On-pathway versus off-pathway folding intermediates

Abstract

Rapidly formed molten globule intermediates accumulate at the start of the folding reactions of several small proteins. Opinion is sharply divided as to whether they are on-pathway or off-pathway intermediates. I discuss recent experiments aimed at resolving this issue. Specific points include whether a 'rollover' in the plot of folding rate versus denaturant concentration implies that a folding intermediate is or is not on-pathway; whether the failure to observe folding intermediates for some small proteins implies a different folding mechanism or only that the intermediates are less stable; possible interpretation of 'fast-track' folding of hen lysozyme; and the significance of recent results in the search for unfolding intermediates.