Fig. 3: Protein conformational changes come from indirect solute effects manifested as water network entropy.

Reaction enthalpy of interactions between proteins (a, DHFR, b, fibronectin) and denaturants (LiBr, urea, and GdnHCl) as measured by isothermal titration calorimetry. Data are presented as mean ± s.d. (n = 3 independently prepared protein and denaturant solutions). c Distributions of molecular entropy of water molecules in 7 M LiBr, LiCl, and NaBr from MD simulations. d Total water entropy penalty decrease in different concentrations of LiBr, LiCl, and NaBr solutions. Data are obtained from MD simulations and calculated via the analytical model (Eq. 1). Data are presented as mean ± s.d. (n = 3 independent simulation runs), however, the error bars are smaller than the data point size. e Schematics of different ion effects on water structures. For LiBr and LiCl, high charge density of Li⁺ ion results in localized (trapped) water molecules and disrupted water network (i), while NaBr induces a more global effect without breaking water network (ii). f Contribution of water network entropy penalty decrease to the total water entropy penalty decrease. g Strong correlation between the theoretical value of water network entropy penalty decrease and the protein denaturation ratio observed from FTIR experiments in LiBr and LiCl solutions. The Pearson correlation coefficient is shown with a two-tailed P value of \(3.44\times {10}^{-11}\). Dashed line represents the best fit. h Free energy landscape of an α-helix peptide (20 amino acids) in pure water and 1, 4, 7 M LiBr from MD simulations. Source data are provided as a Source Data file.