Abstract
The permeability of cell membranes can be transiently increased following the application of external electric fields. Theoretical approaches such as molecular modeling provide a significant insight into the processes affecting, at the molecular level, the integrity of lipid cell membranes when these are subject to voltage gradients under similar conditions as those used in experiments. This article reports on the progress made so far using such simulations to model membrane—lipid bilayer—electroporation. We first describe the methods devised to perform in silico experiments of membranes subject to nanosecond, megavolt-per-meter pulsed electric fields and of membranes subject to charge imbalance, mimicking therefore the application of low-voltage, long-duration pulses. We show then that, at the molecular level, the two types of pulses produce similar effects: provided the TM voltage these pulses create are higher than a certain threshold, hydrophilic pores stabilized by the membrane lipid headgroups form within the nanosecond time scale across the lipid core. Similarly, when the pulses are switched off, the pores collapse (close) within similar time scales. It is shown that for similar TM voltages applied, both methods induce similar electric field distributions within the membrane core. The cascade of events following the application of the pulses, and taking place at the membrane, is a direct consequence of such an electric field distribution.
Similar content being viewed by others
References
Abidor IG, Arakelyan VB, Chernomordink LV, Chizmadzhev YA, Pastushenko VF, Tarasevich MR (1979) Electrical breakdown of BLM: main experimental facts and their qualitative discussion. Bioelectrochem Bioenerg 6:37–52
Aksimentiev A, Schulten K (2005) Imaging α-hemolysin with molecular dynamics: ionic conductance, osmotic permeability, and the electrostatic potential map. Biophys J 88:3745–3761
Allen MP, Tildesley DJ (1987) Computer simulation of liquids. Clarendon Press, Oxford
Anézo C, Vries AHd, Höltje HD, Tieleman DP, Marrink SJ (2003) Methodological issues in lipid bilayer simulations. J Phys Chem B 107:9424–9433
Beebe SJ, Schoenbach KH (2005) Nanosecond pulsed electric fields: a new stimulus to activate intracellular signaling. J Biomed Biotechnol 4:297–300
Benz R, Beckers F, Zimmerman U (1979) Reversible electrical breakdown of lipid bilayer membranes—a charge-pulse relaxation study. J Membr Biol 48:181–204
Berkowitz ML, Raghavan MJ (1991) Computer simulation of a water/membrane interface. Langmuir 7:1042–1044
Berkowitz ML, Bostick DL, Pandit S (2006) Aqueous solutions next to phospholipid membrane surfaces: insights from simulations. Chem Rev 106(4):1527–1539
Bhandarkar M, Brunner R, Chipot C, Dalke A, Dixit S, Grayson P, Gullinsrud J, Gursoy A, Humphrey W, Hurwitz D, Krawetz N, Nelson M, Phillips J, Shinozaki A, Zheng G, Zhu F (2002) NAMD version 2.4. http://wwwksuiucedu/Research/namd
Bockmann RA, de Groot BL, Kakorin S, Neumann E, Grubmuller H (2008) Kinetics, statistics, and energetics of lipid membrane electroporation studied by molecular dynamics simulations. Biophys J 95:1837–1850
Bostick D, Berkowitz ML (2003) The implementation of slab geometry for membrane-channel molecular dynamics simulations. Biophys J 85:97–107
Cascales JJL, Berendsen HJC, de la Torre JG (1996) Molecular dynamics simulation of water between two charged layers of dipalmitoylphosphatidylserine. J Phys Chem 100:8621–8627
Chang DC (1992) Structure and dynamics of electric field-induced membrane pores as revealed by rapid-freezing electron microscopy. In: Guide to electroporation and electrofusion. Academic Press, Orlando, pp 9–27
