Energetics of protein structure and folding

The available experimental date on the kinetics of unfolding and refolding of small proteins are reviewed. Excluding slow transitions in the unfolded protein due to cis–trans isomerization of peptide bonds, the rate‐limiting transition state in both unfolding and refolding is concluded to be a high‐energy distortion of the fully folded state. Partially folded intermediates are undoubtedly important for folding, but their formation is normally not rate limiting. A simple model is used to illustrate some of the aspects of protein‐folding energetics.