The binding of the oxytocin cyclic peptide to its target oxytocin receptor plays a key role for human behaviour. Both binding and receptor activation are affected by the presence of a Mg2+ ion. Unfortunately, the current experimental structural information does not provide a complete picture of the metal coordination chemistry. Here, by using molecular dynamics and taking advantage of an ad hoc force field for the divalent ion, we predict the location of four water molecules completing the octahedral coordination of the metal ion. We also suggest that binding of oxytocin is enhanced by the simultaneous proximity of the C-terminal region of oxytocin and the N-terminal region of the receptor to the Mg2+ ion, while activation also depends on the conformation of transmembrane helices 5 and 6 joined by intracellular loop 3, a region that has not been solved in experimental structures and that has been modelled here in two conformations using state-of-the-art techniques.
Musiani et al. (Thu,) studied this question.