Crucial roles of the subnanosecond local dynamics of the flap tips in the global conformational changes of HIV-1 protease.

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 Phi-Psi rotations of the residues at the flap tips, mainly Psi of Gly49 and Phi 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.