A previously derived structural parametrization of the folding energetics has been used to predict the effect of single amino acid mutations at exposed locations in a-helices. 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 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 ~ 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. The excellent agreement observed between predicted and experimental ~ G values for all amino acids validates the use of this structural parametrization in free energy calculations for folding or binding.
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