INDUSTRY

By Cassie Ferguson, SDSC -- When researchers at Oxford University organized a project to screen compounds for an antidote to anthrax, they were surprised both by the amount of time it took to complete the screening using distributed computing and by an email from San Diego Supercomputer Computer principle scientist Mike Bailey. The scientists at Oxford had helped to screen 3.5 billion molecules that might potentially hook onto the toxin that causes anthrax’s deadly effect. Using a distributed computing model over a million home computers to generate candidates, the entire project took only 24 days to produce 12,000 potential candidates for a cure for the anthrax infection. Bailey read about the project's unprecedented success in HPCwire, a weekly magazine that covers the high performance computing industry. Bailey, who has produced 3-D models of everything from proteins to submarines, sent an email to the Oxford scientists offering to generate a 3-D model of the protein to help with their screening efforts. While he doesn’t think the researchers would pick up the molecule and instantly figure out how a compound could bind to the anthrax toxin, he pointed out that it has helped other scientists visualize the compounds they are studying. "It’s one thing to see a molecule on screen or using other tools to generate a chemical profile. It's quite another to actually hold it in your hands and peer into all of its nooks and crannies," said Bailey. "Scientific insights can be gleaned from them that aren’t available by any other means." Bailey produced the model using data from the Protein Data Bank (entry 1ACC, which corresponds to Anthrax Protective Antigen from the Bacillus anthracis) and fabricated the model on a 3-D rapid prototyping device, a Z402 from Z Corporation that uses a computer-controlled print jet to spray liquid binder–glue into layers of fine powder. This eventually forms a full, three-dimensional object from the cemented powder. "It gives a real feel for the scale of things which is hard to get purely from molecular graphics," said Graham Richards, chairman of the Chemistry Department at Oxford University. "Although we have computer graphics, there is still a lot to be learned from a physical model." Previously, Bailey found that molecular biologists are interested in his models as a way to capture the shape of "molecular machines," or dynamic proteins that are constantly folding, assembling, and moving. To understand those machines, the researchers have to be able to understand the parts such as binding sites or folds. The anthrax protective antigen serves as one ingredient in the three-part anthrax toxin, serving as the delivery mechanism. Secreted by the bacteria as a single chain, it binds to the surface of a cell, where it becomes " armed." It then combines with six other copies of the protein to form a seven-sided ring that extends into the cell membrane. This allows other portions of the toxin to be carried into the cell. A two-dimensional view of the Anthrax toxin can be seen at the PDB’s April 2002 entry in the "Molecular of the Month" series. www.rcsb.org/pdb/molecules/pdb28_2.html