Abstract
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 3(10) helix conformation to regulate hexamer or pentamer assembly, respectively. The cellular polyanion inositol hexakisphosphate (IP(6)) binds to a positively charged pore of CA capsomers rich in arginine and lysine residues mediated by electrostatic interactions. Both IP(6) binding and TVGG coil-to-helix transition are essential for pentamer formation. However, the connection between IP(6) binding and TVGG conformational switch remains unclear. Using extensive atomistic simulations, we show that IP(6) 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. IP(6) facilitates the helix-to-coil transition by allowing the formation of intermediate conformations. Our results suggest a key kinetic role of IP(6) in HIV-1 pentamer formation.