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Macrocyclic β-Sheets Stabilized by Hydrogen Bond Surrogates
Alex Nazzaro1, Brandon Lu1, Nicholas Sawyer1
1Department of Chemistry, New York University, 100 Washington Square East, NY 10013, New York, USA.
Angewandte Chemie (International Ed. in English)
|May 11, 2023
Summary
Researchers created minimal protein beta-sheet mimics using hydrogen bond surrogates. These turn-less macrocycles demonstrate robust beta-sheet formation, with aromatic interactions providing superior stability for biomolecular interaction inhibitors.
Area of Science:
- Biochemistry
- Structural Biology
- Medicinal Chemistry
Background:
- Protein secondary structures like beta-sheets are crucial for biomolecular interactions.
- Mimicking protein structures offers a route to rationally designed inhibitors.
- Existing beta-sheet mimics often rely on synthetic or natural turn segments.
Purpose of the Study:
- To develop conformationally-defined, turn-less macrocyclic beta-sheet mimics.
- To investigate the use of hydrogen bond surrogates (HBS) to replace terminal inter-beta-strand hydrogen bonds.
- To create minimal mimics of protein beta-sheets.
Main Methods:
- Developed a facile solid-phase synthesis protocol for turn-less antiparallel beta-sheet mimics.
- Conducted a bioinformatics survey of protein beta-sheets to identify common interstrand side chain interactions.
- Utilized circular dichroism, NMR spectroscopy, and X-ray crystallography for structural and conformational analysis.
Main Results:
- Identified an over-abundance of aromatic-aromatic, cation-π, and ionic interactions in natural beta-sheets.
- Demonstrated that minimal HBS mimics exhibit robust beta-sheet formation with specific amino acid residue pairings.
- Found that aromatic interactions confer superior conformational stability in isolated beta-sheets compared to ionic or cation-π interactions.
Conclusions:
- Turn-less macrocyclic beta-sheet mimics can be successfully synthesized using HBS.
- Specific amino acid residue pairings, particularly aromatic ones, are critical for stable beta-sheet mimic formation.
- These findings support the design principles for minimal beta-sheet mimics as potential inhibitors of biomolecular interactions.
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