Protein–RNA phase separation gives rise to biomolecular condensates with rich internal organization, yet the molecular rules that connect sequence-encoded interactions to the emergent condensate spatial organization remain poorly understood. Here, using large-scale residue-level coarse-grained simulations, we identify a molecular grammar that governs the formation of multiphase protein–RNA condensates. We show that asymmetries in protein–protein and protein–RNA interactions, together with protein stoichiometry, chain length, and condensate density, collectively determine whether condensates adopt homogeneous, layered, biphasic, or vesicle-like morphologies. Vesicular condensates form spontaneously from well-mixed initial conditions without requiring flux-driven oversaturation or extreme charge imbalance, distinguishing this mechanism from previously proposed routes to condensate hollowing. We rationalize the full morphological progression as sequence-encoded amphiphile self-assembly: the protein–RNA complex behaves as a single-chain amphiphile whose effective packing parameter is set by Domain H/L stoichiometry, spanning micelles, cylinders, hollow vesicles, and inverse phases.
Ramachandran et al. (Sun,) studied this question.