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Simulating the DNA transcription dance

Above, you will find the crystal structure of NF-kappaB (mostly in purple) bound to an I-kappaB (mostly in red). Image courtesy of Nick Schafer.

A single dancer who always moves too quickly or slowly can throw off the entire performance of a ballet. Our bodies are far more complex than a ballet, however, with layers of interdependent, intricate systems. What happens when a single part of one of the lower level systems is out of step?

Nothing good.

"We are studying NF-kappaB and I-kappaB, which are two particularly interesting classes of proteins that spring into action when the cell is under stress," said Nick Schafer, a biophysicist in the Wolynes group at the Center for Theoretical Biological Physics at University of California-San Diego.

Cell stress arises from excess heat, mechanical stress, or the presence of a pathogen such as a virus.

"If NF-kappaB and I-kappaB are not working properly, a phenomenon known as misregulation, there can be disastrous consequences for the cell," Schafer said. Misregulation, he explained, is a broad concept. It refers to any type of regulation that leads to genes producing too many or too few copies of a given protein.

That may sound harmless enough. But misregulation of NF-kappaB and I-kappaB has been linked to cancer, autoimmune disease, and a variety of other illnesses.

If our bodies are the ballet performance, and DNA is our repertoire of dance steps, then transcription factors such as NF-kappaB translate that repertoire into choreography - RNA. RNA in turn generates the protein - dancer - that carries out the choreography.

I-kappaB, on the other hand, is an inhibitor. So long as our bodies are performing as they should, I-kappaB remains attached to NF-kappaB, preventing it from generating RNA. When the cell comes under stress, however, the I-kappaB disintegrates, freeing NF-kappaB to start that process that results in more proteins - including I-kappaB. This system of transcription and inhibition is called the signaling process; when it is functioning properly, NF-kappaB will trigger the creation of a given protein only when the body needs more of that particular protein.

Recently, some of Schafer's experimental collaborators suggested that a certain type of I-kappaB can actively strip NF-kappaB from DNA, cutting the signaling and transcription process short. If this is true, it will change our understanding of the signaling process, and in particular, how NF-kappaB is regulated. The question is, how does this stripping work, and why can only certain types of I-kappaB do it?

To find answers to those questions, Schafer and his colleagues need to run thousands of molecular simulations. In the past, the group has used the CTBP cluster, or the Triton resource at the San Diego Supercomputer Center, said Schafer. But to complete this project, which is a classic case of high-throughput computing, they added the Open Science Grid to their toolkit.

"Many of our simulations can be run efficiently on a single processor but require many of these simulations to run simultaneously, which makes OSG particularly well suited to our purposes," Schafer said. "We have had recent technical advances which, combined with the OSG resources, should allow us to move faster than ever towards determining which specific structural aspects are important in the interactions between NF-kappaB, I-kappaB and DNA."

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