HIV-1 protease flaps spontaneously open and reclose in molecular dynamics simulations

• DOI: 10.1073/pnas.0508452103
• Publication Date: 2006-01-18T03:14:05Z
• Authors: Viktor Hornak; Asim Okur; Robert C. Rizzo; Carlos Simmerling
• Keywords: Conformational change; Protease inhibitor (pharmacology)

We report unrestrained, all-atom molecular dynamics simulations of HIV-1 protease that sample large conformational changes the active site flaps. In particular, unliganded undergoes multiple conversions between “closed” and “semiopen” forms observed in crystal structures inhibitor-bound protease, respectively, including reversal flap “handedness.” Simulations presence a cyclic urea inhibitor yield stable closed Furthermore, we observe several events which flaps open to much greater degree than subsequently return semiopen state. Our data strongly support hypothesis predominantly populates conformation, with fully being minor component overall ensemble. The results also provide model for opening closing is considered be essential enzyme function.