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
Balint-Kurti G
(1991)
The calculation of product quantum state distributions and partial cross-sections in time-dependent molecular collision and photodissociation theory
in Computer Physics Communications
Mulholland AJ
(1996)
Simulations of enzymic reactions.
in Biochemical Society transactions
Mulholland A
(1998)
A model of the condensation step in the citrate synthase reaction
in Journal of Molecular Structure: THEOCHEM
Mulholland A
(1998)
Calculations on the substrates of citrate synthase I. Oxaloacetate
in Journal of Molecular Structure: THEOCHEM
Ridder L
(1999)
Combined quantum mechanical and molecular mechanical reaction pathway calculation for aromatic hydroxylation by p-hydroxybenzoate-3-hydroxylase.
in Journal of molecular graphics & modelling
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
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
Elcock A
(2002)
Combined Quantum and Molecular Mechanical Study of DNA Crosslinking by Nitrous Acid
in Journal of the American Chemical Society
Ridder L
(2003)
Ab Initio QM/MM Modeling of the Hydroxylation Step in p -Hydroxybenzoate Hydroxylase
in The Journal of Physical Chemistry B
Mulholland A
(2004)
A comparison of semiempirical and ab initio transition states for HF elimination in unimolecular decompositions
in International Journal of Quantum Chemistry
Zurek J
(2004)
MM and QM/MM Modeling of Threonyl-tRNA Synthetase: Model Testing and Simulations
in Structural Chemistry
Harvey J
(2006)
QM and QM/MM studies of selectivity in organic and bioorganic chemistry
in Journal of Physical Organic Chemistry
Szefczyk B
(2007)
Quantum chemical analysis of reaction paths in chorismate mutase: Conformational effects and electrostatic stabilization
in International Journal of Quantum Chemistry
Lodola A
(2009)
Insights into the mechanism and inhibition of fatty acid amide hydrolase from quantum mechanics/molecular mechanics (QM/MM) modelling.
in Biochemical Society transactions
Mulholland, AJ
(2009)
Using high-performance computing to model enzyme-catalysed reactions
Karabencheva-Christova Tatyana Georgieva
(2009)
QM/MM modelling of mechanisms of flavin-containing enzymes
Szeto M
(2009)
QM/MM study on the mechanism of peptide hydrolysis by carboxypeptidase A
in Journal of Molecular Structure: THEOCHEM
Hermann JC
(2009)
High level QM/MM modeling of the formation of the tetrahedral intermediate in the acylation of wild type and K73A mutant TEM-1 class A beta-lactamase.
in The journal of physical chemistry. A
Grant Ian M.
(2009)
Conformation and Catalysis in Lysozyme. A computational study
Van Der Kamp M
(2009)
ChemInform Abstract: Computational Enzymology: Insight into Biological Catalyst from Modelling
in ChemInform
Mujika JI
(2009)
Modeling protein splicing: reaction pathway for C-terminal splice and intein scission.
in The journal of physical chemistry. B
Rowlands Heather Ann
(2009)
Modelling of the sugar processing enzymes chitinase B and Phosphomannomutase/ Phosphoglucomutase
Shaw K
(2009)
Compatibility of Quantum Chemical Methods and Empirical (MM) Water Models in Quantum Mechanics/Molecular Mechanics Liquid Water Simulations
in The Journal of Physical Chemistry Letters
Pentikäinen U
(2009)
Lennard-Jones Parameters for B3LYP/CHARMM27 QM/MM Modeling of Nucleic Acid Bases.
in Journal of chemical theory and computation
Woods CJ
(2009)
Multicore Parallelization of Kohn-Sham Theory.
in Journal of chemical theory and computation
RANAGHAN K
(2009)
Insights into enzyme catalysis from QM/MM modelling: transition state stabilization in chorismate mutase
in Molecular Physics
Lonsdale Richard
(2009)
Cytochrome P450 reactivity and specificity from QM/MM modelling
Mulholland Adrian J.
(2009)
PHYS 47-Biomolecular simulations of enzymatic reactions
in ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY
Lawan Narin
(2010)
QM/MM modelling of the reaction mechanism of chorismate synthase and mutase
Ranaghan KE
(2010)
Computer simulations of quantum tunnelling in enzyme-catalysed hydrogen transfer reactions.
in Interdisciplinary sciences, computational life sciences
McGeagh J
(2010)
Kinetics and Dynamics - From Nano- to Bio-Scale
Lodola A
(2010)
Structural Fluctuations in Enzyme-Catalyzed Reactions: Determinants of Reactivity in Fatty Acid Amide Hydrolase from Multivariate Statistical Analysis of Quantum Mechanics/Molecular Mechanics Paths
in Journal of Chemical Theory and Computation
Van Der Kamp MW
(2010)
Testing high-level QM/MM methods for modeling enzyme reactions: acetyl-CoA deprotonation in citrate synthase.
in The journal of physical chemistry. B
Lonsdale R
(2010)
Compound I reactivity defines alkene oxidation selectivity in cytochrome P450cam.
in The journal of physical chemistry. B
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
Lonsdale R
(2010)
ChemInform Abstract: Computational Enzymology
in ChemInform
Pradon Juliette Jeanne Marie
(2010)
Molecular modelling studies of the relationship between structure and mechanism in (beta)-lactamases and related enzymes
Lonsdale R
(2010)
Computational enzymology.
in Chemical communications (Cambridge, England)
Shaw Katherine E.
(2010)
Testing QM/MM Methods Using Free Energy Simulations
Ranaghan K
(2010)
Investigations of enzyme-catalysed reactions with combined quantum mechanics/molecular mechanics (QM/MM) methods
in International Reviews in Physical Chemistry
Lonsdale R
(2010)
Inclusion of Dispersion Effects Significantly Improves Accuracy of Calculated Reaction Barriers for Cytochrome P450 Catalyzed Reactions
in The Journal of Physical Chemistry Letters
Ren Q
(2010)
Optimal control design of laser pulses for mode specific vibrational excitation in an enzyme-substrate complex
in Chemical Physics Letters
Van Der Kamp M
(2011)
"Lethal Synthesis" of Fluorocitrate by Citrate Synthase Explained through QM/MM Modeling
in Angewandte Chemie
Oláh J
(2011)
Understanding the determinants of selectivity in drug metabolism through modeling of dextromethorphan oxidation by cytochrome P450.
in Proceedings of the National Academy of Sciences of the United States of America
Claeyssens F
(2011)
Analysis of chorismate mutase catalysis by QM/MM modelling of enzyme-catalysed and uncatalysed reactions.
in Organic & biomolecular chemistry
Capoferri L
(2011)
Application of a SCC-DFTB QM/MM approach to the investigation of the catalytic mechanism of fatty acid amide hydrolase.
in Journal of molecular modeling
Lonsdale R
(2011)
Comment on "A stationary-wave model of enzyme catalysis" by Carlo Canepa.
in Journal of computational chemistry
McGeagh JD
(2011)
Protein dynamics and enzyme catalysis: insights from simulations.
in Biochimica et biophysica acta
| 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 |