Computational Insights into the Conformational Accessibility and Binding Strength of SARS-CoV-2 Spike Protein to Human Angiotensin-Converting Enzyme 2.

Abstract

The spike protein of SARS-CoV-2 (CoV-2-S) mediates the virus entry into human cells. Experimental studies have shown the stronger binding affinity of the RBD (receptor binding domain) of CoV-2-S to angiotensin-converting enzyme 2 (ACE2) as compared to that of SARS-CoV spike (CoV–S). However, a similar or weaker binding affinity of CoV-2-S compared to that of CoV–S is observed if entire spikes are used in the bioassay. To explore the underlying mechanism, we calculated the binding affinities of the RBDs to ACE2 and simulated the transitions between ACE2-inaccessible and -accessible conformations. We found that the ACE2-accessible angle of CoV-2-S is 52.2° and that the ACE2 binding strength of CoV-2-S RBD is much stronger than that of CoV–S RBD. However, CoV-2-S has much less of an ACE2-accessible conformation and is much more difficult to shift from ACE2-inaccessible to -accessible than CoV–S, making the binding affinity of the entire protein decrease. Further analysis revealed key interactional residues for strong binding and five potential ligand-binding pockets for drug research.