- p53 protein holds the key to tumor suppression.
- Supercomputers function like a computational microscope, illuminating attributes previously invisible to researchers.
- XSEDE computer resources continue to accelerate scientific understanding.
Amaro, a professor in the Department of Chemistry and Biochemistry at the University of California, San Diego, has been studying this important molecule for years. She is motivated by the fact that the p53 protein somehow helps prevent the formation of cancerous cells.
To see this protein, Amaro is using the Stampede supercomputer at the Texas Advanced Computing Center. Stampede acts like a computational microscope, enabling Amarro to model the largest atomic level system of p53 to date — over 1.5 million atoms.
The simulations identify new ‘pockets’ to reactivate p53 which would be a tremendous boost for future anti-cancer drug discovery. P53 is a known tumor suppressor that is inactivated in roughly half of all human cancers. Reactivating p53 is thus a long-sought goal for scientists.
Amaro’s team found that when there is damage to a normally functioning cell, p53 senses something is wrong and engages the elements in other molecules that control things like cell death or cell cycle arrest. This stops the damage where it is in the cell cycle.
Most of the cancer mutations Amaro's team studied show an alteration in single amino acids in the p53 protein. When this change occurs, p53 protein cannot bind to DNA, preventing it from effectively regulating cell growth and division. As a result, DNA damage accumulates in cells, which can allow them to grow and divide in an uncontrolled way to form a cancerous tumor.
Amaro and her colleagues' new work recently published in Oncogene is based on the full length p53. Modeling the full length is challenging because of its complex architecture and multiple highly flexible regions.
"The science challenge represents a level of complexity that's very difficult if not impossible to experimentally test," Amaro notes.
In response, the researchers built atomic-level models 'in silico,' and interrogated the system in unique ways. For the first time, for example, the researchers built a large complex of the p53 molecule with three different sequences of DNA. Two were recognition sequences (P21 and Puma) and the third strand was a negative control.
"That's why Stampede was so terrific — we were able to run this 1.5 million atom system for nearly a microsecond and actually begin to say things about the dynamics at a completely different scale than what was known previously.” ~ Rommie Amaro.
"We could see how when we the full-length p53 was bound to a DNA sequence that was a recognition sequence, the tetramer clamps down and grips onto the DNA – which was unexpected," Amaro says. In contrast, with the negative control DNA p53 stays more open. "It actually relaxes," she said. "It suggested a mechanism by which this molecule could actually change its dynamics depending on the exact sequence of DNA."
The researchers set up three different systems and ran three different copies of each system to test variability in the data for a total of nine different simulations for nearly a microsecond of aggregated dynamics. "The simulations were very computationally intensive. And then to be able to do something new about the biology that wasn't known before – that's the really exciting part and that's what we showed," Amaro says.
"As the systems get bigger, much more computational time is required. Previously the simulations were run for a few nanoseconds. Now we have microseconds of dynamical data, which is 1,000x more. It gives us a much more complete picture of what is actually happening. It's a few steps closer to reality than anything we've been able to accomplish yet," she explains.
Says Amaro: "Computing is getting to the point now where it can have an impact on developing new therapies. It gives us a better understanding of cancer mechanisms and ways to develop possible novel therapeutic avenues. When most people think about cancer research they probably don't think about computers, but these models are getting to the point where they have a great impact on the science."
Amaro is hoping these discoveries will translate into new cancer therapies.
"The ideal situation is that cancers of the breast and prostate could possibly be reduced or eliminated if we were able to develop a compound that reactivated p53. You don't have to wait until the cancer is advanced. The sensing of mutation and then signaling the cell to die is something that happens through the early stages of cancer. It could be detected and fixed before the cancer develops," Amaro concludes.
This research used the Extreme Science and Engineering Discovery Environment (XSEDE). XSEDE supports 16 supercomputers and high-end visualization and data analysis resources across the country. XSEDE is supported by National Science Foundation grant number ACI-1053575.