Collagen is the most abundant protein in the human body and plays major roles in wound healing, tissue regeneration, cancer metastasis. The defining structural feature of collagen is the triple helix (figure a & b). Depending on the specific type of collagen, these triple helices pack into fibrillar bundles which continue to pack in a hierarchical assembly process, eventually forming macroscopic collagen fibers. This PP2 triple helix is also found in a variety of proteins outside the traditional collagen family in bacteria, viruses and the defense collagens of the innate immune system. Despite this ubiquity the structure-stability-function relationship of the collagen triple helix is poorly understood. CMPs differ in critical ways from other well studied proteins in that they lack a hydrophobic core and require a glycine every third amino acid creating a characteristic (Xaa-Yaa-Gly)n repeat (figure a). Design of synthetic triple helices which can mimic collagen are extremely challenging for many reasons, but one of the most apparent is that a system of three peptides A, B and C can self-assemble into at least 27 different compositions and registers. Proper design therefore must stabilize one of these while destabilizing the other 26. I will describe the design, synthesis and characterization of several AAB and ABC heterotrimers and computational methods which allow us to both predict their stability and allow rapid and accurate design of new triple helical systems. An additional challenge in the application of collagen triple helices is their extremely slow rate of folding and relatively poor equilibrium between monomer and trimer. To overcome these limitations we have developed a method of covalent capture (figure c & d) that perfectly preserves its three dimensional architecture while improving thermal stability. With these advances we are now working towards biomaterial applications that allow selective targeting of integrins.

Self-assembly and covalent capture of collagen triple helices

ACS Spring 2022

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