E484K and N501Y SARS-CoV 2 Spike Mutants Increase ACE2 Recognition but Reduce Affinity for Neutralizing Antibody

Chakraborty, Sandipan

SARS-CoV2 mutants emerge as variants of concern (VOC) due to altered selection pressure and rapid replication kinetics. Among them, lineages B.1.1.7, B.1.351, and P.1 contain a key mutation N501Y. B.1.135 and P.1 lineages have another mutation, E484K. Here, we decode the effect of these two mutations on the host receptor, ACE2, and neutralizing antibody (B38) recognition. The gain in binding affinity for the N501Y RBD mutant to the ACE2 is attributed to improved π-π stacking and π-cation interactions. The enhanced receptor affinity of the E484K mutant is caused due to the formation of a specific hydrogen bond and salt-bridge interaction with Glu75 of ACE2. Notably, both the mutations reduce the binding affinity for B38 due to the loss of several hydrogen-bonding interactions. The insights obtained from the study are crucial to interpret the increased transmissibility and reduction in the neutralization efficacy of rapidly emerging SARS-CoV2 VOCs.