A thermodynamic approach to the conformational preferences of the 180-195 segment derived from the human prion protein α2-helix

On consideration that intrinsic structural weakness could affect the segment spanning the α2-helical residues 173-195 of the PrP, we have investigated the conformational stabilities of some synthetic Ala-scanned analogs of the peptide derived from the 180-195 C-terminal sequence, using a novel approach whose theoretical basis originates from protein thermodynamics. Even though a quantitative comparison among peptides could not be assessed to rank them according to the effect caused by single amino acid substitution, as a general trend, all peptides invariably showed an appreciable preference for an α-type organization, consistently with the fact that the wild-type sequence is organized as an α-helix in the native protein. Moreover, the substitution of whatever single amino acid in the wild-type sequence reduced the gap between the α- and the β-propensity, invariably enhancing the latter, but in any case this gap was larger than that evaluated for the full-length α2-helix-derived peptide. It appears that the low β-conformation propensity of the 180-195 region depends on the simultaneous presence of all of the Ala-scanned residues, indirectly confirming that the N-terminal 173-179 segment could play a major role in determining the chameleon conformational behavior of the entire 173-195 region in the PrP. Copyright © 2008 European Peptide Society and John Wiley & Sons, Ltd.