Hybrid peptide hairpins containing α- and ω-amino acids: conformational analysis of decapeptides with unsubstituted β, γ-, and δ-residues at positions 3 and 8

Abstract

The effects of inserting unsubstituted -amino acids into the strand segments of model β-hairpin peptides was investigated by using four synthetic decapeptides, Boc-Leu-Val-Xxx-Val-D-Pro-Gly-Leu-Xxx-Val-Val-OMe: peptide 1 (Xxx=Gly), peptide 2 (Xxx = βGly = βhGly = homoglycine, β-glycine), peptide 3 (Xxx = γAbu = γ-aminobutyric acid), peptide 4 (Xxx = γAva = γ-aminovaleric acid). ¹H NMR studies (500 MHz, methanol) reveal several critical cross-strand NOEs, providing evidence for β-hairpin conformations in peptides 2-4. In peptide 3, the NMR results support the formation of the nucleating turn, however, evidence for cross-strand registry is not detected. Single-crystal X-ray diffraction studies of peptide 3 reveal a β-hairpin conformation for both molecules in the crystallographic asymmetric unit, stabilized by four cross-strand hydrogen bonds, with the γ Abu residues accommodated within the strands. The D-Pro-Gly segment in both molecules (A,B) adopts a type II′ β-turn conformation. The circular dichroism spectrum for peptide 3 is characterized by a negative CD band at 229 nm, whereas for peptides 2 and 4, the negative band is centered at 225 nm, suggesting a correlation between the orientation of the amide units in the strand segments and the observed CD pattern.