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TeraGrid users advance HIV research

June 30, 2006 - In the race to fight AIDS, researchers have long worked to view the moments at which "starter molecules" for HIV are most vulnerable to new drugs. Using NCSAs SGI Altix system, one of the TeraGrids compute resources, a team of scientists led by Carlos Simmerling of Stony Brook University in New York has conducted simulations that offer insight into the mechanics of HIV protease, a molecule that slices the pre-HIV protein chain into pieces that evolve into a mature virus. By modeling how HIV protease works, researchers hope to determine how best to target it with medicines that could stop the molecule from doing its job, thus preventing the virus from developing.

Simmerlings team successfully simulated how HIV protease changes between two forms that have been determined through experiments. More importantly, however, the group was able to capture the protease in a third, fully open state -- one that had never before been directly observed. Their work was published earlier this year in the Proceedings of the National Academy of Sciences and the Journal of the American Chemical Society.

When the structure is open, it is vulnerable to inhibitor drugs that can bind with the molecule and render it harmless. But pristine, crystallized examples of the molecule have shown it only as either closed or barely open, leaving no room for inhibitors to enter.

"We determined that if we knew how HIV protease opened, we could better identify a new and potentially more sensitive drug target," said Simmerling. "The challenge has always been simulating it long enough to see the transformation at work. The structure just doesn't open frequently enough to easily measure it. And when it happens, it happens fast." Scientists estimate that the structure remains open for less than a millionth of a second.

The Simmerling teams simulations are the most extensive ever done on HIV protease. "We can model the full change between the known structures with very high accuracy," Simmerling explained. "We can also see how it opens, and where a drug molecule binds to the protease and causes it to close. And then we can reverse that process, and the protease opens again. These are all things that experiments have not been able to show us."

Such reliability suggests the simulation will prove helpful in testing the potential efficacy of new drugs, and in understanding how variations of HIV can change a drug's behavior.

The researchers employed AMBER, a molecular dynamics application developed in part by Simmerling's lab, to develop the computational simulations. The team typically used 64 processors of NCSA's SGI® Altix® 3700 Bx2 system for each simulation, leaving the remainder of the 1,024-processor resource available for other science and engineering research. The simulations took 20,000 CPU hours; in real time, the project lasted about three months.

This work was supported by National Institutes of Health grant GM6167803 and Department of Energy grant DE-AC02-98CH10886.

V. Hornak, A. Okur, R. Rizzo, and C. Simmerling, HIV-1 protease flaps spontaneously open and recluse in molecular dynamics simulations, Proceedings of the National Academy of Sciences; 103(4): 915-920 (2006).

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