Optimized Magnesium Force Field Parameters for Biomolecular Simulations with Accurate Solvation, Ion-Binding, and Water-Exchange Properties in SPC/E, TIP3P-fb, TIP4P/2005, TIP4P-Ew, and TIP4P-D

Abstract

Magnesium is essential in many vital processes. To correctly describe Mg 2+ in physiological processes by molecular dynamics simulations, accurate force fields are fundamental. Despite the importance, force fields based on the commonly used 12-6 Lennard-Jones potential showed significant shortcomings. Recently progress was made by an optimization procedure that implicitly accounts for polarizability. The resulting microMg and nanoMg force fields (J. Chem. Theory Comput. 2021, 17, 2530−2540) accurately reproduce a broad range of experimental solution properties and the binding affinity to nucleic acids in TIP3P water. Since countless simulation studies rely on available water models and ion force fields, we here extend the optimization and provide Mg 2+ parameters in combination with the SPC/E, TIP3P-fb, TIP4P/2005, TIP4P-Ew, and TIP4P-D water models. For each water model, the Mg 2+ force fields reproduce the solvation free energy, the distance to oxygens in the first hydration shell, the hydration number, the activity coefficient derivative in MgCl 2 solutions, and the binding affinity and distance to the phosphate oxygens on nucleic acids. We present two parameter sets: MicroMg yields water exchange on the microsecond time scale and matches the experimental exchange rate. Depending on the water model, nanoMg yields accelerated water exchange in the range of 10 6 to 10 8 exchanges per second. The nanoMg parameters can be used to enhance the sampling of binding events, to obtain converged distributions of Mg 2+ , or to predict ion binding sites in biomolecular simulations. The parameter files are freely available at https://github.com/bio-phys/ optimizedMgFFs.

Magnesium Force Fields for OPC Water with Accurate Solvation, Ion-Binding, and Water-Exchange Properties: Successful Transfer from SPC/E

“…(B) Mg 2+ - oxygen distance R 1 in the first hydration shell. (C) Cl − - oxygen distance of the first hydration shell obtained with different force fields from the literature 1,30,49,53 . The gray horizontal bar in (B,C) corresponds to the experimental value 60 .…”

“…In our current work, we test the transferability of 12 different Mg 2+ force field parameter sets 1,34 . Each parameter set was previously optimized in combination with the TIP3P 42 , SPC/E 43 , TIP3P-fb 44 , TIP4P/2005 45 , TIP4P-Ew 46 , and TIP4P-D 9 water model.…”

“…In particular, accurate parameters for Mg 2+ are essential since these ions play a vital role in a large variety of physiological processes such as ATP hydrolysis 15 , cellular signaling 16,17 , or the catalytic activity of ribozymes 18–20 . Due to the prominent role of Mg 2+ , a variety of parameters for different water models exists today 1,21–34 . However, the development of accurate parameters for Mg 2+ turned out to be notoriously difficult leading to various shortcomings of the parameters: (i) Simultaneously capturing the solvation free energy and the structure of the first hydration shell failed unless polarization effects were included explicitly 28,35 .…”

“…Recently, progress was made in tackling this problems by using a larger Lennard-Jones (LJ) parameter space and by modifying the standard combination rules 1,34 . In most biomolecular simulations, the pair potential between atoms i and j is modeled as sum of the Coulomb term and the 12-6 Lennard-Jones (LJ) potential, where q i is the charge, r ij the distance, and ɛ 0 the dielectric constant of vacuum.…”

“…By using scaling factors in the Lorentz-Berthelot combination rules 38–41 , the deviations from the standard combination rule can be taken into account. In particular, scaling parameters allowed us to reproduce activity derivatives over a broad range of MgCl 2 concentrations and to correct the excessive binding of the Mg 2+ ions to negatively charged groups on biomolecules 1,34 .…”