Tuning multivalency for optimized ligand presentation

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Project Summary/Abstract Cells probe their biophysical environment by engaging multiple ligands on the extracellular matrix and in solution resulting in receptor oligomerization and clustering at the nanoscale. In the fields of biomaterials science and nanomedicine, there is a significant need to recreate these complex dynamics by presenting ligands from a synthetic substrate with optimal presentation. However, it is very challenging to develop sufficient design criteria at this nano-bio interface due in part to the complexity of the interactions as well as our insufficient ability to precisely control these macromolecular features. We seek to address this fundamental limitation by developing quantitative structure-activity relationship (QSAR) models that will allow us to accurately shape synthetic multivalent ligands with optimized biophysical dynamics for programmable cell signaling. Our approach significantly leverages a new combinatorial platform developed by the PI to precisely fine tune and study these challenging interactions. To do this, our research program has five major thrusts. Thrust 1: Leveraging our automated platform for multivalent ligand synthesis, we will study the spectrum of available hydrodynamic characteristics and learn how to control their structure with high precision. Thrust 2: We will use molecular dynamic (MD) simulations to help us define these macromolecular features then build QSAR models to extract design criteria. Thrust 3: Using surface plasmon resonance (SPR) and super-resolution microscopy, we will probe ligand-receptor interactions and characterize the macromolecular contributions towards avidity, specificity, cooperativity and super-selectivity. Thrust 4: The implications of these features on cell signaling and ligand directed cell behavior will be characterized. Thrust 5: We will apply this new knowledge to a variety of applications including regenerative medicine, nanomedicine and as probes to study signal transduction. These five major thrusts were developed to complement each other towards our long-term goals for developing highly bioactive and customizable ligands for programed cell behavior.