Ionic liquids (ILs) are utilized as enzymatic reaction solvents and as protein structure protectants or denaturants in biotechnological applications. They can develop a wide spectrum of interactions with macromolecules due to their chemical complexity. Understanding how ILs interact with protein conformations is crucial to fine-tuning their action. Here, we investigate the solvation of different ubiquitin folding states in aqueous solutions of four ionic liquids formed by the combination of the cations 1-Ethyl-3-methylimidazolium (EMIM), and 1-Butyl-3-methylimidazolium (BMIM), and the anions Tetrafluoroborate (BF4), and Dicyanamide (DCA). The structure and thermodynamics of the interactions between the protein in various denaturation states and the ILs were evaluated using minimum-distance distribution functions (MDDFs) and the Kirkwood-Buff (KB) theory of solutions. Under most circumstances, the ILs preferentially solvate the protein structures, and are thus considered denaturants. However, even when preferential hydration is obtained for the native structure, denaturation is favored because of strong IL preferential binding to the denatured states. As the protein undergoes denaturation, its surface area increases, and residues with decreased polarity are exposed. The ILs interact favorably with these residues, excluding water, cooperatively stabilizing the exposure of the protein core. Strong specific DCA-protein interactions, which jointly draw cations to the protein surface due to electrostatic correlations, render ILs containing the anion DCA stronger denaturants than those containing BF4.
V. Piccoli, L. Martínez, J. Mol. Liq. 2022: 10.1016/j.molliq.2022.119953