Chen C, Smye SW, Robinson MP, Evans JA (2006) Membrane electroporation theories: a review. Med Biol Eng Comput 44:5–14
Chimerel C, Movileanu L, Pezeshki S, Winterhalter M, Kleinekathofer U (2008) Transport at the nanoscale: temperature dependence of ion conductance. Eur Biophys J 38:121–125
Chipot C, Klein ML, Tarek M (2005) Modeling lipid membranes. In: Yip S (ed) Handbook of materials modeling. Springer, Dordrecht, pp 929–958
Chiu SW, Clark M, Jakobsson E, Subramaniam S, Scott HL (1999) Optimization of hydrocarbon chain interaction parameters: application to the simulation of fluid phase lipid bilayers. J Phys Chem B 103:6323–6327
Chiu SW, Vasudevan S, Jakobsson E, Mashl RJ, Scott HL (2003) Structure of sphingomyelin bilayers: a simulation study. Biophys J 85:3624–3635
Crozier PS, Henderson D, Rowley RL, Busath DD (2001) Model channel ion currents in NaCl extended simple point charge water solution with applied-field molecular dynamics. Biophys J 81:3077–3089
Dahlberg M, Maliniak A (2008) Molecular dynamics simulations of cardiolipin bilayers. J Phys Chem B 112:11655–11663
Damodaran KV, Merz KM (1994) A comparison of DMPC and DLPE-based lipid bilayers. Biophys J 66:1076–1087
Darden T, York D, Pedersen L (1993) Particle mesh ewald—an N log(N) method for Ewald sums in large systems. J Chem Phys 98:10089–10092
Delemotte L, Dehez F, Treptow W, Tarek M (2008) Modeling membranes under a transmembrane potential. J Phys Chem B 112:5547–5550
Delemotte L, Treptow W, Klein ML, Tarek M (2010) Effect of sensor domain mutations on the properties of voltage-gated ion channels: molecular dynamics studies of the potassium channel Kv1.2. Biophys J 99(9):L72–L74
Delemotte L, Tarek M, Klein ML, Amaral C, Treptow W (2011) Intermediate states of the Kv1.2 voltage sensor from atomistic molecular dynamics simulations. Proc Natl Acad Sci USA 108(15):6109–6114
Deng J, Schoenbach KH, Buescher ES, Hair PS, Fox PM, Beebe SJ (2003) The effects of intense submicrosecond electrical pulses on cells. Biophys J 84:2709–2714
Eberhard N, Sowers AE, Jordan CA (1989) Electroporation and electrofusion in cell biology. Plenum Press, New York
Edholm O (2008) Time and length scales in lipid bilayer simulations. In: Feller SE (ed) Computational modeling of membrane bilayers, vol 60. Current topics in membranes. Elsevier, London, pp 91–110
Essmann U, Perera L, Berkowitz ML, Darden T, Pedersen LG (1995) A smooth particle mesh Ewald method. J Chem Phys 103:8577–8593
Feller SE (2000) Molecular dynamics simulations of lipid bilayers. Curr Opin Colloid Interface Sci 5:217–223
Feller SE (2008) Computational modeling of membrane bilayers, vol 60. current topics in membranes. Elsevier, London
Feller SE, Gawrisch K, MacKerell AD (2002) Polyunsaturated fatty acids in lipid bilayers: intrinsic and environmental contributions to their unique physical properties. J Am Chem Soc 124:318–326
Forrest LR, Sansom MSP (2000) Membrane simulations: bigger and better. Curr Opin Struct Biol 10:174–181
Gawrisch K, Ruston D, Zimmerberg J, Parsegian V, Rand R, Fuller N (1992) Membrane dipole potentials, hydration forces, and the ordering of water at membrane surfaces. Biophys J 61:1213–1223
Gennis RB (1989) Biomembranes: molecular structure and function. Springer, Heidelberg
Gillilan RE, Wood F (1995) Visualization, virtual reality, and animation within the data flow model of computing. Comput Graph 29:55–58
Golzio M, Teissie J, Rols M-P (2002) Direct visualization at the single-cell level of electrically mediated gene delivery. Proc Natl Acad Sci USA 99:1292–1297
