Cooperative Intramolecular Hydrogen Bonding Strongly Enforces cis-Peptoid Folding

Andrew W. Wijaya, Andy I. Nguyen, Leah T. Roe, Glenn L. Butterfoss, Ryan K. Spencer, Nan K. Li, Ronald N. Zuckermann

Research output: Contribution to journalArticlepeer-review

Abstract

Sequence-defined peptoids, or N-substituted glycines, are an attractive class of bioispired polymer due to their biostability and efficient synthesis. However, the de novo design of folded peptoids with precise three-dimensional structures has been hindered by limited means to deterministically control backbone conformation. Peptoid folds are generally destabilized by the cis/trans backbone-amide isomerization, and few side-chains are capable of enforcing a specific amide conformation. Here, we show that a novel class of cationic alkyl ammonium ethyl side-chains demonstrates significant enforcement of the cis-amide backbone (Kcis/trans up to 70) using an unexpected ensemble of weak intramolecular CH-O and/or NH-O hydrogen bonds between the side-chain and the backbone carbonyl moieties. These interactions are evidenced by X-ray crystallography, variableerature NMR spectroscopy, and DFT calculations. Moreover, these side-chains are inexpensive, structurally diverse, hydrophilic, and can be integrated into longer peptoid sequences via solid-phase synthesis. Notably, we extended these concepts to synthesize a water-soluble peptoid 10-mer that adopts one predominant fold in solution, as determined by multidimensional NMR spectroscopy. This decamer, to the best of our knowledge, is the longest linear peptoid sequence atomically characterized to retain a well-folded structure. These findings fill a critical gap in peptoid folding and should propel the development of peptoid applications in a broad range of contexts, from pharmaceutical to material sciences.

Original languageEnglish (US)
Pages (from-to)19436-19447
Number of pages12
JournalJournal of the American Chemical Society
Volume141
Issue number49
DOIs
StatePublished - Dec 11 2019

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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