title: HIV-1 protease flaps spontaneously open and reclose in molecular dynamics simulations.
abstract: We report unrestrained, all-atom molecular dynamics simulations of HIV-1 protease that sample large conformational changes of the active site flaps. In particular, the unliganded protease undergoes multiple conversions between the "closed" and "semiopen" forms observed in crystal structures of inhibitor-bound and unliganded protease, respectively, including reversal of flap "handedness." Simulations in the presence of a cyclic urea inhibitor yield stable closed flaps. Furthermore, we observe several events in which the flaps of the unliganded protease open to a much greater degree than observed in crystal structures and subsequently return to the semiopen state. Our data strongly support the hypothesis that the unliganded protease predominantly populates the semiopen conformation, with closed and fully open structures being a minor component of the overall ensemble. The results also provide a model for the flap opening and closing that is considered to be essential to enzyme function.
authors.affiliation: Center for Structural Biology, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Viktor
authors.initials: V
authors.lastname: Hornak
authors.forename: Asim
authors.initials: A
authors.lastname: Okur
authors.forename: Robert C
authors.initials: RC
authors.lastname: Rizzo
authors.forename: Carlos
authors.initials: C
authors.lastname: Simmerling
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000378:metabolism; D000577:Amides / Q000737:chemistry; D003198:Computer Simulation; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry; D013997:Time Factors; D014508:Urea / Q000494:pharmacology; D014867:Water / Q000737:chemistry
chemical_list: D000577:Amides; D008024:Ligands; D011506:Proteins; D014867:Water; D014508:Urea; D016333:HIV Protease