Theoretical Model for HIV‑1 PR That Accountsfor Substrate Recognition and Preferential Cleavage of Natural Substrates

The Human Immunodeficiency Virus type 1 (HIV-1) protease is a crucial target for HIV/AIDS treatment and understanding its catalytic mechanism is the basis on which HIV-1 enzyme inhibitors are developed. Several experimental studies have indicated that HIV-1 protease facilitates the cleavage of the Gag and Gag-Pol polyproteins and it is highly selective with regards to the cleaved amino acid precursors and physical parameters. However, the main theoretical principles of substrate specificity and recognition remain poorly understood theoretically. By means of a one-step concerted transition state modeling, the recognition of natural substrates by HIV-1 PR subtypes (B and C-SA) was studied. This was carried out to compare the activation free energies at varying peptide bond regions (scissile and non-scissile) within the polypeptide sequence using ONIOM calculations. We studied both P3-P3' and P5-P5' natural substrate systems. For P3-P3' substrates, excellent recognition was observed for the MA-CA family but ...