β-Turn Mimicking Crosslinking Provides Hyperstability and Fast Folding Kinetics for Short Collagen Triple Helices

Creating stabilized peptide mimics of the collagen triple helix is challenging, especially for collagen heterotrimers. Interstrand sidechain crosslinking offers a useful approach, though this strategy can suffer from destabilizing structural perturbations, sequence limitations and synthetic complexity. Herein, we show that the geometry of hydrogen bonding in the collagen triple helix is compatible with installation of terminal β-turn-mimicking linkers at the N-terminal and C-terminal ends of the triple helix. These double-turn-containing collagen peptide mimics fold into highly stable, intramolecular triple helical structures, providing access to profoundly miniaturized triple helix mimics. Intramolecular triple helix formation exhibits significantly accelerated folding kinetics. Comprehensive kinetic analysis reveals that the rate-limiting step of folding is distinct at low and high temperatures, affording unique insight into the mechanism.