Metal Affinity/Selectivity of Monophosphate-Containing Signaling/Lipid Molecules

Monophosphate, an essential component of nucleic acids, as well as cell membranes and signaling molecules, is often bound to metal cations. Despite the biological importance of monophosphate-containing cell-signaling or lipid molecules, their propensity to bind the two most abundant cellular dications, Mg²⁺ and Ca²⁺, in a particular mode (inner/outer shell, mono/bidentate) is not well understood. Whether they prefer binding to Mg²⁺ than to Ca²⁺ and if they can outcompete the carboxylates of excitatory Asp/Glu and inhibitory gamma-aminobutyric acid (GABA) neurotransmitters in binding to Mg²⁺/Ca²⁺ remain unclear. To address these questions, we modeled cyclic adenosine/guanosine monophosphate (cAMP/cGMP), nucleoside 2',3'-cyclic phosphate, phosphatidylinositol (PI), phosphatidylserine (PS), and phosphatidylethanolamine (PEA) and determined their most stable metal-binding modes, including those of Asp/Glu and GABA, as well as their selectivity for Mg²⁺/Ca²⁺ using density functional theory combined with the polarizable continuum model. The results obtained, which are consistent with the available experimental findings, reveal that the structurally and functionally diverse monophosphate-containing ligands studied prefer monodentate coordination of Mg²⁺ because of the greater strain encountered upon bidentate coordination, whereas the larger Ca²⁺ imposes less strain upon bidentate binding and has reduced/no preference for monodentate coordination. We further show that in a low-dielectric environment, negatively charged monophosphate-containing ligands favor the better charge-accepting dication, that is, Mg²⁺ rather than Ca²⁺. By promoting Mg²⁺ over Ca²⁺ binding, signaling monophosphates (cAMP/cGMP) do not entrap cellular Ca²⁺ and interfere with signal transduction processes employing Ca²⁺ as a second messenger. In regions with high glutamate cytoplasmic concentration, glutamate may sequester Mg²⁺ bound to isolated five-/six-membered ring phosphates, PI, or neutral PEA, but not anionic phospholipids constituting the inner leaflet of the cell membrane.