Water-mediated dynamic interactions between intrinsically disordered proteins preserve condensate fluidity

Non-specific multivalent interactions between intrinsically disordered proteins (IDPs) drive the formation of membraneless organelles via liquid-liquid phase separation. These interactions must be sufficiently strong to drive phase separation while remaining dynamic enough to maintain condensate fluidity, yet the molecular origin of this balance remains unclear. Here, using all-atom molecular dynamics simulations, we investigate microscopic interactions within condensates formed by the prion-like domains of fused in sarcoma (FUS). In contrast to classical protein-protein binding, which expels interfacial water, we find that IDP-IDP interactions are mediated by abundant, highly mobile water molecules. Rapid hydrogen-bond exchange sustains a dynamic, hydrated interface that enables continuous conformational fluctuations and flexible side-chain contacts. This water-mediated interaction mode promotes condensate fluidity while suppressing backbone hydrogen bonding, potentially disfavoring ordered secondary structure formation. Our results reveal a water-mediated mechanism governing IDP interactions and provide molecular insight into the physical principles underlying biomolecular condensate function.