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
Bunzel H
(2022)
Photovoltaic enzymes by design and evolution
Martí S
(2022)
Impact of Warhead Modulations on the Covalent Inhibition of SARS-CoV-2 Mpro Explored by QM/MM Simulations.
in ACS catalysis
Walters RK
(2022)
The emerging potential of interactive virtual reality in drug discovery.
in Expert opinion on drug discovery
Larsen AH
(2022)
Specific interactions of peripheral membrane proteins with lipids: what can molecular simulations show us?
in Bioscience reports
Hanwarinroj C
(2022)
In silico design of novel quinazoline-based compounds as potential Mycobacterium tuberculosis PknB inhibitors through 2D and 3D-QSAR, molecular dynamics simulations combined with pharmacokinetic predictions.
in Journal of molecular graphics & modelling
Chrestia JF
(2022)
A Functional Interaction Between Y674-R685 Region of the SARS-CoV-2 Spike Protein and the Human a7 Nicotinic Receptor.
in Molecular neurobiology
Pakamwong B
(2022)
Identification of Potent DNA Gyrase Inhibitors Active against Mycobacterium tuberculosis.
in Journal of chemical information and modeling
Chudyk EI
(2022)
QM/MM Simulations Reveal the Determinants of Carbapenemase Activity in Class A ß-Lactamases.
in ACS infectious diseases
Hirvonen VHA
(2022)
Multiscale Simulations Identify Origins of Differential Carbapenem Hydrolysis by the OXA-48 ß-Lactamase.
in ACS catalysis
Song W
(2022)
PyLipID: A Python Package for Analysis of Protein-Lipid Interactions from Molecular Dynamics Simulations.
in Journal of chemical theory and computation
Haldar S
(2022)
Mechanistic Insights into the Ligand-Induced Unfolding of an RNA G-Quadruplex.
in Journal of the American Chemical Society
Caldwell TA
(2022)
Conformational dynamics of the membrane enzyme LspA upon antibiotic and substrate binding.
in Biophysical journal
Thongdee P
(2022)
Virtual Screening Identifies Novel and Potent Inhibitors of Mycobacterium tuberculosis PknB with Antibacterial Activity.
in Journal of chemical information and modeling
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
Lear A
(2023)
Comment on: "Computer Simulations Reveal an Entirely Entropic Activation Barrier for the Chemical Step in a Designer Enzyme"
in ACS Catalysis
Mulholland AJ
(2023)
Science after Brexit: bright spots on the Horizon?
in EMBO reports
Tooke CL
(2023)
Tautomer-Specific Deacylation and O-Loop Flexibility Explain the Carbapenem-Hydrolyzing Broad-Spectrum Activity of the KPC-2 ß-Lactamase.
in Journal of the American Chemical Society
Hanpaibool C
(2023)
Pyrazolones Potentiate Colistin Activity against MCR-1-Producing Resistant Bacteria: Computational and Microbiological Study
in ACS Omega
Kamsri B
(2023)
Bioisosteric Design Identifies Inhibitors of Mycobacterium tuberculosis DNA Gyrase ATPase Activity.
in Journal of chemical information and modeling
Deeks HM
(2023)
Free energy along drug-protein binding pathways interactively sampled in virtual reality.
in Scientific reports
Hanpaibool C
(2023)
Enhancement by pyrazolones of colistin efficacy against mcr-1-expressing E. coli: an in silico and in vitro investigation.
in Journal of computer-aided molecular design
Oliveira ASF
(2023)
SARS-CoV-2 spike variants differ in their allosteric responses to linoleic acid.
in Journal of molecular cell biology
Warman H
(2023)
How proton transfer impacts hachimoji DNA.
in RSC advances
Buzas D
(2023)
In vitro generated antibodies guide thermostable ADDomer nanoparticle design for nasal vaccination and passive immunization against SARS-CoV-2
in Antibody Therapeutics
Oliveira A
(2023)
Fluctuation Relations to Calculate Protein Redox Potentials from Molecular Dynamics Simulations
in Journal of Chemical Theory and Computation
Daniels DE
(2023)
Human cellular model systems of ß-thalassemia enable in-depth analysis of disease phenotype.
in Nature communications
Crossley-Lewis J
(2023)
Interactive molecular dynamics in virtual reality for modelling materials and catalysts.
in Journal of molecular graphics & modelling
Castelli M
(2023)
Decrypting Allostery in Membrane-Bound K-Ras4B Using Complementary In Silico Approaches Based on Unbiased Molecular Dynamics 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
Dommer A
(2023)
#COVIDisAirborne: AI-enabled multiscale computational microscopy of delta SARS-CoV-2 in a respiratory aerosol.
in The international journal of high performance computing applications
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
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 |