The glucans in SARS-CoV-2 can help the virus infect cells

Researchers have created the most comprehensive atomic-level simulation to date of the SARS-CoV-2 spike protein, which the virus uses to enter host cells. The model reveals that glucans not only camouflage the virus from the host’s immune system, as sugars in proteins are known to do. The SARS-CoV-2 glycans also help the spike protein to acquire the conformation that equips it to infect cells (ACS Cent. Sci. 2020, DOI: 10.1021 / acscentsci.0c01056).

“We have an atomic level model of a full-length, glycosylated spike protein, so there’s no more bits missing,” says Rommie Amaro, a computational biophysical chemist at the University of California, San Diego. And looking at the model, she explains, “we realized that a particular pair of glucans not only acted as part of the shield, camouflaging the virus, but also appeared to act as part of the weaponry.”

More than 8 months after the global COVID-19 pandemic caused by SARS-CoV-2, researchers around the world have generated multiple detailed images of the spike protein using a technology called cryoelectron microscopy (cryoEM). But one of the limitations of cryoEM is that it cannot resolve parts of the protein that are very flexible, such as the glycans that cover the outer surface of the virus, including those that cover the spike protein. Glycans “are like little leaves hanging from branches, which are protein residues,” explains Amaro. CryoEM can see where these branches adhere to the spike protein and most branches, but the leaves themselves are invisible to cryoEM.

To better visualize the glucans, Amaro and his colleagues used a computational technique to combine multiple existing cryoEM models of the spike protein with biochemical analyzes that indicate the types of glucans that are present and where in the protein they might be found. From all this information, they created a dynamic movie of how all the atoms in the protein “move and move over time,” he explains.

They noticed two surprising things about glucans: They were unusually numerous, and the behavior of two particular glucans seemed to play a special role. To infect a cell, the spike protein must first undergo a series of conformational changes. Specifically, its receptor-binding domain, a lance-shaped region near the end of the spike, must rise toward the host cell’s receptor to establish the connection. The two glucans appeared to get under this domain and help lift it toward the receptor to infect cells.

To determine whether glucans actually did this work, they collaborated with Jason McLellan at the University of Texas at Austin, whose team was the first to determine the structure of the SARS-CoV-2 spike protein using cryoEM in February. McLellan and his colleagues removed the two glycans by mutating the amino acids they bind to in the spike protein. Laboratory tests showed that compared to the non-mutated spike protein, the mutated proteins were less efficient (by half for a mutant) at interacting with host cell receptors.

Glycans are known to protect or camouflage proteins in the immune system, in addition to helping the proteins fold, explains Amaro. But this study is one of the first to suggest that glucans can directly change the conformational dynamics of a protein. It may be possible to develop therapies that target the glucan processing pathway, Amaro says.

The work provides “a tour-de-force, atom modeling and molecular dynamics simulation,” says Tamar Schlick, a chemist and computational scientist at New York University. The data indicate that glycans play an essential role in binding the spike protein to the host cell receptor, she says.

Amaro and his colleagues are now using their technique to take a closer look at the interaction between the spike protein and the host receptor. “Between the first contact with the human cell and the uptake of the virus by the cell, a lot of conformational changes occur,” he says. These can also offer targets for vaccine or therapeutic efforts.