Identification of structural mechanisms of HIV-1 protease specificity using computational peptide docking: implications for drug resistance.

Drug-resistant mutations (DRMs) in HIV-1 protease are a major challenge to antiretroviral therapy. Protease-substrate interactions that are determined to be critical for native selectivity could serve as robust targets for drug design that are immune to DRMs. In order to identify the structural mechanisms of selectivity, we developed a peptide-docking algorithm to predict the atomic structure of protease-substrate complexes and applied it to a large and diverse set of cleavable and noncleavable peptides. Cleavable peptides showed significantly lower energies of interaction than noncleavable peptides with six protease active-site residues playing the most significant role in discrimination. Surprisingly, all six residues correspond to sequence positions associated with drug resistance mutations, demonstrating that the very residues that are responsible for native substrate specificity in HIV-1 protease are altered during its evolution to drug resistance, suggesting that drug resistance and substrate selectivity may share common mechanisms.