Factors Controlling Metal-Ion Selectivity in the Binding Sites of Calcium-Binding Proteins. The Metal-Binding Properties of Amide Donors. A Crystallographic and Thermodynamic Study

The metal-ion complexing properties of the ligand EDTAM (ethylenediamine-N,N,N‘,N‘-tetraacetamide) are investigated as a model for the role of amide oxygen donors in the binding sites of Ca-binding proteins. The structures of the complexes [Ca(EDTAM)NO₃]NO₃ (1), [La(EDTAM)(H₂O)₄](NO₃)₃·H₂O (2), and [Cd(EDTAM)(NO₃)]NO₃ (3) are reported:  1 monoclinic, P2₁/c, a = 10.853(2) Å, b = 12.893(3) Å, c = 13.407(3) Å, β = 103.28(3)°, Z = 4, R = 0.0281; 2 triclinic, P, a = 8.695(2) Å, b = 9.960(2) Å, c = 16.136(3) Å, α = 95.57(3)°, β = 94.84(3)°, γ = 98.72(3)°, Z = 2, R = 0.0394; 3 monoclinic, P2₁/c, a = 10.767(2) Å, b = 12.952(2) Å, c = 13.273(2) Å, β = 103.572(3)°, Z = 4, R = 0.0167. Compounds 1 and 3 are isostructural, and the EDTAM binds to the metal ion through its two N-donors and four O-donors from the amide groups. Ca(II) in 1 is 8-coordinate with a chelating NO₃^- group, while Cd(II) in 3 may possibly be 7-coordinate, with an asymmetrically coordinated NO₃^- that is best regarded as unidentate. The La(III) in 2 is coordinated to the EDTAM in a manner similar to that of 1 and 3, but it is 10-coordinate with four water molecules coordinated to the La(III). The formation constants (log K₁) for complexes of a variety of metal ions with EDTAM are reported in 0.1 M NaNO₃ at 25.0 ± 0.1 °C. These are compared to the log K₁ values for en (ethylenediamine) and THPED (N,N,N‘,N‘-tetrakis(2-hydroxypropyl)-ethylenediamine). For large metal ions, such as Ca²⁺ or La³⁺, log K₁ increases strongly when the four acetamide groups are added to en to give EDTAM, whereas for a small metal ion, such as Mg²⁺, this increase is small. The log K₁ values for EDTAM compared to THPED suggest that the amide oxygen is a much stronger base than the alcoholic oxygen. Structures of binding sites in 40 Ca-binding proteins are examined. It is shown that the Ca−OC bond angles involving coordinated amides in these sites are large, commonly being in the 150−180° range. This is discussed in terms of the idea that for purely ionic bonding the M−OC bond angle will approach 180°, while for covalent bonding the angle should be closer to 120°. How this fact might be used by the proteins to control selectivity for different metal ions is discussed.