Critical nucleation size in the folding of small apparently two‐state proteins

For apparently two‐state proteins, we found that the size (number of folded residues) of a transition state is mostly encoded by the topology, defined by total contact distance (TCD) of the native state, and correlates with its folding rate. This is demonstrated by using a simple procedure to reduce the native structures of the 41 two‐state proteins with native TCD as a constraint, and is further supported by analyzing the results of eight proteins from protein engineering studies. These results support the hypothesis that the major rate‐limiting process in the folding of small apparently two‐state proteins is the search for a critical number of residues with the topology close to that of the native state.