Targeting the shell of the Ebola virus
Research team looking at ways to destabilize virus, knock it out with antivirals

Date:
October 20, 2020
Source:
University of Delaware
Summary:
As the world grapples with COVID-19, the Ebola virus is again
raging.

Researchers are using supercomputers to simulate the inner workings
of Ebola (as well as COVID-19), looking at how molecules move,
atom by atom, to carry out their functions. Now, they have revealed
structural features of the Ebola virus's protein shell to provide
therapeutic targets to destabilize the virus and knock it out with
an antiviral treatment.



FULL STORY ==========================================================================
As the world grapples with the coronavirus (COVID-19) pandemic, another
virus has been raging again in the Democratic Republic of the Congo
in recent months: Ebola. Since the first terrifying outbreak in 2013,
the Ebola virus has periodically emerged in Africa, causing horrific
bleeding in its victims and, in many cases, death.


==========================================================================
How can we battle these infectious agents that reproduce by hijacking
cells and reprogramming them into virus-replicating machines? Science
at the molecular level is critical to gaining the upper hand -- research
you'll find underway in the laboratory of Professor Juan Perilla at the University of Delaware.

Perilla and his team of graduate and undergraduate students in UD's
Department of Chemistry and Biochemistry are using supercomputers to
simulate the inner workings of Ebola, observing the way molecules move,
atom by atom, to carry out their functions. In the team's latest work,
they reveal structural features of the virus's coiled protein shell,
or nucleocapsid, that may be promising therapeutic targets, more easily destabilized and knocked out by an antiviral treatment.

The research is highlighted in the Tuesday, Oct. 20 issue of the Journal
of Chemical Physics, which is published by the American Institute of
Physics, a federation of societies in the physical sciences representing
more than 120,000 members.

"The Ebola nucleocapsid looks like a Slinky walking spring, whose
neighboring rings are connected," Perilla said. "We tried to find what
factors control the stability of this spring in our computer simulations."
The life cycle of Ebola is highly dependent on this coiled nucleocapsid,
which surrounds the virus's genetic material consisting of a single
strand of ribonucleic acid (ssRNA). Nucleoproteins protect this RNA from
being recognized by cellular defense mechanisms. Through interactions with different viral proteins, such as VP24 and VP30, these nucleoproteins form
a minimal functional unit -- a copy machine -- for viral transcription
and replication.



========================================================================== While nucleoproteins are important to the nucleocapsid's stability, the
team's most surprising finding, Perilla said, is that in the absence of
single- stranded RNA, the nucleocapsid quickly becomes disordered. But
RNA alone is not sufficient to stabilize it. The team also observed
charged ions binding to the nucleocapsid, which may reveal where other important cellular factors bind and stabilize the structure during the
virus's life cycle.

Perilla compared the team's work to a search for molecular "knobs" that
control the nucleocapsid's stability like volume control knobs that can
be turned up to hinder virus replication.

The UD team built two molecular dynamics systems of the Ebola nucleocapsid
for their study. One included single-stranded RNA; the other contained
only the nucleoprotein. The systems were then simulated using the Texas Advanced Computing Center's Frontera supercomputer -- the largest
academic supercomputer in the world. The simulations took about two
months to complete.

Graduate research assistant Chaoyi Xu ran the molecular simulations,
while the entire team was involved in developing the analytical
framework and conducting the analysis. Writing the manuscript was a
learning experience for Xu and undergraduate research assistant Tanya Nesterova, who had not been directly involved in this work before. She
also received training as a next-generation computational scientist
with support from UD's Undergraduate Research Scholars program and
NSF's XSEDE-EMPOWER program. The latter has allowed her to perform the highest-level research using the nation's top supercomputers. Postdoctoral researcher Nidhi Katyal's expertise also was essential to bringing the
project to completion, Perilla said.

While a vaccine exists for Ebola, it must be kept extremely cold,
which is difficult in remote African regions where outbreaks have
occurred. Will the team's work help advance new treatments? "As basic scientists we are excited to understand the fundamental principles of
Ebola," Perilla said. "The nucleocapsid is the most abundant protein
in the virus and it's highly immunogenic -- able to produce an immune
response. Thus, our new findings may facilitate the development of new antiviral treatments." Currently, Perilla and Jodi Hadden-Perilla are
using supercomputer simulations to study the novel coronavirus that
causes COVID-19. Although the structures of the nucleocapsid in Ebola
and COVID-19 share some similarities -- both are rod- like helical protofilaments and both are involved in the replication, transcription
and packing of viral genomes -- that is where the similarities end.

"We now are refining the methodology we used for Ebola to examine
SARS-CoV-2," Perilla said.


========================================================================== Story Source: Materials provided by University_of_Delaware. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Chaoyi Xu, Nidhi Katyal, Tanya Nesterova, Juan R. Perilla. Molecular
determinants of Ebola nucleocapsid stability from molecular
dynamics simulations. The Journal of Chemical Physics, 2020; 153
(15): 155102 DOI: 10.1063/5.0021491 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201020131355.htm

--- up 8 weeks, 1 day, 6 hours, 50 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1337:3/111)