A structural parameterization of the folding energetics has been used to predict the effect of single amino acid mutations at exposed locations in α- helices. The results have been used to derive a structure-based thermodynamic scale of α-helix propensities for amino acids. The structure-based thermodynamic analysis was performed for four different systems for which structural and experimental thermodynamic data are available: T4 lysozyme [Blaber et al. (1994) J. Mol. Biol. 235, 600-6241, barnase [Horovitz et al. (1992) J. Mol. Biol. 227, 560-568], a synthetic leucine zipper [O'Neil and Degrado (1990) Science 250, 646-651], and a synthetic peptide [Lyu et al. (1990) Science 250, 669-673]. These studies have permitted the optimization of the set of solvent-accessible surface areas (ASA) for all amino acids in the unfolded state. It is shown that a single set of structure/thermodynamic parameters accounts well for all the experimental data sets of helix propensities. For T4 lysozyme, the average value of the absolute difference between predicted and experimental ΔG values is 0.09 kcal/mol, for barnase 0.14 kcal/mol, for the synthetic coiled-coil 0.11 kcal/mol, and for the synthetic peptide 0.08 kcal/mol. In addition, this approach predicts well the overall stability of the proteins and rationalizes the differences in α- helix propensities between amino acids. The excellent agreement observed between predicted and experimental ΔC values for all amino acids validates the use of this structural parameterization in free energy calculations for folding or binding.
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