Our research, funded by a UKRI Future Leaders Fellowship, seeks to model computationally the structure, dynamics and interactions of molecules at the atomistic level. In particular, our research goal is to derive improved physical models of biomolecular dynamics and their interactions with potential drug molecules and, thereby, to design software to improve the efficiency of pharmaceutical research and development. Access to Bede will substantially increase the speed at which we can build models and test predictions.
Executive summary of project results
Molecular simulation can give insight into the role of biological molecules in disease and make predictions of the binding affinity of new drug candidates. Ideally, such simulations would be based on the equations of quantum mechanics, but this is impractical for biological time scales. Instead, we rely on approximate computational models (molecular mechanics force fields) to describe interactions between atoms. The Open Force Field initiative is an academic-industry network of researchers working to advance the science and software infrastructure required to build the next generation of force fields. Infrastructure includes automated frameworks for model parameter assignment, curated quantum mechanical and experimental datasets for training, and protocols for accuracy validation. In this project, we have i) built software to assign molecule-specific force field parameters and validated them through protein-ligand binding free energies, ii) investigated new functional forms through the OpenFF infrastructure, and parameterised them against condensed phase physical property data, and iii) built software that enable the use of advanced force fields in molecular design, including validation against small molecule inhibitors of the SARS-CoV-2 main protease.
How has your research benefitted from using Bede?
Training and validating force field parameters that cover all important aspects of chemical space is difficult, but important if the models are to have practical utility in computer-aided drug design. Through Bede, we have been able to train force fields against thousands of physical property data, and validate their accuracy in real-world applications through calculation of rigorous molecular dynamics-based protein-ligand binding free energies.
Has using Bede meant you were able to apply for further research funding?
Yes, using Bede led to successful follow-on funding and enabled us to establish Newcastle University's expertise in the areas of force field development and computer-aided drug design. The projects below build on these research areas by taking new directions in force field research and/or supporting the UK biomolecular research community's hardware/software needs.
Innovate UK Knowledge Transfer Partnership
UKRI "Establishing the Accessible Computational Regimes for Biomolecular Simulations at Exascale"
EPSRC "Supporting the OpenMM Community-led Development of Next-Generation Condensed Matter Modelling Software"
Publications
A transferable double exponential potential for condensed phase simulations of small molecules. Horton JT, Boothroyd S, Behara PK, Mobley DL, Cole DJ. Digital Discovery, 2023, 2, 1178-1187. https://doi.org/10.1039/D3DD00070B
Open Force Field BespokeFit: Automating Bespoke Torsion Parametrization At Scale. Horton JT, Boothroyd S, Wagner J, Mitchell JA, Gokey T, Dotson DL, Behara PK, Ramaswamy VK, Mackey M, Chodera JD, Anwar J, Mobley DL, Cole DJ. Journal of Chemical Information and Modeling, 2022, 62, 5622-5633. https://doi.org/10.1021/acs.jcim.2c01153
An Open-Source Molecular Builder and Free Energy Preparation Workflow. Bieniek MK, Cree B, Pirie R, Horton JT, Tatum NJ, Cole DJ. Communications Chemistry, 2022, 5, 136. https://doi.org/10.1038/s42004-022-00754-9
Exploration and Validation of Force Field Design Protocols through QM-to-MM Mapping. Ringrose C, Horton JT, Wang L-P, Cole DJ. Physical Chemistry Chemical Physics, 2022, 24,17014-17027. https://doi.org/10.1039/D2CP02864F
Modelling Molecular Emitters in Organic Light Emitting Diodes with the Quantum Mechanical Bespoke Force Field. Yang L, Horton JT, Payne MC, Penfold TJ,Cole DJ. Journal of Chemical Theory and Computation, 2021, 17,5021-5033. https://doi.org/10.1021/acs.jctc.1c00135