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
Burt A
(2020)
Complete structure of the chemosensory array core signalling unit in an E. coli minicell strain
in Nature Communications
Lonsdale R
(2010)
Compound I reactivity defines alkene oxidation selectivity in cytochrome P450cam.
in The journal of physical chemistry. B
Woods CJ
(2013)
Computational assay of H7N9 influenza neuraminidase reveals R292K mutation reduces drug binding affinity.
in Scientific reports
Jenkins Jonathan
(2019)
Computational design, construction, and characterisation of artificial peroxidases
Lonsdale R
(2010)
Computational enzymology.
in Chemical communications (Cambridge, England)
Lodola A
(2013)
Computational enzymology.
in Methods in molecular biology (Clifton, N.J.)
Reddy T
(2016)
Computational virology: From the inside out.
in Biochimica et biophysica acta
Çinaroglu S
(2023)
Computed Protein-Protein Enthalpy Signatures as a Tool for Identifying Conformation Sampling Problems
in Journal of Chemical Information and Modeling
Ranaghan KE
(2010)
Computer simulations of quantum tunnelling in enzyme-catalysed hydrogen transfer reactions.
in Interdisciplinary sciences, computational life sciences
Grant Ian M.
(2009)
Conformation and Catalysis in Lysozyme. A computational study
Mcgeagh John David
(2011)
Conformation and cooperativity in homodimeric enzymes investigated by molecular dynamics simulations
Van Der Kamp MW
(2013)
Conformational change and ligand binding in the aristolochene synthase catalytic cycle.
in Biochemistry
Caldwell TA
(2022)
Conformational dynamics of the membrane enzyme LspA upon antibiotic and substrate binding.
in Biophysical journal
Christov CZ
(2013)
Conformational effects on the pro-S hydrogen abstraction reaction in cyclooxygenase-1: an integrated QM/MM and MD study.
in Biophysical journal
Morando MA
(2016)
Conformational Selection and Induced Fit Mechanisms in the Binding of an Anticancer Drug to the c-Src Kinase.
in Scientific reports
Scott AJ
(2021)
Constructing ion channels from water-soluble a-helical barrels.
in Nature chemistry
Watkins DW
(2017)
Construction and in vivo assembly of a catalytically proficient and hyperthermostable de novo enzyme.
in Nature communications
Walker EJ
(2024)
Cooperative Conformational Transitions Underpin the Activation Heat Capacity in the Temperature Dependence of Enzyme Catalysis.
in ACS catalysis
Pennifold RC
(2017)
Correcting density-driven errors in projection-based embedding.
in The Journal of chemical physics
Mulholland AJ
(2020)
COVID19 - Computational Chemists Meet the Moment.
in Journal of chemical information and modeling
Parker JL
(2021)
Cryo-EM structure of PepT2 reveals structural basis for proton-coupled peptide and prodrug transport in mammals.
in Science advances
Laverty D
(2017)
Crystal structures of a GABAA-receptor chimera reveal new endogenous neurosteroid-binding sites
in Nature Structural & Molecular Biology
Twidale RM
(2021)
Crystallography and QM/MM Simulations Identify Preferential Binding of Hydrolyzed Carbapenem and Penem Antibiotics to the L1 Metallo-ß-Lactamase in the Imine Form.
in Journal of chemical information and modeling
Tooke CL
(2020)
Cyclic boronates as versatile scaffolds for KPC-2 ß-lactamase inhibition.
in RSC medicinal chemistry
| 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 |