Clarifying misconceptions of biomolecular condensate formation

Biomolecular condensates are liquid-like phase separations of disordered proteins and other molecules within cells. These membrane-less organelles are essential in critical cellular processes and are aberrant in myriad disease. Yet, the thermodynamics of condensate formation are not entirely understood, thus the mechanisms of condensate function remain elusive. Two assumptions about biomolecular condensates are that they form through liquid-liquid phase separation (LLPS) and require multivalent interactions. Here, we show results and propose thermodynamic frameworks that suggest these assumptions are not always correct. We demonstrate that condensation does not follow canonical LLPS and that liquid-like phase separation can arise from monovalent interactions. These results clarify the mechanism of condensate thermodynamics to reframe our understanding of condensates in cellular function and disease.