Equilibrium dynamics of the pre- and post-cleavage regions of SP1 are separately shifted by the HIV-1 maturation inhibitor Bevirimat

Abstract

Human immunodeficiency virus type 1 (HIV-1) assembly and maturation proceeds in two distinct steps. During assembly, viral Gag oligomerizes into a hexagonal polyprotein lattice incorporating the capsid protein (CA) and spacer peptide 1 (SP1) domains, that constitute the immature Gag lattice. During maturation, CTD-SP1 hexamers formed in the previous step are cleaved by HIV-1 protease, causing a dramatic rearrangement of the immature virion to its mature, infectious form. The first-generation maturation inhibitor (MI) bevirimat (BVM) is reported to block the final cleavage between CA and SP1, thus blocking HIV maturation. In contrast, the host factor inositol hexakisphosphate (IP6) is a co-factor of Gag assembly and facilitates the formation of a quaternary arrangement of SP1 known as the six helix bundle (6HB). Here, starting from a MAS NMR structure and using atomistic free energy calculations, we establish that binding of BVM and IP6 to the immature lattice lacks any cooperativity or avidity. Furthermore, we rationalize the molecular origin of HIV resistance to BVM by determining the role of BVM on the stability of the 6HB and by revealing that SP1 shows independent dynamics for its pre- and post-cleavage regions. Finally, results from our simulations permit us to propose a novel chemical scaffold for the design of maturation inhibitors based on BVM and IP6.