(597f) Identification of Structural Mechanisms of HIV-1 Protease Specificity Using Computational Peptide Docking: Implications for Drug Resistance

HIV-1 protease inhibitors are a critical component of antiretroviral therapies, but their efficacy is limited by the ability of HIV-1 to develop drug resistant mutations (DRMs) that disrupt binding of the inhibitor to the protease. Molecular recognition in HIV-1 protease has been heavily studied and large databases of known cleavable and non-cleavable peptide sequences have been curated. Bioinformatic analyses of this data have revealed some sequence patterns that define cleavability but are incapable of identifying the structural and molecular mechanisms that underlie this specificity. In this study we developed a novel peptide docking algorithm to predict the protease-substrate complex structure for a set of 111 known cleavable and non-cleavable peptides and identify the structural and energetic mechanisms that are responsible for specificity. We found a significant difference in calculated binding energy between cleavable and non-cleavable peptides which further analysis revealed to be predominately due to 9 of 29 active-site protease residues. Seven of these residues were in known DRM-positions, including L23, D30, I47, G48, L76, V82, and I84. The unexpectedly large overlap between these specificity-determining residues and DRM residues implies that drug resistance and substrate specificity may involve shared mechanisms of molecular recognition in HIV-1 protease.