Foldamers controlled by functional triamino acids: structural investigation of α/γ-hybrid oligopeptides.

Peptide-like foldamers controlled by normal amide backbone hydrogen bonding have been extensively studied, and their folding patterns largely rely on configurational and conformational constraints induced by the steric properties of backbone substituents at appropriate positions. In contrast, opportunities to influence peptide secondary structure by functional groups forming individual hydrogen bond networks have not received much attention. Here, peptide-like foldamers consisting of alternating α,β,γ-triamino acids 3-amino-4-(aminomethyl)-2-methylpyrrolidine-3-carboxylate (AAMP) and natural amino acids glycine and alanine are reported, which were obtained by solution phase peptide synthesis. They form ordered secondary structures, which are dominated by a three-dimensional bridged triazaspiranoid-like hydrogen bond network involving the non-backbone amino groups, the backbone amide hydrogen bonds, and the relative configuration of the α,β,γ-triamino and α-amino acid building blocks. This additional stabilization leads to folding in both nonpolar organic as well as in aqueous environments. The three-dimensional arrangement of the individual foldamers is supported by X-ray crystallography, NMR spectroscopy, chiroptical methods, and molecular dynamics simulations. Peptide-like foldamers are known to be controlled by amide backbone hydrogen bonding, however, the influence of functional groups forming individual hydrogen-bond networks remains underexplored. Here, the authors report peptide-like α-γ heterofoldamers consisting of alternating α,β,γ-triamino acids, forming ordered secondary structures and folding in both organic and aqueous environments. [ABSTRACT FROM AUTHOR]