THE ROLES OF PARTLY FOLDED INTERMEDIATES IN PROTEIN-FOLDING

Proteins can fold very rapidly, undoubtedly because they do not do so simply by random searching. The stable, partly folded species that can be detected during protein refolding are, however, of uncertain kinet ic significance, The available kinetic evidence indicates that the int ermediates that are most responsible for the rapidity of folding are e xtremely unstable and not populated detectably; they are less extreme versions of the transition state for folding, Protein folding is most readily studied when it is coupled to disulfide formation, which has t he advantages that the intermediates can be characterized in detail an d their kinetic roles determined unambiguously, The most important asp ects of the disulfide folding pathway of BPTI are understood to at lea st a first approximation, and several other protein disulfide folding pathways are known in outline, These pathways demonstrate that disulfi de folding is not intrinsically different from that not involving disu lfide formation, Pastry folded conformations can increase the rate of folding somewhat by causing productive disulfide bonds to be populated preferentially, bit the most important folding intermediates are not detectable. The essence of folding is to build up the cooperativity be tween the individual interactions that is necessary for a stable confo rmation.