Abstract
The active site of aspartic proteases, such as HIV-1 protease (PR), is covered by one or more flaps, which restrict access to the active site. For HIV-1 PR, X-ray diffraction studies suggested that in the free enzyme the two flaps are packed onto each other loosely in a semi-open conformation, while molecular dynamics (MD) studies observed that the flaps can also separate into open conformations. In this study, the mechanism of flap opening and the structure and dynamics of HIV-1 PR with semi-open and open flap conformations were investigated using molecular dynamics simulations. The flaps showed complex dynamic behavior as two distinct mechanisms of flap opening and various stable flap conformations (semi-open, open and curled) were observed during the simulations. A network of weakly polar interactions between the flaps were proposed to be responsible for stabilizing the semi-open flap conformation. It is hypothesized that such interactions could be responsible for making flap opening a highly sensitive gating mechanism which control access to the active site.
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