Cations in motion: QM/MM studies of the dynamic and electrostatic roles of H⁺ and Mg²⁺ ions in enzyme reactions

Here we discuss current trends in the simulations of enzymatic reactions focusing on phosphate catalysis. The mechanistic details of the proton transfers coupled to the phosphate cleavage is one of the key challenges in QM/MM calculations of these and other enzyme catalyzed reactions. The lack of experimental information offers both an opportunity for computations as well as often unresolved controversies. We discuss the example of small GTPases including the important human Ras protein. The high dimensionality and chemical complexity of these reactions demand carefully chosen computational techniques both in terms of the underlying quantum chemical theory and the sampling of the conformational ensemble. We also point out the important role of Mg²⁺ ions, and recent advances in their transient involvement in the catalytic mechanisms.