Cunning simplicity of a hierarchical folding.

A hierarchic scheme of protein folding does not solve the Levinthal paradox since it cannot provide a simultaneous explanation for major features observed for protein folding: (i) folding within non-astronomical time, (ii) independence of the native structure on large variations in the folding rates of given protein under different conditions, and (iii) co-existence, in a visible quantity, of only the native and the unfolded molecules during folding of moderate size (single-domain) proteins. On the contrary, a nucleation mechanism can account for all these major features simultaneously and resolves the Levinthal paradox.