To understand the underlying mechanisms of the open and closed conformational change of HIV-1 protease (HIV-1 PR) at multiple time scales, we performed serial fully unrestrained, extremely long time molecular dynamics simulations with an explicit solvent model. Spontaneous semiopen to closed conformational transition and inhibitor-collision-induced opening of the flaps were simulated in a real time scale. We found that the rapid, local subnanosecond fluctuations of the flap tips might be the mechanisms triggering the global open and close conformational transitions at the 100-ns time scale. The subnanosecond fluctuation is induced by the Φ-Ψ rotations of the residues at the flap tips, mainly W of Gly49 and O of Ile50, disturbing the interactions between the two tips and then their stability. We further showed that the water molecule W301 is helpful for the stability of the PR-inhibitor complex by acting as a collision buffer for the dynamic interaction between flap tips and the inhibitor. These results might help gain a better insight into the dynamics of HIV-1 PR, especially the local dynamics of the flap tips, which may provide important guidelines for design of novel potent inhibitors.
ASJC Scopus subject areas
- Physical and Theoretical Chemistry
- Materials Chemistry
- Surfaces, Coatings and Films