Thermodynamic perspective of protein disorder and phase separation: model systems

Disordered proteins have been shown to play important roles in cellular function. Thermodynamically, these proteins function via structural transitions between ordered and disordered states, which may modulate the free energy of molecular processes. Here, we review relevant past and present research from ourselves and others on disordered proteins and associated phase separation and put forward our perspective on this growing field of study. Results have indicated that, in disordered proteins, the peptide backbone acts as an entropic reservoir, withdrawing or depositing conformational entropy in response to order–disorder transitions. This entropic effect is opposed by interaction enthalpy, as unfavorable changes in entropy are accompanied by increases in favorable interaction enthalpy and vice versa. Liquid–liquid phase separation (LLPS) occurs in concentrated systems of disordered peptides and is a form of biologically relevant disorder → order transition. Molecular dynamic simulations of LLPS in short glycine-rich peptides confirm the stated thermodynamic hypothesis, indicating that conformational entropy is sacrificed and favorable enthalpic van der Waals and electrostatic interactions, are formed upon phase separation. Developing a thermodynamic framework for evaluating the structural transitions of disordered proteins will help us predict the effect that changes to these systems will have on cellular processes.