Comprehensive density functional theory study on the mechanism of activation of the nonapeptide hormone oxytocin by metal ions.

The physiological functions of oxytocin (OT) may be activated by bivalent metal ions but not by monovalent ones. However, the reason for this phenomenon is unknown. Thus, in the present study, theoretical calculations were performed to determine the structures and thermochemical properties of OT and related species: OT, OT+H, OT+2H, OT+M, and OT+M+H (M(+) = Na(+) and K(+), M(2+) = Co(2+), Ni(2+), Mg(2+), Zn(2+), and Ca(2+)). Their structures and vibrational frequencies were determined by the density functional theory based method. Their relative electronic energies were determined at the BHandHLYP/6-311G(2df,p) level with proper considerations of the basis set superposition errors. The computed structures were used to explain whether the OT species were physiologically active or not, and the mechanism of the activation of OT by divalent metal ions but not by monovalent metal ions was determined. The relative metal ion affinities of OT were found to be responsible for the relative effectiveness of divalent metal ions for the OT activation, which were in the order of Co(2+) > Ni(2+) > Mg(2+) > Zn(2+), with a minimal effect by Ca(2+). Moreover, the recent observation of the coexistence of OT+H, OT+2H, and OT+Na+H in solution in the absence of a divalent metal ion and their disappearance in the presence of Zn(2+) were also explained by the computed free energy changes of the relevant reactions.