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
Thomas F
(2018)
De Novo-Designed a-Helical Barrels as Receptors for Small Molecules.
in ACS synthetic biology
Huggins D
(2018)
Biomolecular simulations: From dynamics and mechanisms to computational assays of biological activity
in WIREs Computational Molecular Science
Van Der Kamp MW
(2018)
Dynamical origins of heat capacity changes in enzyme-catalysed reactions.
in Nature communications
Messiha HL
(2018)
Biocatalytic Routes to Lactone Monomers for Polymer Production.
in Biochemistry
Ainsley J
(2018)
Combined Quantum Mechanics and Molecular Mechanics Studies of Enzymatic Reaction Mechanisms.
in Advances in protein chemistry and structural biology
Rinaldi S
(2018)
Understanding Complex Mechanisms of Enzyme Reactivity: The Case of Limonene-1,2-Epoxide Hydrolases
in ACS Catalysis
Haldar S
(2018)
A Multiscale Simulation Approach to Modeling Drug-Protein Binding Kinetics.
in Journal of chemical theory and computation
Kattnig D
(2018)
Molecular dynamics simulations disclose early stages of the photo-activation of cryptochrome 4
in New Journal of Physics
Acevedo-Rocha C
(2018)
P450-Catalyzed Regio- and Diastereoselective Steroid Hydroxylation: Efficient Directed Evolution Enabled by Mutability Landscaping
in ACS Catalysis
Amaro RE
(2018)
Multiscale Methods in Drug Design Bridge Chemical and Biological Complexity in the Search for Cures.
in Nature reviews. Chemistry
Sartori GR
(2019)
Ligand-induced conformational selection predicts the selectivity of cysteine protease inhibitors.
in PloS one
Kiani YS
(2019)
Molecular Dynamics Simulation Framework to Probe the Binding Hypothesis of CYP3A4 Inhibitors.
in International journal of molecular sciences
Nutho B
(2019)
The reaction mechanism of Zika virus NS2B/NS3 serine protease inhibition by dipeptidyl aldehyde: a QM/MM study.
in Physical chemistry chemical physics : PCCP
Voice A
(2019)
Limitations of Ligand-Only Approaches for Predicting the Reactivity of Covalent Inhibitors.
in Journal of chemical information and modeling
O'Hagan M
(2019)
A Photoresponsive Stiff-Stilbene Ligand Fuels the Reversible Unfolding of G-Quadruplex DNA
in Angewandte Chemie
Jenkins Jonathan
(2019)
Computational design, construction, and characterisation of artificial peroxidases
Hirvonen VHA
(2019)
An Efficient Computational Assay for ß-Lactam Antibiotic Breakdown by Class A ß-Lactamases.
in Journal of chemical information and modeling
Bennie S
(2019)
Teaching Enzyme Catalysis Using Interactive Molecular Dynamics in Virtual Reality
in Journal of Chemical Education
Song W
(2019)
State-dependent Lipid Interactions with the A2a Receptor Revealed by MD Simulations Using In Vivo-Mimetic Membranes.
in Structure (London, England : 1993)
Wu Z
(2019)
Proton Control of Transitions in an Amino Acid Transporter.
in Biophysical journal
De Simone A
(2019)
A computationally designed binding mode flip leads to a novel class of potent tri-vector cyclophilin inhibitors.
in Chemical science
O'Connor M
(2019)
Interactive molecular dynamics in virtual reality from quantum chemistry to drug binding: An open-source multi-person framework
in The Journal of Chemical Physics
Bunzel HA
(2019)
Emergence of a Negative Activation Heat Capacity during Evolution of a Designed Enzyme.
in Journal of the American Chemical Society
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)
Shahane G
(2019)
Physical properties of model biological lipid bilayers: insights from all-atom molecular dynamics simulations.
in Journal of molecular modeling
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)
Nutho B
(2019)
QM/MM Study on Cleavage Mechanism Catalyzed by Zika Virus NS2B/NS3 Serine Protease
in Biophysical Journal
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)
Dunseath O
(2019)
Studies of Black Diamond as an antibacterial surface for Gram Negative bacteria: the interplay between chemical and mechanical bactericidal activity.
in Scientific reports
Hedges L
(2019)
BioSimSpace: An interoperable Python framework for biomolecular simulation
in Journal of Open Source Software
Ali HS
(2019)
Entropy of Simulated Liquids Using Multiscale Cell Correlation.
in Entropy (Basel, Switzerland)
Kamsri P
(2019)
In silico study directed towards identification of the key structural features of GyrB inhibitors targeting MTB DNA gyrase: HQSAR, CoMSIA and molecular dynamics simulations.
in SAR and QSAR in environmental research
Oliveira ASF
(2019)
A General Mechanism for Signal Propagation in the Nicotinic Acetylcholine Receptor Family.
in Journal of the American Chemical Society
Nutho B
(2019)
Quantum Mechanics/Molecular Mechanics (QM/MM) Calculations Support a Concerted Reaction Mechanism for the Zika Virus NS2B/NS3 Serine Protease with Its Substrate.
in The journal of physical chemistry. B
Leferink NGH
(2019)
Experiment and Simulation Reveal How Mutations in Functional Plasticity Regions Guide Plant Monoterpene Synthase Product Outcome.
in ACS catalysis
Rinné S
(2019)
The molecular basis for an allosteric inhibition of K+-flux gating in K2P channels
in eLife
Ranaghan KE
(2019)
Projector-Based Embedding Eliminates Density Functional Dependence for QM/MM Calculations of Reactions in Enzymes and Solution.
in Journal of chemical information and modeling
Meletiou A
(2019)
Tios: The Internet of Simulations. Turning Molecular Dynamics into a Data Streaming Web Application.
in Journal of chemical information and modeling
Evans LE
(2019)
Exploitation of Antibiotic Resistance as a Novel Drug Target: Development of a ß-Lactamase-Activated Antibacterial Prodrug.
in Journal of medicinal chemistry
Oliveira A. S. F.
(2019)
Nicotine-induced conformational changes in the a4ß2 nicotinic receptor
in EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS
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
Sampson C
(2019)
On the magnetosensitivity of lipid peroxidation: two- versus three-radical dynamics.
in Physical chemistry chemical physics : PCCP
Raza S
(2019)
Visualizing protein-ligand binding with chemical energy-wise decomposition (CHEWD): application to ligand binding in the kallikrein-8 S1 Site.
in Journal of computer-aided molecular design
Newport TD
(2019)
The MemProtMD database: a resource for membrane-embedded protein structures and their lipid interactions.
in Nucleic acids research
O'Hagan MP
(2019)
A Photoresponsive Stiff-Stilbene Ligand Fuels the Reversible Unfolding of G-Quadruplex DNA.
in Angewandte Chemie (International ed. in English)
| 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 |