Competition among Metal Ions for Protein Binding Sites: Determinants of Metal Ion Selectivity in Proteins

Metal cations are the simplest, but most versatile, cofactors in protein biochemistry with a plethora of distinctive properties. Intracellular and extracellular fluids contain a mixture of metal cations present in different concentrations. Properties of the metal-binding site such as its relative rigidity and solvent accessibility, as well as the type, number, orientation, and protonation state of the metal coordinating ligands, which determine the metal cavity size, geometry, and charge density, affect metal ion selectivity. In several cases, the host protein alone is not able to withstand attacks from biogenic or alien metal cations, which could displace the cognate metal cofactor from the binding site. Whereas the metal-ligand interaction energy becomes less favorable in going down a main group, it becomes more favorable in going across a row in the periodic table, as the net positive charge on the metal increases, yet monovalent ions can still displace divalent ions in certain proteins.