Anomalous Hard-Wall Repulsion between Polymers in Solvent Mixtures and Its Implication for Biomolecular Condensates

The system of polymers dissolved in a mixture of different solvents is a widely used coarse-grained model to represent biomolecular condensates in intracellular environments. Here, we apply a variational theory to simultaneously control the center of mass of two polymers and perform the first quantification of their interactions in a mixture of solvent and cosolvent. While the polymer can completely dissolve in both solvents, strong polymer-cosolvent affinity induces the occurrence of polymer-assisted cosolvent condensation. Even though all the molecular interactions are soft, the potential of mean force between two polymer-cosolvent condensates exhibits an anomalous feature of hard-wall repulsion upon contact, which cannot be categorized into any existing types of interchain interactions. This repulsion is enhanced as either the affinity or the bulk cosolvent fraction increases. The underlying mechanism is cosolvent regulation manifested as a discontinuous local condensation of cosolvent as two condensates approach. The hard-wall repulsion provides a kinetic barrier to prevent coalescence of condensates and hence highlights the intrinsic role of proteins as a cosolvent in stabilizing biomolecular condensates.