Principles of Protein Structure Determination - G. Schulz 1982

Thermodynamics and Kinetics of Polypeptide Chain Folding
Modeling of the Folding Process
Conclusion

At present, many principles and details of polypeptide chain folding remain poorly understood. We know that this process occurs spontaneously and is therefore governed by basic physicochemical principles, giving us hope that protein folding can be explained and modeled using theoretical approaches. The first steps in this direction have already been taken. Interest in folding is driven not merely by scientific curiosity, but by much deeper reasons. To gain insight into biological processes, we need to know the three-dimensional Structure of various Proteins, including those that cannot be crystallized and are thus inaccessible to X-Ray Diffraction Analysis. Our only hope of deciphering such structures lies in determining them directly from Amino acid sequences. This approach must follow The pathway of natural folding: filtering all possible final structures of a given polypeptide chain based on their Free energy is just as futile as trying to determine whether the native structure corresponds to a local or global energy minimum.

The most challenging problem in folding dynamics is the characterization of intermediate states. Currently, the only structural insights into these states come from the Disulfide Bonds formed within them. Unfortunately, it is quite possible that the folding pathway of proteins containing S—S bonds differs qualitatively from that of other proteins, thus yielding only limited information.

Major efforts are underway to identify nucleation sites—the folding nuclei that are hypothesized to serve as the template for subsequent folding. Such nascent structures must possess exceptional stability. It is conceivable that they could be detected using Antibodies or refolding experiments involving modified proteins. Locating these nuclei would greatly facilitate the modeling of the folding process. In any case, it is clear that a vast amount of further experimental work will be required before the mystery of protein folding is fully unraveled.