Pioneering simulations focus on HIV-1 virus
First computer models developed for deadly virus's envelope and genome
capsid

Date:
February 23, 2022
Source:
University of Texas at Austin, Texas Advanced Computing Center
Summary:
First-ever biologically authentic computer model was completed of
the HIV-1 virus liposome. Key finding from the simulations is the
formation of sphingomyelin and cholesterol rich microdomains. HIV-1
is known to preferentially bud from regions of the host cell
membrane where these constituents are in high abundance. Scientists
are hopeful this basic research into viral envelopes can help
efforts to develop new HIV- 1 therapeutics, as well as laying
a foundation for study of other enveloped viruses such as the
novel coronavirus.



FULL STORY ==========================================================================
When is a container not just a container?

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For the HIV-1 virus, a double layer of fatty molecules called lipids not
only serves as its container, but also plays a key role in the virus's replication and infectivity. Scientists have used supercomputers to
complete the first-ever biologically authentic computer model of the
HIV-1 virus liposome, its complete spherical lipid bilayer.

What's more, this study comes fresh off the heels of a new atomistic model
of the HIV-1 capsid, which contains its genetic material. The scientists
are hopeful this basic research into viral envelopes can help efforts to develop new HIV-1 therapeutics, as well as laying a foundation for study
of other enveloped viruses such as the novel coronavirus, SARS-CoV-2.

"This work represents an investigation of the HIV-1 liposome at
full-scale, and with an unprecedented level of chemical complexity,"
said Alex Bryer, a PhD student in the Perilla Laboratory, Department of Chemistry and Biochemistry, University of Delaware. Bryer is the lead
author of the liposome-modeling research, published January 2022 in the
journal PLOS Computational Biology.

The science team developed a complex chemical model of the HIV-1 liposome
that revealed key characteristics of the liposome's asymmetry. Most such
models assume a geometrically uniform structure and don't capture the
asymmetry inherent in such biological containers.

Lipid Flip-Flop Bryer and his co-authors investigated a mechanism that's
known colloquially as "lipid flip-flop," which is when lipids in one
of the leaflets of the bilayer are moved or transported to the other
leaflet. The leaflets flip-flop the lipids and exchange the molecules
for various purposes such as achieving a dynamic equilibrium.



==========================================================================
"For the spherical vesicle model of the liposome, our simulations show
that asymmetry occurs spontaneously even without embedded proteins, and
the vesicle can flip-flop to maintain an asymmetric composition within
tight tolerances - - even over biological timescales in excess of five microseconds," Bryer said.

Interestingly, the science team did not observe incidence of flip-flop
in a flat membrane system, which suggests that curvature of the envelope
is intimately related to this biological process.

"Nothing like this has ever been simulated before." said study co-author
Juan R. Perilla, an assistant professor in the Department of Chemistry
and Biochemistry, University of Delaware.

"What was surprising for us is this dynamic equilibrium that the vesicle shows," Perilla added. "Lipids are moving in and out, but the overall composition is not changing -- that was surprising." Key Asymmetry This
key finding shows that the complex, asymmetric membrane composition of the HIV-1 virus can lead to macroscopic properties such as the differential displacement between leaflets and lipid microdomain formation.



==========================================================================
That formation might have implications in how membrane proteins, which
often localize within specific lipid microdomains, interact with the
membrane and carry out functions such as binding to host cells and
allowing the virus to enter them.

For HIV-1, it's known that microdomains form and act as a target for
the localization of membrane proteins. One protein in particular, gp41,
is critical for membrane fusion, which is the process of HIV-1 joining
with the host cell membrane and ultimately infecting it.

"It's thought that gp41 localizes to these domains," Bryer said. "What
we showed was that these microdomains can form in the vesicle without
the aid of proteins. They seem to emerge spontaneously." This finding
might also explain the preferential budding behavior in HIV- 1 viral replication, without the need of embedded proteins in mediating the
formation of the microdomains that enable budding.

Supercomputer Simulations The computer model Bryer and colleagues
developed is 150 nm in diameter and consists of 24 different chemical constituents. There are more than 300,000 total lipid molecules,
solvated in water and ionized with sodium chloride, to represent a
biological environment. The science team employed a coarse-grained
model known as MARTINI, which allowed them to reduce the degrees of
freedom in the molecular system and achieve simulation sampling over microsecond timescales.

