Characterization of HIV-2 Protease Structure by Studying Its Asymmetry at the Different Levels of Protein Description

HIV-2 protease (PR2) is a homodimer, which is an important target in the treatment of the HIV-2 infection. In this study, we developed an in silico protocol to analyze and characterize the asymmetry of the unbound PR2 structure using three levels of protein description by comparing the conformation, accessibility, and flexibility of each residue in the two PR2 chains. Our results showed that 65% of PR2 residues have at least one of the three studied asymmetries (structural, accessibility, or flexibility) with 10 positions presenting the three asymmetries in the same time. In addition, we noted that structural and flexibility asymmetries are linked indicating that the structural asymmetry of some positions result from their large flexibility. By comparing the structural asymmetry of the crystallographic and energetically minimized structures of the unbound PR2, we confirmed that the structural asymmetry of unbound PR2 is an intrinsic property of this protein with an important role for the PR2 deformation upon ligand binding. This analysis also allowed locating asymmetries corresponding to crystallization artefacts. This study provides insight that will help to better understand the structural deformations of PR2 and to identify key positions for ligand binding.