Biomolecular condensates driven by liquid–liquid phase separation (LLPS) have received attention as novel activity regulators of living organisms. In intracellular LLPS, an important question is what type of biomolecules form condensates under what conditions. Recently, LLPS condensates have been reported to regulate the membrane structure upon wetting. However, the opposite possibility, i.e., whether membrane wetting regulates the LLPS, remains unexplored. Using variously sized droplets of short polyethylene glycol (PEG) and long dextran blends encapsulated with a lipid membrane, we demonstrate that membrane wetting regulates LLPS in cell-sized spaces and alters the equilibrium state. In small droplets, the two-phase region expands beyond the bulk, and the degree of fractionation increases as the droplet size decreases. We explain the space-size-dependent LLPS from the higher wettability of short PEG than dextran. This shows that cell-sized confinement can regulate LLPS upon competition for membrane wettability among various molecules, rendering this LLPS principle feasible in living cells.
Living cells are characterized by the micrometric confinement of various macromolecules at high concentrations. Using droplets containing binary polymer blends as artificial cells, we previously showed that cell-sized confinement causes phase separation of the binary polymer solutions because of the lengthdependent wetting of the polymers. Here, we demonstrate that the confinement-induced heterogeneity of polymers also emerges in single-component polymer solutions. The resulting structural heterogeneity also leads to a slower transport of small molecules at the center of cell-sized droplets than that in bulk solutions. Coarse-grained molecular simulations support this confinementinduced heterogeneous distribution by polymer length and demonstrate that the effective wetting of the shorter chains at the droplet surface originates from the length-dependent conformational entropy. Our results suggest that cell-sized confinement functions as a structural regulator for polydisperse polymer solutions that specifically manipulates the diffusion of molecules, particularly those with sizes close to the correlation length of the polymer chains.
Biomolecular condensates driven by liquid-liquid phase separation (LLPS) have received attention as novel activity regulators of living organisms. In intracellular LLPS, an important question is what type of biomolecules form condensates under what conditions. In this regard, possible interactions between biomolecules have been investigated. Recently, LLPS condensates have been reported to regulate the membrane structure upon wetting. However, the possibility of membrane wetting, in which the membrane conversely regulates the LLPS, remains unexplored. Using droplets of short polyethylene glycol and long dextran blends encapsulated with a lipid membrane, we demonstrate that membrane wetting regulates LLPS in cell-size spaces and alters the equilibrium state. In smaller droplets, the two-phase region expands beyond the bulk system, and the fractionation degree increases, particularly during the separation between short PEG and long dextran. We explain the space-size dependent LLPS based on the competitive membrane wetting between the polymers. Smaller droplets promote the membrane wetting of short PEG, which enhances the depletion force between long dextran molecules and finally induces LLPS. This shows that competition for membrane wettability among various molecules can regulate LLPS in cell-size spaces, rendering this LLPS principle feasible in living cells.
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