MODELS OF HIV-1 PROTEASE WITH PEPTIDES REPRESENTING ITS NATURAL SUBSTRATES

The substrate specificity of HIV-1 protease has been investigated by m olecular modeling of HIV-I protease with seven peptides representing t he naturally occurring cleavage sites in the gag and gag-pol polyprote in precursors. These peptides contain a wide range of amino acids, alt hough only hydrophobic residues are found at either side of the scissi le peptide bond. Polar amino acid side chains in each substrate may fo rm hydrogen bond interactions with atoms of HIV protease. HIV-1 protea se residues Arg 8, Asp 29, Asp 30, Lys 45, Met 46, Gly 49 and Pro 81 w ere predicted to form hydrogen bond interactions with polar substrate side chains that may provide sequence specific recognition of the subs trates. Several of these protease residues are mutated in inhibitor re sistant strains of HIV. Residues equivalent to HIV-I protease Asp 30 a nd Pro 81 have been shown to be critical components for substrate reco gnition. The calculated interaction energy between HIV protease and th e tetrahedral intermediate of the substrates has a correlation coeffic ient of 71% with the differences in free energy calculated from kineti c measurements. The implications for the reaction pathway are discusse d. (C) 1998 Elsevier Science B.V.