Small, single domain proteins nearly universally appear to fold via a concerted, two-state process lacking observable kinetic intermediates. This has lead to the hypothesis that many of the compact species observed during the folding of larger proteins may in fact be non-productive, or """"""""off pathway,"""""""" and might compete with the productive folding process. Opinion on this important issue, however, remains sharply divided due, in part, to the limited and indirect nature of the experimental evidence suggesting that collapsed intermediates do no occur during the folding of smaller proteins. We therefore propose to use kinetic small angle X-ray scattering experiments to directly monitor the formation of compact species during the refolding of simple, single domain proteins previously suggested to fold in a two-state manner.
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