Transient Occupancy and Pore Dynamics: IP6 Behavior in HIV-1 T = 4 Capsids

The relationship between inositol hexakisphosphate (IP6), capsid architecture, and the surrounding environment is essential to understanding HIV-1 capsid function. Through an intensive in silico approach, molecular dynamics simulations of T = 4 icosahedral capsids, in the presence and absence of IP6, as well as the R18L mutation, reveal critical insights into how local molecular interactions shape global capsid behavior. While IP6 binding is thermodynamically favorable in pentamers, we recapitulate that the R18 ring and β-hairpins act as kinetic barriers that impede spontaneous IP6 translocation, in contrast to the hexamer. Unbiased flooding simulations reveal the spontaneous association and relocation of IP6 at hexameric pores. Remarkably, these local binding events, including the R18L mutation, have minimal influence on global capsid dynamics or ion flux, suggesting that the capsid morphology governs these functional properties. Together, these findings highlight IP6 as a dynamic stabilizer of the HIV-1 capsid and underscore the role of capsid geometry in modulating structural and functional behavior.