Conformational flexibility of the catalytic Asp dyad in HIV-1 protease: An ab initio study on the free enzyme.

The enzyme protease from the human immunodeficiency virus type 1 (HIV-1 PR) is one of the main targets for therapeutic intervention in AIDS. Computer modeling is useful for probing the binding of novel ligands, yet empirical force field-based methods have encountered problems in adequately describing interactions of the catalytic aspartyl pair. In this work we use ab initio dynamic methods to study the molecular interactions and the conformational flexibility of the Asp dyad in the free enzyme. Calculations are performed on model complexes that include, besides the Asp dyad, the conserved Thr26 and Gly27 residues and water molecules present in the active site channel. Our calculations provide proton location and binding mode of the active-site water molecule, which turn out to be different from those of the eukariotic isoenzyme. Furthermore, the calculations reproduce well the structural features of the aspartyl dyad in the protein. Finally, they allow the identification of both dipole/charge interactions and a low-barrier hydrogen bond as important stabilizing factors for the peculiar conformation of the active site. These findings are consistent with site-directed mutagenesis experiments on the 27, 27; positions (Bagossi et al., Protein Eng 1996;9:997-1003). The electric field of the protein frame (included in some of the calculations) does not affect significantly the chemical bonding at the cleavage site. Proteins 2000;39:26-36. Copyright 2000 Wiley-Liss, Inc.