College of LAS « Illinois

Chemistry

Simulated Dynamics

Scientists achieve protein folding's Holy Grail.

Protein Folding

For years, the comparison of simulated and experimental protein folding kinetics has been a "Holy Grail" for biologists and chemists. But scientists seeking to confirm protein-folding theory with laboratory experiments have been unable to cross the microsecond barrier. This obstacle in time existed because experiments could not be performed fast enough, nor simulations run long enough, to permit a direct comparison.

Now, measurements from researchers in LAS and molecular dynamics simulations from Stanford University have at last been compared and found to be in very good agreement.

"By crossing the microsecond barrier, we can directly compare simulated and experimental protein folding dynamics, such as folding rates and equilibrium constants," says Martin Gruebele, a professor of chemistry, physics, and biophysics.

To allow experiment and theory to meet on a microsecond time scale, the researchers designed a small protein based on the work of Barbara Imperiali at the Massachusetts Institute of Technology. Consisting of only 23 amino acids, the protein contains all three basic elements of secondary structure—helices, beta sheets and loops—but can fold simply and rapidly.

At Illinois, Gruebele's team measured folding times using a fast temperature jump experimental procedure. To initiate the folding and unfolding dynamics, the solution was heated rapidly by a single pulse from an infrared laser. As the proteins began twisting into their characteristic shapes, a series of pulses from an ultraviolet laser caused some of the amino acids to fluoresce, revealing to the researchers a time-sequence of folding and unfolding events from which the folding rate constant was obtained.

At Stanford, physical chemist Vijay Pande accumulated more than 700 microseconds of molecular dynamics simulations by dividing the work among more than 30,000 volunteer computers distributed around the world.

"The computational predictions were in extremely good agreement with our experimentally determined folding times and equilibrium constants," Gruebele says. "Our group came up with an average folding time of 7.5 microseconds, while Pande's group came up with 8.0 microseconds."

Updated April 2003