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This new discovery may help to develop more effective antibody against Covid19
Researchers investigated the physical mechanisms underlying the convergent evolution of the three mutations by examining the individual and collective effects of mutations on angiotensin converting enzyme 2 receptor binding, immune escape from neutralizing antibodies, protein stability, and -expression described.
“Understanding the mechanisms underlying antibody escape and the location of mutations in the spike protein will aid in the development of new antibody therapeutics that act against new variants by targeting epitopes with minimal mutations or by developing broad neutralizing antibodies that target multiple epitopes,” Mallela said.
The study found that certain mutations appear repeatedly in newly emerging variants that show convergent evolution. Such evolution occurs at the three amino acid positions K417, E484 and N501 in the receptor binding domain (RBD) of the spike protein. Almost half of the 4.3 million sequence variants in the GISAID database that contain any of these three mutations have all three occurring together. Although individual mutations have both beneficial and deleterious/adverse effects, detrimental/adverse effects are reversed when they come together, leading to improved selection of mutations together.
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They found that the three RBD mutations play very different and specific roles that help improve viral fitness and provide arguments for their positive selection, although individual mutations have deleterious effects that make them susceptible to negative selection. Compared to wild-type, K417T evades class 1 antibodies and exhibits increased stability and expression; however, it decreased ACE2 receptor binding. E484K evades class 2 antibodies; however, it has decreased receptor binding, stability, and expression. N501Y increases receptor binding; however, it has decreased stability and expression. When these mutations come together, the deleterious effects are mitigated due to the presence of compensatory effects. The triple mutant K417T/E484K/N501Y has increased ACE2 receptor binding, escapes both class 1 and class 2 antibodies, and has stability and expression similar to wild-type.
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The authors conclude the collective effect of these mutations is far more advantageous for virus fitness than the individual mutations and the presence of multiple mutations improves the selection of individual mutations.
Mallela concludes, “As SARS-CoV-2 has evolved from Alpha to Omicron, more and more mutations are accumulating. We hope that by providing research that understands the role of these mutations, we can help further propel research and the development of new therapies to better combat new variants.”
Reference: “Convergent Evolution of Multiple Mutations Improves the Viral Fitness of SARS-CoV-2 Variants by Balancing Positive and Negative Selection” by Vaibhav Upadhyay, Casey Patrick, Alexandra Lucas and Krishna M. G. Mallela, 5 May 2022, Biochemistry.
DOI: 10.1021/acs.biochem.2c00132
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