Factors governing 3 10 ‐helix vs α‐helix formation in peptides: Percentage of C α ‐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 α‐helix in peptides, in this paper we describe the results of a three‐dimensional (3D) structural analysis by x‐ray diffraction of the N α ‐acylated heptapeptide alkylamide mBrBz– L ‐Iva– L ‐(αMe)Val– L ‐Abu– L ‐(αMe)Val– L ‐(αMe)Phe– L ‐(αMe)Val– L ‐Iva–NHMe characterized by a single ( L ‐Abu3) C α ‐trisubstituted and six C α ‐tetrasubstituted α‐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 α‐helix. This finding, taken together with the published NMR and x‐ray diffraction data on the all C α ‐methylated parent sequence and its L ‐Val2 analog (also the latter heptapeptide has a single C α ‐trisubstituted α‐amino acid) strongly supports the view that one C α ‐trisubstituted α‐amino acid inserted near the N‐terminus of an N α ‐acylated heptapeptide alkylamide sequence may be enough to switch a regular 3 10 ‐helix into an essentially α‐helical conformation. As a corollary of this work, the x‐ray diffraction structure of the N α ‐protected, C‐terminal tetrapeptide alkylamide Z– L ‐(αMe)Val– L ‐(αMe)Phe– L ‐(αMe)Val– L ‐Iva–NHMe, also reported here, is clearly indicative of the preference of this fully C α ‐methylated, short peptide for the 3 10 ‐helix. As the same terminally blocked sequence is mixed 3 10 /α‐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 α ‐methylated short peptide. © 2002 Wiley Periodicals, Inc. Biopolymers 64: 236–245, 2002