Research could lead to better treatment and vaccines for Ebola, COVID-19

In the midst of a global pandemic with COVID-19, it is difficult to comprehend how fortunate those outside Africa have been in avoiding the deadly disease of the Ebola virus. It irritates its victims shortly after infection with severe diarrhea or diarrhea, leading to death from fluid loss in about 50 percent of those affected. The Ebola virus spreads only through body fluids, indicating a major difference from the COVID-19 virus and one that contributed to the spread of Ebola.

Ebola outbreaks are still on the rise in West Africa, although vaccinations were developed in December 2019 and improvements in care and containment have helped monitor Ebola.

Supercomputer simulations by a University of Delaware team that included an undergraduate with support from the XSEDE EMPOWER program add to the mix and help crack the protection of Ebola coiled genetic material. This new research could help advance better treatment and vaccines for Ebola and other deadly viral diseases such as COVID-19.

“Our main findings are related to the stability of the Ebola nucleocapsid,” said Juan R. Perilla, assistant professor in the Department of Chemistry and Biochemistry at the University of Delaware. Perilla co-authored a study published in October 2020 in the AIP Journal of chemistry physics. It focused on the nucleocapsid, a protein shell that protects against the body’s defenses the genetic material that Ebola uses to reproduce itself.

What we have found is that the Ebola virus has evolved to regulate the stability of the nucleocapsid by creating an electrostatic interaction with its RNA, its genetic material. There is an interplay between the RNA and the nucleocapsid that holds it together. “

Juan R. Perilla, Associate Professor, Department of Chemistry and Biochemistry, University of Delaware

Like coronaviruses, the Ebola virus relies on a rod-like nucleocapsid and is helically shaped to complete its life cycle. In particular, structural proteins called nucleoproteins accumulate in a helical arrangement to form the single-stranded viral RNA (ssRNA) genome that makes up the nucleocapsid.

The study by Perilla and his science team sought molecular decisions in nucleocapside stability, such as the packaging of the genetic material ssRNA, the electrostatic capacity of the system, and the residual arrangement in the assembly helical. This knowledge is crucial for the development of new anti-Ebola medications. But these ideas are out of reach even with the best test centers in the world. Computer symbols can, however, fill that gap.

“You can think of simulation work as a theoretical extension of experimental work,” said study co-author Tanya Nesterova, an undergraduate researcher at the Perilla Lab. “We found that charged RNA is very negative and helps stabilize the nucleocapsid through electrostatic interactions with the predominantly charged nucleoproteins,” she said.

Nesterova received funding through the XSEDE Expert Counseling Scholarship out of Opportunities for Work, Education, and Research (EMPOWER) in 2019, which will support undergraduates to participate in real XSEDE work.

“It was an effective program,” she said. “We used computer facilities such as Bridges in the summer. We had regular communication with the coordinator to keep our progress up to date.”

The imitation team developed the molecular dynamics of the Ebola nucleolapsid, a system containing 4.8 million atoms. They used a cryo-electron microscopy structure of the Ebola virus published in Nature in October of 2018 for their data in building the model.

“We built two systems,” said study co-author Chaoyi Xu, a PhD student at the Perilla Lab. “One system is the Ebola nucleocapsid with the RNA. And the other is just the nucleocapsid as a control.”

“After we constructed the entire tube, we placed each nucleocapsid in a cell-like environment,” Xu explained. They basically added sodium chloride ions, and then changed the density to match those found in the cytoplasm. They also place an inner water box around the nucleocapsid. “And then we ran a very powerful simulation,” Xu added.

The NSF-funded Engineering and Engineering Research Environment (XSEDE) provided team supercomputing allowances on the Stampede2 system at the Texas Advanced Computing Center and the bridge system of the Pittsburgh Supercomputing Center.

“We are very grateful for the supercomputer facilities provided by XSEDE that made this work possible. XSEDE also provided training through helpful online courses,” Xu said.

“On Stampede2, we have access to symbols running on hundreds or even thousands of nodes,” Xu continued. “This makes it possible for us to run simulations of larger systems, for example, the Ebola nucleocapsid. It is impossible to complete this simulation locally. That is very important,” he said.

“I like that with Bridges, when you run an imitation, you can be updated about when it ends and when it started,” said Nesterova. She said that was helpful in creating Slurm scripts, which help manage and organize operations on computer records.

“We just started using Frontera for an Ebola project,” Xu said. Frontera is TACC’s flagship Tier 1 NSF system, ranked # 9 in the world by Top500. “It’s more powerful because it has the latest CPU architecture. And it’s very fast,” he said.

“Frontera is part of the TACC infrastructure,” Perilla said. “We knew what the development tools were going to be, and also the queue system and other complex things of those tools. That helped a lot. In terms of architecture, we know Stampede2, although it’s a tool This is different with Stampede2, let ‘s move quickly to start using Frontera, “he said.

The science team considered the interaction of atoms in the nucleocapside of the Ebola virus and measured how they change over time, extracting useful information about atomic interactions. One of the things they found was that without the RNA, the Ebola nucleocapsid virus retained their tube-like shape. But the packing of the nucleoprotein monomers became disturbed, and its helical symmetry was lost. With the RNA, he held his helix. Their results showed that the RNA binding strengthened the helix and preserved the structure of the Ebola nucleocapsid virus.

The team also found important interactions between nucleoprotein residues and the ssRNA, and also interactions between two nucleoproteins.

“There are two types of interfaces between the pairs of nucleoproteins that make up the helical arrangement. We have determined which of these interfaces play a more important role. We can either target that target. to destabilize the helical alignment or to stabilize the helical alignment to a large extent. so that the nucleocapsid virus cannot disintegrate, “said study co – author Nidhi Katyal, a postdoctoral researcher at the Perilla Lab.

The Ebola virus is one hard organism because it tightly regulates its macromolecular assembly. Perilla suggested that instead of trying to design drugs that destroy the nucleocapsid, it might be a good strategy to do the opposite.

“If you make it too stable, that’s enough to kill the virus,” he said. Borrowing a strategy from his background in HIV research, he wants to find targets for drugs to stabilize and prevent the Ebola virus from releasing its genetic material, main step in reproduction.

Perilla suggested a similar strategy for other tightly controlled pathogens, such as coronaviruses and hepatitis B viruses. “They are a sweet place, so to speak. We know what Other teams can look at whether this is a good site for drugs to make it hypostable or to make it hyperstable, “said Perilla.

Looking ahead, Perilla pointed out that his lab will take a closer look at the details of the ssRNA sequence and whether it stabilizes the Ebola virus nucleocapside tube. If it does, some regions may be open and may be transcribed first, similar to what happens in the cell cloud. Perilla said it would be “abnormal in virus,” and extremely positive behavior toward the RNA regulating transcription.

Perilla said: “We know there will be more pathogens that just keep coming, especially with coronaviruses now, and they can stop the world. It’s beneficial for society to be able to study not only one virus, but take these ways to test for a new virus, something like coronaviruses.In addition, the ability to train new students, like Tanya, provides value for money. taxpayers in terms of training the next generation, transferring knowledge from other viruses, and fighting the current problems. “