A helical peptoid bearing two distinct metal binding ligands at positions i and i+3 (Helix HQT i+3) enables the selective recognition of one or two metal ions depending on its environment, thus mimicking the unique recognition abilities of natural biopolymers.
Metal ions play a significant role in the activity of biological systems including catalysis, recognition and folding. Therefore, introducing metal ions into peptidomimetic oligomers is a potential way for creating biomimetic metal complexes toward applications in sensing, recognition, drug design and catalysis. Herein we report the design, synthesis and characterization of water-soluble chiral N-substituted glycine oligomers, "peptoids," with one and two distinct intramolecular binding sites for metal ions such as copper and cobalt. We demonstrate for the first time the incorporation of the chiral hydrophilic group (S)-(+)-1-methoxy-2-propylamine (Nsmp) within peptoid sequences, which provides both chirality and water solubility. Two peptoids, a heptamer, and a dodecamer bearing two and four 8-hydroxyquinoline (HQ) groups respectively as metal-binding ligands, were synthesized on solid support using the submonomer approach. Using UV-titrations and ESI-MS analysis we demonstrate the creation of a novel metallopeptoid bearing two metal ions in distinct binding sites via intramolecular chelation. Exciton couplet circular dichroism (ECCD) demonstrated chiral induction from the chiral non-helical peptoids to the metal centers.
Helical peptoids bearing 2,2'-bipyridine form ruthenium complexes via intermolecular binding to linear peptoid strands or intramolecular binding to a cyclic scaffold. Ru(ii) binding promoted changes in the conformational order of the peptoids, and chiral induction from the peptoids to their metal center was observed.
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 Cu 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.
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