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 locati ons 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 di fferent systems for which structural and experimental thermodynamic da ta 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 & Degrade (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 al amino acids in the unfolded sta te. It is shown that a single set of structure/thermodynamic parameter s accounts well for all the experimental data sets of helix propensiti es. For T4 lysozyme, the average value of the absolute difference betw een predicted and experimental Delta G values is 0.09 kcal/mol, for ba rnase 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 pr edicts well the overall stability of the proteins and rationalizes the differences in ct-helix propensities between amino acids. The excelle nt agreement observed between predicted and experimental Delta G value s for all amino acids validates the use of this structural parameteriz ation in free energy calculations for folding or binding.