STUDIES OF INTERACTIONS OF SMALL MOLECULES WITH MEMBRANES AND PROTEINS
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Issue Date
2019-12-31Author
Phaniraj, Sahishna
Publisher
University of Kansas
Format
170 pages
Type
Dissertation
Degree Level
Ph.D.
Discipline
Medicinal Chemistry
Rights
Copyright held by the author.
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The modern molecular understanding of biological systems relies on integration of principles, practices, and techniques from diverse fields such as molecular biology, biochemistry, and biophysics. This approach has provided great insights into the molecular complexity of living cells. However, studies of some biological assemblies, such as the dynamic collection of lipids, proteins, and other biomolecules that make up cellular membranes, remains a challenge. To simplify these systems, and enable investigations of their structure and function, a wide range of membrane-mimetic models have been developed. Chapter 1 of this dissertation reviews some of the most important methods for studies of these types of biological systems, including recently developed lipidic nanodiscs. In Chapter 2 of this dissertation, I describe the design and construction of a new class of nanodiscs that are stabilized by covalent crosslinking of a membrane scaffold protein. These nanodiscs, termed SpyDiscs, uniquely enable imaging of pore formation by membrane-disruptive peptides. Another class of molecules that interacts with biological membranes is described in Chapter 3 of this dissertation. In this chapter, we report the synthesis of a new class of hydrophobic fluorescent probes that can be used to visualize the endoplasmic reticulum of living cells. The final chapter of this dissertation describes a fluorescence polarization assay developed to study proteinprotein interactions involved in iron homeostasis in the pathogenic bacterium Pseudomonas aeruginosa. These binding studies along with other observations offer a promising target for inhibition of this pathogen as a strategy to overcome multidrug resistance observed with this superbug.
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