The scientists were awarded supercomputer allocations and training by
XSEDE funded by the National Science Foundation. Through XSEDE, they used
the Stampede2 system at the Texas Advanced Computing Center (TACC) and Bridges-2 at the Pittsburgh Supercomputing Center (PSC). Additionally,
they used Grizzly at the Los Alamos National Laboratory; Blue Waters at
the National Center for Supercomputing Applications; and the Frontera
system at TACC.

"Our study wouldn't have been possible without XSEDE resources,"
Bryer said.

"We can achieve some very high sampling efficiencies using Stampede2
Skylake nodes, both to run the simulations and perform analyses."
"I was able to perform calculations, and without needing to transfer
data, I could set up a visualization session through the TACC portal and analyze and work with my data directly on Stampede2. That's amazing,"
added Bryer. He found that not having to transfer terabytes of data
into a separate visualization computer node was "just huge in terms
of productivity." "We also used quite a bit of the high memory nodes
on Bridges-2 of PSC," Perilla said. They helped power simulations that
compared the control, a flat HIV-1 viral membrane, to the curved one in
dynamic equilibrium.

What's more, the Perilla Lab has transferred the simulation work to
their local cluster, the XSEDE-allocated DARWIN system of the University
of Delaware.

"It's important to highlight the fact that XSEDE does not just provide resources, which are extremely valuable. There's training and other opportunities such as workshops," Perilla said.

"When I joined the group, I had never logged into a supercomputer,"
Bryer said.

He recalled valuable training in XSEDE workshops on OpenMP, MPI, and
OpenACC, which assist scientists in parallelizing their computer code.

Frontera Work Bryer also highlighted the analysis work run on TACC's
Frontera, the fastest academic supercomputer in the world. "Parallel I/O
via Luster is what made a lot of the analyses possible in the manuscript," Bryer said. "On Frontera we were able to classify the volume surrounding
the vesicle quickly and process our data in minutes. We estimated
it might take about three weeks if we were to run the analysis in a
serial naive implementation." The Perilla Lab has focused all of this computing power and expertise into learning more about the mysteries of
what happens to the HIV-1 viral envelope during infection.

"While this study does not provide the whole answer, it's getting there
in what the lipids are doing and what integral membrane proteins are
doing or could be doing; and not only how proteins like gp41 interact
with human receptors but also how they transmit their signals and how
that is related to lipid composition," Perilla said.

"This computational study provides an opportunity for drug development research," Perilla added.

Since lipid symmetry is maintained by the curvature of the envelope,
a promising possibility yet unexplored is development of small molecules
that affect the symmetry and potentially yield a therapeutic target.

HIV-1 Capsid Just prior to the liposome research, Perilla and colleagues
also broke new ground in using supercomputers to build the first-ever
atomistic model of the HIV-1 capsid, the envelope for its genetic
material, in the presence of the metabolite IP6. The work was published November 2021 in the journal Science Advances. It also used the Bridges-2
and Stampede2 supercomputers allocated through XSEDE.

The simulations, validated by cryo-electron tomography data, showed
that IP6 was able to bind in two locations to the capsid, instead of
just one as previously thought. This finding is important because during infection, the capsid is exposed to the cytoplasm and has to go through
the nuclear import mechanism, namely the nuclear pore complex. All these
pieces together point to the capsid being able to "sense" in an as yet
unknown way the concentration of IP6.

Said Perilla: "Computationally, these are very unique simulations
because of the number of degrees of freedom involved. Nobody's
ever walked this path before. We're walking through the dark. And
we're making tools that can help us see beyond where we are." ========================================================================== Story Source: Materials provided by University_of_Texas_at_Austin,_Texas_Advanced_Computing Center. Original written by Jorge Salazar. Note: Content may be edited for style and
length.


========================================================================== Journal Reference:
1. Alexander J. Bryer, Tyler Reddy, Edward Lyman, Juan R. Perilla. Full
scale structural, mechanical and dynamical properties of HIV-1
liposomes.

PLOS Computational Biology, 2022; 18 (1): e1009781 DOI: 10.1371/
journal.pcbi.1009781 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220223133450.htm

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