A UC San Diego research team has discovered how a molecule on the outside of the SARS-Cov-2 tip protein acts as a “gateway” for the virus that causes COVID-19 infection, which could help find a way to fight the virus; it only takes one “key” to block it, says a new study.
Research published Thursday in the journal Nature Chemistry described how glycans (molecules that form a sugar residue around the edges of the ear protein) can allow the virus to enter and infect healthy human cells.
“We essentially found out how the ear opens and infects,” said Rommie Amaro, a computational biophysical chemist at UCSD, who helped develop a detailed visualization of the SARS-CoV-2 ear protein that binds efficiently to cellular receptors.
“We have unlocked an important secret of the rise in how it infects cells. Without this gate, the virus becomes basically incapable of infection,” said Amaro, a professor of chemistry and biochemistry and lead author of the new study.
Amaro said he believes the research team’s discovery opens up possible avenues for new therapies to fight SARS-CoV-2 infection. If glycan gates could be pharmacologically “locked” in the closed position, the virus is prevented from effectively opening upon entry and infection.
Others in the project are co-author Lillian Chong at the University of Pittsburgh, first author and postgraduate student at UCSD Terra Sztain, and co-author and postdoctoral student at UCSD Surl-Hee Ahn.
According to research, the glycan coating of the ear helps to deceive the human immune system, as it is nothing more than a sugary residue. Earlier technologies that imagined these structures represented glycans in open or closed static positions, which initially did not draw much interest from scientists. Supercomputing simulations allowed researchers to develop dynamic “films” that revealed glycan gates that were activated from one position to another, offering an unprecedented piece of the history of infection.
UCSD professor and computational biophysical chemist Rommie Amaro, who helped develop a detailed visualization of the SARS-CoV-2 spike protein that efficiently binds to cellular receptors.
“We were actually able to see the opening and closing,” Amaro said. “This is one of the interesting things that these simulations offer you: the ability to watch very detailed movies.
“When you look at them, you realize you see something we would otherwise have ignored,” he continued. “You just look at the closed structure, and then you look at the open structure and it doesn’t look like anything special. Just because we captured the film of the whole process, you really see it doing what it can do.”
The simulations were run first at “Comet” at UCSD’s San Diego Supercomputer Center and later at “Longhorn” at the University of Texas, Austin. This computing power provided researchers with atomic-level views of the peak protein receptor binding domain, or RBD, from more than 300 perspectives. Research revealed glycane “N343” as the main axis that makes RBD palpable from the “down” to “up” position to allow access to the host cell receptors. Researchers describe glycan activation as similar to a “molecular lever” mechanism.