This project will bring rigorous biophysical knowledge to select protein components of the SARS-CoV2 virus that has catastrophic effects on human health, activity, and economic well-being. Critical events in the viral infection cycle include interaction of the virus with susceptible host cells and a variety of cellular responses post-infection. Experimental studies will be performed to characterize proteins that participate in these stages. By combining the extensive thermodynamic and structural expertise of two research groups, key structural features and molecular interactions will be described and quantified. The data will provide a framework to test the findings in cell-based infectivity assays. Two graduate students will be trained, and the results of this project will be used as the basis for a seminar course on coronaviruses directed at biophysics undergraduate and graduate students to develop future workforce with experience in this area.
A critical interaction between SARS-CoV-2 and host is that between the receptor binding domain (RBD) of the viral spike transmembrane protein and the S1 domain of the human ACE2 transmembrane protein. Binding is required for infection, determining the host range that a particular virus can infect. This project will quantify this critical interaction thermodynamically, determine the virus-host specificity profile, test various mechanisms for the origin and zoonotic events that led to the SARS-CoV-2 pandemic, and generate soluble mimics with favorable stabilities and specificities that can be used to limit or prevent infection. In addition, three accessory proteins, Orf3a, Orf7a, and Orf8, that interfere with or hijack host cellular processes will be characterized, both structurally and functionally using various spectroscopic and hydrodynamic methods. To further probe the evolutionary origins of coronaviruses and their host specificities, ancestral sequence reconstruction methods and consensus design will be applied to these targets.
This EAGER award is made by the Molecular Biophysics Program in the Division of Molecular and Cellular Biosciences, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.
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.
