Is There or Isn't There? The Case for (and Against) Residual Structure in Chemically Denatured Proteins

First raised some 60 years ago, the question of whether chemically denatured proteins are fully unfolded has, in recent years, seen significantly renewed interest. This increased attention has been spurred, in large part, by new spectroscopic and computational approaches that suggest even the most highly denatured polypeptides contain significant residual structure. In contrast, the most recent scattering results uphold the long-standing view that chemically denatured proteins adopt random coil configurations. Here we review the evidence both for and against residual structure in chemically denatured proteins, and attempt to reconcile these seemingly contradictory observations.