A systematic study of the binding affinities of the model biological ligands X: = (CH3)(2)S, CH3S-, CH3NH2, 4-CH3-imidazole (Melmid), C6H5O-, and CH3CO2- to (NH3)(i)(H2O)(3-i)CU(II)-H2O (i = 3, 2, 1, 0) complexes has been carried out using quantum chemical calculations. Geometries have been obtained at the B3LYP/ 6-31G(d) level of theory, and binding energies, Delta H degrees((g)), relative to H2O as a ligand, have been calculated at the B3LYP/6-311 + G(2df,2p)//B3LYP/6-31G(d) level. Solvation effects have been included using the COSMO model, and the relative binding free energies in aqueous solution (Delta G degrees'((aq))) have been determined at pH 7 for process that are Ph dependent. Ch3S(-) (Delta G degrees'((aq)) = -16.0 to -53.5 kJ mol(-1)) and Melmid (Delta G degrees'((aq)) = -18.5 to -35.2 kJ mol(-1)) give the largest binding affinities for Cu(II). PhO- and (CH3)(2)S are poor ligands for Cu(II), Delta G degrees'((aq)) = 20.6 to -9.7 and 19.8 to -3.7 kJ mol(-1), respectively. The binding affinities for CH(3)NH(2)range from -0.8 to - 15.0 kJ mol(-1). CH3CO2 range from -0.8 to -15.0 kJ mol(-1). CH3CO2- has Cu(II) binding affinites in the ranges Delta G degrees'((aq)) = -13.5 to -32.4 kJ mol(-1) if an adjacent OH bond is available for hydrogen bonding and Delta G degrees'((aq)) = 10.1 to -4.6 kJ mol(-1) if this interaction is not present. In the context of copper coordination by the A beta peptide of Alzheimer's disease, the binding affinities suggest preferential binding of Cu(II) to the three histidine residues plus a lysine or the N-terminus. For a 3N1O Cu(II) ligand arrangement, it is more probable that the oxygen ligand comes from an aspartate/glutamate residue side chain than from the tyrosine at position 10. Methionine appears unlikely to be a Cu(II) ligand in A beta.