NCSA's SGI Altix advances HIV research

Story posted June 7, 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 the SGI® Altix® supercomputer at NCSA, 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 and thus prevent the virus from developing.

Simmerling’s team successfully simulated how HIV protease changes between two forms that already have been determined through experiments. More important, however, is that the group was able to capture the protease in a third, fully open state -- one that had previously been hypothesized but never directly observed. Their work was published earlier this year in The Proceedings of the National Academy of Sciences (see http://www.pnas.org/cgi/content/abstract/103/4/915) 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. This lack of knowledge has hindered the progress of HIV drug developers, even as many current drugs specifically target HIV protease.

"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 team’s simulations are the most extensive ever done on HIV protease. Individual simulations modeled only 50 nanoseconds of behavior -- less time than it takes a beam of light to travel 50 feet -- but they still last long enough for the researchers to model HIV protease in unprecedented detail.

"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. “HIV is a very adaptive virus that mutates easily, which can reduce the benefit of a drug," Simmerling said.

The research, however, focuses not solely on the structure of HIV protease but on its mechanics. "If we target its shape with a drug, then any change in shape can diminish the drug's effectiveness. But if we can target its job, the shape doesn't matter as much and it will have a harder time evading the drugs," Simmerling said.

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 projects. The simulations took 20,000 CPU hours; in real time, the project lasted about three months. Simmerling estimates that it would have taken more than a year to complete the work using his lab's Linux® cluster. "It would have been at least six to seven times slower than the Altix, and the cluster doesn't scale as well," he said. "I wouldn't have done it for such a risky project."