Quinary interactions with an unfolded state ensemble.

Anfinsen's thermodynamic hypothesis states that the native three-dimensional fold of a protein represents the structure with the lowest Gibbs free energy. Changes in the free energy of denaturation can arise from changes to the folded state, the unfolded state, or both. It has been recently recognized that quinary interactions, transient contacts that take place only in cells, can modulate protein stability through interactions involving the folded state. Here we show that the cellular environment can also remodel the unfolded state ensemble.