Structure-based thermodynamic scale of alpha-helix propensities in amino acids.

A structural parameterization of the folding energetics has been used to predict the effect of single amino acid mutations at exposed locations in alpha-helices. The results have been used to derive a structure-based thermodynamic scale of alpha-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, 600-624], barnase [Horovitz et al. (1992) J.Mol.Biol.227,560-568], a synthetic leucine zipper [O'Neil & 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 delta G 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 alpha-helix propensities between amino acids. The excellent agreement observed between predicted and experimental delta G values for all amino acids validates the use of this structural parameterization in free energy calculations for folding or binding.