Biophysical Reviews

, Volume 10, Issue 2, pp 473–480 | Cite as

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

  • Yutaka Kuroda


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.


Solubility Precipitation Mutational analysis Thermodynamics analysis Helical polymerization model (HPM) Amorphous aggregation 



This article is dedicated to the 70th birthday anniversary of Professor Fumio Arisaka. I thank laboratory members, especially Drs. Atsushi Kato, Mohammad M. Islam, and Alam M. Khan for discussion and experimental data, and Ms. Patricia McGahan for the English grammar editing. This work was supported by a Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research (KAKENHI-21300110).

Compliance with ethical standards

Conflict of interest

Yutaka Kuroda declares that he has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by the author.


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Copyright information

© International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Department of Biotechnology and Life Sciences, Graduate School of EngineeringTokyo University of Agriculture and TechnologyKoganei-shiJapan

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