Gurtovenko AA, Vattulainen I (2005) Pore formation coupled to ion transport through lipid membranes as induced by transmembrane ionic charge imbalance: atomistic molecular dynamics study. J Am Chem Soc 127:17570–17571
Gurtovenko AA, Vattulainen I (2008) Effect of NaCl and KCl on phosphatidylcholine and phosphatidylethanolamine lipid membranes: insight from atomic-scale simulations for understanding salt-induced effects in the plasma membrane. J Phys Chem B 112:1953–1962
Gurtovenko AA, Jamshed Anwar J, Vattulainen I (2010) Defect-mediated trafficking across cell membranes: insights from in silico modeling. Chem Rev 110:6077–6103
Hu Q, Viswanadham S, Joshi RP, Schoenbach KH, Beebe SJ, Blackmore PF (2005) Simulations of transient membrane behavior in cells subjected to a high-intensity ultrashort electric pulse. Phys Rev E 71:031914
Humphrey W, Dalke A, Schulten K (1996) VMD—visual molecular dynamics. J Mol Graph 14:33–38
Kalé L, Skeel R, Bhandarkar M, Brunner R, Gursoy A, Krawetz N, Phillips J, Shinozaki A, Varadarajan K, Schulten K (1999) Namd2: greater scalability for parallel molecular dynamics. J Comp Phys 151:283–312
Kandasamy SK, Larson RG (2006) Cation and anion transport through hydrophilic pores in lipid bilayers. J Chem Phys 125:074901
Khalili-Araghi F, Tajkhorshid E, Schulten K (2006) Dynamics of K+ ion conduction through Kv1.2. Biophys J 91:L72–L74
Kotnik T, Miklavcic D (2006) Theoretical evaluation of voltage inducement on internal membranes of biological cells exposed to electric fields. Biophys J 90(2):480–491
Kotnik T, Miklavcic D, Slivnik T (1998) Time course of transmembrane voltage induced by time-varying electric fields—a method for theoretical analysis and its application. Bioelectrochem Bioenerg 45(1):3–16
Kutzner C, Grubmüller H, de Groot BL, Zachariae U (2011) Computational electrophysiology: the molecular dynamics of ion channel permeation and selectivity in atomistic detail. Biophys J 101:809–817
Leach AR (2001) Molecular modelling: principles and applications, 2nd edn. Prentice Hall, Englewood Cliffs
Lewis TJ (2003) A model for bilayer membrane electroporation based on resultant electromechanical stress. IEEE Trans Dielectr Electr Insul 10:769–777
Li S (2008) Electroporation protocols: preclinical and clinical gene medicine, vol 423. Methods in molecular biology. Humana Press, Totowa
Li Z, Venable RM, Rogers LA, Murray D, Pastor RW (2009) Molecular dynamics simulations of PIP2 and PIP3 in lipid bilayers: determination of ring orientation, and the effects of surface roughness on a Poisson-Boltzmann description. Biophys J 97:155–163
Liberman YA, Topaly VP (1969) Permeability of biomolecular phospholipid membranes for fat-soluble ions. Biophysics USSR 14:477
Lindahl E, Edholm O (2000) Mesoscopic undulations and thickness fluctuations in lipid bilayers from molecular dynamics simulations. Biophys J 79:426–433
Lindahl E, Sansom MSP (2008) Membrane proteins: molecular dynamics simulations. Curr Opin Struct Biol 18:425–431
MacKerell AD Jr, Bashford D, Bellott M, Dunbrack RL Jr, Evanseck J, Field MJ, Fischer S, Gao J, Guo H, Ha S, Joseph-McCarthy D, Kuchnir L, Kuczera K, Lau FTK, Mattos C, Michnick S, Ngo T, Nguyen DT, Prodhom B, Reiher WE III, Roux B, Schlenkrich M, Smith JC, Stote R, Straub J, Watanabe M, Wiorkiewicz-Kuczera J, Yin D, Karplus M (1998) All-atom empirical potential for molecular modeling and dynamics studies of proteins. J Phys Chem B 102:3586–3616
Marrink SJ, Mark AE (2001) Effect of undulations on surface tension in simulated bilayers. J Phys Chem B 105:6122–6127
