Parallel simulated tempering dynamics of ligand–protein binding with ensembles of protein conformations

Simulated tempering dynamics with the simplified energy model and the ensemble of protein conformations have been performed for the SB203386 inhibitor binding with HIV-1 protease. Equilibrium simulations with multiple protein conformations implicitly incorporate protein flexibility and rank HIV-1 protease conformations according to the average ligand–protein interaction energies. Subsequent energy refinement with a molecular mechanics force field accurately quantifies the energetics of the low-energy ligand binding modes. The results suggest that the mobility of the SB203386 inhibitor is effectively restricted to two symmetry-related binding modes and this may prevent the inhibitor from adapting to distorted binding sites in mutant conformations.