Cooperative folding process

Temperature-sensitive mutations usually arise from a single mutation s effect on the stability of the protein. Temperature-sensitive mutations make the protein just unstable enough to unfold when the normal temperature is raised a few degrees. At normal temperatures (usually 37°C), the protein folds and is stable and active. However, at a slightly higher temperature (usually 40 to 50°C) the protein denatures (melts) and becomes inactive. The reason proteins unfold over such a narrow temperature range is that the folding process is very cooperative—each interaction depends on other interactions that depend on other interactions. 

K. Gadematm, B. Jaun, D. Seebach, R. Peiozzo, L. Scapozza, G. Folkers, Temperature-Dependant NMR and CD Spectra of p-Peptides. On the Thermal Stability of P-Peptide Helices -Is the Folding Process of p-Peptides non-cooperative , Helv. Chim. Acta, 1999,82,1 - 11. 

The consequences of cooperative folding can be illustrated by considering the contents of a protein solution under conditions corresponding to the middle of the transition between the folded and unfolded forms. Under these conditions, the protein is half folded. Yet the solution will contain no half-folded molecules but, instead, will be a 50/50 mixture of fully folded and fully unfolded molecules (Figure 3.57). Structures that are partly intact and partly disrupted are not thermodynamically stable and exist only transiently. Cooperative folding ensures that partly folded structures that might interfere with processes within cells do not accumulate. 

All these studies seem to indicate that the cooperativity of the folding process is due to the specific pattern of tertiary interactions and/or the specific interplay between short- and long-range interactions. This may appear to be a trivial statement, but detailed analysis of the results from the simple, exact model, protein-like models and reduced models of real proteins show several specific requirements for the protein folding cooperativity. It is very encouraging that over the entire spectrum of theoretical model studies of the protein folding process, these requirements essentially overlap [35-37,51,83,92,95]. Naturally, various models place different stress on the specific interactions that may control protein folding and structural uniqueness. 

In conclusion, the results on myoglobin analyzed here tk) not provide a test of the various aspects of the theory developed in Section VIII, mainly for lack of supplementary data. Certainly we do not note discrepanci between the behavior tlK model and experimental results, but our criteria as to what constitutes dkcrepancy are not very stringent Tlte theory presents a particular point of view, which in these cases does allow one to gain a re onable qualitative understanding of the experiments. The basic point in the theory k the instability of the intermediates in the folding process this is well reproduced by the lattice model, which allows one to calculate the kinetic behavior of a cooperative system with results which may, hopefully, be applied to other cooperative systems and in particular to protein molecules. Further experimental studies are needed to establish whether this is in fact the case. 

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