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
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
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
Van Der Kamp M
(2011)
"Lethal Synthesis" of Fluorocitrate by Citrate Synthase Explained through QM/MM Modeling
in Angewandte Chemie
Van Der Kamp MW
(2011)
"Lethal synthesis" of fluorocitrate by citrate synthase explained through QM/MM modeling.
in Angewandte Chemie (International ed. in English)
Sampson C
(2015)
A "Stepping Stone" Approach for Obtaining Quantum Free Energies of Hydration.
in The journal of physical chemistry. B
Ranaghan K
(2014)
A catalytic role for methionine revealed by a combination of computation and experiments on phosphite dehydrogenase
in Chem. Sci.
Amaro RE
(2020)
A Community Letter Regarding Sharing Biomolecular Simulation Data for COVID-19.
in Journal of chemical information and modeling
Mulholland A
(2004)
A comparison of semiempirical and ab initio transition states for HF elimination in unimolecular decompositions
in International Journal of Quantum Chemistry
De Simone A
(2019)
A computationally designed binding mode flip leads to a novel class of potent tri-vector cyclophilin inhibitors.
in Chemical science
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
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
Ryan S
(2016)
A Dynamic and Responsive Host in Action: Light-Controlled Molecular Encapsulation
in Angewandte Chemie
Juan Facundo Chrestia
(2021)
A Functional Interaction Between the SARS-CoV-2 Spike Protein and the Human a7 Nicotinic Receptor
Juan Facundo Chrestia
(2021)
A Functional Interaction Between the SARS-CoV-2 Spike Protein and the Human a7 Nicotinic Receptor
Juan Facundo Chrestia
(2022)
A Functional Interaction Between the SARS-CoV-2 Spike Protein and the Human a7 Nicotinic Receptor
Juan Facundo Chrestia
(2022)
A Functional Interaction Between the SARS-CoV-2 Spike Protein and the Human a7 Nicotinic Receptor
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
Oliveira ASF
(2019)
A General Mechanism for Signal Propagation in the Nicotinic Acetylcholine Receptor Family.
in Journal of the American Chemical Society
Mulholland A
(1998)
A model of the condensation step in the citrate synthase reaction
in Journal of Molecular Structure: THEOCHEM
Grundmann M
(2016)
A Molecular Mechanism for Sequential Activation of a G Protein-Coupled Receptor
in Cell Chemical Biology
Lonsdale R
(2014)
A multiscale approach to modelling drug metabolism by membrane-bound cytochrome P450 enzymes.
in PLoS computational biology
Gervasoni S
(2021)
A multiscale approach to predict the binding mode of metallo beta-lactamase inhibitors
in Proteins: Structure, Function, and Bioinformatics
Haldar S
(2018)
A Multiscale Simulation Approach to Modeling Drug-Protein Binding Kinetics.
in Journal of chemical theory and computation
O'Hagan M
(2019)
A Photoresponsive Stiff-Stilbene Ligand Fuels the Reversible Unfolding of G-Quadruplex DNA
in Angewandte Chemie
O'Hagan MP
(2019)
A Photoresponsive Stiff-Stilbene Ligand Fuels the Reversible Unfolding of G-Quadruplex DNA.
in Angewandte Chemie (International ed. in English)
Oliveira ASF
(2021)
A potential interaction between the SARS-CoV-2 spike protein and nicotinic acetylcholine receptors.
in Biophysical journal
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
Bennie SJ
(2016)
A Projector-Embedding Approach for Multiscale Coupled-Cluster Calculations Applied to Citrate Synthase.
in Journal of chemical theory and computation
Ridder L
(2000)
A Quantum Mechanical/Molecular Mechanical Study of the Hydroxylation of Phenol and Halogenated Derivatives by Phenol Hydroxylase
in Journal of the American Chemical Society
Nett N
(2021)
A robust and stereocomplementary panel of ene-reductase variants for gram-scale asymmetric hydrogenation
in Molecular Catalysis
Woods CJ
(2011)
A water-swap reaction coordinate for the calculation of absolute protein-ligand binding free energies.
in The Journal of chemical physics
Ridder L
(2003)
Ab Initio QM/MM Modeling of the Hydroxylation Step in p -Hydroxybenzoate Hydroxylase
in The Journal of Physical Chemistry B
Ranaghan KE
(2017)
Ab Initio QM/MM Modeling of the Rate-Limiting Proton Transfer Step in the Deamination of Tryptamine by Aromatic Amine Dehydrogenase.
in The journal of physical chemistry. B
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
Brandani GB
(2017)
Adsorption of the natural protein surfactant Rsn-2 onto liquid interfaces.
in Physical chemistry chemical physics : PCCP
Merlicek L
(2025)
AI.zymes - A modular platform for evolutionary enzyme design
Galdadas I
(2021)
Allosteric communication in class A ß-lactamases occurs via cooperative coupling of loop dynamics.
in eLife
Hashem S
(2018)
Allosteric Modulation of Cardiac Myosin Dynamics by Omecamtiv Mecarbil
in Biophysical Journal
Hashem S
(2017)
Allosteric modulation of cardiac myosin dynamics by omecamtiv mecarbil.
in PLoS computational biology
Pucheta-MartÃnez E
(2016)
An Allosteric Cross-Talk Between the Activation Loop and the ATP Binding Site Regulates the Activation of Src Kinase.
in Scientific reports
| 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 |