NSF Award
2304852
With the support of the Macromolecular, Supramolecular and Nanochemistry Program in the Division of Chemistry, Bradley L. Nilsson of the University of Rochester, Cristiano Dias of the New Jersey Institute of Technology (NJIT), and Edward Egelman of the University of Virginia will study the supramolecular self-assembly of peptides into nanofibril biomaterials. Peptides are naturally occurring molecules found in all organisms that perform important biological functions, including acting as signaling hormones, including such bioactive peptides as insulin and oxytocin. Peptides can adopt different conformations that influence how they interact with each other. Beta-sheets are one common peptide structural motif. Peptides that assume beta-sheet conformations often rapidly self-assemble into nanofibrils. Some of these nanofibril assemblies are associated with protein misfolding disorders like Alzheimer’s disease and others have been designed to be functional biomaterials. In this work, the team will study how these peptides the co-assemble into these structures. Novel beta-sheet materials, “rippled” beta-sheets, that are distinct from the “pleated” beta-sheets found in nature, will be studied using experimental and computational techniques. These efforts will provide critical insight into the structure of both natural and artificial beta-sheets and the molecular-scale interactions that dictate the assembly of these materials. This research is directed at opening up new avenues for the design of next generation peptide-based nanomaterials. Outreach activity associated with this work includes an inquiry based mini-course on hydrogels called “The Science of Slime” which will be conducted at the participating institutions for pre-university students from grades 7-12. Additionally, the research teams will host high school interns for six weeks during the summer to provide mentoring and increase exposure to scientific research and to the chemical sciences, in general.<br/><br/>Under this award the collaborative Rochester, NJIT, Virginia team will investigate the supramolecular assembly of beta-sheet nanofibrils composed of mirror-image peptides by determining the structure of these systems with near-atomic precision and by using computer simulations to investigate the forces driving the formation of these assemblies. This work is directed at the rational design of rippled beta-sheet nanofibril systems. In the first objective, cryo-electron microscopy will be used to elucidate the structure of related pleated and rippled beta-sheet assemblies and complementary computational analyses will be used to rationalize their mechanisms of assembly. In the second objective, computational methods will be used to predict and design novel self-assembled beta-sheet peptide materials and these predictions will be tested experimentally. The results of the experiments will be used to validate and improve predictive computations. This work aims to provide key knowledge regarding the molecular basis for peptide self-assembly processes that will be relevant to understanding protein misfolding processes and for the design of biomaterials with potential applications in energy science and biomedicine.<br/><br/>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.
