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
Karabencheva-Christova TG
(2017)
Mechanistic Insights into the Reaction of Chlorination of Tryptophan Catalyzed by Tryptophan 7-Halogenase.
in Scientific reports
Karuppiah V
(2017)
Structural Basis of Catalysis in the Bacterial Monoterpene Synthases Linalool Synthase and 1,8-Cineole Synthase.
in ACS catalysis
Kattnig D
(2018)
Molecular dynamics simulations disclose early stages of the photo-activation of cryptochrome 4
in New Journal of Physics
Kiani YS
(2019)
Molecular Dynamics Simulation Framework to Probe the Binding Hypothesis of CYP3A4 Inhibitors.
in International journal of molecular sciences
King B
(2023)
Tautomerisation Mechanisms in the Adenine-Thymine Nucleobase Pair during DNA Strand Separation.
in The journal of physical chemistry. B
Kwon H
(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
Lang EJM
(2022)
Generalized Born Implicit Solvent Models Do Not Reproduce Secondary Structures of De Novo Designed Glu/Lys Peptides.
in Journal of chemical theory and computation
Larsen AH
(2022)
Specific interactions of peripheral membrane proteins with lipids: what can molecular simulations show us?
in Bioscience reports
Lawan N
(2014)
Comparison of DFT and ab initio QM/MM methods for modelling reaction in chorismate synthase
in Chemical Physics Letters
Lawan N
(2022)
QM/MM Molecular Modeling Reveals Mechanism Insights into Flavin Peroxide Formation in Bacterial Luciferase.
in Journal of chemical information and modeling
Lawan Narin
(2010)
QM/MM modelling of the reaction mechanism of chorismate synthase and mutase
Lear A
(2023)
Comment on: "Computer Simulations Reveal an Entirely Entropic Activation Barrier for the Chemical Step in a Designer Enzyme"
in ACS Catalysis
Leferink NGH
(2020)
Taming the Reactivity of Monoterpene Synthases To Guide Regioselective Product Hydroxylation.
in Chembiochem : a European journal of chemical biology
Leferink NGH
(2019)
Experiment and Simulation Reveal How Mutations in Functional Plasticity Regions Guide Plant Monoterpene Synthase Product Outcome.
in ACS catalysis
Lence E
(2018)
QM/MM simulations identify the determinants of catalytic activity differences between type II dehydroquinase enzymes
in Organic & Biomolecular Chemistry
Lester Hedges
(2019)
BioSimSpace: An interoperable Python framework for biomolecular simulation
in Zenodo
Lester Hedges
(2019)
BioSimSpace: An interoperable Python framework for biomolecular simulation
in Zenodo
Lever G
(2014)
Large-Scale Density Functional Theory Transition State Searching in Enzymes.
in The journal of physical chemistry letters
Limb MAL
(2019)
Quantum Mechanics/Molecular Mechanics Simulations Show Saccharide Distortion is Required for Reaction in Hen Egg-White Lysozyme.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Limb Michael
(2015)
Modelling catalysis in hen egg-white lysozyme
Lodola A
(2008)
Identification of productive inhibitor binding orientation in fatty acid amide hydrolase (FAAH) by QM/MM mechanistic modelling.
in Chemical communications (Cambridge, England)
Lodola A
(2013)
Computational enzymology.
in Methods in molecular biology (Clifton, N.J.)
Lodola A
(2007)
Conformational effects in enzyme catalysis: reaction via a high energy conformation in fatty acid amide hydrolase.
in Biophysical journal
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 |