The energetic effect of water substitution reactions in hexacoordinated [Mn(H2O)(6-n)L-n(z)](2+nz) complexes with L = methanol, formic acid, formamide, formate, imidazole, and diphosphate is quantitatively analyzed at the MP2/triple-xi; level of theory. Subsequently, the state-of-the-art open shell symmetry adapted perturbation theory (SAPT) analysis of the interaction energies of Mn2+center dot center dot center dot ligand dimers with selected O-, S-, and N- binding ligands is presented and compared to similar interactions of Mg2+ and Zn2+ ions. We find that the induction energies in the dimers with manganese are almost twice as large as in dimers with magnesium. The total interaction energies rise in the order Mn2+ < Mg2+ < Zn2+. The calculations of the Mn2+ -> Mg-2 replacement reaction suggest that metal-dependent glycosyltransferases influence the binding preference of Mn2+ over Mg2+ by inserting amino acids that coordinate the metal via nitrogen or sulfur into their active site.