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bioRxiv · 10.64898/2026.02.20.707123

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

Rey, J. S.·Bryer, A. J.·Perilla, J. R.
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Abstract

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.

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Rey, J. S., Bryer, A. J., Perilla, J. R.. 2026-02-21. Stoichiometric binding of Cyclophilin-A to the HIV-1 capsid modulates its mechanoelastic properties. https://doi.org/10.64898/2026.02.20.707123

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