PROTEIN FOLDING - WHATS THE QUESTION

The folding reactions of many small, globular proteins exhibit two-state kinetics, in which the folded and unfolded states interconvert readily without observable intermediates. Typically, the free energy difference, DELTAG, between the native and denatured states of such a protein is quite small, lying in the range of approximately -5 to -15 kcal/mol. We point out that, under these circumstances, a population of native-like molecules will persist, even in the presence of mutations sufficiently destabilizing to change the sign of DELTAG. Therefore, it is not energy per se that determines conformation. A corollary to this argument is that specificity-not stability-would be the more informative focus in future folding studies.