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In its simplest form, linear polymerization of proteins has been described by a nucleation and growth process, analogous to the condensation mechanism associated with gas-liquid phase transitions, where a kinetic barrier needs to be overcome by the gas to condense into a liquid ( 16, 17). The formation of extended structures depends principally on molecular interactions, structure, and symmetry, resulting in a delicate balance between substrate availability, binding, and unbinding rates ( 14, 15). Direct access to the associated molecular mechanisms is thus critical not only for our understanding of physiological function but also of changes associated with disease, and for the development and optimization of routes to intervention. At the same time, pathological conditions such as neurodegenerative disorders ( 8– 10), type 2 diabetes ( 9– 11), and cancer metastasis ( 12, 13) are associated with undesired protein self-assembly.

The formation of noncovalent polymers by proteins underpins a wide range of physiological processes such as cell division and migration, control of cell shape, and intracellular transport ( 1– 7). Our results revise the mechanism of actin nucleation, shed light on the role and function of actin-associated proteins, and introduce a general and quantitative means to studying protein assembly at the molecular level. The resulting model reproduces important aspects of actin polymerization, such as the critical concentration for filament formation and bulk growth behavior. Instead, the key step of filament formation is a slow transition between distinct states of an actin filament mediated by cation exchange or ATP hydrolysis. We find that traditional nucleation-based models cannot account for the observed distributions of actin oligomers.

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Here, we use mass photometry to quantify and monitor the full range of actin oligomers during polymerization with single-molecule sensitivity. Revealing the relevant molecular details is challenging because of the intrinsic heterogeneity of species ranging from few to hundreds of molecules.

Protein assembly is a main route to generating complexity in living systems.