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
Oliveira A
(2019)
A General Mechanism for Signal Propagation in the Nicotinic Acetylcholine Receptor Family
in Journal of the American Chemical Society
Oliveira A. S. F.
(2019)
Nicotine-induced conformational changes in the a4ß2 nicotinic receptor
in EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS
Oliveira ASF
(2019)
Identification of the Initial Steps in Signal Transduction in the a4ß2 Nicotinic Receptor: Insights from Equilibrium and Nonequilibrium Simulations.
in Structure (London, England : 1993)
Oliveira ASF
(2020)
Simulations support the interaction of the SARS-CoV-2 spike protein with nicotinic acetylcholine receptors.
in bioRxiv : the preprint server for biology
Oliveira ASF
(2021)
Dynamical nonequilibrium molecular dynamics reveals the structural basis for allostery and signal propagation in biomolecular systems.
in The European physical journal. B
Oliveira ASF
(2023)
SARS-CoV-2 spike variants differ in their allosteric responses to linoleic acid.
in Journal of molecular cell biology
Oliveira ASF
(2021)
A potential interaction between the SARS-CoV-2 spike protein and nicotinic acetylcholine receptors.
in Biophysical journal
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
Pakamwong B
(2022)
Identification of Potent DNA Gyrase Inhibitors Active against Mycobacterium tuberculosis.
in Journal of chemical information and modeling
Palaiokostas M
(2018)
Effects of lipid composition on membrane permeation
in Soft Matter
Paramo T
(2017)
Functional Validation of Heteromeric Kainate Receptor Models.
in Biophysical journal
Parker JL
(2021)
Cryo-EM structure of PepT2 reveals structural basis for proton-coupled peptide and prodrug transport in mammals.
in Science advances
Pasi M
(2014)
µABC: a systematic microsecond molecular dynamics study of tetranucleotide sequence effects in B-DNA.
in Nucleic acids research
Pennifold RC
(2017)
Correcting density-driven errors in projection-based embedding.
in The Journal of chemical physics
Pentikäinen U
(2008)
Cooperative symmetric to asymmetric conformational transition of the apo-form of scavenger decapping enzyme revealed by simulations.
in Proteins
Pentikäinen U
(2009)
Lennard-Jones Parameters for B3LYP/CHARMM27 QM/MM Modeling of Nucleic Acid Bases.
in Journal of chemical theory and computation
Phintha A
(2021)
Dissecting the low catalytic capability of flavin-dependent halogenases.
in The Journal of biological chemistry
Pradon Juliette Jeanne Marie
(2010)
Molecular modelling studies of the relationship between structure and mechanism in (beta)-lactamases and related enzymes
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
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
Punkvang A
(2019)
Simulations of Shikimate Dehydrogenase from Mycobacterium tuberculosis in Complex with 3-Dehydroshikimate and NADPH Suggest Strategies for MtbSDH Inhibition.
in Journal of chemical information and modeling
Ranaghan K
(2016)
Simulating Enzyme Reactivity - Computational Methods in Enzyme Catalysis
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 |