Marrink SJ, Jähniga F, Berendsen HJ (1996) Proton transport across transient single-file water pores in a lipid membrane studied by molecular dynamics simulations. Biophys J 71:632–647
Marrink SJ, de Vries AH, Tieleman DP (2009) Lipids on the move: simulations of membrane pores, domains, stalks and curves. Biochim Biophys Acta Biomembr 1788:149–168
Mashl RJ, Scott HL, Subramaniam S, Jakobsson E (2001) Molecular simulation of dioleylphosphatidylcholine bilayers at differing levels of hydration. Biophys J 81:3005–3015
Mukhopadhyay P, Monticelli L, Tieleman DP (2004) Molecular dynamics simulation of a palmitoyl-oleoyl phosphatidylserine bilayer with Na+ counterions and NaCl. Biophys J 86:1601–1609
Nickoloff JA (1995) Animal cell electroporation and electrofusion protocols, vol 48. Methods in molecular biology. Humana Press, Totowa
Paganin-Gioannia A, Bellarda E, Escoffrea JM, Rols MP, Teissié J, Golzio M (2011) Direct visualization at the single-cell level of siRNA electrotransfer into cancer cells. Proc Natl Acad Sci USA 108:10443–10447
Pandit SA, Bostick D, Berkowitz ML (2003) Mixed bilayer containing dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylserine: lipid complexation, ion binding, and electrostatics. Biophys J 85:3120–3131
Patel RY, Balaji PV (2008) Characterization of symmetric and asymmetric lipid bilayers composed of varying concentrations of ganglioside GM1 and DPPC. J Phys Chem B 112:3346–3356
Pauly H, Schwan HP (1959) Uber die Impedanz Einer Suspension von Kugelformigen Teilchen mit Einer Schale—Ein Modell fur das Dielektrische Verhalten von Zellsuspensionen und von Proteinlosungen. Z Naturforsch B 14(2):125–131
Pucihar G, Kotnik T, Valic B, Miklavcic D (2006) Numerical determination of transmembrane voltage induced on irregularly shaped cells. Ann Biomed Eng 34:642–652
Pucihar G, Kotnik T, Miklavcic D, Teissié J (2008) Kinetics of transmembrane transport of small molecules into electropermeabilized cells. Biophys J 95:2837–2848
Rog T, Martinez-Seara H, Munck N, Oresic M, Karttunen M, Vattulainen I (2009) Role of cardiolipins in the inner mitochondrial membrane: insight gained through atom-scale simulations. J Phys Chem B 113:3413–3422
Rög T, Murzyn K, Pasenkiewicz-Gierula M (2002) The dynamics of water at the phospholipid bilayer: a molecular dynamics study. Chem Phys Lett 352:323–327
Roux B (1997) Influence of the membrane potential on the free energy of an intrinsic protein. Biophys J 73:2980–2989
Roux B (2008) The membrane potential and its representation by a constant electric field in computer simulations. Biophys J 95:4205–4216
Sachs JN, Crozier PS, Woolf TB (2004) Atomistic simulations of biologically realistic transmembrane potential gradients. J Chem Phys 121:10847–10851
Saiz L, Klein ML (2001) Structural properties of a highly polyunsaturated lipid bilayer from molecular dynamics simulations. Biophys J 81:204–216
Saiz L, Klein ML (2002a) Computer simulation studies of model biological membranes. Acc Chem Res 35:482–489
Saiz L, Klein ML (2002b) Electrostatic interactions in a neutral model phospholipid bilayer by molecular dynamics simulations. J Chem Phys 116:3052–3057
Sotomayor M, Vasquez V, Perozo E, Schulten K (2007) Ion conduction through MscS as determined by electrophysiology and simulation. Biophys J 92:886–902
Sundararajan R (2009) Nanosecond electroporation: another look. Mol Biotechnol 41:69–82
Tarek M (2005) Membrane electroporation: a molecular dynamics simulation. Biophys J 88:4045–4053
Tieleman DP (2004) The molecular basis of electroporation. BMC Biochem 5:10
