Quantum chemistry free energy methods for drug optimisation

Lead Research Organisation: University of Oxford
Department Name: Theory and Modelling in Chem Sci CDT

Abstract

The goal of this project is to overcome the force field limitations in biomolecular free energy calculations by employing large-scale ab initio calculations. To achieve this goal we will develop hybrid free energy methods which start with force fields to compute free energy differences between different ligands but then compute the free energy of mutation from the classical to the quantum description (free energies are thermodynamic state functions so such a transition is well-defined). This work will build on our previous experience in this area and will use the ONETEP linear-scaling DFT program,which we develop in our group. Particular challenges in this project will be the development of free energy methods that have high configurational overlap between the classical and the quantum description and produce accurate ensembles of structures in both descriptions. Relevant to this project are also the development of quantum methods that provide the most accurate description of biomolecular interactions (such as new generations of DFT approaches) while reducing the computational demands, and the calibration of explicit and implicit models for the solvent. The project will involve development of new theory and code within ONETEP and in stand-alone free energy methods programs.

The new methods will be validated in actual protein-ligand targets of relevance to the pharmaceutical industry. The project is supported by Boehringer Ingelheim (BI) and will be co-supervised by researchers from BI and by Professor Chris-Kriton Skylaris, and will involve periods of work with the BI computational chemists in Germany.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/R512333/1 01/10/2017 30/09/2021
1935535 Studentship EP/R512333/1 01/10/2017 30/09/2021 James William Whipham