BPS2026 – The molecular mechanisms of conformational change in HIV-1 capsid protein during virion maturation

Human immunodeficiency virus 1 (HIV-1) virions undergo maturation independent of the host cell in a critical step that is essential for the viral life cycle. During maturation, capsid proteins, which self-assemble to encase the viral genome in a hexamer-pentamer lattice, undergo conformational transitions in which the amino-terminal and carboxy-terminal domains rearrange to form a mature capsid conformation. These structural transitions, however, remain poorly defined experimentally. Using all-atom molecular dynamics simulations, here we resolve the molecular mechanisms of CA maturation. Potential of mean force calculations reveal a stable mature state consistent with crystallographic and cryo-EM structures, as well as a metastable intermediate, while the immature state appears unstable and likely stabilized only within the lattice. Analysis of the maturation pathway indicates that maturation proceeds through stepwise ratcheting transitions, and end-point free-energy calculations identify the specific NTD-CTD residue-residue interactions, particularly charged contacts, which stabilize the mature and intermediate states. Our findings show how HIV-1 capsid protein is primed for self-assembly after dissociation from the Gag lattice, with implications for development of novel maturation inhibitors.