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
Lodola A
(2013)
Computational enzymology.
in Methods in molecular biology (Clifton, N.J.)
Nett N
(2021)
A robust and stereocomplementary panel of ene-reductase variants for gram-scale asymmetric hydrogenation
in Molecular Catalysis
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
RANAGHAN K
(2009)
Insights into enzyme catalysis from QM/MM modelling: transition state stabilization in chorismate mutase
in Molecular Physics
Scott AJ
(2021)
Constructing ion channels from water-soluble a-helical barrels.
in Nature chemistry
Bunzel H
(2021)
Evolution of dynamical networks enhances catalysis in a designer enzyme
in Nature Chemistry
Watkins DW
(2017)
Construction and in vivo assembly of a catalytically proficient and hyperthermostable de novo enzyme.
in Nature communications
Gupta K
(2022)
Structural insights in cell-type specific evolution of intra-host diversity by SARS-CoV-2.
in Nature communications
Rhys GG
(2018)
Maintaining and breaking symmetry in homomeric coiled-coil assemblies.
in Nature communications
Van Den Berg B
(2016)
Structural basis for Mep2 ammonium transceptor activation by phosphorylation.
in Nature communications
Dawson WM
(2021)
Structural resolution of switchable states of a de novo peptide assembly.
in Nature communications
Van Der Kamp MW
(2018)
Dynamical origins of heat capacity changes in enzyme-catalysed reactions.
in Nature communications
Daniels DE
(2023)
Human cellular model systems of ß-thalassemia enable in-depth analysis of disease phenotype.
in Nature communications
Amaro RE
(2018)
Multiscale Methods in Drug Design Bridge Chemical and Biological Complexity in the Search for Cures.
in Nature reviews. Chemistry
Schiffrin B
(2016)
Skp is a multivalent chaperone of outer-membrane proteins.
in Nature structural & molecular biology
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
Kattnig D
(2018)
Molecular dynamics simulations disclose early stages of the photo-activation of cryptochrome 4
in New Journal of Physics
Newport TD
(2019)
The MemProtMD database: a resource for membrane-embedded protein structures and their lipid interactions.
in Nucleic acids research
Pasi M
(2014)
µABC: a systematic microsecond molecular dynamics study of tetranucleotide sequence effects in B-DNA.
in Nucleic acids research
Matheson A
(2018)
Phytosterol-based edible oleogels: A novel way of replacing saturated fat in food.
in Nutrition bulletin
Claeyssens F
(2011)
Analysis of chorismate mutase catalysis by QM/MM modelling of enzyme-catalysed and uncatalysed reactions.
in Organic & biomolecular chemistry
Suardíaz R
(2021)
Catalytic mechanism of the colistin resistance protein MCR-1.
in Organic & biomolecular chemistry
Lence E
(2018)
QM/MM simulations identify the determinants of catalytic activity differences between type II dehydroquinase enzymes
in Organic & Biomolecular Chemistry
Mujika JI
(2012)
Mechanism of C-terminal intein cleavage in protein splicing from QM/MM molecular dynamics simulations.
in Organic & biomolecular chemistry
Sirirak J
(2020)
Benchmarking quantum mechanical methods for calculating reaction energies of reactions catalyzed by enzymes
in PeerJ Physical Chemistry
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 |