Funnels representing an idealized energy landscape for protein folding (a) or a rugged energy landscape with kinetic traps (b), from models of Dill and Chan (80). (a) The unfolded chain starts at the top of an energy landscape, and, as it forms intrachain contacts, lowering its free energy (and descending the funnel), the number of conformations it can sample is progressively reduced, thus eliminating the need for a global search. Ultimately, it reaches the unique native state at the energetic minimum. Note that the number of pathways typically available coming down from the unfolded state may not be unlimited, as depicted here, but may be multiple. (b) Descending a rugged landscape, the polypeptide can lodge in a kinetic trap or can alternatively descend through a narrow path to the native state. Molecular chaperones may act to “smooth” rugged landscapes, preventing polypeptide from descending into a kinetic trap, or rescuing it from one. Reproduced with permission from Nature Structural Biology (80). N, native state.