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Behind the folding funnel diagram
Martin Karplus
This Commentary claries the meaning of the funnel diagram, which has been widely cited in papers on protein folding. To aid in the analysis of the funnel diagram, this Commentary reviews historical approaches to understanding the mechanism of protein folding. The primary role of free energy in protein foldingis discussed, and it is pointed out that the increase in the congurational entropy as the native state is approached hinders folding, rather than guiding it. Diagrams are introduced that provide a less ambiguous representation of the factors governing the protein folding reaction than the funnel diagram.
2011 Nature America, Inc. All rights reserved.
Understanding the mechanismby which proteins fold to their native state remains a problem of
fundamental interest in biology, in spite of the fact that it has been studied for many years1. Moreover, now that misfolding has been shown to be the source of a range of diseases, a knowledge of the factors that determine whether a polypeptide chain will fold to its native state or aggregate has become all the more important.
The folding funnel diagram (see Fig. 1), introduced by Wolynes, Onuchic and Thirumalai2, is intended to providea pictorial representation of how the Levinthal paradox3, which had dominated discussion of protein folding for many years, is resolved. Since the original publication, funnel diagrams have become a xture in papers on protein folding,and they are now being introduced in discussions of other problems, such as ligand binding4. Unfortunately, the funnel diagram has created a misconception in many readers.
The concept introduced by Levinthal is that the appropriate point of reference for protein folding is a random search problem. Taken literally, as it has been by many people, this means that all conformationsof the polypeptide chain (except the native state) are equally probable, so that the native state can be found only by an unbiased random search. For such a search, thetime to nd the native state is given by the number of congurations of the polypeptide chain (on the order of 1070 for a 100-residue protein) multiplied by the time required to nd one conguration (say, 1011 seconds). This leads to an enormously long folding time (say, 1059 seconds or about 1052 years). Given that...