Nonexponential rates support idea of protein folding 'funnel'

June 01, 1999

CHAMPAIGN, Ill. -- Experimental evidence that strongly supports an energy landscape "funnel" model of protein folding has been obtained by researchers at the University of Illinois.

The evidence -- highly nonexponential folding times -- was observed during sub-millisecond folding experiments conducted on two proteins: yeast phosphoglycerate kinase and a ubiquitin mutant.

"Both proteins show strange kinetics with many time scales," said Martin Gruebele, a U. of I. professor of chemistry and a researcher at the university's Beckman Institute for Advanced Science and Technology. "We interpret our observations in terms of downhill folding, which says that a protein will encounter an ensemble of temporary structures en route to its folded state." The traditional view of protein folding "predicts the rate at which proteins curl into their native state will be exponential," Gruebele said. "And in many cases, exponential kinetics have been observed."

However, the "new view" of protein folding -- advocated by U. of I. chemical physics professor Peter Wolynes and others -- emphasizes the rugged appearance of the energy landscape and the resulting heterogeneity of the folding ensemble. "Depending on the roughness of the energy landscape, protein folding can cover many scenarios," Gruebele said. "These range from proteins being temporarily trapped in intermediates, to proteins proceeding via rapid and essentially downhill mechanisms toward the native state."

Because the protein can encounter an enormous number of transition states -- some of which are more conducive to folding than others -- the energy landscape is said to resemble a rough funnel. The protein can therefore fall downhill to its native state on a time scale that is highly variable and not exponential. To measure folding times, Gruebele and his colleagues -- graduate students Jobiah Sabelko and John Ervin -- first unfold the proteins by supercooling them in an aqueous solution. Then, to initiate the folding sequence, the solution is heated rapidly by a single pulse from an infrared laser. As the proteins begin twisting into their characteristic shapes, a series of pulses from an ultraviolet laser cause some of the amino acids to fluoresce, revealing to the researchers a time-sequence of early folding events.

"Our observations show that protein folding is not characterized by just one energy barrier with a single time scale," Gruebele said. "Rather, there are multiple states en route downhill to the native state, resulting in many time scales."

These results are not incompatible with what researchers have seen before, Gruebele said. "In the past, exponential time scales were observed because kinetics experiments were performed at a lower time resolution. Those experiments missed the early steps in the folding process, revealing only what occurred at the very final stage."

The researchers' findings appear in the May 25 issue of the Proceedings of the National Academy of Sciences.
-end-


University of Illinois at Urbana-Champaign

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