Simulating Tiny Invaders February 20, 2024 Science Features ACCESSDeltaHealth SciencesModeling and Simulation Share this page: Twitter Facebook LinkedIn Email By Megan Meave Johnson Imagine your house is burgled on a regular basis. You’d want to stop these incursions, but first, you have to know how someone’s breaking in. Your house has the normal barriers houses usually do – locks on the doors and windows, and porch lights to make your home less friendly to sneaky invaders – but these aren’t working. You might investigate to find out if there’s a way into your house you didn’t know existed. When scientists tackle viruses like Hepatitis B, they need to know how that virus is breaking past the natural barriers the human body puts up to halt its progress. That’s just what Jodi Hadden-Perilla, former UIUC post-doc and now a professor of chemistry and biochemistry at the University of Delaware (UD), is using NCSA’s Delta to do. While there is a vaccine for Hepatitis B, it’s still a major public health problem worldwide. This bloodborne viral infection can become chronic, especially in those infected at a young age. Hadden-Perilla has been studying the virus in an attempt to create an effective treatment for chronic sufferers. “People who suffer from chronic infection of Hepatitis B have an increased risk of developing liver cirrhosis and cancer, so researchers are studying the life cycle of the virus to identify ways to inhibit it,” she said. Jodi Hadden-Perilla holds a GPU from NCSA’s now-decommissioned Blue Waters supercomputer, the machine that enabled her first simulations of the Hepatitis B virus capsid while she was a post-doc in the NAMD development lab at UIUC. Credit: Evan Krape, University of Delaware To do this work, Hadden-Perilla collaborated with Gino Cingolani, a professor of biochemistry and molecular genetics at the University of Alabama (UA). “We investigated a key stage of the life cycle in which the virus binds human proteins called importins and uses them to ‘import’ its genome into the cell nucleus for replication,” Hadden-Perilla explained. “Dr. Cingolani’s group used a specialized microscope to take high-resolution pictures of the virus binding importins, showing for the first time the structural details of this interaction.” Hadden-Perilla further explained that this isn’t as straightforward as it sounds. “We faced two challenges: First, the part of the virus that binds importins is very flexible and only becomes exposed when the virus is ready to travel to the nucleus, so only a small fragment of the virus was visible in Dr. Cingolani’s pictures. Second, previous studies show that nuclear import depends on the virus being modified with phosphates, or being ‘phosphorylated’ by the host cell, but this was not explained by the pictures because the fragment of the virus visualized in contact with importins did not contain any phosphates.” Studying these viral interactions with human cells in real time would be extraordinarily difficult, but supercomputers like Delta are designed specifically to assist in this type of research. Delta’s GPU-based architecture makes it ideal for simulation work. Hadden-Perilla is familiar with using supercomputing resources in her work from her time at UIUC working with the historic Blue Waters. She knew the simulations would provide the perfect tool for her team to make progress on their research. NCSA is proud to continue our long-running support of GPU-accelerated computational science with the Delta supercomputer, currently the largest NSF GPU-accelerated computational resource. As this research demonstrates, Delta is a superb platform for molecular dynamics as well as many other areas of computational science and machine learning/AI. –Brett Bode, Senior Assistant Director, Delta Project Office, NCSA “My research group at UD used all-atom Molecular Dynamic (MD) simulations to characterize the effect of phosphorylation on the virus’s flexible structure, as well as on the virus-importin binding interaction,” she said. “Thanks to GPU resources on NCSA’s Delta supercomputer, we showed that phosphates have both positive and negative consequences for the strength of importin binding to the virus, but that these roughly cancel each other out for no net impact. Dr. Cingolani’s group reached a similar conclusion based on biochemical assays. However, MD simulations also revealed that when the virus is modified with phosphates, its structure becomes more compact, which controls the way the importin binding fragment is displayed for recognition. A more compact virus-importin complex likely also helps the particle pass intact into the nucleus to deposit the genome there.” Delta and the team that manages it also received high praise from Hadden-Perilla. “My students love using Delta because they get excellent performance for their MD simulations on the A100 GPUs,” she said. “The Delta support team was quick to respond when we reached out to them, and we were able to get our MD simulations up and running very quickly after being granted access. NCSA does a great job managing the machine.” Hadden-Perilla’s research puts scientists one step closer to creating a treatment plan that could effectively cure chronic Hepatitis B. “This research is impactful because it explains the structural basis of how the Hepatitis B virus recruits importin proteins to transport its genome into the nucleus, a key step in hijacking the host cell to make copies of itself. Characterizing the all-atom structure of the virus-importin binding interaction, including how it is influenced by phosphorylation, provides a platform for developing inhibitors that could potentially block this interaction and prevent the virus from accessing the nucleus.” Using NCSA Delta GPUs, we were able to obtain over 7 microseconds of sampling for the virus-importin complex, which was really important to interpreting the results because the Hepatitis B virus structure is so flexible. –Jodi Hadden-Perilla, professor of chemistry and biochemistry, University of Delaware As for what comes next, Hadden-Perilla recently received an NSF CAREER award. She plans to put that funding to immediate use, furthering her research in this field. “The NSF CAREER award I received last year is to study the role of phosphorylation in regulating viral life cycle processes, particularly for the Hepatitis B virus, so my group will definitely be expanding on this work. Phosphate modifications affect the virus’s ability to carry out other functions during infection, like packaging its genome, displaying chemical signals, and moving throughout the host cell. The more we understand about how the virus works, the better positioned we become to develop strategies to interfere with it. Dr. Cingolani’s group studies the mechanisms of genome delivery in viruses, so our collaboration was natural on this project. Next, they plan to visualize Hepatitis B inside infected cells using an even more high-powered microscope, which will provide high-quality information for our future modeling and MD simulations, including on NCSA computing resources.” If you’d like to read more about Hadden-Perilla’s research, her team published her findings in Science Advances: Structural basis for nuclear import of hepatitis B virus (HBV) nucleocapsid core Hadden-Perilla’s team used an ACCESS allocation BIO230131 for this work that included time on Purdue’s supercomputer, Anvil. They also used Pittsburgh Supercomputing Center’s (PSC) Anton 2, a specialized supercomputer designed for biomolecular simulation and funded with assistance from the NIH National Institute of General Medical Sciences. ABOUT DELTA NCSA combines next-generation processor architectures and NVIDIA graphics processors with forward-looking user interfaces and file systems to create Delta, a powerful computing and data analysis resource that is part of the national cyberinfrastructure ecosystem through ACCESS. The project partners with the Science Gateways Community Institute to empower broad communities of researchers to easily access Delta and with the University of Illinois Division of Disability Resources & Educational Services and the School of Information Sciences to explore and reduce barriers to access. Delta is funded through NSF OAC 2005572.