R346K Mutation in the Variant of SARS-CoV-2 Alters the Interactions with Monoclonal Antibodies from Class 2: A Free Energy Perturbation Study.

The variant of SARS-CoV-2 has been recently classified as a variant of interest (VOI) by the World Health Organization (WHO) but limited data are available at the moment. In particular, special attention was given to the R346K mutation located in the receptor binding domain (RBD). In the current study, we performed free energy perturbation (FEP) calculations to elucidate its possible impact on a set of neutralizing monoclonal antibodies (mAbs) that have been shown to be strong inhibitors of the most other known COVID-19 variants. Our results show that R346K affects class 2 antibodies but its effect is not so significant (0.66 kcal/mol), i.e., it reduces the binding with antibodies by about 3-fold. An identical value was also calculated in the presence of both class 1 and class 2 antibodies (BD-812/836). Further, a similar reduction in the binding (0.4 kcal/mol) was obtained for the BD-821/771 pair of mAbs. For comparison, the addition of the K417N mutation, present in the newly registered variant in July 2021 in the U.K., affected the class 1 mAbs by strongly reducing the binding by 1.29 kcal/mol or about 10-fold. Thus, the resistance effect of the R346K mutation on the variant is possible but not so significant and is due to the additional decrease of antibody neutralization based on the reduced binding of class 2 antibodies.