POSITION DEPENDENCE OF NONPOLAR AMINO-ACID INTRINSIC HELICAL PROPENSITIES

Until now and based on the success of the helix/coil transition theory it has been assumed that the alpha-helical propensities of the amino acids are position independent. This has been critical to derive the s et of theoretical parameters for the 20 natural amino acids. Here, we have analysed the behavior of several non-polar residues, Val, Ile, Le u, Met and Gly at the N-cap, at each position of the first helical tur n and at a central helical position of a 16-residue peptide model syst em that starts with eight consecutive alanine residues. We have interp reted the results from these experiments with the model of the helix/c oil transition (AGADIR), that indicates that the intrinsic helical pro pensity is position dependent. Gly, Val and lie are more favorable at the first turn than in the middle of the alpha-helix, while for Leu an d Met we observe the opposite behavior. The differences between the ob served helical propensities are as large as 1.0 kcal/mol in some cases . Molecular modelling calculations using the ECEPP/2 force-field equip ped with a hydration potential show that this effect can be explained by the combination of three factors: (a) the sidechains in the first h elix turn are more solvent-exposed; (b) they have fewer intramolecular van der Waals' contacts; and (c) they posses higher configurational e ntropy than that in the central position of an alpha-helix. The positi on-dependent results of the calculations are in reasonable agreement w ith the experimental estimates and with the intrinsic propensities of the amino acids derived from the statistical analysis of the protein s tructure database. (C) 1998 Academic Press Limited.