Liquid-liquid phase separation (LLPS) is widely utilized by the cell to organize and regulate various biochemical processes. Although the LLPS of proteins is known to occur in a sequence dependent manner, it is unclear how sequence properties dictate the nature of the phase transition and thereby influence condensed phase morphology. In this work, we have utilized grand canonical Monte Carlo simulations for a simple coarse-grained model of disordered proteins to systematically investigate how sequence distribution, sticker fraction and chain length influence the phase behavior and regulate the formation of finite-size aggregates preempting macroscopic phase separation for some sequences. We demonstrate that a normalized sequence charge decoration (SCD) parameter establishes a “soft” criterion for predicting the underlying phase transition of a model protein. Additionally, we find that this order parameter is strongly correlated to the critical density for phase separation, highlighting an unambiguous connection between sequence distribution and condensed phase density. Results obtained from an analysis of the order parameter reveals that at sufficiently long chain lengths, the vast majority of sequences are likely to phase separate. Our results predict that classical LLPS should be the dominant phase transition for disordered proteins and suggests a possible reason behind recent findings of widespread phase separation throughout living cells.

Phase separation versus aggregation behavior for model disordered proteins