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
Maingi V
(2015)
Gating-like Motions and Wall Porosity in a DNA Nanopore Scaffold Revealed by Molecular Simulations.
in ACS nano
Malaisree Maturos
(2010)
Understanding of drug-target interactions and substrate binding to neuraminidase of influenza A virus subtypes H5N1 and H1N1-2009
in ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY
Martà S
(2022)
Impact of Warhead Modulations on the Covalent Inhibition of SARS-CoV-2 Mpro Explored by QM/MM Simulations.
in ACS catalysis
Matheson A
(2018)
Phytosterol-based edible oleogels: A novel way of replacing saturated fat in food.
in Nutrition bulletin
Matheson AB
(2017)
The development of phytosterol-lecithin mixed micelles and organogels.
in Food & function
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
May PW
(2016)
Diamond-coated 'black silicon' as a promising material for high-surface-area electrochemical electrodes and antibacterial surfaces.
in Journal of materials chemistry. B
McGeagh J
(2010)
Kinetics and Dynamics - From Nano- to Bio-Scale
McGeagh JD
(2011)
Protein dynamics and enzyme catalysis: insights from simulations.
in Biochimica et biophysica acta
Mcgeagh John David
(2011)
Conformation and cooperativity in homodimeric enzymes investigated by molecular dynamics simulations
Meletiou A
(2019)
Tios: The Internet of Simulations. Turning Molecular Dynamics into a Data Streaming Web Application.
in Journal of chemical information and modeling
Mendoza-Martinez C
(2022)
Energetics of a protein disorder-order transition in small molecule recognition.
in Chemical science
Merlicek L
(2025)
AI.zymes - A modular platform for evolutionary enzyme design
Messiha HL
(2018)
Biocatalytic Routes to Lactone Monomers for Polymer Production.
in Biochemistry
Miles BT
(2017)
Direct Evidence of Lack of Colocalisation of Fluorescently Labelled Gold Labels Used in Correlative Light Electron Microscopy.
in Scientific reports
Minguez Teresa
(2020)
Novel determinants of agonist selectivity in nicotinic ACh receptors
in BRITISH JOURNAL OF PHARMACOLOGY
Minguez-Viñas T
(2021)
A conserved arginine with non-conserved function is a key determinant of agonist selectivity in a7 nicotinic ACh receptors.
in British journal of pharmacology
Mlýnský V
(2014)
Comparison of ab Initio, DFT, and Semiempirical QM/MM Approaches for Description of Catalytic Mechanism of Hairpin Ribozyme.
in Journal of chemical theory and computation
Moore DS
(2018)
Steered molecular dynamics simulations reveal critical residues for (un)binding of substrates, inhibitors and a product to the malarial M1 aminopeptidase.
in PLoS computational biology
Morando MA
(2016)
Conformational Selection and Induced Fit Mechanisms in the Binding of an Anticancer Drug to the c-Src Kinase.
in Scientific reports
Motta S
(2018)
Ligand-induced perturbation of the HIF-2a:ARNT dimer dynamics.
in PLoS computational biology
Mujika J
(2012)
Encyclopedia of Inorganic and Bioinorganic Chemistry
Mujika JI
(2012)
Mechanism of C-terminal intein cleavage in protein splicing from QM/MM molecular dynamics simulations.
in Organic & biomolecular chemistry
Mujika JI
(2009)
Modeling protein splicing: reaction pathway for C-terminal splice and intein scission.
in The journal of physical chemistry. B
Mulholland A
(1998)
A model of the condensation step in the citrate synthase reaction
in Journal of Molecular Structure: THEOCHEM
Mulholland A
(2004)
A comparison of semiempirical and ab initio transition states for HF elimination in unimolecular decompositions
in International Journal of Quantum Chemistry
Mulholland A
(2012)
Enzyme dynamics and catalysis in the mechanism of DNA polymerase
in Theoretical Chemistry Accounts
Mulholland A
(2020)
Letter to the Editor.
in Journal of paediatrics and child health
Mulholland A
(2020)
Catalytic Mechanism of the Colistin Resistance Protein MCR-1
Mulholland A
(1998)
Calculations on the substrates of citrate synthase I. Oxaloacetate
in Journal of Molecular Structure: THEOCHEM
Mulholland A
(2000)
Ab Initio QM/MM Study of the Citrate Synthase Mechanism. A Low-Barrier Hydrogen Bond Is not Involved
in Journal of the American Chemical Society
Mulholland Adrian J.
(2009)
PHYS 47-Biomolecular simulations of enzymatic reactions
in ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY
Mulholland AJ
(1996)
Simulations of enzymic reactions.
in Biochemical Society transactions
Mulholland AJ
(2023)
Science after Brexit: bright spots on the Horizon?
in EMBO reports
Mulholland AJ
(2020)
COVID19 - Computational Chemists Meet the Moment.
in Journal of chemical information and modeling
Mulholland AJ
(2016)
Dispelling the effects of a sorceress in enzyme catalysis.
in Proceedings of the National Academy of Sciences of the United States of America
Mulholland, AJ
(2009)
Using high-performance computing to model enzyme-catalysed reactions
Musgaard M
(2016)
Steered Molecular Dynamics Simulations Predict Conformational Stability of Glutamate Receptors.
in Journal of chemical information and modeling
Naafs B
(2021)
Molecular dynamics simulations support the hypothesis that the brGDGT paleothermometer is based on homeoviscous adaptation
in Geochimica et Cosmochimica Acta
Nesabi A
(2024)
Molecular dynamics simulations as a guide for modulating small molecule aggregation.
in Journal of computer-aided molecular design
Nett N
(2021)
A robust and stereocomplementary panel of ene-reductase variants for gram-scale asymmetric hydrogenation
in Molecular Catalysis
Newport TD
(2019)
The MemProtMD database: a resource for membrane-embedded protein structures and their lipid interactions.
in Nucleic acids research
| 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 |