Riding the Wave: Unveiling the Conformational Waves from RBD to ACE2

The binding affinity between angiotensin-converting enzyme 2 (ACE2) and the receptor-binding domain (RBD) plays a crucial role in the transmission and re-infection of SARS-CoV2. Here, microsecond molecular dynamics simulations revealed that point mutations in the RBD domain induced conformational transitions that determined the binding affinity between ACE2 and RBD. These structural changes propagate through the RBD domain, altering the orientation of both ACE2 and RBD residues at the binding site. ACE2 receptor shows significant structural heterogeneity, whereas its binding to the RBD domain indicates a much greater degree of structural homogeneity. The receptor was more flexible in its unbound state, with the binding of RBD domains inducing structural transitions. The structural heterogeneity observed in the ACE2 unbound form plays a role in the promiscuity of viral entry as it may allow the receptor to interact with various related and unrelated ligands. Furthermore, rigidity may be important for stabilizing the complex and ensuring the proper orientation of the RBD-binding interface with ACE2. The greater structural homogeneity observed in the ACE2-RBD complex revealed the effectiveness of neutralizing antibodies and vaccines that are primarily directed towards the RBD-binding interface. The binding of the B38 monoclonal antibody revealed restricted conformational transitions in the RBD and ACE2 receptor, attributed to its potent binding interaction.