Factors governing 310-helix vs α-helix formation in peptides:: Percentage of Cα-tetrasubstituted α-amino acid residues and sequence dependence

As an additional step toward the dissection of the factors responsible for the onset of 3(10)-helix vs alpha-helix in peptides, in this paper we describe the results of a three-dimensional (3D) structural analysis by x-ray diffraction of the N-alpha-acylated heptapeptide alkylamide mBrBz-L-Iva-L-(alphaMe)Val-L-Abu-L-(alphaMe)Val-L-(alphaMe)Phe-L-(alphaMe)Val-L-Iva-NHMe characterized by a single (L-Abu3) C-alpha-trisubstituted and six C-alpha-tetrasubstituted alpha-amino acids. We find that in the crystal state this peptide is folded in a mixed helical structure with short elements of 3(10)-helix at either terminus and a central region of alpha-helix. This finding, taken together with the published NMR and X-ray diffraction data on the all C-alpha-methylated parent sequence and its L-Val2 analog (also the latter heptapeptide has a single C-alpha-trisubstituted alpha-amino acid) strongly, supports the view that one C-alpha-trisubstituted alpha-amino acid inserted near the N-terminus of an N-alpha-acylated heptapeptide alkylamide sequence may be enough to switch a regular 3(10)-helix into an essentially alpha-helical conformation. As a corollary, of this work, the x-ray diffraction structure of the N-alpha-protected, C-terminal tetrapeptide alkylamide Z-L-(alphaMe)Val-L-(alphaMe)Phe-L-(alphaMe)Val-L-Iva-NHMe, also reported here, is clearly indicative of the preference of this fully C-alpha-methylated, short peptide for the 3(10)-helix. As the same terminally blocked sequence is mixed 3(10)/alpha-helical in the L-Abu3 heptapeptide amide but regular 3(10)-helical in the tetrapeptide amide and in the parent heptapeptide amide, these results point to an evident plasticity even of a fully C-alpha-methylated short peptide. (C) 2002 Wiley Periodicals. Inc.