Their results, reported in the April 19 issue of Science, explain how an important family of proteins, called aquaporins, conducts large volumes of water through cell walls while filtering out other molecules that would disrupt metabolism.

Crucial to the achievement, say the researchers, was access to the Terascale Computing System (TCS) at Pittsburgh Supercomputing Center.

Fully installed in October 2001 with funding from the National Science Foundation, the TCS is the most powerful U.S. computing system committed to unclassified research. Using the TCS, the researchers simulated the structure and function of aquaporin to discern atomic-level details that otherwise couldn't be detected.

"The problem we faced," says Klaus Schulten, director of Theoretical Biophysics at the University of Illinois Beckman Institute, "was that to describe the protein and the cell membrane with water we had to simulate systems that comprise more than 100,000 atoms. These are formidable simulations, particularly since they have to be done at a high level of exactness, with the best simulation conditions that can be achieved today. Only the Terascale system at Pittsburgh permitted us to do this in a timely manner."

The new results culminate more than ten years of effort, first, to find the three-dimensional structure of aquaporin and then to use the structural data to understand how the protein works.

Two years ago, Robert M. Stroud and colleagues at the University of California San Francisco determined the structure of one member of the aquaporin family. Working in collaboration with Stroud's group, Schulten and University of Illinois colleagues Emad Tajkhorshid and Morton Jensen carried out an extensive series of simulations to arrive at the new results.

For these simulations, Schulten and his co-workers used software developed in their laboratory to effectively exploit large-scale parallel computer systems like the TCS, which employ thousands of processors.

Their software, called NAMD, is designed in particular to simulate protein structure and function with the highest possible realism.

"With this machine, the Terascale, and this program that can use it effectively," says Schulten, "we have quite an achievement in terms of technology development for our science."

Aquaporins serve as channels in the wall of biological cells and have the remarkable ability of conducting water through cells at high rates -- up to a billion molecules per second, which adds up to about 400 liters a day in the human kidney -- while strictly excluding electrically charged molecules.

In particular, aquaporins lock out hydrogen ions, protons. This is important because their entry would disrupt the electrochemical difference across cell walls, which provides an energy reservoir for metabolism.

Several other channel proteins allow protons to cross the cell wall, and until now scientists didn't know how aquaporins blocked protons while at the same time permitting such large volumes of water to pass.

Simulations by Schulten and colleagues showed that water molecules move through aquaporin channels in single file, which was also observed experimentally.

Their recent TCS simulations also show, however, that the water molecules do a mid-channel flip-flop. The oxygen atom leads the way in until, at the most constricted point of the channel, the molecule flips and the water molecule's two hydrogen atoms lead the way out.

"The opposite orientation of the water molecules keeps them from conducting protons," says Schulten. "We could see this in simulation, but you can't recognize this orientation difference experimentally. We tested with simulations to see how strongly the channel preferred this orientation, and we found that it is very strongly preferred. As a result, it's a very strong filter against the conduction of protons."

Aquaporins are a large family of membrane proteins widely distributed in all life forms, including bacteria, plants and mammals. They play a critical role in controlling the water content of cells, and their impaired function is involved in several known human diseases, such as cataracts in the eye and diabetes insipidus.

The Pittsburgh Supercomputing Center is a joint effort of Carnegie Mellon University and the University of Pittsburgh together with Westinghouse Electric Company. It was established in 1986 and is supported by several federal agencies, the Commonwealth of Pennsylvania and private industry.

For more information, including color graphics from the simulation, see this URL.

For more information about the Terascale Computing System see this URL.

[Contact: Mike Schneider]

24-Apr-2002