Busting Up the Infection Cycle of Hepatitis B
Researchers at UD use supercomputer to gain insights into virus's genetic blueprint

Date:
August 13, 2020
Source:
University of Delaware
Summary:
Researchers have gained new understanding of the virus that
causes hepatitis B and the 'spiky ball' that encloses its genetic
blueprint.

They looked at how the capsid -- a protein shell that protects the
blueprint and also drives the delivery of it to infect a host cell -
- assembles itself. The capsid is an important target in developing
drugs to treat hepatitis B, a life-threatening and incurable
infection that afflicts more than 250 million people worldwide.



FULL STORY ========================================================================== Researchers at the University of Delaware, using supercomputing resources
and collaborating with scientists at Indiana University, have gained new understanding of the virus that causes hepatitis B and the "spiky ball"
that encloses the virus's genetic blueprint.


==========================================================================
The research, which has been published online, ahead of print, by the
American Chemical Association journal ACS Chemical Biology, provides
insights into how the capsid -- a protein shell that protects the
blueprint and also drives the delivery of it to infect a host cell --
assembles itself.

Computer simulations performed by the UD scientists investigated the
effects of a mutation that impairs the assembly process. Together with collaborators, the researchers revealed that the region of the protein
that contains the mutation, the spike, can communicate with the region of
the protein that links with other subunits to assemble the capsid. They
found evidence that a change in the shape of the capsid protein switches
it into an "on" state for assembly.

Scientists believe that the capsid is an important target in developing
drugs to treat hepatitis B, a life-threatening and incurable infection
that afflicts more than 250 million people worldwide.

"The capsid looks like a spiky ball, with 120 protein dimers that assemble
to form it; each dimer contains a spike," said Jodi A. Hadden-Perilla, assistant professor in UD's Department of Chemistry and Biochemistry and
a co-author of the new paper. "The capsid is key to the virus infection
cycle. If we could disrupt the assembly process, the virus wouldn't be
able to produce infectious copies of itself." The Indiana University researchers had been studying the dimers, which are two- part, T-shaped molecular structures, and investigating whether a mutation could activate
or deactivate a switch to turn on the capsid's assembly mechanism.

They worked with Hadden-Perilla's group, which ran computer simulations
to explain how changes in the protein structure induced by the mutation affected the capsid's ability to assemble.



========================================================================== "What we learned is that this mutation disrupts the structure of the
spike at the top of the dimer," Hadden-Perilla said. "This mutation
slows down assembly, which actually involves a region of the protein
that is far away from the spike. It's clear that these two regions are connected. A change in the shape of the protein, particularly at the
spike, may actually activate or deactivate assembly." Her team did
its work using the National Science Foundation-supported Blue Waters supercomputer at the University of Illinois at Urbana-Champaign, the
largest supercomputer on any university campus in the world, to perform
what are known as all-atom molecular dynamics simulations.

Molecular dynamics simulations allow researchers to study the way
molecules move in order to learn how they carry out their functions in
nature. Computer simulations are the only method that can reveal the
motion of molecular systems down to the atomic level and are sometimes
referred to as the "computational microscope." The paper, titled "The integrity of the intradimer interface of the Hepatitis B Virus capsid
protein dimer regulates capsid self-assembly," can be viewed on the
journal's website.

From Colombia to UD For doctoral student Carolina Pe'rez Segura,
a co-author of the paper, working with data from the supercomputer
simulations was the kind of research experience that first brought her
to the University of Delaware and then inspired her to stay.



==========================================================================
She examined numerous simulations and vast amounts of data to investigate
the effect of the mutation and "made some important discoveries," Hadden-Perilla said. "We threw her into the deep end in my brand-new
research group [last summer], and she did a great job." Pe'rez Segura
came to UD as a participant in the University's Latin American Summer
Research Program. A graduate of the Universidad Nacional de Colombia
(National University of Colombia), the program marked her first time
leaving Colombia and, indeed, her first time traveling by plane. She
planned to conduct research under Hadden-Perilla's mentorship for a
couple of months and then return home.

But, she said, the experience was so meaningful to her that she canceled
her plane ticket home and stayed on to work as a visiting scholar with
Hadden- Perilla while applying to UD's doctoral program in chemistry. She
was accepted and began her studies during spring semester.

It was her fascination with computational chemistry that brought her
to Delaware, she said, and the work with supercomputers that made her
decide to continue that research.

"While I was an undergraduate, I chose that branch of chemistry as
the kind of career I wanted," said Pe'rez Segura, who worked with a
research group in the field, on a smaller scale, in Colombia. "When I
was introduced to the idea that math and physics can help you understand biological processes, I knew that was what I wanted to do.

"I thought it was really amazing to be able to explain biological
processes with numbers and computers. I wanted to learn more, and here,
there's so much more opportunity to learn it." Although the social and
travel restrictions imposed by the coronavirus (COVID- 19) pandemic have limited her ability to fully experience American life and culture, she
said her experience at UD remains very positive. She's eager to be able
to go out more, practice her English and feel a part of American culture,
but meanwhile, she's busy with exciting research, she said.

She's currently also working on research that Hadden-Perilla is conducting
into the virus that causes COVID-19.


========================================================================== Story Source: Materials provided by University_of_Delaware. Original
written by Ann Manser.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Zhongchao Zhao, Joseph Che-Yen Wang, Carolina Perez Segura, Jodi A
Hadden-Perilla, Adam Zlotnick. The integrity of the intradimer
interface of the Hepatitis B Virus capsid protein dimer
regulates capsid self- assembly. ACS Chemical Biology, 2020; DOI:
10.1021/acschembio.0c00277 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200813155829.htm

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