Molecular Simulations of Lipid Electropore Formation and Pore-Mediated Calcium Transport with an Improved Ca2+ Model

Abstract

Molecular dynamics simulations of lipid membranes are widely used to facilitate the understanding of phenomena at the atomic and molecular level that cannot be observed with conventional experimental methods. Molecular dynamics tools are particularly useful for the analysis of electric-field-induced pore formation in lipid bilayers. Atomic and molecular interactions in molecular dynamics simulations are governed by sets of properties and functions called force fields. For our studies of membranes in electric fields, to better understand how the physical and mechanical properties of the membrane constituents and the interactions among them are influenced by the force field, we have compared properties such as area per lipid, lipid order parameter, ion coordination number, and ion binding, specifically for the older GROMOS-OPLS and the newer CHARMM36 force fields. During these comparisons we noticed significant deficiencies in the CHARMM36 Ca2+ model. Here we describe the unacceptable behavior of the standard CHARMM36 Ca2+ model in aqueous systems, and we propose modifications to the model that result in more realistic interactions between Ca2+, water, and phospholipids. We also present initial results from simulations of pore-mediated ion transport in these systems. We track the electric field- and diffusion-driven passage of ions through field-stabilized pores over time, calculate the resulting currents and conductances, and relate these transport properties to the pore geometry. We note, among other things, that equilibration of Ca2+ with a phospholipid bilayer takes at least 10 µs, a much longer time than would be expected from published simulation studies of ion binding to phospholipids.