Hyperstable and Fibril-Forming Collagen-Mimetic Peptides in Shortest Triple Helices: Empowering the Capping by π-systems
Developing collagen-mimetic peptides (CMPs) with short triple helices and fibril-forming ability remains challenging. Herein, we stabilized short CMPs (3–6 GPO repeats) by attaching extended aromatic π-system─fluorenyl groups at the N-terminus and tyrosine at the C-terminus. These modifications promoted triple helix folding through π–π interactions, acting as a “glue” to stabilize the structure and facilitate fibrillation. A single fluorenyl cap required 5 GPO repeats for helix formation, while double fluorenyl capping reduced this to 4 repeats. Notably, at pH 5.5, triple helices formed with only 3 GPO repeats. The double-capped CMPs exhibited hyperstability (Tm = 76 °C) and formed fibrillar networks at physiological pH. Biophysical and computational studies confirmed the role of π–π and CH–π interactions, along with hydrogen bonding, in stabilization. The minimalistic CMPs supported cell viability, demonstrating their potential for biomedical applications. This strategy offers a method to design highly stable, short CMPs that form robust fibrillar networks.
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