Phase transitions of folded proteins

Abstract

Proteins exhibit a rich phase behavior. Even omitting the amyloid structures formed after partial protein unfolding, proteins form crystals, polymers, and other solid aggregates, as well as dense liquids and gels. Some of these condensed phases underlie pathological conditions, others play a crucial role in the biological function of the respective protein or are an essential part of its laboratory or industrial processing. In this review, we first discuss the thermodynamic characteristics of the solution and the interactions between protein molecules in solution, which underlie the protein phase behavior. We highlight the role of water structured at the protein molecular surface as a main contributor to the free energy of the phase transition. We define the driving force for phase transformations. We then summarize the fundamentals and review recent findings on the kinetics of nucleation of dense liquid droplets and crystals. We define the transition from nucleation to spinodal decomposition for these two phase transitions. We review the two-step mechanism of protein crystal nucleation, in which mesoscopic metastable protein clusters serve as precursors to the ordered crystal nuclei. Lastly, we discuss the mechanisms of growth of crystals: the generation of new crystal layers, the pathways of the molecules from the solution into the growth sites, the density of the growth sites and the factors, which determine the activation barriers for association of the molecules to the growth sites.