Factors controlling the selectivity for Na+ over Mg2+ in sodium transporters and enzymes

Na+ and Mg2+ play different crucial roles in biological systems. Both cations are present in comparable amounts in the cytosol, but how monovalent Na+ can compete with the divalent Mg2+, which can better accept charge from negatively charged ligands, in sodium transporters/enzymes has not been investigated. Hence, it is not clear how Na+ and Mg2+ -binding sites have evolved to discriminate the ``right'' cation among non-cognate ones from the surrounding milieu and the physical basis governing the selectivity for Na+ over Mg2+. The results, which are consistent with available experimental data, reveal that in proteins, the selectivity for Na+ over Mg2+ in sodium-binding sites stem mainly from the size, charge, and charge-accepting ability differences between Na+ and Mg2+. A protein could achieve Na+ selectivity by (i) reducing the number of metal-ligating ligands, (ii) maintaining an optimal balance of different ligating-strength ligands whose interactions in the metal-binding site would favor Na+ over rival mono/divalent cations, (iii) increasing the solvent exposure of the metal-binding site, or (iv) increasing binding site rigidity forcing Mg2+ to adopt the coordination distances/geometry of Na+. Sodium-binding proteins use one or more of these factors to achieve Na+ selectivity.