ATP-Ion Complexation and Lithium’s Bioactive Form in Cellular Solutions

Lithium (Li⁺) is a first-line therapy for millions of people with bipolar disorder. However, the molecular mechanism underlying Li⁺’s action remains unclear. Here we resolve a key issue concerning its bioactive form that is central to all hypotheses proposed to explain its therapeutic action─under cellular conditions, it is unclear as to what fraction of Li⁺ is free vs bound to ATP. We address this using molecular dynamics (MD) simulations and kinetic modeling. The polarizable force field (AMOEBA-HFC) employed in MD is benchmarked against quantum mechanical and experimental data, including local ion-ligand interactions, aqueous phase ion properties, and ion-ATP binding free energies. The kinetic model is built using observations from MD and parametrized using MD and experimental data. We discover that Mg²⁺-bound ATP (ATP·Mg) has two binding sites for monovalent cations, and both sites can be loaded simultaneously. In Li⁺’s absence, ATP·Mg predominantly exists as a ternary or quaternary complex with Na⁺ and/or K⁺ ions. Li⁺ also competes for these two sites. Although its standard affinity is stronger than Na⁺ and K⁺, its loading its limited by its low therapeutic concentration. Nevertheless, the extent of Li⁺ loading increases with ATP levels, and 50% of Li⁺ can be sequestered by ATP·Mg at physiological extremes. This means that both Li⁺ forms can be present in high fractions, providing a basis to investigate molecular modes of Li⁺ action. Overall, our work provides new structural, thermodynamic, and kinetic insights into how ATP binds ions in cellular solutions, also revealing Li’s bioactive form.