Putting the pathway back into protein folding.

T he 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 knowledgebased 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.