Insights on SARS-CoV-2's Mutations for Evading Human Antibodies: Sacrifice and Survival

Abstract

Recent mutations on the receptor binding domain (RBD) of the SARS-CoV-2s spike protein have been manifested as the major cause of the wide and rapid spread of the virus. Especially, the variant B.1.351 in South Africa with the hallmark of triple mutations (N501Y, K417N and E484K) is worrisome. Quickly after the outbreak of this new variant, several studies showed that both N501Y and E484K can enhance the binding between RBD and the human ACE2 receptor. However, the mutation K417N seems to be unfavorable because it removes one interfacial salt-bridge. So far, it is still not well understood why the K417N mutation is selected in the viral evolution. Here, we show that despite the loss in the binding affinity (1.48 kcal/mol) between RBD and ACE2 the K417N mutation abolishes a buried interfacial salt-bridge between RBD and the neutralizing antibody CB6 and thus substantially reduces their binding energy by 9.59 kcal/mol, facilitating the variants to efficiently elude CB6 (as well as many other antibodies). Thus, when proliferating from person to person the virus might have adapted to the human immune system through evasive mutations. Taking into account limited and relevant experimental works in the field, we show that our theoretical predictions are consistent with existing experimental findings. By harnessing the revealed molecular mechanism for variants, it becomes feasible to redesign therapeutic antibodies accordingly to make them more efficacious. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/430088v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@1ce030eorg.highwire.dtl.DTLVardef@2a9f85org.highwire.dtl.DTLVardef@4f1265org.highwire.dtl.DTLVardef@140c0be_HPS_FORMAT_FIGEXP M_FIG C_FIG