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
Lonsdale R
(2012)
A practical guide to modelling enzyme-catalysed reactions.
in Chemical Society reviews
Lonsdale R
(2012)
A practical guide to modelling enzyme-catalysed reactions.
in Chemical Society reviews
Lonsdale R
(2010)
ChemInform Abstract: Computational Enzymology
in ChemInform
Lonsdale R
(2012)
ChemInform Abstract: A Practical Guide to Modelling Enzyme-Catalyzed Reactions
in ChemInform
Van Der Kamp M
(2009)
ChemInform Abstract: Computational Enzymology: Insight into Biological Catalyst from Modelling
in ChemInform
Limb MAL
(2019)
Quantum Mechanics/Molecular Mechanics Simulations Show Saccharide Distortion is Required for Reaction in Hen Egg-White Lysozyme.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Slocombe L
(2022)
Proton transfer during DNA strand separation as a source of mutagenic guanine-cytosine tautomers.
in Communications chemistry
Sofia F Oliveira A
(2022)
The fatty acid site is coupled to functional motifs in the SARS-CoV-2 spike protein and modulates spike allosteric behaviour.
in Computational and structural biotechnology journal
Balint-Kurti G
(1991)
The calculation of product quantum state distributions and partial cross-sections in time-dependent molecular collision and photodissociation theory
in Computer Physics Communications
Amaro RE
(2020)
Biomolecular Simulations in the Time of COVID19, and After.
in Computing in science & engineering
Bunzel HA
(2021)
Designing better enzymes: Insights from directed evolution.
in Current opinion in structural biology
Arcus VL
(2020)
Enzyme evolution and the temperature dependence of enzyme catalysis.
in Current opinion in structural biology
Jagger BR
(2020)
Multiscale simulation approaches to modeling drug-protein binding.
in Current opinion in structural biology
Lonsdale R
(2014)
QM/MM modelling of drug-metabolizing enzymes.
in Current topics in medicinal chemistry
Galdadas I
(2021)
Allosteric communication in class A ß-lactamases occurs via cooperative coupling of loop dynamics.
in eLife
Mulholland AJ
(2023)
Science after Brexit: bright spots on the Horizon?
in EMBO reports
Dooher T
(2022)
Environmental stress cracking of polymers: Case studies from industry (ABS and LDPE)
in Engineering Failure Analysis
Ali HS
(2019)
Entropy of Simulated Liquids Using Multiscale Cell Correlation.
in Entropy (Basel, Switzerland)
Oliveira A. S. F.
(2019)
Nicotine-induced conformational changes in the a4ß2 nicotinic receptor
in EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS
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
Walters RK
(2022)
The emerging potential of interactive virtual reality in drug discovery.
in Expert opinion on drug discovery
Chavent M
(2014)
Methodologies for the analysis of instantaneous lipid diffusion in MD simulations of large membrane systems.
in Faraday discussions
Acevedo-Rocha C
(2024)
Artificial, biomimetic and hybrid enzymes: general discussion.
in Faraday discussions
Abramiuk M
(2024)
Biocatalytic pathways, cascades, cells and systems: general discussion.
in Faraday discussions
Althorpe SC
(2016)
Non-adiabatic reactions: general discussion.
in Faraday discussions
Woods CJ
(2014)
Rapid decomposition and visualisation of protein-ligand binding free energies by residue and by water.
in Faraday discussions
Jefferys E
(2014)
NRas slows the rate at which a model lipid bilayer phase separates.
in Faraday discussions
Angulo G
(2016)
New methods: general discussion.
in Faraday discussions
Acevedo-Rocha C
(2024)
Enzyme evolution, engineering and design: mechanism and dynamics: general discussion.
in Faraday discussions
Matheson AB
(2017)
The development of phytosterol-lecithin mixed micelles and organogels.
in Food & function
Hanwarinroj C
(2022)
Discovery of novel and potent InhA inhibitors by an in silico screening and pharmacokinetic prediction.
in Future medicinal chemistry
Naafs B
(2021)
Molecular dynamics simulations support the hypothesis that the brGDGT paleothermometer is based on homeoviscous adaptation
in Geochimica et Cosmochimica Acta
Ingram M
(2020)
Determination of Bubble Size Distribution Using Ultrasound Array Imaging.
in IEEE transactions on ultrasonics, ferroelectrics, and frequency control
Ranaghan KE
(2010)
Computer simulations of quantum tunnelling in enzyme-catalysed hydrogen transfer reactions.
in Interdisciplinary sciences, computational life sciences
Kiani YS
(2019)
Molecular Dynamics Simulation Framework to Probe the Binding Hypothesis of CYP3A4 Inhibitors.
in International journal of molecular sciences
Mulholland A
(2004)
A comparison of semiempirical and ab initio transition states for HF elimination in unimolecular decompositions
in International Journal of Quantum Chemistry
Szefczyk B
(2007)
Quantum chemical analysis of reaction paths in chorismate mutase: Conformational effects and electrostatic stabilization
in International Journal of Quantum Chemistry
Ranaghan K
(2010)
Investigations of enzyme-catalysed reactions with combined quantum mechanics/molecular mechanics (QM/MM) methods
in International Reviews in Physical Chemistry
Tooke C
(2021)
Natural variants modify Klebsiella pneumoniae carbapenemase (KPC) acyl-enzyme conformational dynamics to extend antibiotic resistance
in Journal of Biological Chemistry
Tooke Catherine L.
(2019)
Interactions of ß-lactamases with antibiotics and inhibitors
in JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
Matos GDR
(2017)
Approaches for calculating solvation free energies and enthalpies demonstrated with an update of the FreeSolv database.
in Journal of chemical and engineering data
Bennie S
(2019)
Teaching Enzyme Catalysis Using Interactive Molecular Dynamics in Virtual Reality
in Journal of Chemical Education
Kamsri B
(2023)
Bioisosteric Design Identifies Inhibitors of Mycobacterium tuberculosis DNA Gyrase ATPase Activity.
in Journal of chemical information and modeling
Meletiou A
(2019)
Tios: The Internet of Simulations. Turning Molecular Dynamics into a Data Streaming Web Application.
in Journal of chemical information and modeling
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
Kamsri P
(2020)
Discovery of New and Potent InhA Inhibitors as Antituberculosis Agents: Structure-Based Virtual Screening Validated by Biological Assays and X-ray Crystallography.
in Journal of chemical information and modeling
Punkvang A
(2019)
Simulations of Shikimate Dehydrogenase from Mycobacterium tuberculosis in Complex with 3-Dehydroshikimate and NADPH Suggest Strategies for MtbSDH Inhibition.
in Journal of chemical information and modeling
Loeffler HH
(2015)
FESetup: Automating Setup for Alchemical Free Energy Simulations.
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 | 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 |