NEW YORK (Reuters Health) – Dynamic molecular simulations that captured the structure and movements of the SARS-CoV-2 spike protein have revealed novel potential vaccine targets and confirmed previously identified ones, researchers say.
“To elude the human immune defense, SARS-CoV-2 and other viruses hide their functionally important and conserved sites behind a shield of sugar-like glycans,” Dr. Gerhard Hummer of the Max Planck Institute of Biophysics in Frankfurt explained by email.
“The glycans themselves are chemically identical to those on human proteins, which makes them poor targets for an immune response,” he told Reuters Health. “Viruses also misdirect the immune response to variable sites where antibodies bind weakly, if at all, and viral infection cannot be blocked.”
“We catalog and rank sites at the surface of the SARS-CoV-2 spike protein that are accessible to antibodies,” he said. “Reassuringly, many of the target sites we identified in our computational screen have already been verified. Targeting also the remaining sites opens up another avenue in the fight against COVID-19.”
As reported in PLoS Computational Biology, the spike protein’s surface is key for infection and is the primary antibody target. However, it is covered with highly mobile glycan molecules that could impair antibody binding.
To identify accessible binding sites, the team created molecular dynamics simulations that captured the complete structure of the glycosylated spike embedded in a membrane. The simulations showed that the glycans act as a dynamic shield that helps the virus evade the immune system by flopping back and forth.
Combining the simulations with bioinformatics analyses, the team identified vulnerable sites on the surface of the spike protein that are least protected by the glycan shields. Some of the sites had been previously identified, while others were confirmed in subsequent lab experiments by other research groups.
The authors note that their computational epitope-mapping strategy is generalizable to other viral envelope proteins whose structures have been characterized.
Dr. Hummer added, “Thanks to the genetic encoding of spike in mRNA or adenovirus-based vaccines, engineered constructs could be quickly introduced to guide antibodies towards promising yet rarely targeted sites. Our computational screen provides a list of possible targets. Beyond keeping this list up-to-date as new viral variants emerge, future effort will concentrate on the design of tailor-made antigens and antibodies for SARS-CoV-2 and other targets.”
Dr. Elaine Youngman, an Assistant Professor of Biology at Villanova University in Pennsylvania, commented by email to Reuters Health, “This study and others like it build on decades of fundamental science in protein structure and immunology to computationally predict which specific regions of the coronavirus spike protein might be good vaccine targets. Their method is able to identify targets that we already know work, and they also identify a couple of new regions that look quite promising.”
“There is a worry that new variants of the virus will evade immunity from existing vaccines, or will render monoclonal antibody therapies less effective – and we have already seen some of that happening,” she said. “The good news for clinicians is that these new ideas can be tested and potentially converted to therapies and vaccines so much more quickly than could happen in the past.”
SOURCE: https://bit.ly/3g4kRRr PLoS Computational Biology, online April 1, 2021.
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