Funnel-shaped free energy landscape

How do proteins fold according to the multi-funnel hypothesis It has been proposed that within a multi-funnel shaped free energy landscape, protein folding involves two steps a first, kinetic, step in which a specific funnel is selected (most of the times that funnel being the native funnel) and a second step in which the structure relaxes as its free energy is minimized within the funnel selected, as first proposed by Anfinsen and later incorporated in the single-funnel hypothesis. Within this two-step... 

Figure 1. The funnel shape Gibbs-free energy landscape of protein. The global minimum corresponds to the native state. Left There are no local minima. Two-state folding approximation Right There are many local minima. Presence of intermediate states, the red line corresponds to a folding pathway giving rise to a metastable intermediate state . ...

In 1969, Levinthal posed his famous paradox pointing out that the configurational space of a polypeptide chain is so large that it can never find its native conformation by a random search. Evolution has apparently selected polypeptide chains that find their native fold reliably and quickly. Their free-energy landscapes exhibit minimal ruggedness and the overall shape of a funnel with only shallow local minima. 

Fig. 1 According to the single funnel hypothesis the shape of the free energy landscape of proteins is a funnel and the native structure is well defined because it corresponds to the structure which is found at the bottom of the funnel.

---