Selectivity mechanism of magnesium and calcium in cation-binding pocket structures of phosphotyrosine.

Magnesium (Mg^{2+}) and calcium (Ca^{2+}) are of essential importance in biological activity, but the molecular understanding of their selectivity is still lacking. Here, based on density functional theory calculations and ab initio molecular dynamics simulations, we show that Mg^{2+} binds more tightly to phosphotyrosine (pTyr) and stabilizes the conformation of pTyr, while Ca^{2+} binds more flexibly to pTyr with less structural stability. The key for the selectivity is attributed to the cation-π interactions between the hydrated cations and the aromatic ring together with the synergic interaction between the cations and the side groups in pTyr to form a cation-binding pocket structure, which we refer as side-group-synergetic hydrated cation-π interaction. The existence and relative strength of the cation-π interactions in the pocket structures as well as their structural stability have been demonstrated experimentally with ultraviolet (UV) absorption spectra and ^{1}H NMR spectra. The findings offer insight into understanding the selectivity of Mg^{2+} and Ca^{2+} in a variety of biochemical and physiological essential processes.