Deepening constantly understanding of protein folding problem

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 phenomenological 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. The energy landscape picture replaces the pathway concept of sequential events with the funnel concept of parallel events and emphasizes the ensemble nature of protein conformations, which derives from advances in both experiment and theory. The landscape eliminates the pathway idea and sees folding can funnel to a single stable state by multiple routes in conformations. It has provided a powerful conceptual framework to rationalize protein folding and unfolding. The concept has promoted much of the recent progress in understanding the process of protein folding. Protein folding researches have a close relation with development of techniques. Recently, the techniques for studying protein folding have developed tremendously. Computer-aided molecular dynamics (MD) simulation has become a more and more powerful tool to characterize protein folding/unfolding. Graphics processing unit (GPU) is becoming increasingly useful for probing protein folding with the most computer power. Now, the computer simulation-based techniques have allowed describing protein folding and unfolding at atomistic level. Protein folding simulations are coming of age. Advances in experimental techniques have made it possible to observe detailed information about the successive conformations that occur during the protein folding process. Single molecular operating techniques are becoming important experiment tools to study protein folding/ unfolding. The combined use of experimental data and computer simulations has been shown to be very efficient in protein folding/unfolding. The common goal for theoreticians and experimentalists is to determine the folding process at atomic resolution by combining experimental and computational results. It is evident that protein folding has made significant progress in the past half-century. The energy landscape funnel has provided a correct framework for protein folding based on lots of theory and experiment researches. And the knowledge on protein folding has also promoted understanding of human diseases. However, protein folding is still an open problem such as protein folding in the cell, intrinsically disordered proteins (IDPs) folding and atomic level folding events. So many people are concentrating on the open problem, Arieh Ben-Naim is one of them. In his continual studies, especially the recent paper (Ben-Naim, 2012), he argued that switching from a target-based to a caused-based approach and adopting the hydrophilic paradigm leads straightforwardly to a solution of the protein folding problem. BenNaim argued his view on protein folding by general logical speculations, which is contrary with the main aspect of current studies. His study may give us some new enlightenment for studying the protein folding problem.