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
Voice Angus
(2021)
Modelling the reactivity of cysteine targeting covalent inhibitors
Parker JL
(2021)
Cryo-EM structure of PepT2 reveals structural basis for proton-coupled peptide and prodrug transport in mammals.
in Science advances
Hindson SA
(2021)
Rigidifying a De Novo Enzyme Increases Activity and Induces a Negative Activation Heat Capacity.
in ACS catalysis
SuardÃaz R
(2021)
Catalytic mechanism of the colistin resistance protein MCR-1
in Organic & Biomolecular Chemistry
Singh J
(2021)
Real-time super-resolution mapping of locally anisotropic grain orientations for ultrasonic non-destructive evaluation of crystalline material
in Neural Computing and Applications
Voice AT
(2021)
Mechanism of covalent binding of ibrutinib to Bruton's tyrosine kinase revealed by QM/MM calculations.
in Chemical science
Juan Facundo Chrestia
(2021)
A Functional Interaction Between the SARS-CoV-2 Spike Protein and the Human a7 Nicotinic Receptor
Bunzel HA
(2021)
Designing better enzymes: Insights from directed evolution.
in Current opinion in structural biology
Dinsdale RL
(2021)
An outer-pore gate modulates the pharmacology of the TMEM16A channel.
in Proceedings of the National Academy of Sciences of the United States of America
Simcock PW
(2021)
Membrane Binding of Antimicrobial Peptides Is Modulated by Lipid Charge Modification.
in Journal of chemical theory and computation
Tooke C
(2021)
Natural variants modify Klebsiella pneumoniae carbapenemase (KPC) acyl-enzyme conformational dynamics to extend antibiotic resistance
in Journal of Biological Chemistry
Juan Facundo Chrestia
(2021)
A Functional Interaction Between the SARS-CoV-2 Spike Protein and the Human a7 Nicotinic Receptor
Vinas Teresa Minguez
(2021)
A Conserved Arginine with Non-Conserved Function is a Key Determinant of Agonist Selectivity in Alpha7 Nicotinic Acetylcholine Receptors
in BIOPHYSICAL JOURNAL
Gervasoni S
(2021)
A multiscale approach to predict the binding mode of metallo beta-lactamase inhibitors
in Proteins: Structure, Function, and Bioinformatics
Song W
(2021)
Modulation of adenosine A2a receptor oligomerization by receptor activation and PIP2 interactions.
in Structure (London, England : 1993)
Ansell TB
(2021)
Relative Affinities of Protein-Cholesterol Interactions from Equilibrium Molecular Dynamics Simulations.
in Journal of chemical theory and computation
Dommer A
(2021)
#COVIDisAirborne: AI-Enabled Multiscale Computational Microscopy of Delta SARS-CoV-2 in a Respiratory Aerosol.
in bioRxiv : the preprint server for biology
Twidale Rebecca M.
(2021)
Modelling the reactivity of zinc metalloenzymes and the SARS-CoV-2 main protease
Bunzel HA
(2021)
Evolution of dynamical networks enhances catalysis in a designer enzyme.
in Nature chemistry
Chan HTH
(2021)
Discovery of SARS-CoV-2 Mpro peptide inhibitors from modelling substrate and ligand binding.
in Chemical science
Oliveira ASF
(2021)
A potential interaction between the SARS-CoV-2 spike protein and nicotinic acetylcholine receptors.
in Biophysical journal
Galdadas I
(2021)
Allosteric communication in class A ß-lactamases occurs via cooperative coupling of loop dynamics.
in eLife
Coupland C
(2021)
Structure and Mechanism of Hedgehog Acyl Transferase
Shoemark D
(2021)
Frontispiece: Molecular Simulations suggest Vitamins, Retinoids and Steroids as Ligands of the Free Fatty Acid Pocket of the SARS-CoV-2 Spike Protein
in Angewandte Chemie International Edition
Parker JL
(2021)
Structural basis of antifolate recognition and transport by PCFT.
in Nature
Jenkins JMX
(2021)
Substrate promiscuity of a de novo designed peroxidase.
in Journal of inorganic biochemistry
Scott AJ
(2021)
Constructing ion channels from water-soluble a-helical barrels.
in Nature chemistry
Coupland CE
(2021)
Structure, mechanism, and inhibition of Hedgehog acyltransferase.
in Molecular cell
Corey RA
(2021)
Identification and assessment of cardiolipin interactions with E. coli inner membrane proteins.
in Science advances
Nett N
(2021)
A robust and stereocomplementary panel of ene-reductase variants for gram-scale asymmetric hydrogenation
in Molecular Catalysis
Yang Z
(2021)
Multiscale Workflow for Modeling Ligand Complexes of Zinc Metalloproteins.
in Journal of chemical information and modeling
Phintha A
(2021)
Dissecting the low catalytic capability of flavin-dependent halogenases.
in The Journal of biological chemistry
Oliveira ASF
(2021)
Dynamical nonequilibrium molecular dynamics reveals the structural basis for allostery and signal propagation in biomolecular systems.
in The European physical journal. B
Vickery ON
(2021)
CG2AT2: an Enhanced Fragment-Based Approach for Serial Multi-scale Molecular Dynamics Simulations.
in Journal of chemical theory and computation
Shoemark D
(2021)
Molecular Simulations suggest Vitamins, Retinoids and Steroids as Ligands of the Free Fatty Acid Pocket of the SARS-CoV-2 Spike Protein**
in Angewandte Chemie
Amos STA
(2021)
Membrane Interactions of a-Synuclein Revealed by Multiscale Molecular Dynamics Simulations, Markov State Models, and NMR.
in The journal of physical chemistry. B
Shoemark DK
(2021)
Molecular Simulations suggest Vitamins, Retinoids and Steroids as Ligands of the Free Fatty Acid Pocket of the SARS-CoV-2 Spike Protein*.
in Angewandte Chemie (International ed. in English)
Haldar S
(2021)
Ligand-induced unfolding mechanism of an RNA G-quadruplex
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
| 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 |