How Native and Alien Metal Cations Bind ATP: Implications for Lithium as a Therapeutic Agent

Abstract

Adenosine triphosphate (ATP), the major energy currency of the cell, exists in solution mostly as ATP-Mg. Recent experiments suggest that Mg²⁺ interacts with the highly charged ATP triphosphate group and Li⁺ can co-bind with the native Mg²⁺ to form ATP-Mg-Li and modulate the neuronal purine receptor response. However, it is unclear how the negatively charged ATP triphosphate group binds Mg²⁺ and Li⁺ (i.e. which phosphate group(s) bind Mg²⁺/Li⁺) and how the ATP solution conformation depends on the type of metal cation and the metal-binding mode. Here, we reveal the preferred ATP-binding mode of Mg²⁺/Li⁺ alone and combined: Mg²⁺ prefers to bind ATP tridentately to each of the three phosphate groups, but Li⁺ prefers to bind bidentately to the terminal two phosphates. We show that the solution ATP conformation depends on the cation and its binding site/mode, but it does not change significantly when Li⁺ binds to Mg²⁺-loaded ATP. Hence, ATP-Mg-Li, like Mg²⁺-ATP, can fit in the ATP-binding site of the host enzyme/receptor, activating specific signaling pathways.

Figure 1. M062X/6-311++G(d,p) optimized structures of [ATP-Mg]²⁻ complexes and relative free energies, ∆∆G (kcal/mol), of complex formation in water.

The dashed lines indicate hydrogen bonds, defined by a hydrogen-acceptor distance <1.4 Å and a D–H…A angle >130°. The structures were oriented to give the clearest view of the metal-binding site.

Figure 2. M062X/6-311++G(d,p) optimized structures of [ATP-Li]³⁻ complexes and relative free energies, ∆∆G (kcal/mol), of complex formation in water.

Figure 3. M062X/6-311++G(d,p) optimized structures of Li⁺ bound to ATP-Mg(αβγ), and relative free energies, ∆∆G (kcal/mol), of complex formation in water.

Figure 4. M062X/6-311++G(d,p) optimized structures of Li⁺ bound to ATP-Mg(αβ) (left) or ATP-Mg(βγ) (right) and relative free energies, ∆∆G (kcal/mol), of complex formation in water.

Figure 5

Relative solution free energies, ∆∆G (kcal/mol), of (A) [ATP-Mg]²⁻ (magenta) and [ATP-Li]³⁻ (turquoise) complexes from Figs 1 and 2, respectively, and (B) [ATP-Mg-Li]⁻ complexes from Figs 3 and 4 with the Mg- and Li-binding modes in magenta and turquoise, respectively. The filled circles, crosses and triangles denote mono, bi and tridentate binding, respectively.