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XSEDE-allocated resources at TACC and PSC, together with other national resources, model inositol phosphate interactions with HIV-1 structural proteins


Published on August 9, 2018 by Jorge Salazar

The naturally-occurring compound IP6 (red) facilitates the formation and assembly of HIV-1 structural proteins, results from XSEDE Stampede2 and Anton2 systems show. Image courtesy of Perilla et al.

HIV-1 replicates in ninja-like ways. The human immunodeficiency virus slips through the membrane of vital white blood cells. Inside, HIV-1 copies its genes and scavenges parts to build a protective bubble for its copies. Scientists don't understand many of the details of how HIV-1 can fool our immune system cells so effectively. The virus infects 1.2 million people in the U.S. and 37 million people worldwide in 2018. The Extreme Science and Engineering Discovery Environment (XSEDE) awarded supercomputer time that helped model a key building block in the HIV-1 capsid, its protective shell, and its interaction with a family of small molecules critical for viral function. The discovery could lead to novel strategies for potential therapeutic intervention in HIV-1 replication.


Juan Perilla, Department of Chemistry and Biochemistry, University of Delaware.
Scientists found that the naturally occurring compound inositol hexakisphosphate (IP6) promotes both assembly and maturation of HIV-1. "We discovered, in collaboration with other researchers, that HIV uses this small molecule to complete its function," said Juan R. Perilla, Department of Chemistry and Biochemistry, University of Delaware. "This is a molecule that's extremely available in human cells and in other mammalian cells. HIV has evolved to make use of these small molecules present in our cells to essentially be infectious." Perilla co-authored the study in the journal Nature in August 2018.


Perilla ran simulations of inositol phosphate interactions with HIV structural proteins CA-CTD-SP1 using the Nanoscale Molecular Dynamics (NAMD) software through allocations awarded by XSEDE, which is funded by the National Science Foundation (NSF). "XSEDE provides a unique framework which allows us to use computational resources that are tailored to the needs of a particular scientific problem. In addition, we benefit from the HPC training opportunities provided by XSEDE, which allows us to develop novel analysis tools," Perilla said.


Model. a, Diagram of HIV-1 Gag. Dotted lines indicate protease cleavage sites. b, Diagram of Gag organization in immature virions (left). Following cleavage of Gag by protease (that is, maturation), CA re-organizes to form a mature core around viral RNA (right). c, d, Surface representations of the CASP1 and CA hexamers in the immature (c) and mature virus (d), with IP6 shown in its binding sites. The marked rearrangement of CA upon maturation is evident, as is the change in IP6 binding site between immature and mature viruses. CA NTD , blue; CA CTD , orange; 6HB, purple; IP6 , red. Image courtesy of Perilla et al.
The Perilla group used the XSEDE-allocated systems Stampede2 at the Texas Advanced Computing Center and Bridges at the Pittsburgh Supercomputing Center (PSC), as well as other national resources, to run simulations of the Inositol phosphates IP3, IP4, IP5, IP6 and their interactions with HIV proteins CA-CTD-SP1. "What these systems allowed us to do is establish what the molecular interactions are between the HIV proteins and this small molecule. With them we were able to test the hypothesis that it was stabilizing a particular part of the protein using molecular dynamics. I think Stampede2 and Bridges are great machines, and it's extremely beneficial to the scientific community to have resources like these available on a merit-based system," Perilla said.
"What I would like the public to know is that it's important that these large-scale machines are available," he added. "They are not just a replacement of a small [campus] cluster. These machines really enable new science. If you didn't have machines of this scale, you couldn't do the kind of science that we do."


Side view of the six-helix bundle showing two rings of Lys290 and (cyan) with bound IP6 in the middle. The bundle which holds together the Gag hexamer and facilitates the formation of a curved immature hexagonal lattice underneath the viral membrane. Image courtesy of Perilla et al.
Perilla described the increasing use of the 'computational microscope,' the combination of supercomputers with laboratory data. "With the computational microscope, you can see how things move. Many experimental techniques are just a snapshot. With the computational microscope, you can actually see how things are moving," he said.


Supercomputer modeling of how building blocks of HIV-1 move in time made a difference in this study. "That discovery opens a door for development of new treatments. It's a therapeutic target. Because of that, it makes it very appealing for drug development and therapeutic development," Perilla said.

There remains much to be learned about how HIV-1 behaves, said Perilla. "We're basic scientists. NSF's mission is to understand these systems as living organisms. The overall idea is that we want to understand the virus as a biological problem and ultimately this knowledge will be used to derive therapeutics," Perilla said.

The study, "Inositol phosphates are assembly cofactors for HIV-1," was published in the journal Nature on August 1, 2018. The study authors are Robert A. Dick and Volker M. Vogt of Cornell University; Kaneil K. Zadrozny, Jonathan M. Wagner, Barbie K. Ganser-Pornillos, and Owen Pornillos of the University of Virginia; Chaoyi Xu and Juan R. Perilla of the University of Delaware; Florian K. M. Schur of the European Molecular Biology Laboratory and the Institute of Science and Technology Austria; Terri D. Lyddon, Marc C. Johnson, and Clifton L. Ricana of the University of Missouri. The National Institutes of Health funded the research. This work used the Extreme Science and Engineering Discovery Environment, which is supported by National Science Foundation grant number OCI-1053575. The work also relied on computation on the special-purpose Anton 2 system, which is made available without cost by D.E. Shaw Research and hosted by PSC with funding from grant R01-GM116961 from the National Institutes of Health.

Link to Cornell University press release: