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TitleNMR conformational and dynamic characterization of triple helical peptides
NameXiao, Jianxi (author), Baum, Jean (chair), Taylor, John (internal member), Talaga, David (internal member), Brodsky, Barbara (outside member), Rutgers University, Graduate School - New Brunswick,
Degree Date2009-10
Date Created2009
SubjectChemistry and Chemical Biology,
Peptides,
Collagen,
Nuclear magnetic resonance spectroscopy
DescriptionThe repeating Gly-X-Y sequences and uniform rod-like structure makes collagen-like peptides a unique system for NMR studies. In this dissertation, a number of triple helical peptides modeling biologically important regions in collagen, such as mutation sites, interruption sites and collagenase cleavage sites, are investigated by a variety of NMR techniques. Structure determination strategy combining molecular modeling and NMR spectroscopy have been developed on a classic triple helical peptide. Novel approaches capable of obtaining long-range order restraints, such as residual dipolar coupling and 15N relaxation measurements, are applied to obtain detailed information about the orientation of the N-H bonds, which are crucial in defining collagen structure.
Triple helical peptides modeling Gly mutations involved in Osteogenesis imperfecta (OI), a connective tissue disorder, are investigated to elucidate the structural bases of various OI phenotypes. The level of structural disruption by different Gly substitutions is found to correlate well with the lethality of OI, while Arg/Asp causes larger disruption and is more likely to result in lethal OI. Triple helical peptides modeling natural interruptions in a heterotrimeric rather than homotrimeric environment have been successfully obtained and special features of stability, conformation, dynamics and folding at the interruption sites are detected by NMR.
Triple helical peptides, which model natural cleavage sites and potential but noncleavable sites in collagen, are explored to understand the specific recognition of collagen by matrix metalloproteinases (MMP). A single Ile at the cleavage site shows a distinct chemical shift, an unusual J-coupling value, dramatically increased dynamics and decreased local stability, suggesting that the Ile may be released from the restricted triple helical conformation and recognized by MMPs. The distribution of neighboring imino acids is also shown to be able to affect the local conformation and dynamics at the cleavage sites. This thesis correlates collagen sequence variations to the changes in structural and dynamic features of collagen-like peptides, furthering our understanding of the molecular bases for collagen-involved diseases and recognitions.
Triple helical peptides modeling Gly mutations involved in Osteogenesis imperfecta (OI), a connective tissue disorder, are investigated to elucidate the structural bases of various OI phenotypes. The level of structural disruption by different Gly substitutions is found to correlate well with the lethality of OI, while Arg/Asp causes larger disruption and is more likely to result in lethal OI. Triple helical peptides modeling natural interruptions in a heterotrimeric rather than homotrimeric environment have been successfully obtained and special features of stability, conformation, dynamics and folding at the interruption sites are detected by NMR.
Triple helical peptides, which model natural cleavage sites and potential but noncleavable sites in collagen, are explored to understand the specific recognition of collagen by matrix metalloproteinases (MMP). A single Ile at the cleavage site shows a distinct chemical shift, an unusual J-coupling value, dramatically increased dynamics and decreased local stability, suggesting that the Ile may be released from the restricted triple helical conformation and recognized by MMPs. The distribution of neighboring imino acids is also shown to be able to affect the local conformation and dynamics at the cleavage sites. This thesis correlates collagen sequence variations to the changes in structural and dynamic features of collagen-like peptides, furthering our understanding of the molecular bases for collagen-involved diseases and recognitions.
NotePh.D.
NoteIncludes bibliographical references (p. 150-159)
Noteby Jianxi Xiao
Genretheses
Persistent URLhttp://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.000051923
Languageeng
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work