June 14, 2006 | On June 5 — the 25th anniversary of the month the first AIDS cases were reported in the United States — researchers at Stony Brook University in New York, in collaboration with Silicon Graphics (SGI) and the National Center for Supercomputing Applications (NCSA), announced that they have successfully simulated the HIV protease molecule to view the moments at which a key target for current AIDS treatment is most vulnerable to new drugs.
Working on an SGI Altix system located at NCSA, the Stony Brook team, led by associate professor Carlos Simmerling, modeled how HIV protease works across time, which the team hopes will lead to more targeted medicines to interfere with virus development. The group captured the protease in a transient fully open state — one that had been hypothesized but never directly observed.
Simmerling compares the molecule’s three different conformations — open, semi-open, and closed — to car doors: “The two flaps that cover the binding site are like doors, and when the drug binds they are shut a little bit differently. People have proposed that these flaps open...but there’s no structural picture of how that opening and closing happens.
“Until you know the mechanism of it, you really don’t know how to change it or interfere with it. Our simulations were able to take these closed structures and propagate them in time and say, ‘Look, the door opens, and then it closes when you put in the drug, that’s how it works.’ And it’s that transient open structure that nobody saw before, so we know that these models actually can contribute something.”
Simmerling’s group — with assistance from Roberto Gomperts, principal scientist at SGI — developed the simulations using AMBER, a molecular dynamics application developed in part by Simmerling’s lab. The team typically used 64 processors of NCSA’s SGI Altix 3700 Bx2 system for each simulation. Gomperts says he is now running simulations on even larger SGI Altix systems in house to expand the scope of the research.
“It opens up other areas of pharmaceutical research that early simulations were limited to looking at the wiggling around the structure where you started and you didn’t expect to get good information about structure change,” says Simmerling. “By doing these simulations in a classic test case like HIV protease, it shows us that the computers and the codes are maturing to the point where they’re going to be very useful.”
Although SGI declared Chapter 11 status in May, CEO Dennis McKenna stated, “Our customers will continue to receive the world-class service and support that they have come to expect from SGI. We will continue to meet our customer’s needs for quality products and services and remain committed to developing innovative new products and technologies.” According to SGI’s reorganization statement, the company expects to emerge from Chapter 11 reorganization within the next six months.
Simmerling and colleagues published initial results earlier this year in Proceedings of the National Academy of Sciences and the Journal of the American Chemical Society and anticipate new publications later this year.