![]() ![]() The chief drivers of biomolecular LLPS are multivalent molecules (i.e., those possessing multiple interaction sites) known as ‘scaffolds’ 20. Furthermore, neurodegenerative diseases such as Alzheimer’s, Parkinson’s or ALS have been associated with aberrant or misregulated phase transitions 17, 18, 19. The interest in understanding the molecular grammar 8, 9 and biophysical determinants of cellular LLPS has significantly increased in recent years due, in part, to the realization that condensates take part in a wide-range of cellular functions-including genome silencing 10, 11, signaling 12, buffering cellular noise 13, and formation of super-enhancers 14, among many others 15, 16. Condensates are ubiquitous within cells, with some of the most famous examples including stress granules 4, P granules 5, nuclear speckles 6, and the nucleolus 7. In LLPS, a protein solution demixes into a protein-rich liquid phase-the condensate-in coexistence with a protein-poor liquid matrix. Another, that does not rely on membranes, is the self-assembly of proteins and nucleic acids into biomolecular condensates through the process of liquid–liquid phase separation (LLPS) 1, 2, 3. One way of achieving spatiotemporal organization is via the formation of membrane-bound organelles. To fulfill their biological functions, cells must organize their contents into different compartments. Overall, our work proposes one thermodynamic mechanism to help rationalize how size-conserved coexisting condensates can persist inside cells-shedding light on the roles of protein connectivity, binding affinity, and droplet composition in this process. In contrast, low surfactant-to-scaffold concentrations enable continuous growth and fusion of droplets without restrictions. The multidroplet size-conserved scenario spontaneously arises at increasing surfactant-to-scaffold concentrations, when the interfacial penalty for creating small liquid droplets is sufficiently reduced by the surfactant proteins that are preferentially located at the interface. Our simulations demonstrate that protein connectivity and condensate surface tension regulate the balance between these two scenarios. In this work, using a minimal protein model, we show that phase separation of binary mixtures of scaffolds and low-valency clients that can act as surfactants-i.e., that significantly reduce the droplet surface tension-can yield either a single drop or multiple droplets that conserve their sizes on long timescales (herein ‘multidroplet size-conserved’ scenario’), depending on the scaffold to client ratio. Some membraneless compartments, such as nucleoli, are dispersed as different condensates that do not grow beyond a certain size, or do not present coalescence over time. Biomolecular condensates are liquid-like membraneless compartments that contribute to the spatiotemporal organization of proteins, RNA, and other biomolecules inside cells. ![]()
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