(362j) Water Reorganization Drives Liquid—Liquid Phase Separation

Liquid–liquid phase separation (LLPS), refers to the formation of a dense liquid phase driven by the association of macromolecules in solution. Two types of LLPS play central roles in material and biological sciences—polyelectrolyte complex coacervation and biomolecular condensates—the former involving the formation of a polymer-rich phase by association of oppositely charged polyelectrolytes, and the latter referring to the formation of cellular droplets by protein association. Despite recent advances in understanding LLPS, the thermodynamic driving forces in LLPS remain poorly understood and are subject of controversy. In the case of polyelectrolyte complex coacervation, while experiments usually find the process to be strongly entropy-driven, simulations generally report significant energetic contributions in driving the coacervation. In the case of biomolecular association, a long-standing puzzle is the molecular origin of enthalpy–entropy compensation (EEC): While the overall binding Gibbs free energy remains nearly constant, there is great variation and compensation in the entropic and enthalpic contributions, depending on the species of the paired polymers.

Using coarse-grained simulation and thermodynamics analysis, we find that solvent (water) reorganization is a key component to the entropy change in the LLPS. We resolve the long-standing controversy involving the driving force for polyelectrolyte complex coacervation including the entropy contribution in electrostatic interaction, manifested in the temperature-dependent dielectric constant of water. Our results show that polycation–polyanion complexation in weakly to moderately charged polymers is strongly entropy-driven with negligible energetic contribution, consistent with experiments. On the EEC puzzle, we find that the solvent reorganization is the major source during the binding process, arising from the temperature-dependent hydrophobic interactions. For association in a lower critical solution temperature (LCST) system, the solvent reorganization entropy dominates the favorable free energy change, at the expense of energy. For association in an upper critical solution temperature (UCST) system, the free energy change is dominated by the energy due to solvent reorganization, at the expense of entropy.

Our results highlight the central role of water reorganization in the driving force of LLPS, whose contributions need to be accounted for to properly interpret LLPS thermodynamics. In addition, our work hints at the possibility of harnessing water reorganization entropy/enthalpy for improved binding affinity and thermal stability in molecular design.