What the crystal did not show

Visualization of the multiscale simulation. The structure of the complex formed by the bound lac repressor (shown in green) and DNA is simulated inside an ion-filled water box. The DNA loop connecting the protein-bound DNA segments is modeled as an elastic ribbon (shown in gray); the forces of interaction between the loop and the protein-bound DNA segments (red arrows) are included in the molecular dynamics simulation.

When the researchers examined the results of their multiscale approach, they could show for the first time the entire lac repressor/DNA complex, what Schulten calls "one of the most magnificent biopolymer molecules."

"[We] saw how the protein wrestles with the DNA," he explains. They saw "the ingenious way by which the protein overcomes the resisting DNA--with extreme flexibility and, for lack of a better word, patience."

They learned that it is not through sheer size that the lac repressor protein overpowers and subdues the DNA. It was previously known that the protein has two arms with which to grasp the DNA binding sites; Schulten's simulations showed that these arms grasp the DNA with heads that connect to the protein with thin coils. These coils provide the protein with extreme flexibility. "No matter how the DNA tries to wriggle and bend," Schulten says, "the protein can follow and maintain contact."

In fact, the researchers simulated the application of exaggerated forces to the protein heads. Even under forces 50 times stronger than a real-world system, they found that the lac repressor could maintain its shape and its grip on the DNA loop.

The multiscale combination of mathematical modeling and computational simulation employed by Schulten's group not only provided insight into the structural dynamics of a particular biomolecular system, it also provided a pathway for future investigation. Similar protein-DNA complexes form in the genomes of many living organisms, so the multiscale approach could lead to advances in our knowledge of living things in general, of the human body, and of medicine.

"The story of the lac repressor/DNA loop simulation on the TeraGrid's Mercury system is an exemplary case for computational science, showing how the combination of modern computational techniques, of wise investment, of hard work and great ingenuity leads researchers to learn what experiment cannot tell us," Schulten says. "The computer is becoming more and more like a new microscope that permits views into the world that cannot be obtained by other means."

This research is supported by the National Institutes of Health.

Team members

Alexander Balaeff
Klaus Schulten
Elizabeth Villa

Go Back To Page 1

	Access Online | posted 5-4-05