To elucidate the factors governing metal cation selectivity by proteins, density functional theory (DFT) and continuum dielectric methods (CDM) were used to evaluate the free energy of metal exchange in model binding sites. We studied Mg2+<----> Zn2+ exchange in rigid sites, where the incoming metal retains the coordination geometry of the outgoing metal, as well as inflexible sites that can accommodate some reorganization of the protein Ligands upon metal substitution. The results predict that Zn2+ can dislodge Mg2+ from its octahedral binding site. On the other hand, Mg2+ cannot displace Zn2+ from its tetrahedral binding site, unless a nearby negatively charged side chain can coordinate directly to Mg2+ in an octahedral geometry. The combination of available experimental data with our results suggest that some proteins may have chosen Mg2+ as a natural cofactor due mainly to its natural abundance in living cells. In such cases, it is not the protein that has evolved to select Mg2+ from Other cations; instead, it is the cell machinery, which governs metal selectivity by regulating appropriate concentrations of Mg2+ and other cations (Zn2+ in particular) in various biological compartments. in contrast, Zn2+-binding sites appear to be more selective than Mg2+-binding sites. Hence,. the protein can select Zn2+ against the background of a higher Mg2+ concentration.