Modulating the Structural Properties of α,γ‐Hybrid Peptides by α‐Amino Acid Residues: Uniform 12‐Helix Versus “Mixed” 12/10‐Helix

Abstract

The most important natural α‐ and 310‐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 γ4,4‐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 Ac6c [P6: Boc‐Ac6c‐Aic‐Ac6c‐Aic‐Ac6c‐Aic‐Ac6c‐Aic‐Ac6c‐CONHMe; Ac6c = 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.