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.