From Hydrogel to Crystal: A Molecular Design Strategy that Chemically Modifies Racemic Gel-Forming Peptides to Furnish Crystalline Fibrils Stabilized by Parallel Rippled β‑Sheets

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.