Chen, F.; Han, Y.; Li, X.; Guo, W.; Wu, C.; Xia, J.; Zeng, X.; Shum, H. C.

Nature effectively leverages multivalent interactions among fundamental building blocks in solvents to create remarkable materials for various purposes. One prominent example is the formation of biomolecular condensates through phase separation of proteins and nucleic acids. In particular, these condensates play crucial roles in regulating cellular functions and constructing natural materials. During the phase separation, solvents not only provide liquid environments for solvating molecules but play crucial roles in affecting the material properties of condensates. However, it remains controversial in the literature that alcohol molecules, as one type of solvents, can solidify some condensates while also melt others, leading to liquid-to-solid or solid-to-liquid phase transitions (LSPT or SLPT), respectively. The mechanism underlying the alcohol-induced solid/liquid phase transitions of condensates remains poorly understood. Here, we combine systematic experimental characterizations with molecular dynamics simulations to demonstrate that the phase transitions of condensates depend on their sidechain chemistry and dominant molecular interactions. Specifically, \"hydrophilic\" condensates, which consist of many charged sidechains, undergo LSPT by adding alcohols due to strengthened electrostatic interactions. In contrast, \"hydrophobic\" condensates comprised of abundant aromatic sidechains undergo SLPT with addition of alcohols because of weakened cation-pi and pi-pi interactions. Importantly, these findings are generally applicable for predicting phase transitions of a wide range of condensates formed by synthetic polyelectrolytes and intrinsically disordered proteins based on their sidechain hydrophobicity or amino acid compositions. Our work not only reconciles a conundrum in the literature but provides a fundamental framework for understanding the responsiveness of condensates to environmental stimuli. These insights are instrumental for developing therapeutic drugs to treat pathological aggregates and engineering stimuli-responsive biomaterials from the perspective of sidechain chemistry and molecular interactions.