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
Hedger G
(2019)
Cholesterol Interaction Sites on the Transmembrane Domain of the Hedgehog Signal Transducer and Class F G Protein-Coupled Receptor Smoothened.
in Structure (London, England : 1993)
Hedges L
(2019)
BioSimSpace: An interoperable Python framework for biomolecular simulation
in Journal of Open Source Software
Heiblum Robles A
(2018)
Phase transitions in stigmergic territorial systems
in Physical Review E
Hermann JC
(2009)
High level QM/MM modeling of the formation of the tetrahedral intermediate in the acylation of wild type and K73A mutant TEM-1 class A beta-lactamase.
in The journal of physical chemistry. A
Hinchliffe P
(2017)
Insights into the Mechanistic Basis of Plasmid-Mediated Colistin Resistance from Crystal Structures of the Catalytic Domain of MCR-1.
in Scientific reports
Hindson S
(2021)
Rigidifying a De Novo Enzyme Increases Activity and Induces a Negative Activation Heat Capacity
in ACS Catalysis
Hirvonen V
(2020)
Small Changes in Hydration Determine Cephalosporinase Activity of OXA-48 ß-Lactamases
in ACS Catalysis
Hirvonen VHA
(2019)
An Efficient Computational Assay for ß-Lactam Antibiotic Breakdown by Class A ß-Lactamases.
in Journal of chemical information and modeling
Hirvonen VHA
(2022)
Multiscale Simulations Identify Origins of Differential Carbapenem Hydrolysis by the OXA-48 ß-Lactamase.
in ACS catalysis
Houghton Kerensa
(2011)
Modelling reaction mechanisms and dynamics of cytochrome P450-drug complexes
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
Huggins D
(2018)
Biomolecular simulations: From dynamics and mechanisms to computational assays of biological activity
in WIREs Computational Molecular Science
Hutchins GH
(2023)
An expandable, modular de novo protein platform for precision redox engineering.
in Proceedings of the National Academy of Sciences of the United States of America
Ingram M
(2020)
Determination of Bubble Size Distribution Using Ultrasound Array Imaging.
in IEEE transactions on ultrasonics, ferroelectrics, and frequency control
Jagger BR
(2020)
Multiscale simulation approaches to modeling drug-protein binding.
in Current opinion in structural biology
Jambrina P
(2015)
Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation
in Angewandte Chemie
Jefferys E
(2014)
NRas slows the rate at which a model lipid bilayer phase separates.
in Faraday discussions
Jenkins JMX
(2021)
Substrate promiscuity of a de novo designed peroxidase.
in Journal of inorganic biochemistry
Jenkins Jonathan
(2019)
Computational design, construction, and characterisation of artificial peroxidases
Jitonnom J
(2017)
Quantum Mechanics/Molecular Mechanics Simulations Identify the Ring-Opening Mechanism of Creatininase.
in Biochemistry
Jitonnom J
(2012)
Insights into conformational changes of procarboxypeptidase A and B from simulations: a plausible explanation for different intrinsic activity
in Theoretical Chemistry Accounts
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 |