Developing and Assessing Nonbonded Dummy Models of Magnesium Ion with Different Hydration Free Energy References

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 Mg²⁺ ion targeting different HFE references in TIP3P water, followed by assessments of the designed models in the simulations of MgCl₂ 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 Mg²⁺ such as diffusion constants and water exchange rates using a nonbonded dummy model is demonstrated. Underestimated activity derivative and osmotic coefficient of MgCl₂ 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 metal-containing systems with good accuracy.