Collagen is the most abundant protein in mammals and the main component of their extracellular matrix.^1,2 The chemical synthesis of collagen is attractive for medical and nanotechnological applications³ since it can provide access to structurally defined and functionalizable materials.^4,5 However, the bottom-up design of materials mimicking the fibrous structures of natural collagen is hampered by the entropically unfavorable assembly of short single strands into triple helices.^1,2 To lay the foundation for higher-ordered assemblies of collagen model peptides (CMPs), we covalently connected CMPs by oxime linkages between aminooxyproline (Aop)⁶ and 2‑oxoacetamidoproline (Alp) derivatives placed in neighboring strands. The cross‑linked strands folded into collagen triple helices with remarkably high thermal stabilities (T_m ~80°C). The design of the cross-links was guided by an analysis of the conformational properties of Aop, studies on the stability and functionalization of Aop-containing collagen triple helices, and molecular dynamics calculations. Our findings open new opportunities for the design of functional collagen-based materials forming by the sticky-ended assembly of structurally well-defined triple helices.

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[2] J. Bella, Biochem. J. 2016, 473, 1001.
[3] S. Chattopadhyay, R. T. Raines, Biopolymers 2014, 101, 821.
[4] B. Brodsky, G. Thiagarajan, B. Madhan, K. Kar, Biopolymers 2008, 89, 345.
[5] C. Siebler, R. S. Erdmann, H. Wennemers, Chimia 2013, 67, 891.
[6] F. Liu, A. G. Stephen, R. J. Fisher, T. R. Burke, Bioorg. Med. Chem. Lett 2008, 18, 1096.