After decades of research, the nature of the rate-limiting step in the folding of globular proteins still elicits a range of opinions (1). The properties of the associated transition state (TS) provide critical insights into possible folding mechanisms. However, the characterization of the TS is challenging because atomic level methods cannot be applied to this minimally populated state, and lower resolution methods have produced divergent views. Even the existence of a generalized TS remains actively debated. In PNAS, Guinn et al. (2) dissect the burial properties of the TS for 13 proteins by analyzing the denaturant and temperature dependence of folding rates to distinguish the burial of hydrophobic surface from that of amide groups. With this capability, they propose that the TSs generally are very advanced and often contain the native 2° structure, a level higher than most prior methods have indicated.
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