Tieleman DP, Marrink SJ, Berendsen HJC (1997) A computer perspective of membranes: molecular dynamics studies of lipid bilayer systems. Biochim Biophys Acta 1331:235–270
Tieleman DP, Berendsen JHC, Sansom MSP (2001) Voltage-dependent insertion of alamethicin at phospholipid/water and octane water interfaces. Biophys J 80:331–346
Tobias DJ (2001) Membrane simulations. In: Becker OH, Roux B, Watanabe M (eds) Computational biochemistry and biophysics. Marcel Dekker, New York
Tobias DJ, Tu K, Klein ML (1997) Atomic-scale molecular dynamics simulations of lipid membranes. Curr Opin Colloid Interface Sci 2:15–26
Treptow W, Maigret B, Chipot C, Tarek M (2004) Coupled motions between pore and voltage-sensor domains: a model for Shaker B, a voltage-gated potassium channel. Biophys J 87:2365–2379
Treptow W, Tarek M, Klein ML (2009) Initial response of the potassium channel voltage sensor to a transmembrane potential. J Am Chem Soc 131:2107–2110
Vacha R, Berkowitz ML, Jungwirth P (2009) Molecular model of a cell plasma membrane with an asymmetric multicomponent composition: water permeation and ion effects. Biophys J 96:4493–4501
Vasilkoski Z, Esser AT, Gowrishankar TR, Weaver JC (2006) Membrane electroporation: the absolute rate equation and nanosecond time scale pore creation. Phys Rev E 74:021904
Vernier PT, Ziegler MJ (2007) Nanosecond field alignment of head group and water dipoles in electroporating phospholipid bilayers. J Phys Chem B 111:12993–12996
Vernier PT, Ziegler MJ, Sun Y, Chang WV, Gundersen MA, Tieleman DP (2006a) Nanopore formation and phosphatidylserine externalization in a phospholipid bilayer at high transmembrane potential. J Am Chem Soc 128:6288–6289
Vernier PT, Ziegler MJ, Sun Y, Gundersen MA, Tieleman DP (2006b) Nanopore-facilitated, voltage-driven phosphatidylserine translocation in lipid bilayers—in cells and in silico. Phys Biol 3:233–247
Vernier PT, Levine ZA, Wu H-S, Joubert V, Ziegler MJ, Mir LM, Tieleman DP (2009) Electroporating fields target oxidatively damaged areas in the cell membrane. PLoS ONE 4:e7966
Weaver JC (2003) Electroporation of biological membranes from multicellular to nano scales. IEEE Trans Dielectr Electr Insul 10:754–768
Weaver JC, Chizmadzhev YA (1996) Theory of electroporation: a review. Bioelectrochem Bioenerg 41:135–160
Wiener MC, White SH (1992) Structure of fluid dioleylphosphatidylcholine bilayer determined by joint refinement of X-ray and neutron diffraction data. III. Complete structure. Biophys J 61:434–447
Yang Y, Henderson D, Crozier P, Rowley RL, Busath DD (2002) Permeation of ions through a model biological channel: effect of periodic boundary condition and cell size. Mol Phys 100:3011–3019
Zhong Q, Moore PB, Newns DM, Klein ML (1998) Molecular dynamics study of the LS3 voltage-gated ion channel. FEBS Lett 427:267–270
Ziegler MJ, Vernier PT (2008) Interface water dynamics and porating electric fields for phospholipid bilayers. J Phys Chem B 112:13588–13596
Acknowledgments
The research was conducted in the scope of the EBAM European Associated Laboratory (LEA). Simulations were performed using HPC resources from GENCI-CINES (grant 2010-2011 075137). M. T. acknowledges the support of the French Agence Nationale de la Recherche (grant ANR-10_BLAN-916-03-INTCELL).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Delemotte, L., Tarek, M. Molecular Dynamics Simulations of Lipid Membrane Electroporation. J Membrane Biol 245, 531–543 (2012). https://doi.org/10.1007/s00232-012-9434-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00232-012-9434-6