Macrocyclic β-Sheets Stabilized by Hydrogen Bond Surrogates

Alex Nazzaro, Brandon Lu, Nicholas Sawyer, Andrew M. Watkins, Paramjit S. Arora

Research output: Contribution to journalArticlepeer-review

Abstract

Mimics of protein secondary and tertiary structure offer rationally-designed inhibitors of biomolecular interactions. β-Sheet mimics have a storied history in bioorganic chemistry and are typically designed with synthetic or natural turn segments. We hypothesized that replacement of terminal inter-β-strand hydrogen bonds with hydrogen bond surrogates (HBS) may lead to conformationally-defined macrocyclic β-sheets without the requirement for natural or synthetic β-turns, thereby providing a minimal mimic of a protein β-sheet. To access turn-less antiparallel β-sheet mimics, we developed a facile solid phase synthesis protocol. We surveyed a dataset of protein β-sheets for naturally observed interstrand side chain interactions. This bioinformatics survey highlighted an over-abundance of aromatic–aromatic, cation-π and ionic interactions in β-sheets. In correspondence with natural β-sheets, we find that minimal HBS mimics show robust β-sheet formation when specific amino acid residue pairings are incorporated. In isolated β-sheets, aromatic interactions endow superior conformational stability over ionic or cation-π interactions. Circular dichroism and NMR spectroscopies, along with high-resolution X-ray crystallography, support our design principles.

Original languageEnglish (US)
Article numbere202303943
JournalAngewandte Chemie - International Edition
Volume62
Issue number41
DOIs
StatePublished - Oct 9 2023

Keywords

  • Constrained Peptides
  • Macrocycles
  • Protein Mimics
  • Protein-Protein-Interactions
  • β-Sheets

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry

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