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Understanding the mechanism of protein folding is a notoriously difficult problem for both experiment and simulation (1, 2). In this issue of PNAS, through a combination of theory (Karanicolas and Brooks; ref. 3) and experiment (Nyguen et al.; ref. 4), progress toward the bridge between simulation and experiment is beautifully demonstrated. Indeed, lead by predictions made by Karanicolas and Brooks, Nyguen et al. demonstrate the utility of a new generation of model systems for protein folding in which a small model protein (the WW domain) can be tuned from simple two-state behavior to more complex three-state folding merely by changing the temperature. Because such qualitative differences in the folding pathway can be induced through relatively subtle changes in the experimental conditions, this WW domain makes an ideal test system for our understanding of protein folding, both in terms of theory, simulation, and one's conceptualization of the relevant physical forces driving folding. Typically, proteins are categorized as two-state (single exponential kinetics) or three state (biexponential kinetics). Indeed, after Jackson and Fersht first demonstrated two-state folding kinetics in CI2 (5), much attention has been paid primarily to two-state proteins as a simpler model system, a natural first challenge before going on to more complex, multistate kinetic folders. Moreover, a common rule of thumb is that small proteins (<100 residues) would have simpler, two-state kinetics, and large proteins would likely have more complex multistate folding. The behavior of FBP WW domain is unusual, not as an exception to this rule of size, but for the ability to switch between the two- and three-state worlds. Nyguen et al. (4) examined the folding of the FBP WW-domain, a stable three-stranded β-sheet protein by laser temperature jump measurements. They examined several variants of this domain, including several single point and truncation mutants. The most …

Meeting halfway on the bridge between protein folding theory and experiment