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Abstract

Metal cations are essential in many vital processes. In order to capture the role of different cations in all-atom molecular dynamics simulations of biological processes, an accurate parametrization is crucial. Here, we develop force field parameters for the metal cations Li⁺, Na⁺, K⁺, Cs⁺, Mg²⁺, Ca²⁺, Sr²⁺, and Ba²⁺ in combination with the TIP3P water model that is frequently used in biomolecular simulations. In progressing toward improved force fields, the approach presented here is an extension of previous efforts and allows us to simultaneously reproduce thermodynamic and kinetic properties of aqueous solutions. We systematically derive the parameters of the 12-6 Lennard-Jones potential which accurately reproduces the experimental solvation free energy, the activity derivative, and the characteristics of water exchange from the first hydration shell of the metal cations. In order to reproduce all experimental properties, a modification of the Lorentz-Berthelot combination rule is required for Mg²⁺. Using a balanced set of solution properties, the optimized force field parameters aim to capture the fine differences between distinct metal cations including specific ion binding affinities and the kinetics of cation binding to biologically important anionic groups.