RBD spatial orientation of the spike protein and its binding to ACE2: insight into the high infectivity of the SARS-CoV-2 Delta variant from MD simulations

The spike glycoprotein on the surface of the SARS-CoV-2 envelope plays an important role in its invasion into host cells. The binding of the spike glycoprotein RBD to the angiotensin-converting enzyme 2 (ACE2) receptor as a critical step in the spread of the virus has been explored intensively since the outbreak of COVID-19, but the high transmissibility of the virus such as the Delta variant is still not fully understood. Here, molecular simulations on the binding interactions of the wild-type spike protein and its four variants (Beta, Kappa, Delta, and Mu) with ACE2 and the antibody were performed, and the present results reveal that the residue mutations will not strengthen the binding affinity of the variant for ACE2, but remarkably influences the spatial orientation of the spike protein. Only the up-right conformational receptor binding domain (RBD) can bind ACE2, which is stabilized by the nearby RBDs in the down state, revealing that the RBD bears dual functional characteristics. The present results provide new insights into plausible mechanisms for high infectivity of the virus variants and their immune escape.