Cunning simplicity of protein folding landscapes.

Funnel-like landscapes are widely used to visualize protein folding. It might seem that any funnel-like energy landscape helps to avoid the 'Levinthal paradox', i.e. to avoid sampling the impossibly large number of conformations for a folding protein. This cunning suggestion, reinforced by beautiful drawings of the energy funnels, stimulated some simple models of protein folding; one of them [D.J. Bicout and A. Szabo (2000) Protein Sci., 9, 452-465] is especially straightforward and instructive. A thorough analysis of this strict funnel model (which does not consider a nucleation of phase separation in the course of folding) shows that it cannot provide a simultaneous explanation for both major features observed for protein folding: (i) folding within non-astronomical time, and (ii) co-existence of the native and the unfolded states during the folding process. On the contrary, the nucleation mechanism of protein folding can account for both these major features simultaneously.