A Pure Polyproline Type I‐like Peptoid Helix by Metal Coordination

Peptoids, N‐substituted glycine oligomers, are an important class of foldamers that can adopt polyproline‐type helices (PP‐I and PP‐II), given that the majority of their sequence consists of chiral, bulky side chains. Herein a new approach for the stabilization of a pure PP‐I‐like peptoid helix through metal coordination is introduced. A systematic spectroscopic study was performed on a series of peptoid heptamers bearing two 8‐hydroxyquinoline ligands at fixed positions, and a mixture of chiral benzyl and alkyl substituents in varied positions along the peptoid backbone. When the benzyl groups are located at the 3rd and 4th positions, the peptoid (7P6) gives upon Cu2+ binding a circular dichroism (CD) signal similar to that of a PP‐I helix. Exciton couplet CD spectroscopy and EPR spectroscopy, as well as modifications to the length of 7P6 and derivatization through acetylation provided insights into the unique folding of 7P6 upon Cu binding, showing that it is led by two competing driving forces, namely coordination geometry and sequence. Wrap it up: The secondary structure of a peptoid oligomer incorporating two N‐hydroxyquinoline ligands is significantly altered upon its binding to Cu2+ ions, as suggested by CD spectroscopy. The spectra of the unbound peptoid, which reflects a mixture of PP‐I and PP‐II helices, transformed upon Cu2+ binding to resemble the spectra of a pure PP‐I helix. Studies on a series of peptoids revealed a battle between two driving forces for folding, namely coordination geometry and sequence.