Crystallographic Characterization of Helical Secondary Structures in 2:1 and 1:2 α/β-Peptides

Oligomers containing both α- and β-amino acid residues (“α/β-peptides”) are intriguing as potential foldamers. A large set of α/β-peptide backbones can be generated by combining α- and β-amino acid residues in different patterns; however, most research to date has focused on the simplest pattern, 1:1 α:β. We have begun to explore the range of variation that can be achieved with α-residue/β-residue combinations by examining the folding behavior of oligomers that contain 2:1 and 1:2 α:β patterns. The β-residues in our systems have a five-membered-ring constraint (trans-2-aminocyclopentanecarboxylic acid (ACPC) residues), because these preorganized subunits strongly promote helical folding for 1:1 α:β backbones and pure β backbones. Previously we concluded that two helical conformations are available to 2:1 and 1:2 α/β-peptides containing ACPC or analogously constrained β-residues, one helix defined by i,i+3 CO···H−N backbone hydrogen bonds and the other defined by i,i+4 CO···H−N hydrogen bonds. These deductions were based on 2D NMR analysis of a 2:1 heptamer and a 1:2 hexamer in methanol. Crystallographic analysis of a pair of analogous nonpolar α/β-peptides showed only the i,i+3 hydrogen-bonded helical conformations. We now report four new crystal structures of 2:1 α/β-peptides, ranging in length from 5 to 11 residues, and six new crystal structures of 1:2 α/β-peptides, ranging in length from 6 to 10 residues. All 10 of these new structures are fully helical, and all helices display the i,i+3 CO···H−N hydrogen bonding pattern. These crystallographic data sets, collectively, provide high structural definition for the i,i+3 hydrogen-bonded helical secondary structures available to these foldamer backbones.