Scientists have been relentlessly searching for the mechanism that allows severe acute respiratory syndrome coronavirus 2 to infect healthy human cells since the beginning of the COVID pandemic.
Rommie Amaro from the University of California San Diego, a computational biophysical scientist, developed a detailed visualization of SARS-CoV-2 spike proteins that latch onto cells.
Amaro and her colleagues at UC San Diego and University of Pittsburgh, University of Texas at Austin and Columbia University discovered that glycansmolecules, which make up a sugary residue at the spike protein's edges, act as infection gateways.
Published in Nature Chemistry on August 19, a research paper by Amaro and Lillian Chong, University of Pittsburgh's senior author, Terra Sztain, first author, and UC San Diego graduate scholar Surl-Hee Ahn describes the discovery of glycan gates that allow entry to SARS-CoV-2.
Amaro, a professor in chemistry and biochemistry, and senior author of the study said that "we essentially figured out the way the spike actually opens" "We have discovered a key secret about the spike and how it infects cells. This gate renders the virus virtually indestructible.
Supercomputing-driven simulations depict the glycan N343 (magenta) acting as a molecular crowbar to pry open the SARS-CoV-2 spikes receptor binding domain, or RBD (cyan), from a down to an "up" position. Credit: Terra Sztain, Surl-Hee Ahn, Lorenzo Casalino (Amaro Lab, UC San Diego)
Amaro believes that the gate discovery by Amaro's research team opens up potential avenues for new therapies to combat SARS-CoV-2. The virus can be effectively stopped from entering the body by locking the glycan gate in a closed position.
Because the spike's glycans are coated on it, it deceives the immune system. It appears to be nothing more than a sugary residue. These structures were first imaged using previous technologies, but these images didn't attract much attention from scientists. The researchers were able to create dynamic movies using supercomputing simulations, which showed glycan gates activating in different positions. This was a new piece of the infection story.
Amaro said, "We were actually allowed to see the opening and closing." Amaro said, "That's one the coolest things about these simulations-the ability to see very detailed movies. You see things that you wouldn't otherwise notice. It's easy to see the closed structure and the open structure. But it doesn’t look special. You can only see the entire process in motion because we took the video.
Chong stated that standard techniques would have taken years to simulate the opening process. However, using my lab's advanced simulation tools called 'weighted ensemble,' we were able capture it in just 45 days.
The glycan gate opens: Supercomputing-driven simulations depict the glycan N343 (magenta) acting as a molecular crowbar to pry open the SARS-CoV-2 spikes receptor binding domain, or RBD (cyan), from a down to an "up" position. Credit: Terra Sztain, Surl-Hee Ahn, Lorenzo Casalino (Amaro Lab, UC San Diego)
These computationally demanding simulations were first performed on Comet at San Diego Supercomputer Center (UC San Diego) and then on Longhorn at Texas Advanced Computing Center (UT Austin). These computing resources allowed researchers to see the RBD from an atomic level, from over 300 perspectives. Glycan "N343", the linchpin, was identified in the investigations as it pries RBD from the "down” to the "up" position to permit access to the ACE2 receptor of the host cell. Researchers describe N343 glycan activation to be similar to a "molecular crownbar" mechanism.
Jason McLellan is an associate professor of molecular biology at UT Austin. He and his team developed variants of the spike proteins and tested how a lack in the glycan gates affected the RBD's ability open.
McLellan stated, "We demonstrated that the RBD of spike protein cannot take the conformation it requires to infect cells without this gate."
More information: The glycan gates control the opening of the SARS CoV-2 spike protein, Nature Chemistry (2021). www.nature.com/articles/s41557-021-00758-3 Journal information: Nature Chemistry A glycan gate controls opening of the SARS-CoV-2 spike protein,(2021). DOI: 10.1038/s41557-021-00758-3
