Solvent-responsive solid/liquid phase transitions of condensates depend on trade-off molecular interactions

Nature effectively leverages multivalent interactions among fundamental building blocks in solvents to build structures of remarkable complexity and functionality. For example, biomolecular condensates, formed through phase separation of biomolecules driven by multivalent interactions, play crucial roles in forming adhesives for marine animals and orchestrating enzymatic reactions within cells. However, understanding how molecular interactions dictate macroscopic properties of condensates remains a substantial challenge. Here, combining multiscale experiments and molecular dynamics simulations, we demonstrate that different molecular interactions exhibit divergent solvent-responsiveness, the balance of which dictates the material properties and phase transitions of condensates. In particular, condensates with mainly charged sidechains exhibit hydrophilic environments and are solidified upon alcohol addition due to strengthened electrostatic interactions. In contrast, condensates rich in aromatic residues show relatively hydrophobic environments and are dissolved in the presence of alcohol due to weakened cation-π and π-π interactions. These findings are generalized into a predictive framework correlating condensate phase transitions to the hydrophobic scale of constituent monomers, applicable to both synthetic polyelectrolytes and intrinsically disordered proteins. As a proof of concept, we leverage these insights to engineer adhesives that are recyclable or maintain stability under varying cosolvent conditions. Our findings not only resolve a conundrum in the field but also bridge molecular-level interactions with macroscopic properties and phase transitions of condensates, offering promising insights for industrial and biomedical applications.