Peptide Hairpins with Strand Segments Containing \alpha - and \beta - Amino Acid Residues: Cross- Strand Aromatic Interactions of Facing Phe Residues

Abstract

The incporation of \beta -amino acid residues into the strand segments of designed \beta -hairpin leads to the formation of polar sheets, since in the case of \beta -peptide strands, all adjacent carbonyl groups point in one direction and the amide groups orient in the opposite direction. The conformational analysis of two designed peptide hairpins composed of \alpha /\beta -hybrid segments are described: Boc-Leu-\beta Phe-Val-D-Leu-\beta -OMe (1) and Boc-\beta Leu-Phe-\beta Val-DPro-Gly-\beta Leu-Phe-\beta Val-OMe (2). A 500-MHz 1H-NMR (nuclear magnetic resonance) analysis in methanol supports a signi.cant population of hairpin conformations in both peptides. Diagnostic nuclear Overhauser effects (NOEs) are observed in both cases. X-ray diffraction studies on single crystals of peptide 1 reveal a \beta -hairpin conformation in both the molecules, which constitute the crystallographic asymmetric unit. Three cross-strand hydrogen bonds and a nucleating type II0 \beta -turn at the D-Pro-Gly segment are observed in the two independent molecules. In peptide 1, the \beta Phe residues at positions 2 and 7 occur at the nonhydrogen-bonding position, with the benzyl side chains pointing on opposite faces of the \beta -sheet. The observed aromatic centroid-to-centroid distances are 8.92A (molecule A) and 8.94A (molecule B). In peptide 2, the aromatic rings must occupy facing positions in antiparallel strands, in the NMR-derived structure