Self-Immolative Bolaamphiphiles for Signal Transduction Across Bilayer Membranes

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With the support of the Macromolecular, Supramolecular and Nanochemistry Program in the Division of Chemistry, Professor Bradley Smith of the University of Notre Dame will develop a series of molecules that can transmit chemical signals across thin membranes similar to those that surround and protect all living cells. Much of the research work will use simple membrane bubbles called liposomes, and a set of experiments will elucidate the chemical and physical factors controlling the speed and intensity of the transmembrane signaling. The signaling molecules are designed to span the membrane and transduce an enzyme-catalyzed chemical reaction input on one side of the membrane into an observable optical signal on the other. These studies are expected to deepen fundamental understanding of how signals are transduced across membranes and will help pave the way toward successful development of synthetic living cells. As part of a complementary educational project, Professor Smith and his students will modernize the free internet workbook Organic Structure Elucidation which is used by hundreds of high school and college-level STEM instructors for remote learning. All planned activities will be conducted by a diverse group of talented graduate and undergraduate students, who will receive integrated training in experimental chemical research, data analysis, and scientific communication.The membrane-spanning synthetic signaling molecules being targeted here, self-immolative bolaamphiphiles, have chemical structures comprised of a hydrophilic trigger group connected by a self-immolative oligomeric linker to a releasable fluorophore. Enzymatic cleavage of the trigger group (input signal) will occur outside a bilayer membrane and the signal will subsequently be transduced by spontaneous depolymerization (self-immolation) of the linker into an observable fluorescence response (output signal) on the other side of the membrane. The results of bulk-phase fluorescence experiments are expected to provide atomic-level insight concerning the crucial molecular and physical factors that control the kinetics of transmembrane signal transduction. Studies using phase-separated membranes will test central concepts concerning membrane domain clustering as a process to modulate enzyme-triggered transmembrane signaling. Imaging experiments that compare the same signal transduction process occurring simultaneously in a cohort of separate giant liposomes will enable quantification of system heterogeneity. A practical outcome will be a new class of sensing liposomes with fluorescent output that can simultaneously image spatiotemporal changes of several different enzymes within living cells.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.