The problem of protein folding has achieved tremendous advances over the past few decades although huge challenges still remain. The famous Anfinsen experiment showed that protein can fold reversibly, implying that native structures of some small globular proteins are thermodynamically stable states, and therefore are conformations at the global minima of their accessible free energies. Levinthal made the argument that there are too many possible conformations for proteins to find the native structure in the conformational space by random searching only based on simple phenomenologi-cal kinetics models. Levinthal concluded that proteins must fold by specific folding pathways. The argument led to a search for folding pathways. The classical experiments generally probe only the average behavior of the protein and are not able to resolve much atomic detail. Some confusion has arisen for using the single term pathway for both microscopic and macroscopic ideas.
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