Ambidextrous α,γ-Hybrid Peptide Foldamers

Molecular chirality is ubiquitous in nature. The natural biopolymers, proteins and DNA, preferred a right-handed helical bias due to the inherent stereochemistry of the monomer building blocks. Here, we are reporting a rare co-existence of left- and right-handed helical conformations and helix-terminating property at the C-terminus within a single molecule of alpha,gamma-hybrid peptide foldamers composed of achiral Aib (alpha-aminoisobutyric acid) and 3,3-dimethyl-substituted gamma-amino acid (Adb; 4-amino-3,3-dimethylbutanoic acid). At the molecular level, the left- and right-handed helical screw sense of alpha,gamma-hybrid peptides are representing a macroscopic tendril perversion. The pronounced helix-terminating behaviour of C-terminal Adb residues was further explored to design helix-Schellman loop mimetics and to study their conformations in solution and single crystals. The stereochemical constraints of dialkyl substitutions on gamma-amino acids showed a marked impact on the folding behaviour of alpha,gamma-hybrid peptides.