The development of advanced simulation methodology to address challenges in the calculation of protein-ligand binding affinities

点击翻译按钮获取中文摘要

Research area:computational and theoretical chemistry.Despite rigorous free energy calculations becoming increasingly widely used in industry and academia, there are still many situations where their agreement with experimental binding free energies is so poor as to be useless. The reasons for these failures are almost invariably associated with either inadequate configurational sampling during the molecular dynamics or Monte Carlo simulation, or an inadequate force field. In this project, both areas will be addressed. First, a hybrid Monte Carlo (HMC) framework will be developed allowing a range of novel move types to be assessed. Hybrid Monte Carlo combines conventional molecular dynamics and Monte Carlo into a single approach, whereby molecular dynamics is used to sample the configuration space of a system, but with some bias introduced, and the effect of the bias is removed by the associated Monte Carlo test. In the first instance, we will take our grand canonical Monte Carlo method and couple it to molecular dynamics through HMC, but in the longer term we will look to introduce novel biasing moves including sampling from a biased velocity distribution or changes in ligand protonation. In this way we hope to be able to explore the configuration space of the protein-ligand complex more efficiently and hence yield more accurate binding affinities.Second, to address force field deficiencies, our hybrid QM/MM methodology will be extended from calculating simple hydration free energies to protein-ligand binding free energies. While we have had considerable success with calculating hydration free energies, preliminary studies suggest that protein-ligand binding is a much harder problem, although the precise reasons for this are unclear. As a prototypical system, we will start by calculating the binding free energies of bound waters in the neuraminidase protein-ligand system, since obtaining a QM/MM ensemble of configurations is possible for such a small QM region (a single water molecule). Taking the lessons learned from this study, we will extend the simulations to real protein-ligand systems of pharmaceutical relevance.