A Looplike Secondary Structure Uncovered in a Family of Peptoid Hexamers

Abstract

Peptoids, or N-substituted glycine oligomers, are a unique class of biomimetic foldamers. Peptoid oligomers are indeed capable of adopting well-defined ordered structures despite their intrinsic flexibility, which is primarily attributable to the cis/trans isomerism of the main chain tertiary amide bonds. Controlling the geometry of the amides can lead to a diversity of diastereomeric structures. Here, we report for the first time that peptoid hexamers can adopt a unique looplike structure with a cis–cis–trans–cis–cis arrangement of the backbone amides. We found that a neutral zwitterionic state is necessary for the formation and stabilization of this structure by ion–pair interaction between the positively and negatively charged N- and C-termini. The novel loop structure exhibits a remarkable stability in chloroform and acetonitrile. In methanol, the oligomers adopt the more common polyproline type I (PPI) helical conformation. A comprehensive NMR solution structure determination was carried out on a hexamer containing four central (S)–N-(1-phenylethyl)glycines (Nspe) and two N-tert-butylglycines at the terminal ends. Our study reveals a distinct circular dichroism (CD) fingerprint for loop-shaped peptoids containing chiral aromatic Nspe monomers. The structure in solution was corroborated by a high-resolution crystal structure. Furthermore, we provide evidence that substituting the aromatic Nspe units with aliphatic (S)–N-(1-cyclohexylethyl)glycines (Nsch) or (S)–N-(1-tert-butylethyl)glycines (Nstbe) monomers does not impact loop folding processes. Finally, we demonstrate a reversible conformational switch between the loop structure and the PPI helix in response to external acid–base stimuli. This reversible stimulus-driven structural reorganization opens up opportunities to develop on/off switchable systems for next-generation smart applications.