Residual structure in unfolded proteins

The denatured state ensemble (DSE) of unfolded proteins, once considered to be well-modeled by an energetically featureless random coil, is now well-known to contain flickering elements of residual structure. The position and nature of DSE residual structure may provide clues toward deciphering the protein folding code. This review focuses on recent advances in our understanding of the nature of DSE collapse under folding conditions, the quantification of the stability of residual structure in the DSE, the determination of the location and types of residues involved in thermodynamically significant residual structure and advances in detection of long-range interactions in the DSE.

► Denatured state ensemble collapse is mediated by backbone hydrogen bonds.
► Denaturant concentration affects the Ramachandran plot.
► Site-specific determination of residual structure stability is now possible.
► Long-range nativelike topology exists in the denatured state ensemble.