Supercomputer simulation points way to new Ebola treatment

Researchers at the University of Delaware have built a complex model to simulate the molecular dynamics within the Ebola virus. Their findings could assist the development of new treatments for Ebola and other viral diseases such as Covid-19.

 Ebola outbreaks have continued to flare up in West Africa, even after the development of a vaccine and improvements in care and containment. The Ebola virus is only transmitted through bodily fluids, marking a key difference from the more readily transmissible SARS-CoV-2 virus responsible for Covid-19.

Now, supercomputer simulations have been used to help crack the defences of Ebola’s genetic material, contributing to breakthroughs in treatment and vaccines for Ebola and other viruses.

“Our main findings are related to the stability of the Ebola nucleocapsid,” said Professor Juan Perilla. The nucleocapsid is a protein shell which protects the RNA from the host body’s defences.

“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. There’s an interplay between the RNA and the nucleocapsid that keeps it together.”

Like coronaviruses, the Ebola virus lifecycle depends on a rod-like nucleocapsid, formed when structural proteins called nucleoproteins assemble in a helical arrangement to envelope the RNA genome. This study focused on factors contributing to nucleocapsid stability, such as how the genetic material is packaged, the electrostatic potential of the system, and the residue arrangement in the structure.

While this information is essential for developing new treatments against Ebola, it remains out of reach to even the world’s most sophisticated experimental labs. The researchers filled this gap using computer simulations.

“You can think of simulation work as a theoretical extension of experimental work,” said undergraduate researcher and co-author Tanya Nesterova. “We found that RNA is highly negatively charged and helps stabilise the nucleocapsid through electrostatic interaction with the mostly positively charged nucleoproteins.”

The team developed a molecular dynamics simulation of the Ebola nucleocapsid – a system containing 4.8 million atoms – building from the cryo-electron microscopy structure of the virus published in 2018. One system is the nucleocapsid with the RNA, while the other is the nucleocapsid as a control.

They put each structure in an environment similar to a cell, adding sodium chloride ions and adjusting the concentration to match that found in the cytoplasm, and a water box inside around the nucleocapsid. They then ran a simulation using the Stampede2 system at the Texas Advanced Computing Center and the Bridges system of the Pittsbughr Supercomputing Center, with the help of the Extreme Science and Engineering Discovery Environment.

Doctoral student Chaoyi Xu explained: “On Stampede2, we have access to run simulations on hundreds or even thousands of nodes. This makes it possible for us to run simulations of larger systems, for example, the Ebola nucleocapsid. This simulation is impossible to finish locally.”

The team measured how the atoms in the nucleocapsid change with time, yielding useful information about the atomic interactions in the structure. They discovered that without the RNA the nucleocapsid retained its tube-like shape while with the RNA it kept its helix, demonstrating how RNA binding stabilises the helical structure of the nucleocapsid.

Perilla suggested that instead of trying to devise drugs which destroy the Ebola nucleocapsid, an alternative strategy would be to do the opposite: “If you make it too stable, that’s enough to kill the virus,” he said.

Mirroring a strategy used in HIV treatment, a hypothetical Ebola treatment could over-stabilise the virus and prevent it from releasing its genetic material: a key step in its replication. This strategy could be applied to other tightly-regulated viruses, such as coronaviruses and hepatitis B viruses.

“They’re a sweet spot, so to speak,” he continued. “We know what confers stability. Other teams can look to see if maybe this is a good druggable stie for making it hypostable or making it hyperstable.”