Nanoscopic Cell Membrane and Pore Profiles Combining Molecular Dynamics and a 3D Electromagnetic Tool

Nanosecond, megavolt-per-meter electric pulses applied to biological cells can target subcellular structures with minimal loss of plasma membrane integrity, opening up new perspectives for intracellular manipulations. Experimentally observed effects of intense nanopulses include intracellular calcium release, externalization of phosphatidylserine (PS) from the inner to the outer leaflet of the plasma membrane, and non-thermal cell death by apoptosis. Molecular dynamics (MD) simulations have shown that PS re-distribution occurs after the electric-field-driven formation of nanometer-sized pores in the plasma membrane and is facilitated by electrophoresis of PS along the pore walls. Nanopulse-induced pore creation occurs on a nanosecond time scale, but the underlying molecular mechanisms are not yet clear. Experimental observations of the process of pore formation are challenging because of the time and spatial scales required.In this study, we combine MD simulations and a quasi-static approach using a custom implementation of 3D finite-difference analysis to investigate the physical mechanisms of electropore creation. First, MD simulations of pore formation in phospholipid bilayers in external electric fields are performed at nanoscopic scale. From these simulations we extract the charge densities across the electroporated bilayer. Second, the charge densities are injected into a new, custom, quasi-static algorithm based on the Poisson equation. The software computes 3D nanoscopic profiles of the transmembrane potential, electric field, and electric field gradient. The goal of the two-step simulation is to establish whether and how electric field gradients, water and phospholipid head group dipole moments, and the site of initial water intrusion in pore initiation are correlated.