Binding of VIVO2+ to the Fe binding sites of human serum transferrin. A theoretical study

The binding of (VO2+)-O-IV to human serum transferrin (hTF) at the Fe-III binding sites is addressed. Geometry optimization calculations were performed for the binding of (VO2+)-O-IV to the N-terminal lobe of hTF (hTF(N)), and indicate that in the presence of CO3 (2-) or HCO3 (-), V-IV is bound to five atoms in a distorted geometry. The structures of (VO)-O-IV-hTF(N) species optimized at the semiempirical level were also used to calculate the V-51 and N-14 A tensors by density functional theory methods, and were compared with the reported experimental values. Globally, of all the calculated (VO)-O-IV-hTF structures, the one that yields the lowest calculated heats of formation and minimum deviations from the experimental values of the V-51 and N-14 A tensor components is the structure that includes CO3 (2-) as a synergistic anion. In this structure the V=O bond length is approximately 1.6 , and the vanadium atom is also coordinated to the phenolate oxygen atom of Tyr188 (at approximately 1.9 ), the aspartate oxygen atom of Asp63 (at approximately 1.9 ), the His249 N tau atom (at approximately 2.1 ), and a carbonate oxygen atom (at approximately 1.8 ). The Tyr95 phenolic ocygen atom is approximately 3.3 from the metal center, and thus is very weakly bound to V-IV. All of these oxygen atoms are able to establish dipolar interactions with groups of the protein.