Molecular Dynamics Simulations of Ion Transport Through Electrically Stressed Biological Membranes

The cell membrane is a selectively permeable barrier that controls the transport of ions, molecules, and other materials into and out of a cell. The manipulation of the cell membrane permeability is the basis for several biotechnological and biomedical applications, including electroporation. Electroporation (or electropermeabilization) occurs when the application of an external electric pulse causes water intrusion into the membrane interior and the formation of conductive transmembrane electropores. These electropores allow drugs, genetic material, and other normally impermeant molecules to enter a cell. Despite years of study, the complex mechanisms underlying this process are still not well understood. Molecular dynamics (MD) simulations of lipid membranes can be used to facilitate the understanding of this phenomenon at the atomic scale, which is inaccessible with conventional experimental methods. In this research, we focus our attention on electric-field-induced pore formation in lipid bilayers at the atomic and molecular level using MD simulations. We started with a simplified model of a cell membrane with various dimensions and lipid compositions in the presence of different ions, such as Ca2+, Na+ and K+ . We then studied the interactions that these ions have with the lipid bilayers and how they can influence the electropore formation. We also assessed the impact of moving from an old force field, GROMOS-OPLS, to a new force field, CHARMM36. We confirmed the unacceptable behavior that the standard CHARMM36 Ca2+ model showed in aqueous systems, and we implemented the improved ECCR Ca2+ model in a computationally efficient manner that better represents the Ca2+ properties in the presence of lipid bilayers. In systems with K + or Na+ , the relationship between pore radius and applied field amplitude is known: the increase of the amplitude of the applied field generates pores with a bigger pore radius. Our results are consistent with the literature data and show that systems with Ca2+ do not have the same linear behavior. Ca2+ conductance is also less than K+ , Na+ and Cl- conductance. Together with experimental data, we showed that in MD simulations, under specific conditions, it is possible to cancel the pore formation process by reversing the external sustaining field. We also performed 2 ns bipolar pulse cancellation experiments with different ns delays on U-937 cells, monitoring YO-PR1 uptake before, during and after reversing the applied field, and compared them with MD results. We observed that pores are more likely to survive with the application of higher fields and longer reversal times