Unified theoretical description of the kinetics of protein aggregation

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.