NMR as a tool to identify and characterize protein folding intermediates

NMR spectroscopy is one of the few biophysical methods that can provide atomic-level insight into the conformation of partially folded states and/or intermediates present along the protein folding pathway. Such studies are important not only within the context of the protein folding problem, but also to push forward the technique, due to the challenging nature of the systems studied. In fact, new NMR methods have been created, and applied, in an attempt to characterize the conformational features of the states along the folding pathway. Describing the structures along the folding landscape is of key importance to comprehend the folding reaction, design new proteins and to understand how several polypeptide chains are implicated in pathogenic amyloid states. The last advances in several approaches, which use NMR: (i) to monitor the protein folding pathway and/or, (ii) to characterize the structure of the intermediate states in such reaction are reviewed in this work.

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► Structures of intermediates at atomic-resolution have been obtained by NMR.
► Intermediates have native-like topology.
► Intermediates have non-native contacts.
► The NMR view of folding agrees with that provided by other biophysical probes.