Design, Structure and Applications of Collagen-Mimetic Peptides

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dc.contributor.advisorHartgerink, Jeffrey Den_US
dc.contributor.advisorMatsuda, Seiichi Pen_US
dc.creatorAcevedo-Jake, Amanda Men_US
dc.date.accessioned2017-08-01T17:56:11Zen_US
dc.date.available2018-05-01T05:01:07Zen_US
dc.date.created2017-05en_US
dc.date.issued2017-04-25en_US
dc.date.submittedMay 2017en_US
dc.date.updated2017-08-01T17:56:11Zen_US
dc.description.abstractThe collagen triple helix is a unique protein fold found in all domains of life where is has diverse roles from imparting structure and strength to tissue, to initiating an immune response. While many factors affecting the structure and stability of the triple helix have previously been elucidated, much remains unknown about collagen. Using collagen-mimetic peptides, it is possible to investigate the molecular structure of the triple helix, determine new pairwise interactions of amino acids, characterize disease models and also create designer collagens that will preferentially hybridize to natural collagen-rich tissue. First a selective labeling scheme is used to thoroughly characterize a well-folded triple helical region, and then to determine the degree of localized unfolding at the N- and C-termini. Though terminal fraying extends farther than previously shown, small sequence alterations at the N-terminus have a drastic influence on local stability (~15C). Next, a single register heterotrimeric mimic of the type I collagen disease Osteogenesis Imperfecta is used to investigate single point glycine mutations in the B chain, the A chain or both chains. Unlike past reports, a combination of NMR analysis and molecular modelling is used to generate structures of the mutated helices and visualize the underlying mechanisms of helix destabilization in OI. For the first time it is proven that these mutations cause compositional as well as structural disruptions. Additionally, while several hundred pairwise interactions are possible in the triple helix, to date only two interactions are wellunderstood and commonly incorporated into CMP design. To expand on the library of known interactions, the structure and stability of helices containing serine, threonine, phospho-serine and phospho-threonine were investigated. Notably, when phospho-serine is paired with lysine a new highly stabilizing (49.5 C) axial interaction is possible. Finally, the design of a collagen type II targeting peptide is described, and NMR, CD and confocal microscopy are used to investigate the hybridization of the synthetic peptide with the natural partner strands.en_US
dc.embargo.terms2018-05-01en_US
dc.format.mimetypeapplication/pdfen_US
dc.identifier.citationAcevedo-Jake, Amanda M. "Design, Structure and Applications of Collagen-Mimetic Peptides." (2017) Diss., Rice University. <a href="https://hdl.handle.net/1911/96078">https://hdl.handle.net/1911/96078</a>.en_US
dc.identifier.urihttps://hdl.handle.net/1911/96078en_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.subjectprotein designen_US
dc.titleDesign, Structure and Applications of Collagen-Mimetic Peptidesen_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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