Kinetic implications of IP₆ anion binding on the molecular switch of HIV-1 capsid assembly

HIV-1 capsid (CA) proteins self-assemble into a fullerene-shaped CA, enabling cellular transport and nuclear entry of the viral genome. A structural switch comprising the Thr-Val-Gly- Gly (TVGG) motif either assumes a disordered coil or a 3₁₀ helix conformation to regulate hexamer or pentamer assembly, respectively. The cellular polyanion inositol hexakisphosphate (IP₆) binds to a positively charged pore of CA capsomers rich in arginine and lysine residues mediated by electrostatic interactions. Both IP₆ binding and TVGG coil-to-helix transition are essential for pentamer formation. However, the connection between IP₆ binding and TVGG conformational switch remains unclear. Using extensive atomistic simulations, we show that IP₆ imparts structural order at the central ring, which results in multiple kinetically controlled events leading to the coil-to-helix conformational change of the TVGG motif. IP₆ facilitates the helix-to-coil transition by allowing the formation of intermediate conformations. Our results suggest a key kinetic role of IP₆ in HIV-1 pentamer formation.