Stereochemical Requirements for β-Hairpin Formation: Model Studies with Four-Residue Peptides and Depsipeptides

Abstract

Spectroscopic and crystallographic data are presented for a series of tetrapeptides and analogous depsipeptides that can form a minimal β-hairpin (two intramolecular hydrogen bonds). These model compounds have been used to test the hypothesis that “mirror image” β-turns promote β-hairpin formation. This hypothesis was inspired by a statistical survey of β-hairpins in globular proteins (Sibanda, B. L.; Thornton, J. M. Nature 1985, 316, 170), which showed that mirror image β-turns (type I‘ and type II‘), although rare in general, are very commonly associated with β-hairpins containing a two-residue loop between the strand segments. Each of our four-residue molecules contains proline at the second position, to promote a central β-turn. The β-turn is induced to be either “common” or “mirror-image”, relative to the outer residues, by choice of residue configuration (l vs d). In methylene chloride, end-capped tetrapeptide Ac−l-Val-d-Pro-d-Ala-l-Leu-NMe2 folds largely into the β-hairpin conformation, while the d...