Osmolyte-Induced Effects on the Hydration Behavior and the Osmotic Second Virial Coefficients of Alkyl-Substituted Urea Derivatives: Critical Assessment of Their Structure-Making/Breaking Behavior

We analyzed the hydration behavior of alkyl-substituted urea osmolytes in terms of their deviation from Lewis–Randall solution ideality and characterized their structure-making/breaking tendency according to a proposed solvation formalism that provides a rigorous cause–effect connection between the system microstructure and its solution thermodynamic nonidealities. After a brief introduction of the rationale behind the use of Lewis–Randall over alternative solution ideality references, we (i) assessed the effect of the nature and type of alkyl substitution on the osmolyte-induced perturbation of the solution microstructure as a function of composition, (ii) analyzed their microstructural responses to changes in temperature and pressure, and (iii) demonstrated the structure-breaking nature of urea and the magnifying behavior of its alkyl-substituted osmolytes, whose trend follows the increasingly positive deviation of the osmolyte solutions from Lewis–Randall ideality. Then, we discussed the falsifiability of a pair of frequently used conjectured structure-making/breaking criteria, supported by the derived exact relationships between the structure-making/breaking parameter, the solution thermodynamic nonideality, and the osmotic second virial coefficient of the aqueous osmolytes. Finally, we provided an outlook on how the proposed approach could guide the quest for a truly (microstructural to free energy) causative explanation for the denaturation mechanism of proteins.