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Kinetics, Statistics, and Energetics of Lipid Membrane Electroporation Studied by Molecular Dynamics Simulations

Rainer A. Böckmann ^*, Bert L. de Groot , Sergej Kakorin , Eberhard Neumann  and Helmut Grubmüller 

^* Theoretical & Computational Membrane Biology, Center for Bioinformatics, Saarland University, Saarbrücken, Germany; Computational Biomolecular Dynamics Group, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany; Physical Chemistry III (Bio-PC), Department for Chemistry, University of Bielefeld, Bielefeld, Germany; and Theoretical and Computational Biophysics Department, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany

Correspondence: Address reprint requests to Rainer A. Böckmann, E-mail: rainer{at}bioinformatik.uni-saarland.de.

Membrane electroporation is the method to directly transfer bioactive substances such as drugs and genes into living cells, as well as preceding electrofusion. Although much information on the microscopic mechanism has been obtained both from experiment and simulation, the existence and nature of possible intermediates is still unclear. To elucidate intermediates of electropore formation by direct comparison with measured prepore formation kinetics, we have carried out 49 atomistic electroporation simulations on a palmitoyl-oleoyl-phosphatidylcholine bilayer for electric field strengths between 0.04 and 0.7 V/nm. A statistical theory is developed to facilitate direct comparison of experimental (macroscopic) prepore formation kinetics with the (single event) preporation times derived from the simulations, which also allows us to extract an effective number of lipids involved in each pore formation event. A linear dependency of the activation energy for prepore formation on the applied field is seen, with quantitative agreement between experiment and simulation. The distribution of preporation times suggests a four-state pore formation model. The model involves a first intermediate characterized by a differential tilt of the polar lipid headgroups on both leaflets, and a second intermediate (prepore), where a polar chain across the bilayer is formed by 3–4 lipid headgroups and several water molecules, thereby providing a microscopic explanation for the polarizable volume derived previously from the measured kinetics. An average pore radius of 0.47 ± 0.15 nm is seen, in favorable agreement with conductance measurements and electrooptical experiments of lipid vesicles.