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
Haldar S
(2018)
A Multiscale Simulation Approach to Modeling Drug-Protein Binding Kinetics.
in Journal of chemical theory and computation
Haldar S
(2022)
Mechanistic Insights into the Ligand-Induced Unfolding of an RNA G-Quadruplex.
in Journal of the American Chemical Society
Haldar S
(2021)
Ligand-induced unfolding mechanism of an RNA G-quadruplex
Hanpaibool C
(2023)
Pyrazolones Potentiate Colistin Activity against MCR-1-Producing Resistant Bacteria: Computational and Microbiological Study
in ACS Omega
Hanpaibool C
(2023)
Enhancement by pyrazolones of colistin efficacy against mcr-1-expressing E. coli: an in silico and in vitro investigation.
in Journal of computer-aided molecular design
Hanwarinroj C
(2022)
In silico design of novel quinazoline-based compounds as potential Mycobacterium tuberculosis PknB inhibitors through 2D and 3D-QSAR, molecular dynamics simulations combined with pharmacokinetic predictions.
in Journal of molecular graphics & modelling
Hanwarinroj C
(2022)
Discovery of novel and potent InhA inhibitors by an in silico screening and pharmacokinetic prediction
in Future Medicinal Chemistry
Harvey J
(2006)
QM and QM/MM studies of selectivity in organic and bioorganic chemistry
in Journal of Physical Organic Chemistry
Harvey JN
(2006)
Comment on "Molecular dynamics DFT:B3LYP study of guanosinetriphosphate conversion into guanosinemonophosphate upon Mg2+ chelation of alpha and beta phosphate oxygens of the triphosphate tail" by Alexander A. Tulub, Phys. Chem. Chem. Phys., 2006, 8, 2187.
in Physical chemistry chemical physics : PCCP
Harvey JN
(2006)
QM/MM modeling of compound I active species in cytochrome P450, cytochrome C peroxidase, and ascorbate peroxidase.
in Journal of computational chemistry
Hashem S
(2017)
Allosteric modulation of cardiac myosin dynamics by omecamtiv mecarbil
in PLOS Computational Biology
Hazell G
(2018)
Studies of black silicon and black diamond as materials for antibacterial surfaces.
in Biomaterials science
Hedger G
(2019)
Cholesterol Interaction Sites on the Transmembrane Domain of the Hedgehog Signal Transducer and Class F G Protein-Coupled Receptor Smoothened.
in Structure (London, England : 1993)
Hedges L
(2019)
BioSimSpace: An interoperable Python framework for biomolecular simulation
in Journal of Open Source Software
Heiblum Robles A
(2018)
Phase transitions in stigmergic territorial systems
in Physical Review E
Hermann JC
(2006)
Molecular mechanisms of antibiotic resistance: QM/MM modelling of deacylation in a class A beta-lactamase.
in Organic & biomolecular chemistry
Hermann JC
(2009)
High level QM/MM modeling of the formation of the tetrahedral intermediate in the acylation of wild type and K73A mutant TEM-1 class A beta-lactamase.
in The journal of physical chemistry. A
Hinchliffe P
(2017)
Insights into the Mechanistic Basis of Plasmid-Mediated Colistin Resistance from Crystal Structures of the Catalytic Domain of MCR-1.
in Scientific reports
Hindson S
(2021)
Rigidifying a De Novo Enzyme Increases Activity and Induces a Negative Activation Heat Capacity
in ACS Catalysis
Hirvonen V
(2020)
Small Changes in Hydration Determine Cephalosporinase Activity of OXA-48 ß-Lactamases
in ACS Catalysis
Hirvonen VHA
(2019)
An Efficient Computational Assay for ß-Lactam Antibiotic Breakdown by Class A ß-Lactamases.
in Journal of chemical information and modeling
Hirvonen VHA
(2022)
Multiscale Simulations Identify Origins of Differential Carbapenem Hydrolysis by the OXA-48 ß-Lactamase.
in ACS 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 |