How Salt and\nTemperature Drive Reentrant Condensation\nof Aβ40

Within the framework of liquid–liquid\nphase separation (LLPS),\nbiomolecular condensation orchestrates vital cellular processes, and\nits dysregulation is implicated in severe pathological conditions.\nRecent studies highlight the role of intrinsically disordered proteins\n(IDPs) in LLPS, yet the influence of microenvironmental factors has\nremained a puzzling factor. Here, via computational simulation of\nthe impact of solution conditions on LLPS behavior of neurologically\npathogenic IDP Aβ40, we chanced upon a salt-driven reentrant\ncondensation phenomenon, wherein Aβ40 aggregation increases\nwith low salt concentrations (25–50 mM), followed by a decline\nwith further salt increments. An exploration of the thermodynamic\nand kinetic signatures of reentrant condensation unveils a nuanced\ninterplay between protein electrostatics and ionic strength as potential\ndrivers. Notably, the charged residues of the N-terminus exhibit a\nnonmonotonic response to salt screening, intricately linked to the\nrecurrence of reentrant behavior in hydrophobic core-induced condensation.\nIntriguingly, our findings also unveil the reappearance of similar\nreentrant condensation phenomena under varying temperature conditions.\nCollectively, our study illuminates the profoundly context-dependent\nnature of Aβ40s liquid–liquid phase separation behavior,\nextending beyond its intrinsic molecular framework, where microenvironmental\ncues wield significant influence over its aberrant functionality.