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
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(2021)
#COVIDisAirborne: AI-Enabled Multiscale Computational Microscopy of Delta SARS-CoV-2 in a Respiratory Aerosol.
in bioRxiv : the preprint server for biology
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#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
Sampson C
(2015)
A "Stepping Stone" Approach for Obtaining Quantum Free Energies of Hydration.
in The journal of physical chemistry. B
Ranaghan K
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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
Macrae Stephen J.
(2008)
A computational study of catalysis in Bacillus subtilis chorismate mutase
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
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
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A General Mechanism for Signal Propagation in the Nicotinic Acetylcholine Receptor Family
in Journal of the American Chemical Society
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in Cell chemical biology
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A multiscale approach to modelling drug metabolism by membrane-bound cytochrome P450 enzymes.
in PLoS computational biology
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(2022)
A multiscale approach to predict the binding mode of metallo beta-lactamase inhibitors.
in Proteins
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A Multiscale Simulation Approach to Modeling Drug-Protein Binding Kinetics.
in Journal of chemical theory and computation
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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
Bennie S
(2016)
A Projector-Embedding Approach for Multiscale Coupled-Cluster Calculations Applied to Citrate Synthase
in Journal of Chemical Theory and Computation
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
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
Van Der Kamp MW
(2007)
Ab initio QM/MM modelling of acetyl-CoA deprotonation in the enzyme citrate synthase.
in Journal of molecular graphics & modelling
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 |