Exploring a metal-involved biochemical process at a molecular level often requires a reliable description of metal properties in aqueous solution by classical nonbonded models. An additional C 4 term for considering ion-induced dipole interactions was previously proposed to supplement the widely used Lennard-Jones 12-6 potential (known as the 12-6-4 LJ-type model) with good accuracy. Here, we demonstrate an alternative to modeling divalent metal cations (M 2+ ) with the traditional 12-6 LJ potential by developing nonbonded point charge models for use with 11 water models: TIP3P, SPC/E, SPC/E b , TIP4P-Ew, TIP4P-D, and TIP4P/2005 and the more recent OPC3, TIP3P-FB, OPC, TIP4P-FB, and a99SB-disp. Our designed models simultaneously reproduce the experimental hydration free energy, ion−oxygen distance, and coordination number in the first hydration shell accurately for most of the metal cations, an accuracy equivalent to that of the complex 12-6-4 LJ-type and double exponential potential models. A systematic comparison with the existing M 2+ models is presented as well in terms of effective ion radii, diffusion constants, water exchange rates, and ion−water interactions. Molecular dynamics simulations of metal substitution in Escherichia coli glyoxalase I variants show the great potential of our new models for metalloproteins.

A large diversity in the targeted hydration free energies (HFEs) during model parameterization of metal ions was reported in the literature with a difference by dozens of kcal/mol. Here, we developed a series of nonbonded dummy models of the Mg 2+ ion targeting different HFE references in TIP3P water, followed by assessments of the designed models in the simulations of MgCl 2 solution and biological systems. Together with the comparison of existing models, we conclude that the difference in the targeted HFEs has a limited influence on the model performance, while the usability of these models differs from case to case. The feasibility of reproducing more properties of Mg 2+ such as diffusion constants and water exchange rates using a nonbonded dummy model is demonstrated. Underestimated activity derivative and osmotic coefficient of MgCl 2 solutions in high concentration reveal a necessity for further optimization of ion-pair interactions. The developed dummy models are applicable to metal coordination with Asp, Glu, and His residues in metalloenzymes, and the performance in predicting monodentate or bidentate binding modes of Asp/Glu residues depends on the complexity of metal centers and the choice of protein force fields. When both the binding modes coexist, the nonbonded dummy models outperform point charge models, probably in need of considering polarization of metal-binding residues by, for instance, charge calibration in classical force fields. This work is valuable for the use and further development of magnesium ion models for simulations of metalcontaining systems with good accuracy.