Even with nonnative interactions, the updated folding transition states of the homologs Proteins G & L are extensive and similar

Significance An outstanding issue in protein science is identifying the relationship between sequence and folding, e.g., do sequences having similar structures have similar folding pathways? The homologs Proteins G & L have been cited as a primary example where sequence variations dramatically affect folding dynamics. However, our new results indicate that the homologs have similar folding behavior. At the highest point on the reaction surface, the pathways converge to similar ensembles. These findings are distinct from descriptions based on the widely used mutational ϕ analysis, partly due to nonnative behavior. Our study emphasizes that significant challenges remain both in characterizing and predicting transition state ensembles even for relatively simple proteins whose folding behavior is believed to be well understood.