First Crystal Structures of alpha,delta-Peptidic Foldamers and Solution State NMR Show an Unusual 13/11 Helix: Rational Design and Application as a Minimalist Aldolase Mimic

Abstract

We report the first structures of an unusual 13/11-helix (alternating i,i+1 {NH--O=C} and i,i+3 {C=O--H—N} H-bonds) formed by a heteromeric 1:1 se-quence of alpha- and delta-amino acids, using both XRD and NMR. Whilst intramolecular hydrogen bonds (IMHBs) are the clear driver of helix formation, we also observe an apolar interaction between the ethyl residue of one delta-amino acid and the cyclohexyl group of the next delta-residue in the sequence that seems to stabilize one type of helix over another. Using this structural information, we have inserted two ornithine residues within the helix to install bis-amine functionality. The resulting foldamer acts as a minimalistic aldolase mimic.