Correlation Engine 2.0
Clear Search sequence regions

Sizes of these terms reflect their relevance to your search.

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.© 2023 Wiley-VCH GmbH.


Alex Nazzaro, Brandon Lu, Nicholas Sawyer, Andrew M Watkins, Paramjit S Arora. Macrocyclic β-Sheets Stabilized by Hydrogen Bond Surrogates. Angewandte Chemie (International ed. in English). 2023 May 11:e202303943e202303943

PMID: 37170337

View Full Text