The E484K Mutation in SARS-CoV-2 RBD increases the binding affinity with hACE2, but reduces the interactions with neutralizing antibodies and nanobodies: Studies to calculate the free energy of binding

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J Mol graph model. September 17, 2021; 109: 108035. doi: 10.1016 / j.jmgm.2021.108035. Online before printing.

ABSTRACT

The COVID-19 disease pandemic caused by SARS-CoV-2 has resulted in more than 200 million infections and over 4 million deaths worldwide. Advances in the development of effective vaccines and neutralizing antibody therapeutics give hope to eradicate the threat posed by COVID-19. However, SARS-CoV-2 continues to mutate, and several new variants have emerged. Among the various naturally occurring mutations, the E484K mutation, shared by many variants, raised serious concerns that could potentially increase receptor binding affinity and reduce the immune response. In the present study, the molecular mechanism behind the effects of the E484K mutation on the binding affinity of the receptor binding domain (RBD) with the human angiotensin converting enzyme 2 (hACE2) of the receptor was investigated using molecular dynamics simulations (MD) combined with the generalized molecular mechanics Born surface method (MMGBSA). Our results show that the E484K mutation leads to more favorable electrostatic interactions that compensate for the burial of the charged and polar groups in binding RBD to hACE2, which significantly improves the RBD-hACE2 binding affinity. In addition, the E484K mutation also causes the conformational rearrangements of the loop region containing the mutated residue, resulting in a tighter binding interface of RBD with hACE2 and the formation of some new hydrogen bonds. The tighter binding interface and the formation of new hydrogen bonds also contribute to the improved binding affinity of RBD to the hACE2 receptor. In addition, six neutralizing antibodies and nanobodies complexed with RBD were selected to investigate the effects of the E484K mutation on the recognition of these antibodies against RBD. The simulation results show that the E484K mutation significantly reduces the binding affinities for RBD for most of the neutralizing antibodies / nanobodies investigated and that the decrease in binding affinities is mainly due to the unfavorable electrostatic interactions caused by the mutation. Our studies have shown that the E484K mutation can improve the binding affinity between RBD and the hACE2 receptor, which implies a higher transferability of the E484K-containing variants, and weakens the binding affinity between RBD and the neutralizing antibodies / nanobodies studied, which leads to a decrease Indicates effectiveness of this antibody / nanobody. Our results provide valuable information for effective vaccine development and antibody / nanobody drug design.

PMID: 34562851 | DOI: 10.1016 / j.jmgm.2021.108035

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