Biophysical Reviews

, Volume 11, Issue 2, pp 191–208 | Cite as

Unified theoretical description of the kinetics of protein aggregation

  • Nami Hirota
  • Herman Edskes
  • Damien HallEmail author


Solution conditions chosen for the production of amyloid can also promote formation of significant extents of amorphous protein aggregate. In one interpretation, the amyloid and amorphous aggregation pathways are considered to be in competition with each other. An alternative conceptualization involves considering amorphous aggregation as an obligatory intermediate process of the amyloid formation pathway. Here, we review recently developed macroscopic-level theories of protein aggregation that unify these two competing models into a single paradigm. Key features of the unified model included (1) a description of the amorphous aggregate as a second liquid phase with the degree of liquid-like character determined by the mobility of the monomer within it, and (2) heterogeneous growth pathways based on nucleation, growth, and fragmentation of amyloid occurring within different phases and at their interfacial boundary. Limiting-case behaviors of the protein aggregation reaction, either singly involving amyloid or amorphous aggregate production, and mixed-case behaviors, involving competitive and/or facilitated growth of amorphous and amyloid species, are presented and reviewed in context. This review principally describes an approach developed by Hirota and Hall 2019 (Hirota, N. and Hall, D. 2019. Protein Aggregation Kinetics: A Unified Theoretical Description. Chapter 7 of ‘Protein Solubility and Amorphous Aggregation: From Academic Research to Applications in Drug Discovery and Bioindustry’ edited by Y. Kuroda and F. Arisaka. CMC Publishers). Sections of that work are translated from the original Japanese and republished here with the full permission of CMC Publishing Corporation.


Kinetics Protein aggregation Amyloid United model 



NH would like to thank supporting funds from Do International Trading House. HE: This research was supported, in part, by the Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Initial and later aspects of the work of DH were respectively supported by funds and resources associated with an Australian National University (ANU) Senior Research Fellowship and an Associate Professorship at the Institute for Protein Research, Osaka University. DH would also like to express thanks to The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) for financial support in the form of a two-month visiting fellowship in July and August of 2018.

Compliance with ethical standards

Conflict of interest

Nami Hirota declares that she has no conflict of interest. Herman Edskes declares that he has no conflict of interest. Damien Hall declares that he has no conflict of interest.

Ethical approval

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


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Copyright information

© International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Do International Trading HouseNishinomiyaJapan
  2. 2.Laboratory of Biochemistry and GeneticsNIDDK, NIHBethesdaUSA
  3. 3.Institute for Protein ResearchOsaka UniversityOsakaJapan

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