Researchers from the USP (University of São Paulo) Faculty of Medicine (FMRP) and Dentistry (FORP) on the Ribeirão Preto campus identified one of the factors that made the new variant of the Sars-CoV-2 coronavirus B117 more infectious. originally from the UK and with two cases confirmed in Brazil by the Adolf Lutz Institute.
Using bioinformatics tools, they found that the spike protein of the new strain of virus, which forms the crown structure that gives the coronavirus family its name, creates greater molecular interaction strength with the ACE2 receptor present on the surface of cells and with which the coronavirus binds to make the infection viable.
The increase in the molecular interaction strength of the new strain is caused by a mutation already identified in amino acid residue 501 of the coronavirus spike protein called N501Y, which led to the new variant of the virus, the researchers found.
The results of the work supported by Fapesp were published on the bioRxiv platform in an article that has not yet been peer-reviewed.
“We saw that the interaction between the spike protein of the new coronavirus strain and the N501Y mutation is much greater than that of the first strain of the virus isolated in Wuhan, China,” says Geraldo Aleixo Passos, professor at FMRP and Fapesp FORP-USP agency and project coordinator. Another author of the study who carried out the bionformatic analyzes is Jadson Santos, who is doing his doctorate at the FMRP-USP under the direction of Passos.
With the emergence of the B117 strain in the United Kingdom, the researchers hypothesized that the N501Y mutation present in the spike protein of the new variant, which results from the substitution of an amino acid asparagine (N501) by a type of tyrosine (N501Y), one could be factors that are responsible for the high risk of infection of the new coronavirus strain.
“There are other mutations in the genome of this strain that we haven’t analyzed. We are concentrating on the N501Y because it is involved in the binding of the spike protein to ACE2, ”explains Passos.
To test the hypothesis that the high infectivity of the B117 strain could be due to changes in the strength of the interaction between the mutated spike protein and the ACE2 receptor, structures of the spike protein from the Sars-CoV-2 coronavirus in Wuhan were identified and Wuhan isolated line B117, deposited in a protein database, the protein database.
With the public domain software PyMOL it was possible to visualize the interaction between the amino acid residue 501 of the coronavirus spike protein and the Y41 residue of the human ACE2 protein and to simulate and analyze the interactions resulting from the in B117 found N501Y mutation with revealed the cell receptor.
“This software enables the visualization of images of these molecular structures with an approximation of 3.5 Feldangstrom, which is much larger than the images that were generated with an ultramicroscope”, compares Passos.
Another publicly available software called PDBePISA was used to compare the interaction of spike proteins from the wild-type coronavirus and the mutant strain with the human ACE2 receptor.
The results of the analyzes showed that the N501Y mutation in the spike protein of the new variant causes a stronger interaction with the ACE2 receptor compared to the wild strain of the virus. The interactions were mostly weaker, the researchers found.
“The sum of several weak links between the mutated spike protein of the new variant of the coronavirus and the human ACE2 receptor leads to stronger molecular interactions that allow the virus to more easily penetrate cells and trigger the replication system,” explains Passos.
The study also found that the N501Y mutation changed the distance between the amino acid residues of the spike protein, allowing even more interactions with the ACE2 receptor.
“Together, these changes confirmed the hypothesis that the spike protein of the B117 strain interacts more strongly with the ACE2 receptor,” says Passos.
According to the researcher, the results of the study, conducted through computer simulations in silico, will guide new experiments in vitro aimed at assessing the infectivity of the new coronavirus variant in human cell cultures in the laboratory.
According to the researchers, the rapid spread of the Sars-CoV-2 coronavirus among humans is driving their molecular evolution. So far, the virus has accumulated mutations at a rate of up to two nucleotides per month, and newer isolates show at least 20 nucleotide changes in their genome compared to the wild strain isolated in January 2020. Most of the mutations are in the spike protein.
Discovered in early September and described by the Covid-19 Genomics UK Consortium in the United Kingdom in December 2020, strain B117, which is already registered in 17 other countries, including Brazil, is, among other things, an example of the rapid molecular evolution of the new coronavirus.
However, it surprised the scientists with the accumulation of 17 mutations, eight of which are in the gene that encodes the spike protein on the virus surface.
“This new strain collects a lot of mutations. A lower number is observed with other virus strains, ”compares Passos.
Since the description of this new variant is new, it is not yet possible to determine the phenotype more precisely, ie whether it is more or less pathogenic, explains the researcher.