Coarse-grained simulations elucidate the role of Inositol Hexakisphosphate (IP6) in HIV-1 mature viral capsid self-assembly

The human immunodeficiency virus (HIV) maturation process is engineered by capsid (CA) protein, which self-assembles into a cone-shaped shell to encase and protect the viral RNA. Naturally occurring inositol hexakisphosphates (IP6) facilitate mature capsid assembly by coordinating a ring of arginines at the pores distributed throughout the capsid lattice surface. In this work, we adopted a Coarse-Graining approach to study the structural basis of CA and IP6 interaction during maturation since it is difficult to effectively address the implicated time and length scale using a fine-grained atomistic model. We use coarse-grained molecular dynamics simulations to elucidate the molecular mechanisms that enable IP6 to have crucial roles in the HIV replication cycle. We find that in the absence of IP6, CA prefers tubular morphology which is primarily comprised of hexameric CA components. The mechanistic details of self-assembly reveal that at physiologically relevant concentrations, IP6 stabilizes the capsid lattice by binding at the regions of high curvature during maturation and increases the stable life of the capsid. The self-assembly process is accelerated by IP6 and favors rapid incorporation of CA pentamers which leads to increased structural pleomorphism in mature capsids.