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Author ORCID Identifier
Campus-Only Access for One (1) Year
Doctor of Philosophy (PhD)
Molecular and Cellular Biology
Year Degree Awarded
Month Degree Awarded
Biochemistry, Biophysics, and Structural Biology
Conformational isomers are essential in biological systems and may be involved in several different disease states, including amyloids. Identifying and characterizing the structural details of conformational isomers is necessary to understand their role in biological processes. However, these systems are hard to identify and study using traditional structural biology methods. Native mass spectrometry (MS) and ion mobility (IM) have emerged as a powerful methods to gain structural information and identify conformational isomers. Combining native MS and IM with additional gas phase techniques like collision induced unfolding (CIU) and surface induced dissociation (SID) provides more information about conformational isomers and their distinguishing features. This dissertation investigated the ability of CIU and SID in combination with native MS and IM to characterize conformational isomers. A combination of CIU experiments and computational modeling was developed to distinguish subtly different conformational isomers based on their unfolding pathways. We demonstrated that SID provides experimental evidence for a protein complex's subunit arrangement and connectivity. Further, SID was used to estimate the properties of protein-protein interfaces based on the appearance energy of dissociation. To demonstrate the utility of the methods developed conformational isomers of the pre-amyloid tetramer of β2 microblobulin (β2m) were investigated to understand the structural changes needed for amyloid formation. Future directions will finish developing a SID based model to estimate protein-protein interfaces and complete the characterization of the computational models of β2m tetramer isomers to gain insight into Cu(II)-induced amyloid formation. The work with β2m will demonstrate the ability of both approaches developed in this work to character conformational isomers of hard to study systems like pre-amyloid oligomers.
Nash, Stacey G., "Investigating Conformational Isomers of Protein Oligomers using Native Mass Spectrometry" (2023). Doctoral Dissertations. 2837.
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