Rethinking Cellular Organization: Phase Separation as a Unifying Principle in Molecular Biology.

Dimerization, liquid-liquid condensate formation, and amyloid deposition are all examples of macromolecular assembly and phase transitions essential for healthy cellular function but that become dysregulated in disease. A common underlying mechanism in these transitions is the dehydration of macromolecule surfaces. Through this lens, a deeper understanding emerges of how changing solvent conditions (e.g., solvent polarity, temperature, pH) affect the intracellular solubility of macromolecules. The cell cycle can be reframed as a cyclical change in solvent conditions, which, at an atomic scale, corresponds to the cyclical precipitation and solubilization of nucleic acid-binding proteins interacting with RNA or DNA. To solubilize nucleic acid-binding proteins, a negative counterion is required to pair with the Lysine/Arginine cations. ATP is the primary intracellular counterion, linking solubilization and precipitation dynamics directly to cellular metabolism. This framework highlights how cellular, in vivo conditions vary dramatically across time and space, revealing complexities that in vitro experiments often fail to capture. Recent advances in understanding these cyclical solvent-driven transitions are crucial to furthering progress in cell biology.