On the interplay between phase separation and aggregation*

Interactions among proteins in living cells can lead to both coexisting phases as well as aggregates of different sizes. Both processes play an important role in the spatial organization of cells and the regulation of biological function as well as dysfunction. A key challenge is to better understand the interplay between aggregation and phase separation. Here, we investigate how phase coexistence influences aggregation equilibrium and how, in turn, aggregation affects the properties of coexisting phases. To this end, we propose a theory for a multicomponent mixture that contains aggregates of different sizes. Aggregates can nucleate, grow, shrink, and phase separate from the solvent. At thermodynamic equilibrium, we find that the size distributions of aggregates are significantly different between the dilute and the dense phase. Strikingly, we show that the aggregation equilibrium differs from the stationary state of the same system where phase separation is suppressed. Moreover, we find a gelation transition of the dense phase that coexists with a dilute phase mainly composed of small aggregates. We then study the aggregation kinetics of coexisting phases initially composed of monomers. We show that the formation of aggregates affects the size of the dense phase and its composition. Our findings show that aggregation kinetics can strongly affect the properties of coexisting phases and are consistent with recent experimental observations of densification and volume changes of protein droplets.