Critical Interactions Between the SARS-CoV-2 Spike Glycoprotein and the Human ACE2 Receptor

Abstract

ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects human cells upon binding of its spike (S) glycoproteins to ACE2 receptors and causes the coronavirus disease 2019 (COVID-19). Therapeutic approaches to prevent SARS-CoV-2 infection are mostly focused on blocking S-ACE2 binding, but critical residues that stabilize this interaction are not well understood. By performing all-atom molecular dynamics (MD) simulations, we identified an extended network of salt bridges, hydrophobic and electrostatic interactions, and hydrogen bonding between the receptor-binding domain (RBD) of the S protein and ACE2. Mutagenesis of these residues on the RBD was not sufficient to destabilize binding but reduced the average work to unbind the S protein from ACE2. In particular, the hydrophobic end of RBD serves as the main anchor site and unbinds last from ACE2 under force. We propose that blocking the hydrophobic surface of RBD via neutralizing antibodies could prove an effective strategy to inhibit S-ACE2 interactions.