opinion in structural biology
Hirvonen VHA
(2022)
Multiscale Simulations Identify Origins of Differential Carbapenem Hydrolysis by the OXA-48 ß-Lactamase.
in ACS catalysis
Yang Z
(2021)
Multiscale Workflow for Modeling Ligand Complexes of Zinc Metalloproteins.
in Journal of chemical information and modeling
Tooke C
(2021)
Natural variants modify Klebsiella pneumoniae carbapenemase (KPC) acyl-enzyme conformational dynamics to extend antibiotic resistance
in Journal of Biological Chemistry
Angulo G
(2016)
New methods: general discussion.
in Faraday discussions
Oliveira A. S. F.
(2019)
Nicotine-induced conformational changes in the a4ß2 nicotinic receptor
in EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS
Althorpe SC
(2016)
Non-adiabatic reactions: general discussion.
in Faraday discussions
Chudyk E
(2013)
Nonempirical Energetic Analysis of Reactivity and Covalent Inhibition of Fatty Acid Amide Hydrolase
in The Journal of Physical Chemistry B
Minguez Teresa
(2020)
Novel determinants of agonist selectivity in nicotinic ACh receptors
in BRITISH JOURNAL OF PHARMACOLOGY
Jefferys E
(2014)
NRas slows the rate at which a model lipid bilayer phase separates.
in Faraday discussions
Samsudin F
(2016)
OmpA: A Flexible Clamp for Bacterial Cell Wall Attachment.
in Structure (London, England : 1993)
Sampson C
(2019)
On the magnetosensitivity of lipid peroxidation: two- versus three-radical dynamics
in Physical Chemistry Chemical Physics
Arcus VL
(2016)
On the Temperature Dependence of Enzyme-Catalyzed Rates.
in Biochemistry
Ren Q
(2010)
Optimal control design of laser pulses for mode specific vibrational excitation in an enzyme-substrate complex
in Chemical Physics Letters
Heiblum Robles A
(2018)
Phase transitions in stigmergic territorial systems
in Physical Review E
Jambrina P
(2015)
Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation
in Angewandte Chemie
Bunzel H
(2022)
Photovoltaic enzymes by design and evolution
Mulholland Adrian J.
(2009)
PHYS 47-Biomolecular simulations of enzymatic reactions
in ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY
Shahane G
(2019)
Physical properties of model biological lipid bilayers: insights from all-atom molecular dynamics simulations.
in Journal of molecular modeling
Matheson A
(2018)
Phytosterol-based edible oleogels: A novel way of replacing saturated fat in food.
in Nutrition bulletin
Ranaghan KE
(2019)
Projector-Based Embedding Eliminates Density Functional Dependence for QM/MM Calculations of Reactions in Enzymes and Solution.
in Journal of chemical information and modeling
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 |