The collagen triple helical folding motif differs in critical ways from other well studied proteins in that it lacks a hydrophobic core and requires a glycine every third amino acid creating a characteristic (Xaa-Yaa-Gly) repeat. Despite these oddities, collagen is the most abundant protein in humans and plays many critical roles in bones, connective tissue and throughout the extracellular matrix. Well beyond animals, the characteristic collagen structure is also found in fungus, bacteria and viruses. Study of the structure, stability and design of collagen and collagen-like peptides is potentially important for biomaterials applications in bioregeneration and as novel anti-baterial anti-fungal and anti-viral strategies. While triple helix stability can be maximized through the use of Proline in the Xaa position and Hydroxyproline in the Yaa position, these amino acids are not required and in nature are present only appoximately 1/3 of the time which allows natural collagen significant chemical diversity and the opportunity to assemble into A2B and ABC heterotrimers which further diversify and complicate triple helix structure through the introduction of different registrations between the 3 peptide strands. A triple helix with an ABC composition can in principle take on any of 6 different canonical registrations. A critical design feature used by our group is the axial-charged pair between a Lysine in a Yaa position of one peptide strand to a Aspartate or Glutamate in an Xaa position in the adjacent strand offset one triple from the Yaa position toward the c-termini. This specific geometry results in substantial stabilization of the triple helix. In contrast, either of these amino acids alone will destabilize the triple helix. This combination is perfect to achieve both stability and specificity in triple helix design and has allowed us to create well folded AAB and ABC heterotrimers and unusual non-canonical triple helical offsets that can be used to drive triple helix assembly to higher levels of organization. I will describe the design, synthesis and characterization of AAB and ABC heterotrimers and computational methods which allow us to accurately predict the melting temperature of synthetic triple helices and estimate the stability of natural collagens. I will also describe how these systems can be selectively covalently captured and the applications these types of covalently stabilized helices will allow.

Design, synthesis, self-assembly, and covalent capture of heterotrimeric collagen helices

2019 Spring National Meeting

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