Stereochemical Control of Hairpin Formation in β-Peptides Containing Dinipecotic Acid Reverse Turn Segments

Abstract

We examine the relationship between covalent structure and conformational propensity among a series of β-amino acid tetramers. These experiments focus on the hairpin folding motif. Among conventional peptides, the minimum increment of β-sheet secondary structure is a “β-hairpin,” in which two strands are connected via a short loop. The present studies are aimed at optimizing hairpin stability among β-peptides. Previous work from our laboratory has identified optimal substitution patterns for residues that form strands in an antiparallel β-peptide sheet (Krauthäuser et al. J. Am. Chem. Soc. 1997, 119, 11719), and we have shown that a dinipecotic acid segment can promote sheet-type interactions between attached strand residues (Chung et al. J. Am. Chem. Soc. 1998, 120, 10555). Here we compare all four possible configurations of the dinipecotic acid segment, (R,S), (S,R), (R,R) and (S,S), for the ability to induce sheet formation with a constant set of enantiomerically pure strand residues. We show that both heterochiral dinipecotic acid segments promote hairpin formation, although one is distinctly superior. Neither of the homochiral dinipecotic acid supports hairpin folding. When the strand residues are β-alanine (achiral), the heterochiral dinipecotic acid segment is again superior to the homochiral segment, but we find a difference between hairpin conformations in solution and in the solid state.