Generalized View of Protein Folding: In Medio Stat Virtus

Proteins are often described in textbooks as being only “marginally stable” but many proteins, specifically those with a high free energy of unfolding are, in fact, so stable that they exist only in the fully folded state except under harsh denaturing conditions. Proteins that are truly only marginally stable, those with a low free energy of unfolding, exist as an equilibrium mixture of folded and unfolded forms under “normal” conditions. To some extent such proteins have some features in common with “intrinsically disordered” proteins. We analyzed the relationship between these marginally stable proteins and intrinsically disordered proteins in order to fully understand the twilight zone that distinguishes the two ensembles in the hope of clarifying the fuzzy borders of the current classification that divides the protein world into folded and intrinsically disordered ones. Our analysis suggests that the division may be too drastic and misleading, because it puts within the same category proteins with ver...