Abstract
A novel coronavirus SARS-CoV-2 is associated with the current global pandemic of Coronavirus Disease 2019 (COVID-19). Spike protein receptor-binding domain (RBD) of SARS-CoV-2 is the critical determinant of viral tropism and infectivity. To investigate whether the mutations in the RBD have altered the receptor binding affinity and caused these strains more infectious, we performed molecular dynamics simulations of the binding affinity between the mutant SARS-CoV-2 RBDs to date and the human ACE2 receptor. Among 1609 genomes of global SARS-CoV-2 strains, 32 non-synonymous RBD mutants were identified and clustered into 9 mutant types under high positive selection pressure. Three mutant types (V367F, W436R, and D364Y) emerging in Wuhan, Shenzhen, Hong Kong, and France, displayed higher human ACE2 affinity, and probably higher infectivity. This is due to the enhanced structural stabilization of the RBD beta-sheet scaffold. High frequencies of RBD mutations were identified: V367F from five France and one Hong Kong mutants, 13 V483A and 7 G476S mutants from the U.S.A. This suggested they originated as novel sub-lineages. The enhancement of the binding affinity of the mutant type (V367F) was further validated by the receptor-ligand binding ELISA assay. The molecular dynamics simulations also indicated that it would be difficult for bat SARS-like CoV to infect humans. However, the pangolin CoV is potentially infectious to humans. The analysis of critical RBD mutations provides further insights into the evolutionary history of SARS-CoV-2 under high selection pressure. An enhancement of the SARS-CoV-2 binding affinity to human ACE2 receptor reveals higher infectivity of the mutant strains.
Importance A novel coronavirus SARS-CoV-2 has caused the pandemic of COVID-19. The origin of SARS-CoV-2 was associated with zoonotic infections. The spike protein receptor-binding domain (RBD) is identified as the critical determinant of viral tropism and infectivity. Thus, whether the mutations in the RBD of the circulating SARS-CoV-2 strains have altered the receptor binding affinity and caused these strains more infectious, should be paid more attentions to. Here, 32 non-synonymous RBD mutants were identified and clustered into 9 mutant types under high positive selection pressure, suggesting they originated as novel sub-lineages. Three mutant types displayed higher human ACE2 affinity, and probably higher infectivity, one of which (V367F) was validated by wet bench. The RBD mutation analysis provides insights into SARS-CoV-2 evolution. The emergence of RBD mutations with increased human ACE2 affinity reveals higher risk of severe morbidity and mortality during a sustained COVID-19 pandemic, particularly if no effective precautions are implemented.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
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