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

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.