Utilizing Pairwise Interactions to Understand Collagen Triple Helix Assembly

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dc.contributor.advisorHartgerink, Jeffrey D.en_US
dc.contributor.committeeMemberMarti-Arbona, Angelen_US
dc.creatorCole, Carson Calvinen_US
dc.date.accessioned2024-08-30T18:49:29Zen_US
dc.date.created2024-08en_US
dc.date.issued2024-07-30en_US
dc.date.submittedAugust 2024en_US
dc.date.updated2024-08-30T18:49:29Zen_US
dc.descriptionEMBARGO NOTE: This item is embargoed until 2026-08-01en_US
dc.description.abstractCollagen, the most abundant protein in the human body, exhibits diverse physical structures upon assembly. Despite the remarkable similarity in the chemical sequence of amino acids within the collagen triple helix, the origins of the resulting macromolecular properties remain poorly understood in some cases. This thesis investigates collagen supramolecular assembly by synthesizing, characterizing, and applying a range of collagen mimetic peptides to elucidate pairwise interaction geometry, collagen folding, and polymerization. Collagenous proteins have the canonical amino acid sequence of Xaa-Yaa-Gly, where the Xaa is frequently proline and the Yaa is 4-hydroxyproline, respectively. Substitutions of the Xaa and Yaa positions lead to the relative stability of a pairwise interaction in the triple helix. By analyzing the stabilizing and destabilizing effects of pairwise cation-π interaction geometries between cationic and aromatic amino acids in two sequential relationships, axial and lateral, we showed only the axial relationship is stabilizing. By understanding the nuances of amino acid presentation in the triple helix, lateral charge pairs stabilized the triple helix when the cation was in the Xaa position, and the anion was in the Yaa position. As a result, we expanded the design toolbox for collagen mimetic design. Most natural collagens are heterotrimeric, where the three strands are nonequivalent. Incorporating these pairwise interactions yielded an ABC-type heterotrimeric crystal structure with excellent specificity. This specificity enhanced the folding rate of the triple helix, and we confirmed that the folding paradigm was concentration-independent. We further demonstrated that heterotrimeric collagens undergo an equilibrium-mediated assembly process that necessitates complete unfolding before adopting its constituent strands’ correct ABC register. Furthermore, this work incorporated cation-π interactions to develop a hydrogel material emulating fibrous collagens. The peptide structure formed diverse, porous, and fibrous networks upon assembly. In addition, by simple oxidation, we demonstrated that templating the cation-π interaction can introduce intrahelical and inter-helical covalent bonds. Given the critical role of the triple helix as the foundation for the macromolecular properties found in the human body, these findings demonstrate the potential to advance our understanding of collagen folding in disease and create next-generation biomimetic scaffolds.en_US
dc.embargo.lift2026-08-01en_US
dc.embargo.terms2026-08-01en_US
dc.format.mimetypeapplication/pdfen_US
dc.identifier.citationCole, Carson Calvin. Utilizing Pairwise Interactions to Understand Collagen Triple Helix Assembly. (2024). PhD diss., Rice University. https://hdl.handle.net/1911/117847en_US
dc.identifier.urihttps://hdl.handle.net/1911/117847en_US
dc.language.isoengen_US
dc.rightsCopyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.en_US
dc.subjectCollagenen_US
dc.subjectSelf-Assemblyen_US
dc.subjectChemistryen_US
dc.subjectProtein Designen_US
dc.subjectPairwise interactionsen_US
dc.subjectcation-pien_US
dc.subjectSupramolecular chemistryen_US
dc.subjectprotein designen_US
dc.subjectde novo designen_US
dc.titleUtilizing Pairwise Interactions to Understand Collagen Triple Helix Assemblyen_US
dc.typeThesisen_US
dc.type.materialTexten_US
thesis.degree.departmentChemistryen_US
thesis.degree.disciplineNatural Sciencesen_US
thesis.degree.grantorRice Universityen_US
thesis.degree.levelDoctoralen_US
thesis.degree.nameDoctor of Philosophyen_US
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