SQSig · Oligo-Squaramide Rigid-Rods for Artificial Transmembrane Signaling

G-protein coupled receptors (GPCRs) are transmembrane proteins that are used by cells to transmit information through their membranes; binding of a ligand to their extracellular region provokes a conformational change, initiating a biological process in the cytosol. Copying this type of signaling pathway, which is fundamental to cells and thus a key target in medicinal chemistry, is a fascinating challenge that could allow researchers to bypass endogenous signaling pathways in cells and lead to true synthetic biology. In this project we propose to exploit the self-assembly properties of squaramides (SQs) to create a relay of information through a bilayer membrane. Monomeric SQs self-assemble as head-to-tail aggregates, forming ribbons with all the SQs oriented in the same direction. We have designed a family of scaffolded oligo-SQ arrays that will form intramolecular hydrogen-bonded ribbons aligned in either one direction or the other. We hypothesize that inverting the directionality of the terminal SQ of the ribbon will initiate a domino effect that switches the orientation of the whole array. By functionalizing the terminal SQ of the oligo-SQ relay with a binding site and the opposite end with a spectroscopic reporter, followed by insertion in model membranes, we will show that binding of an external ligand to the terminal SQ switches the directionality of the entire SQ-ribbon and provokes a spectroscopic response from the reporter located at the other side of the membrane. Thus this system will act as a synthetic GPCR, able to transmit conformational information from one side of a bilayer membrane to the other. The action combines the experience of the researcher in the preparation and study of SQs with the expertise of the host group in the development of transmembrane devices. While the fellow will bring new knowledge in synthetic and supramolecular chemistry to the host group, he will acquire valuable experience in the analysis and biophysics of membranes.