Biophysical studies of protein solubility and amorphous aggregation by systematic mutational analysis and a helical polymerization model.

At concentrations above solubility, a protein aggregates, most often into amorphous aggregates, and loses its function. However, unlike amyloidogenic aggregates, which are β-sheeted fibrillar aggregates often related to neurodegenerative diseases, amorphous aggregates, where proteins aggregate/oligomerize without forming specific high-order structures, are rarely the focus of biophysical studies. Hence, protein solubility with respect to amorphous aggregation remains to be fully characterized from a biophysical viewpoint. Here, I briefly describe the structural nature of proteins in amorphous aggregates before discussing systematic mutational analyses that aim to rationalize the contribution of individual amino acids to the solubility of a protein. The discussion is expected to demonstrate that protein solubility, and, accordingly, amorphous aggregation, can be understood using thermodynamic and biophysical rationales similar to those used in the study of protein stability or, more recently, amyloidogenesis. Finally, I will argue that the mathematical formalism of the helical polymerization model (HPM) proposed by Oosawa, Kasai, and Asakura's group can be readily adapted to provide a thermodynamic description of a system containing amorphous aggregates and soluble particles. The HPM and HPM-derived models imply the presence of nuclei or seeds for amorphous aggregates, similar to those hypothesized in crystallogenesis and amyloidogenesis.