- Researchers have discovered how glycans—molecules that make up a sugary residue around the spike protein’s edges—act as infection gateways.
- The study team’s gate finding might lead to novel treatments to combat SARS-CoV-2 illness.
- The computationally complex simulations were initially conducted on Comet at UC San Diego’s San Diego Supercomputer Center.
Discovery of Glycan Gates
Scientists have been pursuing the mysteries of the processes that allow the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to penetrate and infect healthy human cells since the beginning of the COVID pandemic.
Rommie Amaro, a computational biophysical chemist at the University of California San Diego, helped build a comprehensive picture of the SARS-CoV-2 spike protein that efficiently hooks onto human cell receptors early in the pandemic.
Now, Amaro and her colleagues from UC San Diego, the University of Pittsburgh, the University of Texas at Austin, Columbia University, and the University of Wisconsin-Milwaukee have discovered how glycans—molecules that make up a sugary residue around the spike protein’s edges—act as infection gateways.
Amaro, along with co-senior author Lillian Chong of the University of Pittsburgh, first author and UC San Diego graduate student Terra Sztain, and co-first author and UC San Diego postdoctoral scholar Surl-Hee Ahn, published a study in the journal Nature Chemistry on August 19 that describes the discovery of glycan “gates” that open to allow SARS-CoV-2 entry.
Solving the infection puzzle
According to Amaro, the study team’s gate finding might lead to novel treatments to combat SARS-CoV-2 illness. The virus is successfully stopped from opening to entrance and infection if glycan gates can be pharmacologically locked in the closed state.
The spike’s glycan coating deceives the human immune system by seeming to be nothing more than a sugary residue. Previous technologies that scanned these structures showed glycans in static open or closed states, which didn’t pique scientists’ curiosity at first. The researchers used supercomputing models to create dynamic videos that showed glycan gates activating from one location to another, providing an unprecedented piece of the infection puzzle.
The computationally complex simulations were initially conducted on Comet at UC San Diego’s San Diego Supercomputer Center, then on Longhorn at UT Austin’s Texas Advanced Computing Center. The researchers were able to get atomic-level images of the spike protein receptor-binding domain, or RBD, from over 300 different angles because of this computer capacity. Glycan “N343” was discovered to be the linchpin that pries the RBD from the “down” to the “up” position, allowing access to the ACE2 receptor on the host cell. N343 glycan activation is compared to a “molecular crowbar” process by the researchers.
Jason McLellan, an associate professor of molecular biosciences at the University of Texas at Austin, and his colleagues produced spike protein variants and examined how the absence of the glycan gate affected the RBD’s capacity to open.
“We showed that without this gate, the RBD of the spike protein can’t take the conformation it needs to infect cells,” McLellan said.