Ligand interactions and the protein order-disorder energetic continuum.

Intrinsically disordered proteins as computationally predicted account for ∼1/3 of eukaryotic proteomes, are involved in a plethora of biological functions, and have been linked to several human diseases as a result of their dysfunctions. Here, we present a picture wherein an energetic continuum describes protein structural and conformational propensities, ranging from the hyperstable folded proteins on one end to the hyperdestabilized and sometimes functionally disordered proteins on the other. We distinguish between proteins that are folding-competent but disordered because of marginal stability and those that are disordered due mainly to the absence of folding code-completing structure-determining interactions, and postulate that disordered proteins that are unstructured by way of partial population of protein denatured states represent a sizable proportion of the proteome.