Insights into the role of magnesium triad in myo-inositol monophosphatase: metal mechanism, substrate binding, and lithium therapy.

myo-Inositol monophosphatase (IMPase) plays a pivotal role in the intracellular phosphatidylinositol cell signaling pathway. It has attracted considerable attention as a putative therapeutic target for lithium therapy in the treatment of bipolar disorder. A trio of activated cofactor Mg2+ ions is required for inositol monophosphate hydrolysis by IMPase. In the present study, computational studies, including two-layered ONIOM-based quantum mechanics/mechanical mechanics (QM/MM) calculations, molecular modeling, and molecular dynamics (MD) simulations, were performed to ascertain the role of the Mg2+ triad in the IMPase active site. The QM/MM calculations show that the structural identity of the nucleophilic water molecule W1 shared by Mg2+-1 and Mg2+-3, activated by Thr95/Asp47 dyad, is a hydroxide ion. Moreover, Mg2+-3 needs to be conjugated with Mg2+-1 in the binding site to create the activated nucleophilic hydroxide ion in accordance with the three-metal ion catalytic mechanism. The MD simulation of th...