Critical Mechanistic Features of HIV-1 Viral Capsid Assembly

Abstract

The maturation of HIV-1 capsid protein (CA) into a cone-shaped lattice encasing the condensed RNA genome is critical for viral infectivity. CA can self-assemble into a wide range of capsid morphologies made of ~175-250 hexamers and exactly 12 pentamers. Most recently, cellular polyanion inositol hexakisphosphate (IP6) has been demonstrated to facilitate conical capsid formation by coordinating a ring of arginine residues within the central cavity of capsid hexamers and pentamers. However, the precise interplay of events during IP6 and CA coassembly is unclear. In this work, we use Coarse-Grained Molecular Dynamics (CGMD) simulations to elucidate the underlying molecular mechanism that allows IP6 to have crucial roles in HIV-1 maturation. We show that IP6 promotes curvature generation by trapping pentameric defects in the growing lattice and shifts assembly behavior towards kinetically favored outcomes. Our analysis suggests that IP6 can stabilize metastable capsid intermediates and may induce structural pleomorphism in mature capsids.

Structural insights into HIV-1 polyanion-dependent capsid lattice formation revealed by single particle cryo-EM

“…A recent molecular dynamics simulation analysis of capsid assembly (50) lends further support to this model, suggesting that IP6 has a higher affinity for pentameric CA than for hexameric CA within capsids and that IP6 is critical for assembly of a high-curvature lattice.…”

“…A recent molecular dynamics simulation analysis of capsid assembly (50) lends further support to this model, suggesting that IP6 has a higher affinity for pentameric CA than for hexameric CA within capsids and that IP6 is critical for assembly of a high-curvature lattice. Moreover, a cryo-ET analysis (23) of capsid cores from native virions reported that the central pores of viral pentamers contained two strong densities that were predicted to be IP6.…”

“…Hexamer pores contained much weaker density, although exposure of the capsid cores to excess IP6 yielded hexamer structures with clearer densities. The number and mobility of IP6 molecules coordinated by capsid CA in nature remains an area of active research (32,51,23,50), but our work suggests that IP6 coordination within the pentamer is likely quite stable. We also found that dNTPs can substitute for IP6 to drive full assembly of SUV-templated CA lattice.…”

Bottom-up Coarse-Graining: Principles and Perspectives

“…303,304 It must be noted that the UCG approach has already achieved notable success in treating realistic and highly complex biomolecular systems, an example of which is the assembly of the HIV-1 virus capsid from the more than 1,000 copies of its capsid (CA) protein component. 81,84,305 4-3. Structural Representability.…”

“…299,300 In a coarser description (lower resolution), UCG models based largely on the SST limit have been applied to capture the dynamic self-assembly behavior originating from many-protein HIV viral capsids. 81,84,305 As such, when conformational transitions in complex biomolecules rarely occur, the SST limit can effectively embed the finely detailed chemical nature into a reduced level of representation.…”