Role of Mg2+ ions in protein kinase phosphorylation: insights from molecular dynamics simulations of ATP-kinase complexes

Phosphorylation of protein kinases (PKs) plays a central role in the signal transduction of cells by transferring a phosphate group from adenosine triphosphate (ATP) to the side chains of particular serine, threonine or tyrosine residues of substrates. Previous studies have shown that Mg2+ ions are crucial for the formation of transition state of phosphoryl transfer reaction. However, the roles of Mg2+ ions in other steps of phosphorylation remain poorly understood. Here, we performed molecular dynamics simulations to study the interactions of ATP with PKs in the presence and the absence of Mg2+ ions in the active sites, respectively. Affinity analysis showed that the binding-free energies of ATP to the PK active sites in the presence of Mg2+ ions are lower than those in the absence of Mg2+ ions, suggesting that Mg2+ ions in the active sites could enhance the binding affinities of ATP to the PKs. This enhancement is mainly attributed to the electrostatic interactions induced by Mg2+ ions. Thus, this study shows that Mg2+ ions also play a very important role in the binding of ATP to PKs, and thereby gains a better understanding of how Mg2+ ions function in protein phosphorylation.