It is important to determine the binding pathways and mechanisms of ligand molecules to target proteins in order to effectively design therapeutic drugs. Molecular dynamics (MD) is a promising computational tool that allows us to simulate protein-drug binding at an atomistic level. However, the gap between timescales of current simulations and those of many drug binding processes has limited the usage of conventional MD, which has been reflected in studies of the HIV protease. Here, we have applied a robust enhanced simulation method, Gaussian accelerated molecular dynamics (GaMD), to sample binding pathways of the XK263 ligand and associated protein conformational changes in the HIV protease1. During two of ten independent GaMD simulations performed over 500 – 2,500 ns, the ligand was observed to successfully bind to the protein active site. Although GaMD-derived free energy profiles were not fully converged due to insufficient sampling of the complex system, the simulations still allowed us to identify relatively low-energy intermediate conformational states during ligand binding to the HIV protease. Relative to the X-ray crystal structure, the XK263 ligand reached a minimum RMSD of 2.26 Å during 2.5 μs of GaMD simulation. In comparison, the ligand RMSD reached a minimum RMSD of only ~5.73 Å during an earlier 14 μs conventional MD simulation. Therefore, GaMD provides powerful enhanced sampling and is widely applicable to studies of drug-receptor interactions for the HIV protease and by extension many other target proteins.

Ligand binding pathways and conformational transitions of the HIV protease

256th National Meeting (2018)

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