β-hairpins generated from hybrid peptide sequences containing both α- and β-amino acids

Abstract

The incorporation of the β-amino acid residues into specific positions in the strands and β-turn segments of peptide hairpins is being systematically explored. The presence of an additional torsion variable about the C(α)-C(β) bond (θ) enhances the conformational repertoire in -residues. The conformational analysis of three designed peptide hairpins composed of α/β-hybrid segments is described: Boc-Leu-Val-Val-^DPro-βPhe-Leu-Val-Val-OMe (1), Boc-Leu-Val-βVal-^DPro-Gly-βLeu-Val-Val-OMe (2), and Boc-Leu-Val-βPhe-Val-^DPro-Gly-Leu-βPhe-Val-Val-OMe (3). 500-MHz ¹H-NMR Analysis supports a preponderance of β-hairpin conformation in solution for all three peptides, with critical cross-strand NOEs providing evidence for the proposed structures. The crystal structure of peptide 2 reveals a β-hairpin conformation with two β-residues occupying facing, non-H-bonded positions in antiparallel β-strands. Notably, βVal(3) adopts a gauche conformation about the C(α)-C(β) bond (θ=+65°) without disturbing cross-strand H-bonding. The crystal structure of 2, together with previously published crystal structures of peptides 3 and Boc-βPhe-βPhe-^DPro-Gly-βPhe-βPhe-OMe, provide an opportunity to visualize the packing of peptide sheets with local 'polar segments' formed as a consequence of reversal peptide-bond orientation. The available structural evidence for hairpins suggests that β-residues can be accommodated into nucleating turn segments and into both the H-bonding and non-H-bonding positions on the strands.