Mechanism of polymorphism and curvature of HIV capsid assemblies probed by 3D simulations with a novel coarse grain model.

BACKGROUND: During the maturation process, HIV capsid proteins self-assemble into polymorphic capsids. The strong polymorphism precludes high resolution structural characterization under in vivo conditions. In spite of the determination of structural models for various in vitro assemblies of HIV capsid proteins, the assembly mechanism is still not well-understood. METHODS: We report 3D simulations of HIV capsid proteins by a novel coarse grain model that captures the backbone of the rigid segments in the protein accurately. The effects of protein dynamics on assembly are emulated by a static ensemble of subunits in conformations derived from molecular dynamics simulation. RESULTS: We show that HIV capsid proteins robustly assemble into hexameric lattices in a range of conditions where trimers of dimeric subunits are the dominant oligomeric intermediates. Variations of hexameric lattice curvatures are observed in simulations with subunits of variable inter-domain orientations mimicking the conformation distribution in solution. Simulations with subunits based on pentameric structural models lead to assembly of sharp curved structures resembling the tips of authentic HIV capsids, along a distinct pathway populated by tetramers and pentamers with the characteristic quasi-equivalency of viral capsids. CONCLUSIONS: Our results suggest that the polymorphism assembly is triggered by the inter-domain dynamics of HIV capsid proteins in solution. The assembly of highly curved structures arises from proteins in conformation with a highly specific inter-domain orientation. SIGNIFICANCE: Our work proposes a mechanism of HIV capsid assembly based on available structural data, which can be readily verified. Our model can be applied to other large biomolecular assemblies.