N501Y and K417N Mutations in the Spike Protein of SARS-CoV‑2 Alter the Interactions with Both hACE2 and Human-Derived Antibody: A Free Energy of Perturbation Retrospective Study

The N501Y and K417N mutations in
the spike protein of SARS-CoV-2
and their combination gave rise to questions, but the data on their
mechanism of action at the molecular level were limited. In this study,
we present free energy perturbation (FEP) calculations, performed
at the end of December 2020, for the interactions of the spike S1
receptor-binding domain (RBD) with both the ACE2 receptor and an antibody
derived from COVID-19 patients. Our results showed that the S1 RBD-ACE2
interactions were significantly increased whereas those with the STE90-C11
antibody dramatically decreased. The K417N mutation in a combination
with N501Y fully abolished the antibody effect. However, Lys417Asn
seems to have a compensatory mechanism of action increasing the S1
RBD-ACE2 free energy of binding. This may explain the increased spread
of the virus observed in the U.K. and South Africa and also gives
rise to an important question regarding the possible human immune
response and the success of the already available vaccines. Notably,
when the experimental data became available confirming our calculations,
it was demonstrated that protein–protein FEP can be a useful
tool for providing urgent data to the scientific community.