Protein folding hits a speed limit

May 07, 2003

CHAMPAIGN, Ill. -- To carry out their functions, proteins must first fold into particular structures. How rapidly this process can occur has been both a source of debate and a roadblock to comparing protein folding theory and experiment.

Now, researchers at the University of Illinois at Urbana-Champaign have observed a protein that hit a speed limit when folding into its native state.

"Some of our proteins were folding as fast as they possibly could -- in only one or two microseconds," said Martin Gruebele, an Illinois professor of chemistry, physics and biophysics. A paper describing the work is to appear in the May 8 issue of the journal Nature.

To study protein folding at the speed limit, Gruebele and graduate student Wei Yuan Yang took a small protein and, by replacing some of the amino acids with others that improved the molecular interactions, made it fold faster. By the time they finished souping up their protein, it was folding nearly 1,000 times faster than normal.

The researchers then used a fast temperature-jump procedure to measure folding times with nanosecond resolution. To initiate the folding sequence, a solution of unfolded proteins was heated rapidly by a single pulse from an infrared laser. As the proteins twisted into their characteristic shapes, pulses from an ultraviolet laser caused some of the amino acids to fluoresce, revealing a time-sequence of folding events.

"Because a protein can follow more than one pathway to its native state, a variety of folding times will result," Gruebele said. "Plotting these times usually yields an exponential decay rate, because we are averaging over lots of molecules at once."

But, in addition to the normal exponential decay rate -- which did not exceed 10 microseconds -- Gruebele and Yang detected a much faster behavior that occurred on shorter time scales below one or two microseconds.

"That's the speed limit," Gruebele said. "That's the speed at which segments of the protein can physically change their positions -- the speed at which the protein would fold if it took the shortest possible path and made the least possible mistakes."

Before the experiment, time estimates ranged from as little as 10 nanoseconds to as long as 100 microseconds, Gruebele said. The right answer lay in the middle of that range.

"Of course, different proteins will have different speed limits," Gruebele said. "Longer molecules have to move around more to fold, and therefore have slower speed limits."

By modifying their protein to fold extremely fast over a reduced energy barrier, the researchers moved from timing macroscopic kinetics of protein folding over an energy barrier to timing the movement of the protein's polymer chain. This molecular time scale is also where transition state theory breaks down.

"Because we can measure both the molecular time scale and the activated kinetics normally associated with transition state theory in one experiment, we can determine the activation energy on an absolute scale," Gruebele said. "This allows us to directly compare experimental and computational folding rates, and therefore calibrate the theory."
-end-
The Camille and Henry Dreyfus Foundation funded the work.

University of Illinois at Urbana-Champaign

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