Calcium Parameters in CHARMM Force Field Revisited

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The accuracy of molecular dynamics (MD) simulations depends on the accuracy of underlying force field parameters that describe bonding and non-bonding interactions. The parameters of Lennard Jones (LJ) potential for describing cation-anion pair interactions in additive force fields are usually developed to reproduce experimental data in infinitely dilute solutions, and hence, can cause artifacts in finite concentrations. For example, it has been shown that in NaCl solutions of more than 2 M concentration, Na+ and Cl- overly bind together if the distance of minimum pairwise potential, Rmin, is not tuned accurately. Considering the fact that ions are more concentrated in the vicinity of a charged surface than in the bulk, they are prone to over-bind to lipid head-groups in MD simulations if the pairwise LJ parameter Rmin is not tuned for high ion concentrations. This can result in inaccurate bilayer properties such as area or order parameter of lipids. The artifacts are even more severe when simulated systems involve divalent ions, because their effects on the surface potential and surface charge density are more profound than monovalent ions. As such, calcium has not been extensively involved in MD simulations of biological systems so far, although it plays a pivotal role in the physiology and biochemistry of the cell, such as in signal transduction, maintaining potential difference across cell membranes, and enzymatic reactions. In this study, we revise LJ parameters in CHARMM force field for pairwise interactions of calcium ions with chloride and with negatively charged groups of phospholipids. This is achieved by simulating osmosis and electrophoresis phenomena for calcium salts and matching simulation results and experimental data. The parameters are then validated by simulating lipid bilayers in mixtures of calcium chloride and sodium chloride solutions and comparing the bilayer properties with experimental data.