Download MendeleyFrom Hydrogel to Crystal: A Molecular Design Strategy that Chemically Modifies Racemic Gel-Forming Peptides to Furnish Crystalline Fibrils Stabilized by Parallel Rippled beta-Sheets.
Samdin, T.D., Lubkowski, J., Anderson, C.F., Schneider, J.P.(2025) J Am Chem Soc 147: 14377-14387
- PubMed: 40252045
- DOI: https://doi.org/10.1021/jacs.5c00671
- Primary Citation of Related Structures:
9DOX, 9DOY, 9DP0 - PubMed Abstract:
Rippled β-sheets are an underutilized secondary structural motif that hold promise in the rational design of peptide hydrogel materials with unique and desirable properties. Fully capitalizing on the design potential of this structural element, however, requires a high-resolution molecular understanding of the interactions they form within the supramolecular assemblies comprising the material - which are absent in all reports to date. Herein, we develop a molecular design strategy to modulate the phase state of β-hairpin peptides prone to form fibrillar gels into ones that assemble into crystal lattices, making high-resolution structural analysis possible. Truncating, cyclizing and Cα-methylating enantiomeric gel-forming peptides affords mirror-image macrocyclic peptides. Crystallography reveals that the enantiomeric macrocycles coassemble to form racemic fibril-like assemblies of unprecedented structure. Extended arrays of sheet-rich fibrils contain alternating blocks of enantiopure β-hairpins that assemble to form both canonical pleated β-sheets as well as stereocomplexed rippled β-sheets. This structure illuminates new molecular interactions to leverage in the design of next generation peptide hydrogels and provides the first crystallographic evidence of a parallel rippled β-sheet.
Organizational Affiliation:
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States.
