Molecular switch that controls cell behavior identified - Could have substantial future implications

12/17/2013 - 00:00

If scientists can control cellular functions such as movement and development, they can cripple cells and pathogens that are causing disease in the body.

Supported by National Institutes of Health grants, researchers at Oak Ridge National Laboratory (ORNL), the University of Tennessee (UT), and the UT–ORNL Joint Institute for Computational Sciences (JICS) discovered a molecular “switch” in a receptor that controls cell behavior using detailed molecular dynamics simulations on a computer called Anton built by D. E. Shaw Research in New York City. To study an even larger signaling complex surrounding the switch, the team is expanding these simulations on the 27-petaflop, CPU–GPU machine Titan—the nation’s most powerful supercomputer, managed by the Oak Ridge Leadership Computing Facility at ORNL.

Researchers identified the molecular switch on Anton (which was designed to perform speedy molecular dynamics simulations) by simulating 140,000 atoms that make up the signaling part of the Tsrchemoreceptor that controls motility in E. coli. Like other receptors, Tsr spans the cell membrane, communicating to proteins inside the cell in order to respond to threats or opportunities in the environment.

The results, published in Nature Communications, stand apart from previous research because of the computational power applied to the problem. “This work exemplifies the growing importance of numerical experiments in biology,” said Jerome Baudry, assistant professor in the UT Biochemistry and Cellular and Molecular Biology Department and the UT–ORNL Center for Molecular Biophysics.

The team led by Baudry and Igor Zhulin, distinguished research and development staff member in the ORNL Computer Science and Mathematics Division, joint professor in the UT Department of Microbiology, and JICS joint faculty member determined that a single pair of phenylalanine amino acids called Phe396 located at the chemoreceptor tip was acting as a receptor switch.

“For decades proteins have been viewed as static molecules, and almost everything we know about them comes from static images, such as those produced with X-ray crystallography,” Zhulin said. “But signaling is a dynamic process, which is difficult to fully understand using only snapshots.”

The Phe396 pair is restless, always flipping 180 degrees back and forth relative to the receptor, but researchers identified a clear pattern.  “It is like a crazy light switch,” Zhulin said. “When you switch it on to light up your room, it occasionally flips down giving you moments of darkness, and when you switch it off to go to sleep, it occasionally goes up flashing.”

When the receptor is in signal-on mode, the switch spends more time in the “on” position. When the receptor is in signal-off mode, the switch spends more time in the “off” position.

“To our knowledge, this is the first time this switch has been described,” said Davi Ortega, lead author and postdoctoral fellow in Zhulin’s lab.