Tuning biological processes co-solutes: from single proteins to protein condensates - the case of α-elastin condensation.

Protein condensates as membrane-less compartments play a pivotal role in cellular processes. The stabilization of protein condensation can be tuned using cosolutes which directly impact biological function. In this study, we report the result of a rigorous study of the influence of cosolutes changes on hydration entropy and enthalpy upon condensate formation, by means of THz-calorimetry. Our results unveil quantitative insights into the fine tuning of the free energy imbalance, hydrophobic/entropic and hydrophilic/enthalpic hydration which can result in cosolute-mediated stabilization or destabilization of protein condensates. These results shed new light on the regulatory potential of co-solutes within cells, to tune Liquid-Liquid Phase Separation (LLPS). Furthermore, we demonstrate the transferability of the underlying molecular concepts of cosolute addition to two fundamental biological processes: protein folding and denaturation. This study provides a blueprint for controlled modulating LLPS cosolute additions, with promising implications in both biological and medical applications.