Effects of hydrogen-bond deletion on peptide helices: Structural characterization of depsipeptides containing lactic acid

The insertion of a-hydroxy acids into peptide chains provides a convenient means for investigating the effects of hydrogen bond deletion on polypeptid e secondary structures. The crystal structures of three oligopeptides conta ining L-lactic acid (Lac) residue have been determined. Peptide 1, Boc-Val- Ala-Leu-Aib-Val-Lac-Leu-Aib-Val-Ala-Leu-OMe (Boc: tert-butyloxycarbonyl; Ai b: alpha -aminoisobutyric acid; OMe: methyl ester), and peptide 2, Boc-Val- Ala-Leu-Aib-Val-Lac-Leu-Aib-Val-Leu-Ome, adopt completely helical conformat ions in the crystalline state with the Lac(6) residue comfortably accommoda ted in the center of a helix. The distance between the O atoms of Leu(3) CO group and the Lac(6) O (ester) in both the structures is 3.1-3.3 Angstrom. The NMR and CD studies of peptide I and its all-amide analogue 4, Boc-Val- Ala-Leu-Aib-Val-Ala-Leu-Aib-Val-Ala-Leu-OMe, provide firm evidence for a co ntinuous helical conformation in solution in both the cases. In a 14-residu e peptide 3, Boc-Val-Ala-Leu-Aib-Val-Ala-Leu-Val-Ala-Leu-Aib-Val-Lac-Leu-OM e, residues Val(1)-Leu-(10) adopt a helical conformation. Aib(11) is the si te of chiral reversal resulting in helix termination by formation of a Sche llman motif Residues 12-14 adopt nonhelical conformations. The loss of the hydrogen bond near the C-terminus appears to facilitate the chiral reversal at Aib(I 1). (C) 2001 John Wiley & Sons, Inc.(dagger).