Are there pathways for protein folding?

Denatured proteins, which have had essentially all of their native three-dimensional structure disrupted, can refold from their random disorderd state into a well-defined unique structure, in which the biological activity is virtually completely restored. This experimental result has lead to the suggestion that a native protein exists in some kind of thermodynamic configurational equilibrium, with the biologically active state being the one of lowest configurational energy. An alternative view is that the native protein is in a uniquely selected metastable state, in which the configurational energy is at a local minimum but not necessarily at an absolute minimum. In this latter model, the protein is not assumed to be in an equilibrium state, and one must postulate some sequence of events which takes place for each molecule so that the protein reaches the correct metastable state.