Design of Chiral β‐Double Helices from γ‐Peptide Foldamers

Abstract

Chirality is ubiquitous in nature, and homochirality is manifested in many biomolecules. Although β‐double helices are rare in peptides and proteins, they consist of alternating L‐ and D‐amino acids. No peptide double helices with homochiral amino acids have been observed. Here, we report chiral β‐double helices constructed from γ‐peptides consisting of alternating achiral (E)‐α,β‐unsaturated 4,4‐dimethyl γ‐amino acids and chiral (E)‐α,β‐unsaturated γ‐amino acids in both single crystals and in solution. The two independent strands of the same peptide intertwine to form a β‐double helix structure, and it is stabilized by inter‐strand hydrogen bonds. The peptides with chiral (E)‐α,β‐unsaturated γ‐amino acids derived from α‐L‐amino acids adopt a (P)‐β‐double helix, whereas peptides consisting of (E)‐α,β‐unsaturated γ‐amino acids derived from α‐D‐amino acids adopt an (M)‐β‐double helix conformation. The circular dichroism (CD) signature of the (P) and (M)‐β‐double helices and the stability of these peptides at higher temperatures were examined. Furthermore, ion transport studies suggested that these peptides transport ions across membranes. Even though the structural analogy suggests that these new β‐double helices are structurally different from those of the α‐peptide β‐double helices, they retain ion transport activity. The results reported here may open new avenues in the design of functional foldamers.