News ID: 278431
Published: 1003 GMT December 21, 2020

Targeting the deadly coils of Ebola

Targeting the deadly coils of Ebola
Molecular surface representation of the Ebola virus nucleocapsid with bound RNA

In the midst of a global pandemic with COVID-19, it's hard to appreciate how lucky those outside of Africa have been to avoid the deadly Ebola virus disease. It incapacitates its victims soon after infection with massive vomiting or diarrhea, leading to death from fluid loss in about 50 percent of the afflicted. The Ebola virus transmits only through bodily fluids, marking a key difference from the COVID-19 virus and one that has helped contain Ebola's spread.

Ebola outbreaks continue to flare up in West Africa, although a vaccine developed in December 2019 and improvements in care and containment have helped keep Ebola in check. Supercomputer simulations by a University of Delaware team that included an undergraduate supported by the XSEDE EMPOWER program are adding to the mix and helping to crack the defenses of Ebola's coiled genetic material. This new research could help lead to breakthroughs in treatment and improved vaccines for Ebola and other deadly viral diseases such as COVID-19, reported. 

"Our main findings are related to the stability of the Ebola nucleocapsid," said Juan R. Perilla, an assistant professor in the Department of Chemistry and Biochemistry at the University of Delaware. Perilla coauthored 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 Ebola uses to replicate itself.

"What we've found is that the Ebola virus has evolved to regulate the stability of the nucleocapsid by forming electrostatic interactions with its RNA, its genetic material," Perilla said. "There is an interplay between the RNA and the nucleocapsid that keeps it together."

Like coronaviruses, the Ebola virus depends on a rod-like and helically-shaped nucleocapsid to complete its life cycle. In particular, structural proteins called nucleoproteins assemble in a helical arrangement to encapsulate the single-stranded viral RNA genome (ssRNA) that forms the nucleocapsid.

The study by Perilla and his science team sought the molecular determinants of the nucleocapsid stability, such as how the ssRNA genetic material is packaged, the electrostatic potential of the system, and the residue arrangement in the helical assembly. This knowledge is essential for developing new therapeutics against Ebola. Yet these insights remain out of reach even by the world's best experimental labs. Computer simulations, however, can and did fill that gap.

"You can think of simulation work as a theoretical extension of experimental work," said study coauthor Tanya Nesterova, an undergraduate researcher in the Perilla Lab. "We found that RNA is highly negatively charged and helps stabilize the nucleocapsid through electrostatic interaction with the mostly positively charged nucleoproteins," she said.

Nesterova was awarded funding through an XSEDE Expert Mentoring Producing Opportunities for Work, Education, and Research (EMPOWER) scholarship in 2019, which supports undergrads participate in the actual work of XSEDE.

"It was an effective program," she said. "We used computational resources such as Bridges this summer. We also had regular communication with the coordinator to keep our progress on track."

The team developed a molecular dynamics simulation of the Ebola nucleocapsid, a system that contains 4.8 million atoms. They used the 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 coauthor Chaoyi Xu, a Ph.D. student in the Perilla Lab. "One system is the Ebola nucleocapsid with the RNA. And the other one is just the nucleocapsid as a control."

"After we built the whole tube, we put each nucleocapsid in an environment that is similar to the cell," Xu explained. They basically added sodium chloride ions, and then adjusted the concentration to match that found in the cytoplasm. They also put a water box inside around the nucleocapsid. "And then we ran a very powerful simulation," Xu added.

The NSF-funded Extreme Science and Engineering Discovery Environment (XSEDE) awarded the team supercomputing allocations on the Stampede2 system at the Texas Advanced Computing Center and the Bridges system of the Pittsburgh Supercomputing Center.

"We are very thankful for the supercomputer resources provided by XSEDE that allowed this work to be possible. XSEDE also provided training through online courses that was helpful," Xu said.

"On Stampede2, we have access to run simulations 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. This simulation is impossible to finish locally. That's very important," he said.

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