They say you can’t judge a book by its cover. But the human immune system does just that when it comes to finding and attacking harmful microbes such as coronavirus. It relies on the ability to recognize foreign intruders and generate antibodies to destroy them. Unfortunately, coronavirus uses a sweet coating of molecules called glycans to camouflage itself as harmless defense antibodies.
Simulations on the National Science Foundation’s (NSF) Frontera supercomputer funded by the Texas Advanced Computing Center (TACC) revealed the atomic composition of the sweet coronavirus shield. In addition, simulation and modeling show that glycans are also the first to become infected by altering the shape of its advanced protein. Scientists hope this basic research will add to the arsenal of knowledge needed to defeat the COVID-19 virus.
Sugar-like molecules called glycans cover each of the 65 advanced proteins that adorn coronavirus. Glycans account for about 40 percent of peak protein by weight. Advanced proteins are essential for cell infection because they lock on the cell surface, giving viruses entry into the cell.
“You really see how effective his glycan shield is,” said Rommie Amaro, a professor of chemistry and biochemistry at the University of California, San Diego. “‘is because you see glycans covering the surface of the viral peak protein, which is the most exposed bit and the part that is responsible for the initial infection in the human cell,” she says.
Amaro is the corresponding author of a study published on June 12, 2020 on bioRxiv.org — an open-access repository of electronic preprints — that has discovered a potential structural role of protective glycans that cover the advanced SARS-CoV-2 protein. “You can see very clearly that from open conformation, the advanced protein has to undergo a big structural change to actually enter the human cell,” Amaro said.
But even to make an initial connection, she said that one of the pieces of the advanced protein in her receptor binding domain must lift. “When this receptor binding area rises in open conformation, it actually lifts important pieces of the protein over the glycan shield,” Amaro explained.
This contrasts with the closed conformation, where the shield covers the advanced protein. “Your analysis gives a potential reason why it does have to undergo these conformational changes, because if it just stays in the down position these glycans will essentially block the bond from actually occurring,” she said.
Another aspect of their study showed how changes in glycan conformations triggered changes in the structure of advanced proteins. “One thing that really jumped on us is that in open conformation, there are two glycans that essentially support protein in this open conformation,” Amaro said.
“It was really surprising to see. This is one of the main results of our study. It suggests that the role of glycans in this case goes beyond the protection of potentially having these chemical groups actually involved in the dynamics of the peak protein,” she added.
She compared the action of the glycan to pulling the trigger of a firearm. “When this tip goes up, the finger is on the trigger of the infection machine. That’s when it’s in its most dangerous mode, it’s locked and loaded,” Amaro said. “When he gets like this, all he has to do is run into an ACE2 receptor in the human cell, and then he’s going to bond super tightly and the cell is basically infected.”
Amaro and his colleagues use computational methods to build data-centric models of the SARS-CoV-2 virus, then use computer simulations to explore different scientific questions about the virus.
They began with various sets of experimental data that revealed the structure of the virus. This included cryo-EM structures from the Jason McLellan Lab at the University of Texas at Austin; and David Veesler’s lab at the University of Washington. “Their structures are really amazing because they give researchers an image of what these important molecular machines really look like,” Amaro said.
Unfortunately, even the most powerful microscopes on Earth still cannot solve the movement of the protein at the atomic scale. “What we do with computers is we take the beautiful, wonderful and important data they give us, but then we use methods to build bits of information,” Amaro said.
What’s more, the details of glycan shielding were too difficult to solve for experiments. “What people really want to know, such as vaccine developers and drug developers, is what vulnerabilities are in this shield,” Amaro said.
Computer simulations allowed Amaro and his colleagues to create a coherent picture of the advanced protein that includes glycans. “The reason TACC’s IT resources are so important is that we can’t understand what these glycans look like if we don’t use simulation,” Amaro said.
Amaro obtained computational time on the NSF-funded Frontera supercomputer. His team used approximately 2.3 million knot hours for molecular dynamics and modeling simulations, the most of all researchers using the system to study VOCIDE-19. She used up to 4,000 knots, or about 250,000 treatment cores. Frontera, the leadership class system of NSF’s cyber infrastructure ecosystem, ranks fifth among the world’s most powerful supercomputers and the fastest university system in the world, according to Top500’s November 2019 ranking.
In order to animate the dynamics of the 1.7 million atomic system under study, a lot of computing power was needed, Amaro said. “This is really where Frontera has been fantastic, because we need to sample relatively long dynamics, microsecond time scales to milliseconds, to understand how this protein actually works.”
“We were able to do that with Frontera and the COVID-19 HPC Consortium,” Amaro said. “Now we’re trying to share our data with as many people as possible, because people want a dynamic understanding of what’s going on, not only with other academic groups, but also with different pharmaceutical and biotech companies that lead the development of neutralizing antibodies,” she said.
Basic research makes a difference by winning the war against the SARS-CoV-2 virus, Amaro said. “The more we know, the more we will be able to pick up and eliminate them,” she added.
Said Amaro: “It’s so important that we learn as much as we can about the virus. And then I hope that we can translate these understandings into things that will be useful either in the clinic, or on the streets, for example if we try to reduce transmission for what we now know about aerosols and wearing masks. All these things will be part of it. Fundamental research has a huge role to play in the war against COVID-19. And I’m happy to be a part of it. It is a force that we have Frontera and TACC in our arsenal.
The study, Shielding and Beyond: The Roles of Glycans in SARS-CoV-2 Spike Protein, was published bioRxiv.org, June 12, 2020. The authors of the study are Lorenzo Casalino, Zied Gaieb, Abigail C. Dommer, Rommie E. Amaro of the Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA; and Aoife M Harbison, Carl A Fogarty, Elisa Fadda of the Department of Chemistryinstitute Hamilton, Maynooth University, Dublin, Ireland. This work was supported by NIH GM132826, NSF RAPID MCB-2032054, an award from the RCSA Research Corp., a UC San Diego Moore Cancer Center 2020 SARM-COV-2 seed grant, the Visible Molecular Cell Consortium, and the Irish Research Council.
Massive coronavirus simulations performed on the Frontera supercomputer
Lorenzo Casalino et al. Shielding and Beyond: The Roles of Glycans in SARS-CoV-2 Spike Protein, bioRxiv DOI: 10.1101/2020.06.11.146522
Texas Advanced Computing Center
Coronavirus sugar coating locks and loads for infection (2020, June 13)
recovered on June 13, 2020
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