A PhD position of 3.5 years in the Dept. of Chemistry (Univ. of Manchester, Britain) is available for an outstanding and ambitious computational/theoretical physicist or chemist.

You will work in the area of force field design:

By its novel architecture the in-house force field FFLUX aims to make a step change in the reliability of modelling of peptides/proteins in aqueous solution. The machine learning method Gaussian Process Regression is used to create knowledgeable quantum atoms that accurately predict energies and multipole moments. FFLUX combines accurate electrostatics and polarisation with an original treatment of short-range interaction and dispersion. The molecular dynamics program DL_FFLUX (derived from DL_POLY) enables geometry optimisation and simulation.

Project Title: Accurate evaluation of solvation free energies of drug molecules using FFLUX

Principal Investigator: Prof Paul Popelier

Industrial collaborators: Ben Symons, Michael Bodkin

Company: Evotec

Project description:

Accurate calculation of binding free energy of protein-ligand complexes is highly important as it is typically a good predictor of drug potency. Calculations are difficult because QM methods are too computationally expensive, but MM is rarely accurate enough. Classical water potentials (TIP3P, SPC, etc.) are known to model water poorly. The conformations of biomolecules predicted using classical force fields have been shown to be highly dependent on the choice of force field, with success for a given system rarely translating to other systems. We will apply FFLUX to simulate ligands in vacuo and with explicit solvent to enable highly accurate calculation of solvation free energy as well as investigation of conformational change. The impact will predominantly be in the lead optimisation stage of the drug discovery pipeline. Improving the accuracy of solvation free energies of ligands will lead to better estimates for the overall binding free energy thus making FFLUX a powerful tool for improving potency. Deeper analysis of the simulations will help to gain insight into the non-trivial changes that ligands undergo during solvation as well as the way they interact with water.

The post is tenable from 1^st Oct 2022.

Please contact Prof Popelier for further information on [email protected] .