Preferential Binding of Cations Modulates Electrostatically Driven Protein Aggregation and Disaggregation

Protein aggregation resulting in either ordered amyloids or amorphous aggregates is not only restricted to deadly human diseases but also associated with biotechnological challenges encountered in the therapeutic and food industries. Elucidating the key structural determinants of protein aggregation is important to devise targeted inhibitory strategies, but it still remains a formidable task owing to the underlying hierarchy, stochasticity, and complexity associated with the self-assembly processes. Additionally, alterations in solution pH, salt types, and ionic strength modulate various noncovalent interactions, thus affecting the protein aggregation propensity and the aggregation kinetics. However, the molecular origin and a detailed understanding of the effects of weakly and strongly hydrated salts on protein aggregation and their plausible roles in the dissolution of aggregates remain elusive. In this study, using fluorescence and circular dichroism spectroscopy in combination with electron microscopy and light scattering techniques, we show that the ionic size, valency, and extent of hydration of cations play a crucial role in regulating the protein aggregation and disaggregation processes, which may elicit unique methods for governing the balance between protein self-assembly and disassembly.