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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(2020)
Visualizing the protons in a metalloenzyme electron proton transfer pathway.
in Proceedings of the National Academy of Sciences of the United States of America
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IMPRESSION - prediction of NMR parameters for 3-dimensional chemical structures using machine learning with near quantum chemical accuracy.
in Chemical science
Minguez Teresa
(2020)
Novel determinants of agonist selectivity in nicotinic ACh receptors
in BRITISH JOURNAL OF PHARMACOLOGY
Shoemark DK
(2021)
Molecular Simulations suggest Vitamins, Retinoids and Steroids as Ligands of the Free Fatty Acid Pocket of the SARS-CoV-2 Spike Protein*.
in Angewandte Chemie (International ed. in English)
Voice AT
(2021)
Mechanism of covalent binding of ibrutinib to Bruton's tyrosine kinase revealed by QM/MM calculations.
in Chemical science
Voice Angus
(2021)
Modelling the reactivity of cysteine targeting covalent inhibitors
Parker JL
(2021)
Cryo-EM structure of PepT2 reveals structural basis for proton-coupled peptide and prodrug transport in mammals.
in Science advances
Shoemark D
(2021)
Molecular Simulations suggest Vitamins, Retinoids and Steroids as Ligands of the Free Fatty Acid Pocket of the SARS-CoV-2 Spike Protein**
in Angewandte Chemie
Scott AJ
(2021)
Constructing ion channels from water-soluble a-helical barrels.
in Nature chemistry
Simcock PW
(2021)
Membrane Binding of Antimicrobial Peptides Is Modulated by Lipid Charge Modification.
in Journal of chemical theory and computation
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(2021)
Substrate promiscuity of a de novo designed peroxidase.
in Journal of inorganic biochemistry
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(2021)
Dissecting the low catalytic capability of flavin-dependent halogenases.
in The Journal of biological chemistry
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(2021)
A Conserved Arginine with Non-Conserved Function is a Key Determinant of Agonist Selectivity in Alpha7 Nicotinic Acetylcholine Receptors
in BIOPHYSICAL JOURNAL
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in Journal of Biological Chemistry
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in Neural Computing and Applications
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Discovery of SARS-CoV-2 Mpro peptide inhibitors from modelling substrate and ligand binding.
in Chemical science
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(2021)
Frontispiece: Molecular Simulations suggest Vitamins, Retinoids and Steroids as Ligands of the Free Fatty Acid Pocket of the SARS-CoV-2 Spike Protein
in Angewandte Chemie International Edition
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(2021)
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in The European physical journal. B
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(2021)
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(2021)
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in Nature chemistry
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in The journal of physical chemistry. B
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(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
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(2021)
A multiscale approach to predict the binding mode of metallo beta-lactamase inhibitors
in Proteins: Structure, Function, and Bioinformatics
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(2021)
Relative Affinities of Protein-Cholesterol Interactions from Equilibrium Molecular Dynamics Simulations.
in Journal of chemical theory and computation
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(2021)
A robust and stereocomplementary panel of ene-reductase variants for gram-scale asymmetric hydrogenation
in Molecular Catalysis
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(2021)
Identification and assessment of cardiolipin interactions with E. coli inner membrane proteins.
in Science advances
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(2021)
Designing better enzymes: Insights from directed evolution.
in Current opinion in structural biology
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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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(2021)
Modelling the reactivity of zinc metalloenzymes and the SARS-CoV-2 main protease
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(2021)
Evaluating the Performance of Water Models with Host-Guest Force Fields in Binding Enthalpy Calculations for Cucurbit[7]uril-Guest Systems.
in The journal of physical chemistry. B
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(2021)
Molecular dynamics simulations support the hypothesis that the brGDGT paleothermometer is based on homeoviscous adaptation
in Geochimica et Cosmochimica Acta
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(2021)
A potential interaction between the SARS-CoV-2 spike protein and nicotinic acetylcholine receptors.
in Biophysical journal
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(2021)
Exploring human-guided strategies for reaction network exploration: Interactive molecular dynamics in virtual reality as a tool for citizen scientists.
in The Journal of chemical physics
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(2021)
Exploration of the structural requirements of Aurora Kinase B inhibitors by a combined QSAR, modelling and molecular simulation approach.
in Scientific reports
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(2021)
Allosteric communication in class A ß-lactamases occurs via cooperative coupling of loop dynamics.
in eLife
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(2021)
Rigidifying a De Novo Enzyme Increases Activity and Induces a Negative Activation Heat Capacity.
in ACS catalysis
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(2021)
Modulation of adenosine A2a receptor oligomerization by receptor activation and PIP2 interactions.
in Structure (London, England : 1993)
Shoemark DK
(2021)
Frontispiz: Molecular Simulations suggest Vitamins, Retinoids and Steroids as Ligands of the Free Fatty Acid Pocket of the SARS-CoV-2 Spike Protein.
in Angewandte Chemie (Weinheim an der Bergstrasse, Germany)
Yang Z
(2021)
Multiscale Workflow for Modeling Ligand Complexes of Zinc Metalloproteins.
in Journal of chemical information and modeling
Twidale RM
(2021)
Crystallography and QM/MM Simulations Identify Preferential Binding of Hydrolyzed Carbapenem and Penem Antibiotics to the L1 Metallo-ß-Lactamase in the Imine Form.
in Journal of chemical information and modeling
Dawson WM
(2021)
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in Nature communications
Suardíaz R
(2021)
Catalytic mechanism of the colistin resistance protein MCR-1
in Organic & Biomolecular Chemistry
| 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 | 09/2013 |
| 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 |