Macrocyclic β-Sheets Stabilized by Hydrogen Bond Surrogates

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

Automated summary

Mimics of protein secondary and tertiary structure can be used as inhibitors of biomolecular interactions. By replacing inter-beta-strand hydrogen bonds with hydrogen bond surrogates (HBS), we have designed a minimal mimic of a protein beta-sheet without the need for natural or synthetic beta-turns. A bioinformatics survey of protein beta-sheets revealed an abundance of aromatic-aromatic, cation-p and ionic interactions, which we incorporated into our design. Experimental techniques like circular dichroism, NMR spectroscopy, and X-ray crystallography support our design.