A γ‑Amino Acid That Favors 12/10-Helical Secondary Structure in α/γ‑Peptides

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 (1<i>R</i>,2<i>R</i>,3<i>S</i>)-2-(1-<i>a</i>mino<i>p</i>ropyl)-<i>c</i>yclo<i>h</i>exanecarboxylic 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

Evaluation of a Cyclopentane-Based γ‑Amino Acid for the Ability to Promote α/γ-Peptide Secondary Structure

We report the asymmetric synthesis of the γ-amino acid (1<i>R</i>,2<i>R</i>)-2-aminomethyl-1-cyclopentane carboxylic acid (AMCP) and an evaluation of this residue’s potential to promote secondary structure in α/γ-peptides. Simulated annealing calculations using NMR-derived distance restraints obtained for α/γ-peptides in chloroform reveal that AMCP-containing oligomers are conformationally flexible. However, additional evidence suggests that an internally hydrogen-bonded helical conformation is partially populated in solution. From these data, we propose characteristic NOE patterns for the formation of the α/γ-peptide 12/10-helix and discuss the apparent conformational frustration of AMCP-containing oligomers

Evaluation of a Cyclopentane-Based γ‑Amino Acid for the Ability to Promote α/γ-Peptide Secondary Structure

We report the asymmetric synthesis of the γ-amino acid (1<i>R</i>,2<i>R</i>)-2-aminomethyl-1-cyclopentane carboxylic acid (AMCP) and an evaluation of this residue’s potential to promote secondary structure in α/γ-peptides. Simulated annealing calculations using NMR-derived distance restraints obtained for α/γ-peptides in chloroform reveal that AMCP-containing oligomers are conformationally flexible. However, additional evidence suggests that an internally hydrogen-bonded helical conformation is partially populated in solution. From these data, we propose characteristic NOE patterns for the formation of the α/γ-peptide 12/10-helix and discuss the apparent conformational frustration of AMCP-containing oligomers