Robert F. Service:
It has been nearly impossible to get a good look at Rommie Amaro's favorite protein in action. Called p53, the protein sounds the alarm to kill cells with DNA damage and prevent them from becoming cancerous—one reason why it has been called the “guardian of the genome.” But it is big and floppy, a molecular shapeshifter that is hard to follow with standard imaging tools. So Amaro, a computational biologist at the University of California (UC), San Diego, turned to supercomputers. She plugged in new x-ray snapshots of p53 fragments and beefed up her program to make a movie of the quivering activity of each of the protein's 1.6 million atoms over a full microsecond, an eternity on the atomic scale that required about a month of supercomputer time. She watched as four copies of p53 linked up and wrapped themselves around a DNA strand, an essential dance the protein performs before it sends off messages for cellular self-destruction.
Amaro wasn't just interested in the behavior of healthy p53: She wanted to understand the effects of mutations that the gene for p53 is prone to. In dozens of simulations, she and her colleagues tracked how common p53 mutations further destabilize the already floppy protein, distorting it and preventing it from binding to DNA. Some simulations also revealed something else: a fingerhold for a potential drug. Once in a while, a small cleft forms in the mutated protein's core. When Amaro added virtual drug molecules into her models, the compounds lodged in that cleft, stabilizing p53 just enough to allow it to resume its normal functions. For Amaro and a few other researchers, those computer simulations are an inspiration. “A long-standing dream of cancer biology is to find small molecule drug compounds to restore the activity of p53,” Amaro says. “We're very excited about this.”