Prediction of protein-folding mechanisms from free-energy landscapes derived from native structures

Guided by recent experimental results suggesting that protein-folding rates and mechanisms are determined largely by native-state topology, we develop a simple model for protein folding free-energy landscapes based on native- state structures. The configurations considered by the model contain one or two contiguous stretches of residues ordered as in the native structure wi th all other residues completely disordered; the free energy of each config uration is the difference between the entropic cost of ordering the residue s, which depends on the total number of residues ordered and the length of the loop between the two ordered segments, and the favorable attractive int eractions, which are taken to be proportional to the total surface area bur ied by the ordered residues in the native structure. Folding kinetics are m odeled by allowing only one residue to become ordered/disordered at a time, and a rigorous and exact method is used to identify free-energy maxima on the lowest free-energy paths connecting the fully disordered and fully orde red configurations, The distribution of structure in these free-energy maxi ma, which comprise the transition-state ensemble in the model, are reasonab ly consistent with experimental data on the folding transition state for fi ve of seven proteins studied. Thus, the model appears to capture, at least in part, the basic physics underlying protein folding and the aspects of na tive-state topology that determine protein-folding mechanisms.