Small Molecules for the Selective Recognition of Biomembrane Components

This dissertation describes the design and evaluation of small molecules that interact specifically with certain components of the cell plasma membrane surface and interior. A series of Zn2+-DPA coordination compounds has been developed that can report the presence of phosphatidylserine in the outer leaflet of a cell membrane in the same manner as the protein Annexin V, but with no need for calcium. These compounds include fluorescent probes suitable for flow cytometry and fluorescence microscopy, as well as a biotinylated sensor for phosphatidylserine that can be adapted to sensing applications for which suitable streptavidin conjugates are available. Direct conjugation of these phosphatidylserine-binding compounds to quantum dots resulted in a sensor useful for prolonged exposure imaging applications without bleaching of the fluorophore. A second series of amphiphilic compounds designed to partition into the bilayer hydrocarbon region and interact with membrane proteins is also presented. These molecules include derivatives of the lipid phosphatidylcholine, and all have either thymine or urea functionalities that likely embed in the bilayer and form hydrogen bonds to targeted transmembrane protein residues. All compounds presented in this work have either immediate applications in diagnostic imaging or the potential to help us understand more about the process of molecular recognition in a cell membrane interior.