Interface-mediated secondary phase separation

Inside living cells, many types of biomolecular condensates coexist and interact. Recent experiments have shown that new phases often form at the surface of preexisting condensates. However, the mechanisms for this interface-mediated phase transition remain elusive despite its importance to numerous biological processes. Here, we show that interface-mediated secondary phase separation is a universal pathway for forming a new phase in multicomponent solutions. Using Cahn-Hilliard simulations, we successfully generate puncta of client protein on the surface of scaffold condensates. Based on a quasistatic protocol, we theoretically demonstrate that an interfacial instability triggers new-phase formation and predict the amount of client protein needed for the instability to occur. Remarkably, our quasistatic theory successfully predicts the onset of secondary phase separation even if the client is rapidly added or both the client and scaffold are rapidly added. In the latter case, coarsening of the primary condensates drives secondary phase separation. Our work reveals that cells can exploit existing condensates to lower nucleation barriers of new phases, with important implications for protein aggregation.