A molecular dynamics (MD) scheme is combined with a distributed circuit model for a self-consistent analysis of the transient membrane response for cells subjected to an ultrashort (nanosecond) high-intensity (approximately 0.01-V/nm spatially averaged field) voltage pulse. The dynamical, stochastic, many-body aspects are treated at the molecular level by resorting to a course-grained representation of the membrane lipid molecules. Coupling the Smoluchowski equation to the distributed electrical model for current flow provides the time-dependent transmembrane fields for the MD simulations. A good match between the simulation results and available experimental data is obtained. Predictions include pore formation times of about 5-6 ns. It is also shown that the pore formation process would tend to begin from the anodic side of an electrically stressed membrane. Furthermore, the present simulations demonstrate that ions could facilitate pore formation. This could be of practical importance and have direct relevance to the recent observations of calcium release from the endoplasmic reticulum in cells subjected to such ultrashort, high-intensity pulses.

A combined MD simulator and time dependent Laplace solver are used to analyze the electrically driven phosphatidylserine externalization process in cells. Time dependent details of nanopore formation at cell membranes in response to a high-intensity (100 kV/cm), ultrashort (10 ns) electric pulse are also probed. Our results show that nanosized pores could typically be formed within about 5 ns. These predictions are in very good agreement with recent experimental data. It is also demonstrated that defect formation and PS externalization in membranes should begin on the anode side. Finally, the simulations confirm that PS externalization is a nanopore facilitated event, rather than the result of molecular translocation across the trans-membrane energy barrier.

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The temporal dynamics of electroporation of cells subjected to ultrashort voltage pulses are studied based on a coupled scheme involving the Laplace, Nernst-Plank, and Smoluchowski equations. A pore radius dependent energy barrier for ionic transport, accounts for cellular variations. It is shown that a finite time delay exists in pore formation, and leads to a transient overshoot of the transmembrane potential V(mem) beyond 1.0 V. Pore resealing is shown to consist of an initial fast process, a 10(-4) s delay, followed by a much slower closing at a time constant of about 10(-1) s. This establishes a time-window during which the pores are mostly open, and hence, the system is most vulnerable to destruction by a second electric pulse. The existence of such a time window for effective killing by a second pulse is amply supported by our experimental data for E. coli cells. The time constant for the longer process also matches experiments. The study suggests that controlled manipulation of the pore "open times" can be achieved through multiple, ultrashort pulses.

A self-consistent model analysis of electroporation in biological cells has been carried out based on an improved energy model. The simple energy model used in the literature is somewhat incorrect and unphysical for a variety of reasons. Our model for the pore formation energy E(r) includes a dependence on pore population and density. It also allows for variable surface tension, incorporates the effects of finite conductivity on the electrostatic correction term, and is dynamic in nature. Self-consistent calculations, based on a coupled scheme involving the Smoluchowski equation and the improved energy model, are presented. It is shown that E(r) becomes self-adjusting with variations in its magnitude and profile, in response to pore population, and inhibits uncontrolled pore growth and expansion. This theory can be augmented to include pore-pore interactions to move beyond the independent pore picture.