Explicit solvent dynamics and energetics of HIV-1 protease flap opening and closing

An accurate description of the conformational dynamics of the β-hairpin flaps of HIV-1 protease is of central importance in elucidating the functional recognition of the enzyme by ligands. Using all-atom molecular dynamics simulations in explicit solvent, with a total of 461 trajectories of ∼50 ns each, we report the closed, semiopen, open, and wide-open flap conformation of the free wild-type protease. The free energy of flap opening and closing from the semiopen state is 0.9 ± 0.2 and 2.4 ± 0.4 kcal/mol, respectively. The mean relaxation time of opening is ∼8 ns, in good agreement with NMR data. The explicit solvent simulations quantitatively confirm the hypothesis that the semiopen state is the dominant population in the free protease whilst fast flap tip fluctuations lead frequently to an open state. More pronounced flap rearrangements lead to a rare wide-open state with the catalytic site completely exposed to the solvent. The structures of the different flap conformations provided herein are of general interest for improved drug design of HIV-1 protease, in particular, the wide-open conformation could be favored by the large Gag and GagPol polyprotein chains. Strategies that take into account multiple flap-gating mechanisms may lead to more effective inhibitors.