Molecular Model of Multi-Phasic Biomolecular Condensates

Biomolecular condensates formed via liquid-liquid phase separation (LLPS) typically display multi-layered structuring. These structures are understood as LLPS of components into distinct phases and their subsequent spatial rearrangement into layered morphologies. Using a minimalistic system, comprising of a Prion-like disordered polypeptide (PDP), an Arginine-rich disordered polypeptide (RDP), and RNA, we investigate the thermodynamics of multicomponent intracellular phase behavior. We show that the ternary system forms two stable co-existing condensates, namely, PDP condensates and RDP-RNA condensates. The morphology of these condensates sensitively depend on the mixture stoichiometry and the amino acid sequence composition. Experiments and simulations indicate that these morphological changes are due to variable intermolecular interactions at the liquid-liquid interface. Predictive control of these interactions enabled us to design a diverse set of morphologies, such as completely engulfed, partially-engulfed, completely-detached and Janus-like condensates. Our findings illuminate a relation between molecular-level interactions and interactions between liquid phases at the mesoscale, highlighting a plausible mechanism for spatial organization of multiphasic condensates.