Collagen mimetic peptides (CMPs) self-assemble into a triple helix reproducing the most fundamental aspect of the collagen structural hierarchy. They are therefore important for both further understanding this complex family of proteins and use in a wide range of biomaterials and biomedical applications. While recent advances have significantly improved our ability to control the self-assembly of triple helices, their use is complicated by a number of factors, such as the slow rate of folding and relatively poor monomer−trimer equilibrium. However, all these problems can be solved through the formation of isopeptide bonds between lysine and glutamate. This pairwise interaction serves two purposes: to first direct self-assembly, allowing for composition and register control within the triple helix, and subsequently can be covalently linked, fixing the composition and register of the assembled structure without perturbing the triple helical conformation. The formation of an isopeptide bond between lysine and glutamate (K−E) is shown to increase the thermal stability, improve the refolding capabilities, and enhance the triple helical structure as compared to K−E supramolecular interactions, observed by circular dichroism. The crystal structure of a triple helix captured through the formation of three K−E isopeptide bonds unequivocally demonstrates the connectivity of the amide bonds formed while also confirming the preservation of the canonical triple helix. In this talk, I will describe how covalent capture was subsequently shown to be useful in a biomaterial application by effectively limiting the degradation of peptide by matrix metalloproteinase-1 (MMP-1). MMP degradation can lead to peptide biomaterials having shortened lifetime and efficacy in the body. Therefore, limiting peptide degradation would be of benefit. The rate of reaction and yield for covalently captured K−E triple helices along with the excellent preservation of triple helical structure demonstrate that this approach can be used to effectively capture and stabilize this important biological motif for many applications.

Covalent capture of collagen triple helices with limited matrix metalloproteinase-1 degradation

ACS Spring 2022

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