ANALYSIS OF THE STRUCTURE OF HIV-1 PROTEASE COMPLEXED WITH A HEXAPEPTIDE INHIBITOR .2. MOLECULAR DYNAMIC STUDIES OF THE ACTIVE-SITE REGION

Six models of the catalytic site of HIV-1 protease complexed with a re duced peptide inhibitor, MVT-101, were investigated, These studies foc used on the details of protonation of the active site, its total net c harge and hydrogen bonding pattern, which was consistent with both the observed coplanar configuration of the acidic groups of the catalytic aspartates (Asp-25 and Asp-125) and the observed binding mode of the inhibitor, Molecular dynamic simulations using AMBER 4.0 indicated tha t the active site should be neutral, The planarity of the aspartate dy ad may be due to the formation of two hydrogen bonds: one between the inner O-delta 1 oxygen atoms of the two catalytic aspartates and anoth er between the O-delta 2 atom of Asp-125 and the nitrogen atom of the reduced peptide bond of the bound inhibitor, This would require two ad ditional protonations, either of both aspartates, or of one Asp and th e amido nitrogen atom of Nle-204, Our results favor the Asp-inhibitor protonation but the other one is not excluded, Implications of these f indings for the mechanism of enzymatic catalysis are discussed, Dynami c properties of the hydrogen bond network in the active site and an an alysis of the interaction energy between the inhibitor and the proteas e are presented. (C) 1997 Wiley-Liss, Inc.