Binding of SARS-CoV-2 to Cell Membrane: Molecular to Whole-virus Simulation and Search for Potential Inhibitors

yal310@lehigh.edu Understanding the SARS-CoV-2 mechanism of infection is crucial in the development of potential therapeutics and vaccines. The infection process is triggered by direct binding of the SARS-CoV-2 receptor-binding domain (RBD) to the host cell receptor, Angiotensin-converting enzyme 2 (ACE2). Many efforts have been made to design or repurpose therapeutics to deactivate RBD or ACE2 and prevent the initial binding. In addition to direct inhibition strategies, small chemical compounds might be able to interfere and destabilize the meta-stable, pre-fusion complex of ACE2-RBD. This approach can be employed to prevent the further progress of virus infection at its early stages. Molecular docking is used to analyze the binding of two potential chemical compounds, SSAA09E2 and Nilotinib, with the druggable pocket of the ACE2-RBD complex. The structural changes as a result of interference with the ACE2-RBD complex are analyzed by molecular dynamics simulations. Moreover, we are developing a multiscale, coarse-grained model of SARS-CoV-2 virus and ACE2 receptors to study the early stages of infection, i.e., virus entry to cell, at the whole-virus scale. Such a model can be employed in analyzing the virus-host interactions at a larger scale that is hardly accessible for all-atomistic molecular dynamics. The flexibility of spike proteins and their interactions with the coarse-grained ACE2 complex will be tuned by all-atomistic results. The multiscale model along with steered molecular dynamics will be employed to study the effects of ACE2 surface expression on the free energy of virus-host cell binding. Discussion of infectivity and open problems If you found this video useful, please check out our other videos on computational modeling, infection and immunology: https://youtube.com/playlist?list=PLiEtieOeWbMKh9VcQoinSwODcSZKMTGat Please consider joining our IMAG/MSM WG on Multiscale Modeling and Viral Pandemics: https://www.imagwiki.nibib.nih.gov/content/msm-viral-pandemics-meetings Please also consider joining the Global Alliance for Immune Prediction and Intervention: http://glimprint.org/