Access: Getting a Grip on AIDS

After adding an Alliance SGI Origin2000 to their supercomputing arsenal, a research team from the Pittsburgh Supercomputing Center and Carnegie Mellon University further improved their understanding of an enzyme that is part of the virus that causes AIDS.

Although AIDS awareness programs and research leading to powerful drugs such as AZT have reduced AIDS-related mortality, AIDS remains one of the most pressing U.S. public-health problems, with incidence rising in some areas and population groups. In less developed parts of the world, furthermore, AIDS is virtually out of control. In South Africa, AIDS infects a third of the current populace of 43 million, compared to under 1 percent here, and is the leading cause of death, with no abatement in sight.

Because of their high cost, the drug "cocktails" that control HIV, the virus that causes AIDS, have been of little use in Africa. Even at their most successful, these drugs aren't a cure-all. By retarding HIV's ability to reproduce in humans, they save many lives, but the quest for AIDS researchers remains, as it has been, to find a cureÑnot just therapeutic agents that manage the disease, but a knockout punch.

Physicist Marcela Madrid of the Pittsburgh Supercomputing Center (PSC) and Carnegie Mellon University biologist Jonathan Lukin are contributing to this effort. Their computer simulations have revealed new understanding of an enzyme, HIV-1 reverse transcriptase (RT), that enters the body in the package of proteins and ribonucleic acid that comprise HIV. RT plays an essential role in reproducing the virus and is an important target for drugs.

The crystal structure of RT compared to the simulated structure with DNA (green). Coil thickness corresponds to the crystallographic B-factors and simulated movements. The entire molecule is represented, with the active-site subunit shown in dark olive (crystal structure) and light olive (simulation) and RT's other subunit in corresponding light and dark purple.

Madrid specializes in simulating biological molecules, and in 1998 she began collaborating on RT with a team of structural biologists. Because RT is a very large molecule, about 1,000 amino acids, it hadn't been simulated before, and Madrid's effort, using PSC's CRAY T3E supercomputer, broke new ground. By providing a moving picture of RT, her work filled in details unavailable from the molecule's static structure. Beyond this, her results went a long way toward showing that this kind of computer simulation, called molecular dynamics, can be a valuable partner with laboratory studies in furthering AIDS research.

With these simulations as groundwork, Madrid and Lukin this year took the next step: including water molecules that surround RT in the living cellular environment. This greatly expanded the computational demands of the project, challenging memory limitations of PSC's CRAY T3E. Madrid turned to the Alliance's SGI Origin2000 array at NCSA. Their results from this recent work, which also relied partly on PSC's Intel cluster, offer fresh insight into the details of how this enzyme interacts with other molecules to reproduce the virus.

Access Online | Posted 9-19-2000