Abstract
The maturation of HIV-1 viral particles is essential for viral infectivity. During maturation, many copies of the capsid protein (CA) self-assemble into a capsid shell to enclose the viral RNA. The mechanistic details of the initiation and early stages of capsid assembly remain to be delineated. We present coarse-grained simulations of capsid assembly under various conditions, considering not only capsid lattice self-assembly but also the potential disassembly of capsid upon delivery to the cytoplasm of a target cell. The effects of CA concentration, molecular crowding, and the conformational variability of CA are described, with results indicating that capsid nucleation and growth is a multi-stage process requiring well-defined metastable intermediates. Generation of the mature capsid lattice is sensitive to local conditions, with relatively subtle changes in CA concentration and molecular crowding influencing self-assembly and the ensemble of structural morphologies.
Highlights
The maturation of HIV-1 viral particles is essential for viral infectivity
There is a dynamic population of capsid protein (CA) conformations dictated by the flexible linker between the N-terminal domains (NTDs) and C-terminal domains (CTDs)
While care should be taken in assuming any CG model to be a direct representation of a real, fully atomistically resolved system, the reproduction of specific experimental phenomena suggests that our CG model can capture the early and intermediate stages of nucleation and growth of the capsid lattice
Summary
Many copies of the capsid protein (CA) self-assemble into a capsid shell to enclose the viral RNA. Generation of the mature capsid lattice is sensitive to local conditions, with relatively subtle changes in CA concentration and molecular crowding influencing self-assembly and the ensemble of structural morphologies. Enzymatic cleavage of Gag polypeptide[4] releases capsid protein (CA) to self-assemble into a conical lattice structure enclosing the viral RNA (the capsid, Fig. 1). Given suitable conditions in vitro, CA can spontaneously self-assemble into a wide variety of structures[11,12,13,14,15,16,17,18], but the prototypical mature virion contains a single conical capsid with a complex of viral RNA and nucleocapsid protein (NC) condensed within the broader terminus. Rapid dilution destabilizes the CA lattice in vitro under physiological salt concentrations[12], but the potential significance of this effect on capsid stability is unclear
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