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
Dooher T
(2022)
Environmental stress cracking of polymers: Case studies from industry (ABS and LDPE)
in Engineering Failure Analysis
Douglas-Gallardo O
(2020)
Electronic structure benchmark calculations of CO 2 fixing elementary chemical steps in RuBisCO using the projector-based embedding approach
in Journal of Computational Chemistry
Douglas-Gallardo O
(2022)
Carbon dioxide fixation in RuBisCO is protonation state dependent and irreversible
Douglas-Gallardo O
(2022)
Carbon Dioxide Fixation in RuBisCO Is Protonation-State-Dependent and Irreversible
in ACS Catalysis
Douglas-Gallardo O
(2022)
Carbon dioxide fixation in RuBisCO is protonation state dependent and irreversible
Dunn J
(2024)
Diffusion mechanisms and preferential dynamics of promoter molecules in ZSM-5 zeolite
in Catalysis Science & Technology
Dunseath O
(2019)
Studies of Black Diamond as an antibacterial surface for Gram Negative bacteria: the interplay between chemical and mechanical bactericidal activity.
in Scientific reports
Elcock A
(2002)
Combined Quantum and Molecular Mechanical Study of DNA Crosslinking by Nitrous Acid
in Journal of the American Chemical Society
Espejo-Román JM
(2022)
Selective Anticancer Therapy Based on a HA-CD44 Interaction Inhibitor Loaded on Polymeric Nanoparticles.
in Pharmaceutics
Espejo-Román JM
(2023)
N-aryltetrahydroisoquinoline derivatives as HA-CD44 interaction inhibitors: Design, synthesis, computational studies, and antitumor effect.
in European journal of medicinal chemistry
Evans LE
(2019)
Exploitation of Antibiotic Resistance as a Novel Drug Target: Development of a ß-Lactamase-Activated Antibacterial Prodrug.
in Journal of medicinal chemistry
Fan Betty
(2017)
Stage IV breast cancer is increased by omitting screening mammography
in ANNALS OF SURGICAL ONCOLOGY
Fonseca F
(2012)
The Basis for Carbapenem Hydrolysis by Class A ß-Lactamases: A Combined Investigation using Crystallography and Simulations
in Journal of the American Chemical Society
Freeman SL
(2023)
Heme binding to the SARS-CoV-2 spike glycoprotein.
in The Journal of biological chemistry
Fröhlich C
(2024)
Epistasis arises from shifting the rate-limiting step during enzyme evolution of a ß-lactamase.
in Nature catalysis
Fröhlich C
(2024)
Author Correction: Epistasis arises from shifting the rate-limiting step during enzyme evolution of a ß-lactamase
in Nature Catalysis
Fröhlich, Christopher
(2024)
Epistasis arises from shifting the rate-limiting step during enzyme evolution of a ß-lactamase
Galdadas I
(2021)
Allosteric communication in class A ß-lactamases occurs via cooperative coupling of loop dynamics.
in eLife
Ge Y
(2017)
Identification of the quinolinedione inhibitor binding site in Cdc25 phosphatase B through docking and molecular dynamics simulations.
in Journal of computer-aided molecular design
| 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 |