The SARS-CoV-2 exerts a distinctive strategy for interacting with the ACE2 human receptor

Esther S. Brielle; Dina Schneidman-Duhovny; Michal Linial

To gain access to host cells, coronaviruses rely on spike proteins, which are membrane-anchored trimers containing a receptor-binding S1 segment and a membrane-fusion S2 segment (6) . The S1 segment contains a receptor binding domain (RBD) that recognizes and binds to a host cell receptor. The angiotensin-converting enzyme 2 (ACE2) was identified as the critical receptor for mediating SARS-2002 entry into host cells (7, 8) . Binding of the spike protein to the receptor is a critical phase where the levels of the ACE2 expressed on the cell membrane correlates with viral infectivity, and govern clinical outcomes (9) . Consistent with the clinical pulmonary manifestation, ACE2 is widely expressed in almost all tissues, with the highest expression levels in the epithelium of the lung (10) . Similar to the SARS-2002 virus, the COVID-19 virus enters the host cell by RBD binding to the host cell ACE2 receptor (7, 11, 12) . Host receptor recognition for cell entry is, however, not specified by the CoV genus classification. MERS-CoV is a member of the BCoV genus but does not recognize the ACE2 receptor. In contrast, HCoV-NL63 is a member of the ACoV genus and does recognize the ACE2 receptor (13) . Herein, we analyze the binding of several CoV RBDs to ACE2 with molecular dynamics (MD) simulations and compare the stability, relative interaction strength, and dynamics of the interaction between the viral spike protein and the human ACE2 receptor.