Combined quantum mechanics/molecular mechanics (QM/MM) Monte Carlo free energy simulations: a feasibility study
Lead Research Organisation:
University of Bristol
Department Name: Chemistry
Abstract
Despite the advances of science, millions of people still die every year from incurable diseases. Unfortunately, the costs of drug development are so high that the focus of medicinal research is into profitable Western diseases. To reduce the costs of developing new medicinal drugs, we would like to be able to use computers to model how a potential drug works within the body, and to use this knowledge to design new and better drugs. Building computational models like this is challenging, requiring a delicate balance between putting enough detail into the model to get realistic behaviour, and making the model as simple as possible so that it doesn't take too long to run the calculations. Until now, the majority of models used have been very simple, modelling the atoms of a drug as balls on springs. By treating the atoms as solid balls, the models neglect the atom's most chemically important part, namely the electrons. This is a severe oversight, as it is the interactions of electrons that determine whether the drug could dissolve in your blood, work its way into your cells, and bind to, and thus neutralize, the proteins of any attacking bacteria or virus. It is possible to model electrons in molecules using quantum mechanics. However, to model the entire protein/drug system using quantum mechanics would be too computationally expensive. We propose to research the use of quantum mechanics to model just the electrons that are part of, and near to, the drug molecule. The rest of the protein can still be treated by simple ball and springs models to make the calculations possible. The new methods we will develop add important extra detail, making them more realistic and better able to model how drugs interact. At the same time, this combined approach should mean that the calculations are practical to do. What makes our planned work different is that it will involve the development of a mixed model specifically tailored for medicinal drug design. Creating a mixed model for this use will require that significant challenges are overcome, and that new ways are developed to handle the interactions between the quantum mechanics part of the model with the ball on springs part.
Organisations
Publications
Chudyk Ewa Iwona
(2013)
Calculating free energy profiles for enzyme catalysed reactions
Lodola A
(2013)
Computational enzymology.
in Methods in molecular biology (Clifton, N.J.)
Woods CJ
(2013)
Computational assay of H7N9 influenza neuraminidase reveals R292K mutation reduces drug binding affinity.
in Scientific reports
Christov C
(2013)
Conformational Effects on the pro - S Hydrogen Abstraction Reaction in Cyclooxygenase-1: An Integrated QM/MM and MD Study
in Biophysical Journal
Van Der Kamp MW
(2013)
Conformational change and ligand binding in the aristolochene synthase catalytic cycle.
in Biochemistry
Román-Meléndez GD
(2014)
Role of active site residues in promoting cobalt-carbon bond homolysis in adenosylcobalamin-dependent mutases revealed through experiment and computation.
in Biochemistry
Lonsdale R
(2014)
A multiscale approach to modelling drug metabolism by membrane-bound cytochrome P450 enzymes.
in PLoS computational biology
Mlýnský V
(2014)
Comparison of ab Initio, DFT, and Semiempirical QM/MM Approaches for Description of Catalytic Mechanism of Hairpin Ribozyme.
in Journal of chemical theory and computation
Jefferys E
(2014)
NRas slows the rate at which a model lipid bilayer phase separates.
in Faraday discussions
Pasi M
(2014)
µABC: a systematic microsecond molecular dynamics study of tetranucleotide sequence effects in B-DNA.
in Nucleic acids research
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A catalytic role for methionine revealed by a combination of computation and experiments on phosphite dehydrogenase
in Chem. Sci.
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(2014)
Comparison of DFT and ab initio QM/MM methods for modelling reaction in chorismate synthase
in Chemical Physics Letters
Jitonnom J
(2014)
QM/MM free-energy simulations of reaction in Serratia marcescens Chitinase B reveal the protonation state of Asp142 and the critical role of Tyr214.
in The journal of physical chemistry. B
Lever G
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Large-Scale Density Functional Theory Transition State Searching in Enzymes.
in The journal of physical chemistry letters
Daniels AD
(2014)
Reaction mechanism of N-acetylneuraminic acid lyase revealed by a combination of crystallography, QM/MM simulation, and mutagenesis.
in ACS chemical biology
Chavent M
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Methodologies for the analysis of instantaneous lipid diffusion in MD simulations of large membrane systems.
in Faraday discussions
Woods CJ
(2014)
Rapid decomposition and visualisation of protein-ligand binding free energies by residue and by water.
in Faraday discussions
Von Glehn Patrick
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Modelling the reactivity of glutamate mutase and heme dioxygenase enzymes
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in Acta crystallographica. Section D, Biological crystallography
Ross G
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Water Sites, Networks, And Free Energies with Grand Canonical Monte Carlo
in Journal of the American Chemical Society
Loeffler HH
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FESetup: Automating Setup for Alchemical Free Energy Simulations.
in Journal of chemical information and modeling
Wells S
(2015)
Structure and Function in Homodimeric Enzymes: Simulations of Cooperative and Independent Functional Motions
in PLOS ONE
Kaiyawet N
(2015)
High-level QM/MM calculations support the concerted mechanism for Michael addition and covalent complex formation in thymidylate synthase.
in Journal of chemical theory and computation
Jambrina P
(2015)
Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation
in Angewandte Chemie
Limb Michael
(2015)
Modelling catalysis in hen egg-white lysozyme
Woods CJ
(2015)
Combined quantum mechanics/molecular mechanics (QM/MM) simulations for protein-ligand complexes: free energies of binding of water molecules in influenza neuraminidase.
