Protein folding--what's 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, delta G, 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 delta G. 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.