Microenvironment Drives Reentrant Condensation of Aβ40

Within the framework of liquid-liquid phase separation (LLPS), biomolecular condensation orchestrates vital cellular processes and its dysregulation is implicated in severe pathological conditions. Recent studies highlight the role of intrinsically disordered proteins (IDPs) in LLPS, yet the influence of microenvironmental factors has remained a puzzling factor. Here, via computationally simulating the impact of solution conditions on LLPS behavior of neurologically pathogenic IDP Aβ40, we chanced upon a salt-driven reentrant condensation phenomenon, wherein Aβ40 aggregation increases with low salt concentrations (25-50 mM), followed by a decline with further salt increments.. An exploration into the thermodynamic and kinetic signatures of reentrant condensation unveils a nuanced interplay between protein electrostatics and ionic strength as potential drivers. Notably, the charged residues of the N-terminus exhibit a non-monotonic response to salt screening, intricately linked to the recurrence of reentrant behavior in hydrophobic core-induced condensation. Intriguingly, our findings also unveil the reappearance of similar reentrant condensation phenomena under varying temperature conditions. Collectively, our study illuminates the profoundly context-dependent nature of Aβ40’s liquid-liquid phase separation behavior, extending beyond its intrinsic molecular framework, where microenvironmental cues wield significant influence over its aberrant functionality.