Crystallographic Characterization of 12-Helical Secondary Structure in β-Peptides Containing Side Chain Groups

Helices are the most extensively studied secondary structures formed by beta-peptide foldamers. Among the five known beta-peptide helices, the 12-helix is particularly interesting because the internal hydrogen bond orientation and macrodipole are analogous to those of alpha-peptide helices (alpha-helix and 3(10)-helix). The beta-peptide 12-helix is defined by i, i+3 C=O center dot center dot center dot H-N backbone hydrogen bonds and promoted by beta-residues with a five-membered ring constraint. The 12-helical scaffold has been used to generate beta-peptides with specific biological functions, for which diverse side chains must be properly placed along the backbone and, upon folding, properly arranged in space. Only two crystal structures of 12-helical beta-peptides have previously been reported, both for homooligomers of trans-2-aminocyclopentanecarboxylic acid (ACPC). Here we report five additional crystal structures of 12-helical beta-peptides, all containing residues that bear side chains. Four of the crystallized beta-peptides include trans-4,4-dimethyl-2-aminocyclopentanecarboxylic acid (dm-ACPC) residues, and the fifth contains a beta(3)-hPhe residue. These five beta-peptides adopt fully folded 12-helical conformations in the solid state. The new crystal structures, along with previously reported data, allow a detailed characterization of the 12-helical conformation; average backbone torsion angles of beta-residues and helical parameters are derived. These structural parameters are found to be similar to those for i, i+3 C=O center dot center dot center dot H-N hydrogen-bonded helices formed by other peptide backbones generated from alpha- and/or beta-amino acids. The similarity between the conformational behavior of dm-ACPC and ACPC is consistent with previous NMR-based conclusions that 4,4-disubstituted ACPC derivatives are compatible with 12-helical folding. In addition, our data show how a beta(3)-residue is accommodated in the 12-helix, thus enhancing understanding of the diverse conformational behavior of this flexible class of beta-amino acids.