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
Larsen AH
(2022)
Specific interactions of peripheral membrane proteins with lipids: what can molecular simulations show us?
in Bioscience reports
Lawan N
(2022)
QM/MM Molecular Modeling Reveals Mechanism Insights into Flavin Peroxide Formation in Bacterial Luciferase.
in Journal of chemical information and modeling
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
Martà S
(2022)
Impact of Warhead Modulations on the Covalent Inhibition of SARS-CoV-2 Mpro Explored by QM/MM Simulations.
in ACS catalysis
Bunzel H
(2022)
Photovoltaic enzymes by design and evolution
Gupta K
(2022)
Structural insights in cell-type specific evolution of intra-host diversity by SARS-CoV-2
in Nature Communications
Walters RK
(2022)
The emerging potential of interactive virtual reality in drug discovery.
in Expert opinion on drug discovery
Hanwarinroj C
(2022)
Discovery of novel and potent InhA inhibitors by an in silico screening and pharmacokinetic prediction.
in Future medicinal chemistry
Chrestia JF
(2022)
A Functional Interaction Between Y674-R685 Region of the SARS-CoV-2 Spike Protein and the Human a7 Nicotinic Receptor.
in Molecular neurobiology
Douglas-Gallardo O
(2022)
Carbon Dioxide Fixation in RuBisCO Is Protonation-State-Dependent and Irreversible
in ACS Catalysis
Pakamwong B
(2022)
Identification of Potent DNA Gyrase Inhibitors Active against Mycobacterium tuberculosis.
in Journal of chemical information and modeling
Haldar S
(2022)
Mechanistic Insights into the Ligand-Induced Unfolding of an RNA G-Quadruplex.
in Journal of the American Chemical Society
Douglas-Gallardo O
(2022)
Carbon dioxide fixation in RuBisCO is protonation state dependent and irreversible
Hirvonen VHA
(2022)
Multiscale Simulations Identify Origins of Differential Carbapenem Hydrolysis by the OXA-48 ß-Lactamase.
in ACS catalysis
Dooher T
(2022)
Environmental stress cracking of polymers: Case studies from industry (ABS and LDPE)
in Engineering Failure Analysis
Chudyk EI
(2022)
QM/MM Simulations Reveal the Determinants of Carbapenemase Activity in Class A ß-Lactamases.
in ACS infectious diseases
Chayanin Hanwarinroj
(2022)
Discovery of novel and potent InhA inhibitors by an in silico screening and pharmacokinetic prediction
Thongdee P
(2022)
Virtual Screening Identifies Novel and Potent Inhibitors of Mycobacterium tuberculosis PknB with Antibacterial Activity.
in Journal of chemical information and modeling
Douglas-Gallardo O
(2022)
Carbon dioxide fixation in RuBisCO is protonation state dependent and irreversible
Songsiriritthigul C
(2022)
Inhibition of Mycobacterium tuberculosis InhA by 3-nitropropanoic acid.
in Proteins
Chayanin Hanwarinroj
(2022)
Discovery of novel and potent InhA inhibitors by an in silico screening and pharmacokinetic prediction
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
Song W
(2022)
PyLipID: A Python Package for Analysis of Protein-Lipid Interactions from Molecular Dynamics Simulations.
in Journal of chemical theory and computation
Sofia F Oliveira A
(2022)
The fatty acid site is coupled to functional motifs in the SARS-CoV-2 spike protein and modulates spike allosteric behaviour.
in Computational and structural biotechnology journal
Juan Facundo Chrestia
(2022)
A Functional Interaction Between the SARS-CoV-2 Spike Protein and the Human a7 Nicotinic Receptor
Slocombe L
(2022)
Proton transfer during DNA strand separation as a source of mutagenic guanine-cytosine tautomers.
in Communications chemistry
Juan Facundo Chrestia
(2022)
A Functional Interaction Between the SARS-CoV-2 Spike Protein and the Human a7 Nicotinic Receptor
Caldwell TA
(2022)
Conformational dynamics of the membrane enzyme LspA upon antibiotic and substrate binding.
in Biophysical journal
Mendoza-Martinez C
(2022)
Energetics of a protein disorder-order transition in small molecule recognition.
in Chemical science
Espejo-Román JM
(2022)
Selective Anticancer Therapy Based on a HA-CD44 Interaction Inhibitor Loaded on Polymeric Nanoparticles.
in Pharmaceutics
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
Hutchins GH
(2023)
An expandable, modular de novo protein platform for precision redox engineering.
in Proceedings of the National Academy of Sciences of the United States of America
Espejo-Román JM
(2023)
N-aryltetrahydroisoquinoline derivatives as HA-CD44 interaction inhibitors: Design, synthesis, computational studies, and antitumor effect.
in European journal of medicinal chemistry
Winokan M
(2023)
Multiscale simulations reveal the role of PcrA helicase in protecting against spontaneous point mutations in DNA.
in Scientific reports
| 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 |