Abstract Viral capsids are dynamic macromolecular assemblies whose stability and immunogenicity are modulated by environmental parameters such as hydrostatic pressure and temperature. Here, we combine all-atom molecular dynamics simulations with integrative structural analyses to map the pressure–temperature (P–T) response landscape of the tobacco mosaic virus coat protein (TMVcp). Using a 21-state protocol spanning 1–2500 bar at 300 K followed by cooling to 255 K under constant high pressure, we reveal a hydration-driven cooperative collapse of the capsid lattice, coupled to significant remodeling of RNA-protein interactions and antigenic epitope landscapes. At elevated pressures, TMVcp undergoes a transition from a flexible, native-like ensemble into a rigidified compact state, characterized by a ~21% reduction in radius of gyration, an ≈88% decrease in RNA-binding free energy, and near-complete masking of canonical epitopes. High-pressure hydration drives water penetration into buried cavities and inter-subunit interfaces, reorganizing hydrogen-bond networks and suppressing configurational entropy. Upon cooling at constant 2500 bar, the ensemble partially recovers structural diversity and epitope accessibility through immobilization and reorganization of hydration shells, yielding kinetically trapped compact basins with modest restoration of solvent exposure (+12%) and RNA-channel geometry (+5%). This work provides a quantitative P–T structural map linking hydration dynamics, RNA-channel mechanics, and epitope remodeling, establishing TMV as a model system for pressure-assisted modulation of viral structure and antigenicity. Our findings offer actionable mechanistic insights for engineering thermomechanically tunable viral nanocarriers and for rational vaccine design strategies exploiting controlled antigen exposure.
Bonafé et al. (Mon,) studied this question.