in The journal of physical chemistry. B
Sampson C
(2015)
A "Stepping Stone" Approach for Obtaining Quantum Free Energies of Hydration.
in The journal of physical chemistry. B
Ding W
(2015)
Effects of Lipid Composition on Bilayer Membranes Quantified by All-Atom Molecular Dynamics.
in The journal of physical chemistry. B
Maingi V
(2015)
Gating-like Motions and Wall Porosity in a DNA Nanopore Scaffold Revealed by Molecular Simulations.
in ACS nano
Pucheta-Martínez E
(2016)
An Allosteric Cross-Talk Between the Activation Loop and the ATP Binding Site Regulates the Activation of Src Kinase.
in Scientific reports
Calabrò G
(2016)
Elucidation of Nonadditive Effects in Protein-Ligand Binding Energies: Thrombin as a Case Study.
in The journal of physical chemistry. B
Ranaghan K
(2016)
Simulating Enzyme Reactivity - Computational Methods in Enzyme Catalysis
Pucheta-Martinez E
(2016)
Changes in the folding landscape of the WW domain provide a molecular mechanism for an inherited genetic syndrome.
in Scientific reports
May PW
(2016)
Diamond-coated 'black silicon' as a promising material for high-surface-area electrochemical electrodes and antibacterial surfaces.
in Journal of materials chemistry. B
Musgaard M
(2016)
Steered Molecular Dynamics Simulations Predict Conformational Stability of Glutamate Receptors.
in Journal of chemical information and modeling
Bennie S
(2016)
A Projector-Embedding Approach for Multiscale Coupled-Cluster Calculations Applied to Citrate Synthase
in Journal of Chemical Theory and Computation
Reddy T
(2016)
Computational virology: From the inside out
in Biochimica et Biophysica Acta (BBA) - Biomembranes
Van Den Berg B
(2016)
Structural basis for Mep2 ammonium transceptor activation by phosphorylation.
in Nature communications
Bueren-Calabuig JA
(2016)
Impact of Ser17 Phosphorylation on the Conformational Dynamics of the Oncoprotein MDM2.
in Biochemistry
Trick JL
(2016)
Functional Annotation of Ion Channel Structures by Molecular Simulation.
in Structure (London, England : 1993)
Schiffrin B
(2016)
Skp is a multivalent chaperone of outer-membrane proteins.
in Nature structural & molecular biology
Morando MA
(2016)
Conformational Selection and Induced Fit Mechanisms in the Binding of an Anticancer Drug to the c-Src Kinase.
in Scientific reports
Althorpe SC
(2016)
Non-adiabatic reactions: general discussion.
in Faraday discussions
Samsudin F
(2016)
OmpA: A Flexible Clamp for Bacterial Cell Wall Attachment.
in Structure (London, England : 1993)
Angulo G
(2016)
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in Faraday discussions
Arcus VL
(2016)
On the Temperature Dependence of Enzyme-Catalyzed Rates.
in Biochemistry
Byrne MJ
(2016)
The Catalytic Mechanism of a Natural Diels-Alderase Revealed in Molecular Detail.
in Journal of the American Chemical Society
Suardíaz R
(2016)
Understanding the Mechanism of the Hydrogen Abstraction from Arachidonic Acid Catalyzed by the Human Enzyme 15-Lipoxygenase-2. A Quantum Mechanics/Molecular Mechanics Free Energy Simulation.
in Journal of chemical theory and computation
Grundmann M
(2016)
A Molecular Mechanism for Sequential Activation of a G Protein-Coupled Receptor.
in Cell chemical biology
Description | EPSRC |
Amount | £188,950 (GBP) |
Funding ID | E/EP/G007705/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2013 |
End | 03/2014 |
Title | Sire 2007.1 |
Description | 2007.1 (first official) release of the Sire molecular simulation framework. This included new methods developed to calculate QM/MM free energies. |
Type Of Technology | Software |
Year Produced | 2007 |
Open Source License? | Yes |
Impact | Sire is used in several pharmaceutical companies. This version of the code was used to run the simulations in "An efficient method for the calculation of quantum mechanics/molecular mechanics free energies" Christopher J. Woods, Frederick R. Manby and Adrian J. Mulholland J. Chem. Phys. 128 014109 (2008) doi:10.1063/1.2805379 The combination of quantum mechanics (QM) with molecular mechanics (MM) offers a route to improved accuracy in the study of biological systems, and there is now significant research effort being spent to develop QM/MM methods that can be applied to the calculation of relative free energies. Currently, the computational expense of the QM part of the calculation means that there is no single method that achieves both efficiency and rigor; either the QM/MM free energy method is rigorous and computationally expensive, or the method introduces efficiency-led assumptions that can lead to errors in the result, or a lack of generality of application. In this paper we demonstrate a combined approach to form a single, efficient, and, in principle, exact QM/MM free energy method. We demonstrate the application of this method by using it to explore the difference in hydration of water and methane. We demonstrate that it is possible to calculate highly converged QM/MM relative free energies at the MP2/aug-cc-pVDZ/OPLS level within just two days of computation, using commodity processors, and show how the method allows consistent, high-quality sampling of complex solvent configurational change, both when perturbing hydrophilic water into hydrophobic methane, and also when moving from a MM Hamiltonian to a QM/MM Hamiltonian. The results demonstrate the validity and power of this methodology, and raise important questions regarding the compatibility of MM and QM/MM forcefields, and offer a potential route to improved compatibility. |
URL | http://www.siremol.org/Sire/Home.html |