Understanding how ions bind to biomolecules and how their binding modulates biomolecular structure and dynamics requires analysis of both their local and distant interactions. Molecular mechanics (MM) simulations can, in principle, provide such details. However, this raises the question of how well MM force fields perform at describing relative contributions from local and distant interactions, which together yield ion bulk solvation properties? Here, we address this using the divalent Mg 2+ ion as a model, which plays vital roles in many physiological processes, such as serving as an enzyme cofactor and providing stability to genetic material. In earlier work, we showed that the polarizable AMOEBA-HFC force field reproduced Mg 2+ ’s interactions with directly coordinating waters and small molecules and simultaneously its bulk phase properties, including hydration free energies, binding free energies, coordination numbers and inner shell water exchange rates (JCP 2020, JCIM 2024, JACS 2025). We take this a step further now to demonstrate the same for Mg 2+ binding to protein. We show that AMOEBA-HFC performs excellently at estimating interactions of Mg 2+ with peptide clusters and at reproducing absolute binding free energy and geometry of Mg 2+ binding to calbindin determined from experiments. This suggests that polarizable force fields can balance local and distant interactions of Mg 2+ with water, small molecules and proteins. In contrast, we find that none of the existing non-polarizable force fields simultaneously capture both local and bulk phase properties, where large imbalances exist between local and distant interactions of Mg 2+ with water and protein. Together, these observations suggest a critical role of explicitly modeling electronic polarization in balancing local and distant interactions of ions in solution.
Schillaci et al. (Sun,) studied this question.