Modulating the Structural Properties of α,γ-Hybrid Peptides by α-Amino Acid Residues: Uniform 12-Helix Versus "Mixed" 12/10-Helix.

The most important natural α- and 3 -helices are stabilized by unidirectional intramolecular hydrogen bonds along the helical cylinder. In contrast, we report here on 12/10-helical conformations with alternately changing hydrogen-bond directionality in sequences of α,γ-hybrid peptides P1-P5 [P1: Boc-Ala-Aic-Ala-Aic-COOH; P2: Boc-Leu-Aic-Leu-Aic-OEt; P3: Boc-Leu-Aic-Leu-Aic-Leu-Aic-Aib-OMe; P4: Boc-Ala-Aic-Ala-Aic-Ala-Aic-Ala-OMe; P5: Boc-Leu-Aic-Leu-Aic-Leu-Aic-Leu-Aic-Aib-OMe; Aic=4-aminoisocaproic acid, Aib=2-aminoisobutyric acid] composed of natural α-amino acids and the achiral γ -dimethyl substituted γ-amino acid Aic in solution and in single crystals. The helical conformations are stabilized by alternating i→i+3 and i→i-1 intramolecular hydrogen bonds. The experimental data are supported by ab initio MO calculations. Surprisingly, replacing the natural α-amino acids of the sequence by the achiral dialkyl amino acid Ac c [P6: Boc-Ac c-Aic-Ac c-Aic-Ac c-Aic-Ac c-Aic-Ac c-CONHMe; Ac c = 1-aminocyclohexane-1-carboxylic acid] led to a 12-helix with unidirectional hydrogen bonds showing an entirely different backbone conformation. The results presented here emphasize the influence of the structure of the α-amino acid residues in dictating the helix types in α,γ-hybrid peptide foldamers and demonstrate the consequences for folding of small structural variations in the monomers.