RAPID: Computational studies of the structural dynamics, function and inhibition of the SARS-CoV-2 coronavirus spike protein

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This NSF Rapid response Research (RAPID) project funded by the Molecular Biophysics Program in the Division of Molecular and Cellular Biosciences will support a project that is aimed to thoroughly characterize the dynamical transitions the coronavirus membrane-surface spike (S) glycoprotein by computer simulations both locally upon receptor/antigen binding and globally upon fusion. The spike protein binds a receptor on the surface of the cell and undergoes a long-time, large-scale conformational transition that triggers fusion. This project will emphasize the role of deploying recent advances in enhanced sampling simulations to obtaining thermal and kinetic averages that make valid connection to the timescales of the experiments. Lessons learned from this project will not only improve the understanding of the structure and dynamics of the SARS-CoV-2 spike protein but will deepen the molecular biophysics understanding of viruses in general. In addition to direct scientific insights, the project will impact the education of graduate, undergraduate, and middle-school students, inform a large research community, and engage the broader public through outreach activities.The 2019 novel coronavirus, identified as the cause for the pneumonia pathology reported in Wuhan, spread quickly and became a global pandemic. The project will employ novel computational techniques grounded in rigorous statistical mechanics to understand the role of the dynamics for the function of the spike protein, the key macromolecular component whose structural rearrangements are responsible for antibody neutralization and entry to the host cell for infection. In its recently released prioritization recommendation, the World Health Organization stressed the need for antigens to target this spike protein. This project will help in the interpretation of biochemical measurements on neutralization sensitivity, receptor reactivity, and immunity response changes due to widespread infection.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.