The High Transmission of SARS-CoV-2 Omicron (B.1.1.529) Variant is Not Only Due to Its hACE2 binding: A Free Energy of Perturbation Study (preprint)

The mutations in the spike protein of SARS-CoV-2 Omicron variant (B.1.1.529 lineage) gave rise to questions, but the data on the mechanism of action at the molecular level is limited. In this study, we present the Free energy of perturbation (FEP) data about the RBD-hACE2 binding of this new variant. We identified two groups of mutations located close to the most contributing substitutions Q498R and Q493R, which altered significantly the RBD-hACE2 interactions. The Q498R, Y505H and G496S mutations, in addition to N501Y, highly increased the binding to hACE2. They enhanced the binding by 98, 14 and 13 folds, respectively, which transforms the S1-RBD to a picomolar binder. However, in contrast to the case in mice the Q493R/K mutations, in a combination with K417N and T478K, dramatically reduced the S1 RBD binding by over 100 folds. The N440K, G446S and T478K substitutions had lesser contribution. Thus, the total effect of these nine mutations located on the interaction surface of RBD-hACE2 turns out to be similar to that observed in the Alpha variant. In a special circumstances it could be further altered by the E484A and S477N mutations and even lower binding capacity is likely to be detected. Finally, we provide a structural basis of the observed changes in the interactions. These data may explain only partially the observed in South Africa extremely high Omicron spread and is in support to the hypothesis for multiple mechanisms of actions involved in the transmission. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/471246v1_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@144d901org.highwire.dtl.DTLVardef@10310e7org.highwire.dtl.DTLVardef@4ac7dborg.highwire.dtl.DTLVardef@1870231_HPS_FORMAT_FIGEXP M_FIG C_FIG

The R346K Mutation in the Mu Variant of SARS-CoV-2 Alter the Interactions with Monoclonal Antibodies from Class 2: A Free Energy of Perturbation Study (preprint)

The Mu 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, a special attention was given to the R346K mutation located in the receptor binding domain (RBD). In the current study we performed Free energy of perturbation (FEP) calculations to elucidate it possible impact on a set of neutralizing monoclonal antibodies (mAbs) which have been shown to be strong inhibitors of the most other known COVID-19 variants. Our results show that R346K affects the class 2 antibodies but its effect is not so significant (0.66 kcal/mol); i.e. reduces the binding with RBD about 3 times. An identical value was calculated also 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 BD-821/771 pair of mAbs. For comparison, the addition of K417N mutation, present in the newly registered Mu variant in July 2021 in UK, affected the class 1 mAbs by 1.29 kcal/mol reducing stronger the binding by about 10 times. Thus, the resistance effect of R346K mutation in the Mu 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.

The SARS-CoV-2 S1 spike protein mutation N501Y alters the protein interactions with both hACE2 and human derived antibody: A Free energy of perturbation study (preprint)

The N501Y mutation in Covid-19 arise many question but a small amount of data are currently available. An urgent understanding of N501Y mechanism of action at molecular level is highly required. Here, we present the preliminary results of our Free energy perturbation (FEP) and Molecular dynamics (MD) calculations for the interaction of the spike S1 receptor binding domain (RBD) with both the ACE2 receptor and an antibody, STE90-C11, derived from COVID-19 patients. The results shown that the S1 RBD-ACE2 interaction was increased whereas those with the STE90-C11 antibody significantly decreased (over about 160 times). This may explain the observed in UK more spread of the virus but also emerge an important question about the possible human immune response and already available vaccines. Indeed, the latter may still act well but our data indicate some possible reduction of their effect. Further studies of N501Y mutation are need.