HIV-1 Protease Cleavage Mechanism Elucidated with Molecular Dynamics Simulation Article

Chatfield, DC, Brooks, BR. (1995). HIV-1 Protease Cleavage Mechanism Elucidated with Molecular Dynamics Simulation . JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 117(20), 5561-5572. 10.1021/ja00125a018

cited authors

  • Chatfield, DC; Brooks, BR

authors

abstract

  • The cleavage mechanism of HIV-1 protease is investigated with molecular dynamics simulation of substrate-, inhibitor-, and gem-diol intermediate-bound protease. Initial structures are based on X-ray crystallographic coordinates for the protease bound to the inhibitor JG-365.1'2 The conformation space explored by atoms near the active site on the 100 ps time scale at 300 K is analyzed for structures likely to initiate reaction. Conformations suitable for reaction initiation are generated for both general acid-general base and direct nucleophilic attack mechanisms. The simulations suggest that (1) both types of mechanism are plausible; (2) the catalytic Asp of monomer B is protonated when reaction begins; (3) if the mechanism is general acid-general base, the catalytic Asp of monomer A is protonated when the second reaction step is initiated; (4) the carbonyl oxygen is more likely than the scissile nitrogen to be protonated in the early stages of reaction; (5) water 3011 stabilizes productive conformations of reactants and intermediates, but it does not participate directly in reaction; and (6) a lytic water, if present, has very little mobility. © 1995, American Chemical Society. All rights reserved.

publication date

  • January 1, 1995

published in

Digital Object Identifier (DOI)

start page

  • 5561

end page

  • 5572

volume

  • 117

issue

  • 20