Stoichiometric Binding of Cyclophilin-A to The HIV-1 Capsid Modulates Its Mechanoelastic Properties.

Abstract

Protein nanocapsules balance structural rigidity with mechanical deformability to perform their biological functions. The HIV-1 capsid, a ∼ 120 nm conical shell assembled from over 1000 capsid protein (CA) subunits, exemplifies this challenge: it must be stable to protect the viral cargo while remaining sufficiently deformable to traverse the ∼ 45 nm nuclear pore complex. Cyclophilin A (CypA), a host protein that binds the capsid, regulates nuclear entry; however, its role in modulating capsid nanomechanics remains unresolved. Here, atomic force microscopy nanoindentation simulations of CypA-decorated capsids reveal that CypA acts as a stoichiometric regulator of capsid mechanical response. The capsid exhibits curvature-dependent mechanical heterogeneity, with stiffness and transverse deformability varying across regions of distinct local lattice geometry. CypA binding progressively increases capsid brittleness, promoting structural failure at lower deformations. This effect is observed across wild-type and mutant capsids, and at high CypA:CA ratios, dominates over intrinsic sequence-dependent differences in ductility. A stoichiometry-dependent model is proposed in which partial CypA decoration preserves the mechanical flexibility required for nuclear entry, whereas excessive binding renders the capsid overly brittle, compromising nuclear import. These findings highlight how surface ligand binding programs the mechanical response of protein nanocapsules, offering principles for stimuli-responsive biomolecular materials.