infection
Supercomputing-derived movies reveal details of deceptive sugar coating
on spike protein, presenting new possibilities to block cell entry and infection

Date:
August 19, 2021
Source:
University of California - San Diego
Summary:
Unprecedented visualizations of SARS-CoV-2 have allowed researchers
to discover how the virus enters and infects healthy human cells.

Supercomputing movies have revealed how glycans -- molecules that
make up a sugary residue around the edges of the SARS-CoV-2 spike
protein -- act as infection 'gates' that open to allow access to
our cell's receptors.



FULL STORY ========================================================================== Since the early days of the COVID pandemic, scientists have aggressively pursued the secrets of the mechanisms that allow severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to enter and infect healthy human
cells.


========================================================================== Early in the pandemic, University of California San Diego's Rommie
Amaro, a computational biophysical chemist, helped develop a detailed visualization of the SARS-CoV-2 spike protein that efficiently latches
onto our cell receptors.

Now, Amaro and her research colleagues from UC San Diego, University
of Pittsburgh, University of Texas at Austin, Columbia University
and University of Wisconsin-Milwaukee have discovered how glycans --
molecules that make up a sugary residue around the edges of the spike
protein -- act as infection gateways.

Published August 19 in the journal Nature Chemistry, a research study led
by Amaro, co-senior author Lillian Chong at 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, describes
the discovery of glycan "gates" that open to allow SARS-CoV-2 entry.

"We essentially figured out how the spike actually opens and infects,"
said Amaro, a professor of chemistry and biochemistry and a senior
author of the new study. "We've unlocked an important secret of the
spike in how it infects cells. Without this gate the virus basically is rendered incapable of infection." Amaro believes the research team's
gate discovery opens potential avenues for new therapeutics to counter SARS-CoV-2 infection. If glycan gates could be pharmacologically locked
in the closed position, then the virus is effectively prevented from
opening to entry and infection.



==========================================================================
The spike's coating of glycans helps deceive the human immune system
since it comes across as nothing more than a sugary residue. Previous technologies that imaged these structures depicted glycans in static
open or closed positions, which initially didn't draw much interest from scientists. Supercomputing simulations then allowed the researchers to
develop dynamic movies that revealed glycan gates activating from one
position to another, offering an unprecedented piece of the infection
story.

"We were actually able to watch the opening and closing," said
Amaro. "That's one of the really cool things these simulations give you --
the ability to see really detailed movies. When you watch them you realize you're seeing something that we otherwise would have ignored. You look
at just the closed structure, and then you look at the open structure,
and it doesn't look like anything special. It's only because we captured
the movie of the whole process that you actually see it doing its thing." "Standard techniques would have required years to simulate this opening process, but with my lab's 'weighted ensemble' advanced simulation tools,
we were able to capture the process in only 45 days," said Chong.

The computationally intensive simulations were first run on Comet at the
San Diego Supercomputer Center at UC San Diego and later on Longhorn at
the Texas Advanced Computing Center at UT Austin. Such computing power
provided the researchers with atomic-level views of the spike protein
receptor binding domain, or RBD, from more than 300 perspectives. The investigations revealed glycan "N343" as the linchpin that pries the RBD
from the "down" to "up" position to allow access to the host cell's ACE2 receptor. The researchers describe N343 glycan activation as similar to a "molecular crowbar" mechanism.

Jason McLellan, an associate professor of molecular biosciences at UT
Austin and his team created variants of the spike protein and tested to
see how a lack of the glycan gate affected the RBD's ability 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.

The full author list includes: Terra Sztain, Surl-Hee Ahn, Anthony
Bogetti, Lorenzo Casalino, Jory Goldsmith, Evan Seitz, Ryan McCool, Fiona Kearns, Francisco Acosta-Reyes, Suvrajit Maji, Ghoncheh Mashayekhi,
J. Andrew McCammon, Abbas Ourmazd, Joachim Frank, Jason McLellan,
Lillian Chong and Rommie Amaro.

========================================================================== Story Source: Materials provided by
University_of_California_-_San_Diego. Original written by Mario
Aguilera. Note: Content may be edited for style and length.


========================================================================== Related Multimedia:
* YouTube_video:_The_glycan_gate_opens ========================================================================== Journal Reference:
1. Terra Sztain, Surl-Hee Ahn, Anthony T. Bogetti, Lorenzo Casalino,
Jory A.

Goldsmith, Evan Seitz, Ryan S. McCool, Fiona L. Kearns, Francisco
Acosta- Reyes, Suvrajit Maji, Ghoncheh Mashayekhi, J. Andrew
McCammon, Abbas Ourmazd, Joachim Frank, Jason S. McLellan, Lillian
T. Chong, Rommie E.

Amaro. A glycan gate controls opening of the SARS-CoV-2 spike
protein.

Nature Chemistry, Aug. 19, 2021; DOI: 10.1038/s41557-021-00758-3 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210819113057.htm

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