Science Success Story

Supercomputers Simulate New Pathways for Potential RNA Virus Treatment

XSEDE allocations lead to important viral inhibitor discovery

By Robbin Ray, UNH Communications, and Kimberly Mann Bruch, SDSC Communications

Structural changes in RNA on drug binding/unbinding. Credit: Lev Levintov, University of New Hampshire

University of New Hampshire (UNH) researchers recently used the XSEDE-allocated Comet at the San Diego Supercomputer Center (SDSC) and Stampede2 at the Texas Advanced Computing Center (TACC) to identify new inhibitor binding/unbinding pathways in an RNA-based virus. The findings could be beneficial in understanding how these inhibitors react and potentially help develop a new generation of drugs to target viruses with high death rates, such as HIV-1, Zika, Ebola, and SARS-CoV2, the virus that causes COVID-19.

"When we first started this research, we never anticipated that we'd be in the midst of a pandemic caused by an RNA virus," said Harish Vashisth, associate professor of chemical engineering at UNH. "As these types of viruses emerge, our findings will hopefully offer an enhanced understanding of how viral RNAs interact with inhibitors and be used to design better treatments."

Similar to how humans encode their genome using DNA, many viruses have a genetic makeup of RNA molecules. These RNA-based genomes contain potential sites where inhibitors can attach and deactivate the virus. Part of the challenge in drug development is that variations or mutations in the viral genome may prevent the inhibitors from attaching.

In their study, recently published in the Journal of Physical Chemistry Letters, Vashisth and his team created molecular dynamics simulations using the Comet and Stampede2 supercomputers to look specifically at an RNA fragment from the HIV-1 virus and its interaction with acetylpromazine, a small molecule that is known to interfere with the virus replication process.

Comet and Stampede2 provided exceptional platforms to enhance the impact of our work carried out via existing grants," said UNH Associate Professor of Chemical Engineering Harish Vashisth, who has been using XSEDE resources for almost a decade. "The XSEDE initiative has been a game changer in biomolecular simulations by providing access to a large number of pre-installed software tools, training for students and principal investigators such as myself, data analysis and visualization tools, and long-term data storage.

The scientists focused on the structural elements from the HIV-1 RNA genome because they are considered a good model for studying the same processes across a wide range of RNA viruses. These simulations enabled them to discover the pathways of the inhibitor unbinding from the viral RNA in several rare events – which are often difficult to observe experimentally – that unexpectedly showed a coordinated movement in many parts of the binding pocket that are the building blocks of RNA.

Thanks to the National Science Foundation's (NSF) Extreme Science and Engineering Environment (XSEDE) allocations on Comet and Stampede2, the researchers were able to run hundreds of simulations at the same time to observe what are called rare base-flipping events involved in the inhibitor binding/unbinding process that provided the new details of the underlying mechanism of this process.

"Our hope is that this adds new possibilities to a field traditionally focused on static biomolecular structures and leads to new medications," Vashisth said.

Funding for this study was provided by NSF (CBET-1554558) and NSF (OIA-1757371). Access to Comet and Stampede2 was provided by NSF XSEDE allocation (TG-MCB160183).

 

At a Glance

  • University of New Hampshire researchers use XSEDE allocations to better understand how viral RNAs interact with inhibitor.
  • Stampede2 and Comet were used for simulations to show new inhibitor binding/unbinding pathways in an RNA-based virus.
  • The findings could potentially help develop new medications to target viruses like SARS-CoV2, the virus that causes COVID-19.