Stoichiometric binding of Cyclophilin-A to the HIV-1 capsid modulates its mechanoelastic properties.

HIV-1 nuclear entry requires a capsid that is sufficiently stable to protect and transport the viral genome yet sufficiently deformable to traverse the nuclear pore complex. Cyclophilin A (CypA), a host cell factor that binds the capsid in the cytoplasm, regulates early replication events; however, its effects on capsid mechanics remain unresolved. Here, we used atomic force microscopy nanoindentation simulations of CypA-decorated HIV-1 capsids across binding stoichiometries to characterize their mechanical response. The capsid exhibits curvature-dependent mechanical heterogeneity, with stiffness and transverse deformability varying along its surface. CypA binding progressively increased capsid brittleness, promoting structural failure at lower deformations. At high CypA:CA ratios, CypA binding overrides intrinsic sequence-dependent differences in ductility across wild-type and mutant capsids. These findings establish a direct link between CypA binding and capsid mechanoelastic properties, supporting a stoichiometry-dependent model in which balanced CypA binding preserves flexibility for nuclear entry, whereas excessive binding compromises nuclear import.