Department: Chemical & Physical Biology
Faculty Mentor: Jens Meiler, Ph.D.
Dissertation Description: Predicting Covalent and non-Covalent Binding of Lipids and Sterols to G-protein Coupled Receptors
G-Protein Coupled Receptors (GPCRs) represent the largest family of membrane proteins encoded in the human genome. They transduce extracellular signals across the membrane that activate varied signaling cascades leading to its involvement in many physiological processes. This involvement has led to GPCRs being the target for approximately 30 % of pharmaceutical drugs. However, GPCRs exist in lipid bilayers where they interact with different lipids and sterols adding a layer of complexity to the formation of these drugs. In recent history there has been an explosion in the amount of crystal structures of GPCRs deposited in the Protein Data Bank (PDB). Some of these PDBs include non-covalently bound lipids and sterols and covalently bound lipids that through experimentation have been shown to affect downstream signaling, desensitization, and membrane location. Under the mentorship of Jens Meiler and with the Rosetta Suite, I can adapt protocols and methodology to predict the covalent and non-covalent binding of some of these biologically relevant lipids and sterols. Furthermore, I will be able to categorize these lipid/sterol interacting GPCRs by their effect on each receptor type individually. After reaching adequate methodology benchmarks I will move into the wet lab where I will design these predicted GPCRs and replicate effects seen in one lipid/sterol modified GPCR on another type by inducing the interactions, tail length and secondary structure formations in the other GPCR.