Preservation of HIV-1 Gag Helical Bundle Symmetry by Bevirimat Is Central to Maturation Inhibition.

ABSTRACT: The assembly and maturation of human immunodeficiency virus type 1 (HIV-1) require proteolytic cleavage of the Gag polyprotein. The rate-limiting step resides at the junction between the capsid protein CA and spacer peptide 1, which assembles as a six-helix bundle (6HB). Bevirimat (BVM), the first-in-class maturation inhibitor drug, targets the 6HB and impedes proteolytic cleavage, yet the molecular mechanisms of its activity, and relatedly, the escape mechanisms of mutant viruses, remain unclear. Here, we employed extensive molecular dynamics (MD) simulations and free energy calculations to quantitatively investigate molecular structure-activity relationships, comparing wild-type and mutant viruses in the presence and absence of BVM and inositol hexakisphosphate (IP6), an assembly cofacto

SUBMITTER: Pak AJ 

PROVIDER: S-EPMC8610020 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature