The temperature dependence of the Hofmeister series: thermodynamic fingerprints of cosolute–protein interactions

Abstract

The Hofmeister series is a universal homologous series to rank ion-specific effects on biomolecular properties such as protein stability or aggregation propensity. Although this ranking is widely used, outliers and exceptions are discussed controversially and a molecular level understanding is still lacking. Studying the thermal unfolding equilibrium of RNase A, we here show that this ambiguity arises from the oversimplified approach to determine the ion rankings. Instead of measuring salt effects on a single point of the protein folding stability curve (e.g. the melting point T), we here consider the salt induced shifts of the entire protein 'stability curve' (the temperature dependence of the unfolding free energy change, ΔG(T)). We found multiple intersections of these curves, pinpointing a widely ignored fact: the Hofmeister cation and anion rankings are temperature dependent. We further developed a novel classification scheme of cosolute effects based on their thermodynamic fingerprints, reaching beyond salt effects to non-electrolytes.

Proteins in Ionic Liquids: Current Status of Experiments and Simulations

“…Despite all the issues concerning the “correct” ranking of the ions, the concept of a Hofmeister series is often used in the literature and has proven to be valuable to explain trends for the interaction with proteins [54, 55, 67, 68] in various fields of applications as sketched in Fig. 5 and discussed in the following sections.…”

“…In fact, native protein structure is only marginally stable as visible by the slightly positive Gibbs free energy of unfolding [68]describing the transition from the native to an unfolded state. The low value of is based on the mutual compensation of significant enthalphic () and entropic () contributions [68], which can be shifted by adding co-solvents like ionic liquids.…”

“…The low value of is based on the mutual compensation of significant enthalphic () and entropic () contributions [68], which can be shifted by adding co-solvents like ionic liquids. For example, choline dihydrogen phosphate stabilizes cytochrome c [110, 121] and lysozyme [122] for months.…”

“…Ebbinghaus and co-workers reported that the protein stability is also a function of the ion concentration [68]: At low ion concentration () almost all aqueous ionic liquid mixtures denature proteins. At higher ionic liquid concentration above ion-specific effect becomes dominant and the Hofmeister series more meaningful [68].…”

The properties of residual water molecules in ionic liquids: a comparison between direct and inverse Kirkwood–Buff approaches

“…As a result, the local number of water molecules around the electrodes increases at higher apparent voltages, such that the width of the electrochemical window becomes smaller when compared to neat ILs 19 . Whereas most of the above-mentioned investigations focused on low water concentrations, recent reviews and studies also discussed the opposite case in terms of low concentrated ionic liquids in aqueous solution 16,39,[42][43][44][45][46][47][48][49][50][51][52][53] . It was pointed out, that these socalled aqueous ILs have a broad applicability in several biotechnological processes and protein stabilization mechanisms 43,46,47 .…”