Molecular basis for higher affinity of SARS-CoV-2 spike RBD for human
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused
substantially more infections, deaths, and economic disruptions than the
2002-2003 SARS-CoV. The key to understanding SARS-CoV-2’s higher
infectivity lies partly in its host receptor recognition mechanism.
Experiments show that the human ACE2 protein, which serves as the
primary receptor for both CoVs, binds to the receptor binding domain
(RBD) of CoV-2’s spike protein stronger than SARS-CoV’s spike RBD. The
molecular basis for this difference in binding affinity, however,
remains unexplained from X-ray structures. To go beyond insights gained
from X-ray structures and investigate the role of thermal fluctuations
in structure, we employ all-atom molecular dynamics simulations.
Microseconds-long simulations reveal that while CoV and CoV-2 spike-ACE2
interfaces have similar conformational binding modes, CoV-2 spike
interacts with ACE2 via a larger combinatorics of polar contacts, and on
average, makes 45\% more polar contacts. Correlation
analysis and thermodynamic calculations indicate that these differences
in the density and dynamics of polar contacts arise from differences in
spatial arrangements of interfacial residues, and dynamical coupling
between interfacial and non-interfacial residues. These results
recommend that ongoing efforts to design spike-ACE2 peptide blockers
will benefit from incorporating dynamical information as well as
allosteric coupling effects.