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

Area of Science:

• Biochemistry
• Molecular Biology
• Biophysics

Background:

• Adenosine triphosphate (ATP) is the primary cellular energy currency, predominantly existing as ATP-Mg complexes in solution.
• Recent studies indicate that lithium ions (Li⁺) can co-bind with Mg²⁺ to ATP, forming ATP-Mg-Li complexes that modulate neuronal purine receptor activity.
• The precise binding sites and modes of Mg²⁺ and Li⁺ on the ATP triphosphate group, and their influence on ATP conformation, remain largely uncharacterized.

Purpose of the Study:

• To elucidate the preferred binding modes of Mg²⁺ and Li⁺, individually and in combination, to adenosine triphosphate (ATP).
• To investigate how different metal cation binding modes affect the solution conformation of ATP.
• To understand the structural basis for the biological activity of ATP-Mg-Li complexes in relation to ATP-Mg complexes.

Main Methods:

• Computational modeling and simulation techniques were employed to study the interactions between ATP and metal cations (Mg²⁺ and Li⁺).
• Analysis of preferred binding sites (specific phosphate groups) and coordination modes (bidentate, tridentate) for each cation.
• Conformational analysis of ATP in solution under different cation binding conditions.

Main Results:

• Magnesium (Mg²⁺) preferentially binds tridentately to all three phosphate groups of ATP.
• Lithium (Li⁺) exhibits a bidentate binding preference, primarily to the terminal two phosphates of ATP.
• While ATP conformation is sensitive to cation type and binding mode, it remains largely unchanged upon Li⁺ co-binding to Mg²⁺-ATP complexes.

Conclusions:

• The study defines specific, distinct binding preferences of Mg²⁺ and Li⁺ to ATP's phosphate groups.
• ATP-Mg-Li complexes maintain a conformation similar to Mg²⁺-ATP, allowing them to fit into ATP-binding sites of enzymes and receptors.
• This structural compatibility suggests a mechanism by which ATP-Mg-Li can effectively activate specific cellular signaling pathways, similar to native Mg²⁺-ATP.