8DPY

Synthetic Beta Sheet Macrocycle Stabilized by Hydrogen Bond Surrogates

Summary for 8DPY

• Entry DOI: 10.2210/pdb8dpy/pdb
• Descriptor: beta sheet-forming peptide with flexible linker (2 entities in total)
• Functional Keywords: synthetic peptide, beta sheet, de novo protein
• Biological source: synthetic construct
• Total number of polymer chains: 2
• Total formula weight: 2867.26

Authors

Lu, B.,Vecchioni, S.,Nazzaro, A.,Arora, P.S. (deposition date: 2022-07-18, release date: 2023-05-24, Last modification date: 2024-10-09)

Primary citation

Nazzaro, A.,Lu, B.,Sawyer, N.,Watkins, A.M.,Arora, P.S.
Macrocyclic beta-Sheets Stabilized by Hydrogen Bond Surrogates.
Angew.Chem.Int.Ed.Engl., 62:e202303943-e202303943, 2023

PubMed 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.

PubMed: 37170337
DOI: 10.1002/anie.202303943

Experimental method

X-RAY DIFFRACTION (1 Å)