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-NMe 2 folds largely into the β-hairpin conformation, while the diastereomer Ac- l -Val- l -Pro- l -Ala- l -Leu-NMe 2 displays little or no β-hairpin folding. For each diastereomer, the hydrogen-bonded driving force for β-hairpin folding is identical, and the dramatic difference in folding behavior therefore reflects a variation in the intrinsic conformational properties of the diastereomeric backbones. Similar behavior is seen for the diastereomeric peptide pair Ac- l -Val- d -Pro-Gly- l -Leu-NMe 2 vs Ac- l -Val- l -Pro-Gly- l -Leu-NMe 2, and for the analogous depsipeptides with a lactic acid or glycolic acid residue at the third position. Thus, our results show not only that mirror-image Pro-X turns strongly promote β-hairpin folding, but also that common β-turns strongly discourage formation of a β-hairpin with a two-residue loop.