By XSEDE
By stretching the amount of time proteins can be simulated in their natural state of wiggling and gyrating, a team of researchers at Colorado State University, using XSEDE high-performance supercomputers, has identified a critical protein structure that could serve as a molecular Achilles heel able to inhibit the replication of dengue virus and potentially other flaviviruses such as West Nile and Zika virus.
As described in the current edition of PLOS Computational Biology, the simulations home in on a small segment of a viral enzyme called non-structural protein 3 (NS3), that plays a critical role in replicating the dengue RNA genome, which the virus requires to survive and spread.
“Our analyses identify a previously underappreciated part of the NS3 enzyme known as ‘motif V’ that serves as a communication hub between two critical binding sites needed for RNA replication,” said Martin McCullagh, assistant professor of chemistry at Colorado State University and the study’s principal investigator. “Our results suggest that this hub could be a novel target for NS3 inhibitors.”
Over the past couple of decades, researchers around the world have considered NS3 a primary target for developing drugs capable of inhibiting and preventing the replication of the dengue virus. But many worry that since NS3’s protein sequence has similarities to related human proteins, drugs capable of inhibiting this enzyme might create unwanted side effects, even affecting a cell’s natural antiviral response.
For this reason, researchers have been trying to further clarify how this viral enzyme works on a molecular scale. The new study does just that through microsecond-long molecular dynamic supercomputer simulations. Though microseconds (millionths of a second) sound extremely brief, the 12.5 microseconds of simulation reported in the current study is 100 times longer than previously reported simulations on dengue NS3.
Advanced software and the rapid calculation speeds of Comet, based at the San Diego Supercomputer Center at UC San Diego; and Bridges, based at the Pittsburgh Supercomputing Center, made the current simulations possible. In particular, the graphics processing units (GPUs) on Comet enabled the team to simulate the motion more efficiently than possible if they had used only the central processing units (CPUs) present on most supercomputers.
“Running the simulations on Comet cut out almost a year – 360 days – of run time,” said McCullagh.
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