Crystallographic Characterization of Helical Secondary Structures in α/β-Peptides with 1:1 Residue Alternation

Oligomers that contain both α- and β-amino acid residues in a 1:1 alternating pattern have recently been shown by several groups to adopt helical secondary structures in solution. The β-residue substitution pattern has a profound effect on the type of helix formed and the stability of the helical conformation. On the basis of two-dimensional NMR data, we have previously proposed that β-residues with a five-membered ring constraint promote two different types of α/β-peptide helix. The “11-helix” contains i,i+3 CO···H−N hydrogen bonds between backbone amide groups; these hydrogen bonds occur in 11-atom rings. The α/β-peptide “14/15-helix” contains i,i+4 CO···H−N hydrogen bonds, which occur in alternating 14- and 15-atom rings. Here we provide crystallographic data for 14 α/β-peptides that form the 11-helix and/or the 14/15-helix. These results were obtained for a series of oligomers containing β-residues derived from (S,S)-trans-2-aminocyclopentanecarboxylic acid (ACPC) and α-residues derived from α-aminoisobutyric acid (Aib) or l-alanine (Ala). The crystallized α/β-peptides range in length from 4 to 10 residues. Nine of the α/β-peptides display the 11-helix in the solid state, three display the 14/15-helix, and two display conformations that contain both i,i+3 and i,i+4 CO···H−N hydrogen bonds, but not bifurcated hydrogen bonds. Only 3 of the 14 crystal structures presented here have been previously described. These results suggest that longer α/β-peptides prefer the 14/15-helix over the 11-helix, a conclusion that is consistent with previously reported NMR data obtained in solution.