Oligomers that contain both alpha- and beta-amino acid residues in a 1:1 alternating pattern have recently been shown by several groups to adopt helical secondary structures in solution. The beta-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 beta-residues with a five-membered ring constraint promote two different types of alpha/beta-peptide helix. The "11-helix" contains i, i+3 CO...H-N hydrogen bonds between backbone amide groups; these hydrogen bonds occur in 11-atom rings. The alpha/beta-peptide "14/15-helix" contains i, i+4 CO...H-N hydrogen bonds, which occur in alternating 14- and 15-atom rings. Here we provide crystallographic data for 14 alpha/beta-peptides that form the 11-helix and/or the 14/15-helix. These results were obtained for a series of oligomers containing beta-residues derived from ( S,S)- trans-2-aminocyclopentanecarboxylic acid (ACPC) and alpha-residues derived from alpha-aminoisobutyric acid (Aib) or l-alanine (Ala). The crystallized alpha/beta-peptides range in length from 4 to 10 residues. Nine of the alpha/beta-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 CO...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 alpha/beta-peptides prefer the 14/15-helix over the 11-helix, a conclusion that is consistent with previously reported NMR data obtained in solution.
We report crystallographic data for a set of homologous γ-peptides that contain a Boc-protected residue derived from the flexible gabapentin monomer at the N-terminus and cyclically constrained γ-residues at all other positions. The crystallized γ-peptides range in length from 3 to 7 residues. Previously only one atomic-resolution structure had been available for a short γ-peptide 14-helix. The new data provided here allow derivation of characteristic parameters for the γ-peptide 14-helix, and establish guidelines for characterizing 14-helical folding in solution via 2D NMR. In addition, the results suggest that the substitution pattern of a γ-residue has a profound effect on the propensity for 14-helical folding.
Oligomers containing both alpha- and beta-amino acid residues ("alpha/beta-peptides") are intriguing as potential foldamers. A large set of alpha/beta-peptide backbones can be generated by combining alpha- and beta-amino acid residues in different patterns; however, most research to date has focused on the simplest pattern, 1:1 alpha:beta. We have begun to explore the range of variation that can be achieved with alpha-residue/beta-residue combinations by examining the folding behavior of oligomers that contain 2:1 and 1:2 alpha:beta patterns. The beta-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 alpha:beta backbones and pure beta backbones. Previously we concluded that two helical conformations are available to 2:1 and 1:2 alpha/beta-peptides containing ACPC or analogously constrained beta-residues, one helix defined by i,i+3 CO...H-N backbone hydrogen bonds and the other defined by i,i+4 CO...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 alpha/beta-peptides showed only the i,i+3 hydrogen-bonded helical conformations. We now report four new crystal structures of 2:1 alpha/beta-peptides, ranging in length from 5 to 11 residues, and six new crystal structures of 1:2 alpha/beta-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 CO...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.
H-bonded helices in conventional peptides (containing exclusively homochiral α-amino acid residues) feature a uniform H-bonding directionality, N-terminal side C═O to C-terminal side NH. In contrast, heterochiral α-peptides can form helices in which the H-bond directionality alternates along the backbone because neighboring amide groups are oriented in opposite directions. Alternating H-bond directions are seen also in helices formed by unnatural peptidic backbones, e.g., those containing β- or γ-amino acid residues. In the present study, we used NMR spectroscopy and crystallography to evaluate the conformational preferences of the novel γ-amino acid (1R,2R,3S)-2-(1-aminopropyl)-cyclohexanecarboxylic acid (APCH), which is constrained by a six-membered ring across its Cα-Cβ bond. These studies were made possible by the development of a stereoselective synthesis of N-protected APCH. APCH strongly enforces the α/γ-peptide 12/10-helical secondary structure, which features alternating H-bond directionality. Thus, APCH residues appear to have a conformational propensity distinct from those of other cyclically constrained γ-amino acid residues.
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