Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 4, Pages 915-920Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0508452103
Keywords
AIDS; HIV protease; molecular dynamics simulations; protein dynamics
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Funding
- NIGMS NIH HHS [GM6167803, R01 GM061678-06A1, R01 GM061678] Funding Source: Medline
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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.
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