Computational study of the strong binding mechanism of SARS-CoV-2 spike and ACE2
2021
The spike protein of SARS-CoV-2 (SARS-CoV-2-S) helps
the virus attach to and infect human cells. With various
computational methods applied in this work, the accessibility of its RBD to
ACE2, its key residues for stronger binding to ACE2 than the SARS-CoV spike
(SARS-CoV-S), the origin of the stronger binding, and its potential sites for
drug and antibody design were explored. It was found that the SARS-CoV-2-S
could bind ACE2 with an RBD-angle ranging from 52.2o to 84.8o, which demonstrated
that the RBD does not need to fully open to bind ACE2. Free energy calculation
by an MM/GBSA approach not only revealed much stronger binding of SARS-CoV-2-S
to ACE2 (ΔG=-21.7~-29.9 kcal/mol)
than SARS-CoV-S (ΔG=-10.2~-16.4
kcal/mol) at different RBD-angles but also demonstrated that the binding becomes
increasingly stronger as the RBD-angle increases. In comparison with the experimental
results, the free energy decomposition disclosed more key residues interacting strongly
with ACE2 than with the SARS-CoV-S, among which the Q493 might be the decisive
residue variation (-5.84 kcal/mol) to the strong binding. With the mutation of
all 18 different residues of SARS-CoV-S on the spike-ACE2 interface to the
corresponding residues of SARS-CoV-2-S, it was found that the mutated
SARS-CoV-S has almost the same binding affinity as SARS-CoV-2-S to ACE2,
demonstrating that the remaining mutations outside the spike-ACE2 interface have
little effect on its binding affinity to ACE2. Simulation of the conformational change pathway
from “down” to “up” states disclosed 5 potential
ligand-binding pockets correlated to the conformational change. Taking
together the key residues, accessible RBD-angle and pocket correlation, potential sites for
drug and antibody design were proposed, which should be helpful for
interpreting the high infectiousness of SARS-CoV-2 and for developing a cure.
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