Putting the pathway back into protein folding

Abstract

The article by Liwo et al. in this issue of PNAS (1) on ab initio simulations of the folding pathway of a number of representative small proteins marks a renaissance in efforts to simulate the mechanism of protein folding without prior knowledge of the native structure. While there has been recent progress in predicting the three-dimensional native structure of a protein (2, 3), the most successful approaches incorporate many knowledge-based features (e.g., use of already solved protein structures and predicted secondary structure) that render the assembly mechanism provided by such simulations physically meaningless. On the other hand, the first principles of simulation of the folding process at complete atomic detail, including water that starts from the random state and finishes with the native structure, is computationally intractable for all but the simplest systems (4). For the near future, as in Liwo et al. (1), reduced models that describe the protein by a subset of its constituent atoms and implicitly treat solvent and that search conformational space by using Langevin or molecular dynamics (5) offer the most promising way of exploring how proteins fold. Remarkably, although Liwo et al. (1) examined the folding of only seven proteins, representing all secondary structural classes, their simulations demonstrate a richness that addresses key questions in protein folding. Is there native-like secondary (6) or even tertiary structure in the denatured state (7)? Does a protein collapse first and then the secondary structure (helices and β-sheets) appears, or does the secondary structure appear first, and then the native tertiary assembles (8)? Alternatively, perhaps secondary and at least loose, tertiary structures simultaneously assemble (9)? Partial evidence supporting the first and third scenarios is provided in the Liwo et al. (1) article. Furthermore, a molten globule state (10) is believed to form quite rapidly, with more or …