Electrostatic Charge Shielding Effect of ATP: Implications for Therapeutic Intervention

Adenosine triphosphate (ATP) is recognized as the primary "energy currency" in cells, but its chemical structure, particularly the highly anionic triphosphate chain, also confers strong electrostatic properties independent of catalysis. ATP consists of an adenosine moiety attached to a chain of three phosphate groups. At physiological pH, these phosphates collectively carry approximately four negative charges, typically coordinated with Mg²⁺ to form a Mg²⁺/ATP complex. The high charge density of the triphosphate tail enables ATP to neutralize or shield electrostatic interactions. Importantly, the cytosol maintains ATP at millimolar concentrations (~5-10 mM), far exceeding what is required for enzymatic catalysis. One proposed rationale for this unusually high abundance is that Mg²⁺/ATP electrostatically maintains protein solubility and prevents non-specific aggregation. Mg²⁺/ATP is a central electrostatic regulator in cell physiology and a potential therapeutic molecule for diseases involving aberrant biomolecular condensation. This review summarizes the electrostatic charge shielding roles of Mg²⁺/ATP in three major contexts: (1) modulation of membrane interactions and vesicle fusion, (2) stabilization of nucleic acids, and (3) inhibition of protein aggregation.