Coronaviruses have created multiple infectious diseases in the last two decades with dreadful global impact, including most recently COVID-19 caused by the SARS-CoV-2 virus. The SARS-CoV-2 virus binds to the human angiotensin-converting enzyme (hACE2) using the spike glycoprotein. While ACE2 acts as a receptor for both SARS-CoV-2 and SARS-CoV, it binds much more strongly (∼4 times) to the spike glycoprotein of SARS-CoV-2. To investigate this difference in binding affinity, we modeled two RBD-hACE2 complex systems for the two viruses by adding appropriate glycans at the N- and O-glycosylation sites as suggested by mass spectroscopy experiments. We performed multiple microsecond-length molecular dynamics simulations of the RBD-hACE2 complex for viruses. Our analysis demonstrates that the glycan shielding in this complex behaves differently between SARS-CoV-2 and SARS-CoV. Additionally, we also show that each of the glycans has a specific interaction pattern that is unique to each virus. Finally, we compute rigorously the free energy change for mutating residues on the RBD-ACE2 interface identified from the equilibrium molecular dynamics simulation. Collectively, we cogently explain why hACE2 interacts more favorably with the RBD of SARS-CoV-2 compared to that from SARS-CoV.
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