Effects of macromolecular crowding on protein folding and aggregation studied by density functional theory: Statics

Proteins are neither purified nor diluted inside the living cell. Thus it is indispensable to take into account various interactions between the protein of interest and other macromolecules for understanding the properties of proteins in physiological conditions. Here we focus on excluded volume interactions which are omnipresent in dense or crowded solutions of proteins and macromolecules or “crowding agents.” A protein solution with macromolecular crowding agents is modeled by means of a density functional theory. Effects of macromolecular crowding on protein aggregation and stability are investigated in particular. Phase diagrams are obtained in various parameter spaces by solving the equation of state. Two generic features are found: the addition of the crowding agent (1) enhances the aggregation of the denatured proteins, and (2) stabilizes the native protein unless the aggregation occurs. The present theory is qualitatively in good agreement with experimental observations and unifies previous theories regarding the crowding effects on protein stability and aggregation.