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A series of studies on the small protein barnase in the 1990s established it as a paradigm for protein folding in which there is a kinetically important intermediate. But, a recent study in PNAS claims that there are no stable intermediates on the folding pathway. I summarize the evidence that proves that the folding kinetics of barnase is inconsistent with the absence of a folding intermediate. I reinterpret the major evidence presented against the intermediate (an inflection in the unfolding limb of a chevron plot) and show that the inflection is precisely what is predicted from the energy diagram for a three-state reaction with a kinetically significant on-pathway intermediate. The inflection is indicative of a change of rate determining step from the formation to breakdown of an intermediate on unfolding. Other evidence presented against the intermediate is, in fact, consistent with a kinetically important intermediate. I show how the complexities in the kinetics provide a means for measuring otherwise unobtainable rate constants and provide a strategy for mapping the structure of the early transition state in folding. Rather than refute multistate kinetics, the presence of the inflection in the unfolding plot constitutes a novel type of evidence for on-pathway folding intermediates.

A kinetically significant intermediate in the folding of barnase