Abstract
The large plasticity, dynamics and adaptability of biological membranes allow different modes of intrinsic and inducible permeability. These phenomena are of physiological importance for a number of natural functions related to cell death and can also be manipulated artificially for practical purposes like gene transfer, drug delivery, prevention of infections or anticancer therapy. For these advances to develop in a controllable and specific way, we need a sufficient understanding of the membrane permeability phenomena. Since the formulation of early concepts of pore formation, there has been an enormous effort to describe membrane permeability by using theory, simulations and experiments. A major breakthrough has come recently through theoretical developments that allow building continuous trajectories of pore formation both in the absence and presence of stress conditions. The new model provides a coherent quantitative view of membrane permeabilization, useful to test the impact of known lipid properties, make predictions and postulate specific pore intermediates that can be studied by simulations. For example, this theory predicts unprecedented dependencies of the line tension on the pore radius and on applied lateral tension which explain previous puzzling results. In parallel, important concepts have also come from molecular dynamics simulations, of which the role of water for membrane permeabilization is of special interest. These advances open new challenges and perspectives for future progress in the study of membrane permeability, as experiments and simulations will need to test the theoretical predictions, while theory achieves new refinements that provide a physical ground for observations.
Graphic Abstract
Similar content being viewed by others
References
Abidor IG, Arakelyan VB, Chernomordik LV, Chizmadzhev YA, Pastushenko VF, Tarasevich MR (1979) Electric breakdown of bilayer lipid membranes I. The main experimental facts and their qualitative discussion. Bioelectrochem Bioenerg 6:37–52. https://doi.org/10.1016/0302-4598(79)85005-9
Afacan NJ, Yeung ATY, Pena OM, Hancock REW (2012) Therapeutic potential of host defense peptides in antibiotic-resistant infections. Curr Pharm Des 18:807–819. https://doi.org/10.2174/138161212799277617
Akimov SA, Kuzmin PI, Zimmerberg J, Cohen FS (2007) Lateral tension increases the line tension between two domains in a lipid bilayer membrane. Phys Rev E 75(1):011919. https://doi.org/10.1103/physreve.75.011919
Akimov SA, Volynsky PE, Galimzyanov TR, Kuzmin PI, Pavlov KV, Batishchev OV (2017a) Pore formation in lipid membrane I: continuous reversible trajectory from intact bilayer through hydrophobic defect to transversal pore. Sci Rep 7(1):12152. https://doi.org/10.1038/s41598-017-12127-7
Akimov SA, Volynsky PE, Galimzyanov TR, Kuzmin PI, Pavlov KV, Batishchev OV (2017b) Pore formation in lipid membrane II: energy landscape under external stress. Sci Rep 7(1):12509. https://doi.org/10.1038/s41598-017-12749-x
Awasthi N, Hub JS (2016) Simulations of pore formation in lipid membranes: reaction coordinates, convergence, hysteresis, and finite-size effects. J Chem Theory Comput 12:3261–3269. https://doi.org/10.1021/acs.jctc.6b00369
Ayuyan AG, Cohen FS (2008) Raft composition at physiological temperature and pH in the absence of detergents. Biophys J 94:2654–2666. https://doi.org/10.1529/biophysj.107.118596
Bangham AD, Standish MM, Watkins JC (1965) Diffusion of univalent ions across the lamellae of swollen phospholipids. J Mol Biol 13:238. https://doi.org/10.1016/S0022-2836(65)80093-6
Bennett WFD, Tieleman DP (2014) The importance of membrane defects—lessons from simulations. Acc Chem Res 47:2244–2251. https://doi.org/10.1021/ar4002729
Bennett WFD, Sapay N, Tieleman DP (2014) Atomistic simulations of pore formation and closure in lipid bilayers. Biophys J 106:210–219. https://doi.org/10.1016/j.bpj.2013.11.4486
Böckmann RA, de Groot BL, Kakorin S, Neumann E, Grubmüller H (2008) Kinetics, statistics, and energetics of lipid membrane electroporation studied by molecular dynamics simulations. Biophys J 95:1837–1850. https://doi.org/10.1529/biophysj.108.129437
Brochard-Wyart F, de Gennes PG, Sandre O (2000) Transient pores in stretched vesicles: role of leak-out. Phys A 278:32–51. https://doi.org/10.1016/S0378-4371(99)00559-2
Chernomordik LV, Kozlov MM, Melikyan GB, Abidor IG, Markin VS, Chizmadzhev YA (1985) The shape of lipid molecules and monolayer membrane fusion. Biochim Biophys Acta 812:643–655. https://doi.org/10.1016/0005-2736(85)90257-3
Deamer D (2016) Membranes and the origin of life: a century of conjecture. J Mol Evol 83:159–168. https://doi.org/10.1007/s00239-016-9770-8
Deryagin B, Gutop YV (1962) Theory of the breakdown (rupture) of free films. Kolloidn Zh 24:370–374
Esteban-Martín S, Salgado J (2007) Self-assembling of peptide/membrane complexes by atomistic molecular dynamics simulations. Biophys J 92:903–912. https://doi.org/10.1529/biophysj.106.093013
Esteban-Martín S, Risselada HJ, Salgado J, Marrink SJ (2009) Stability of asymmetric lipid bilayers assessed by molecular dynamics simulations. J Am Chem Soc 131:15194–15202. https://doi.org/10.1021/ja904450t
Evans E, Smith BA (2011) Kinetics of hole nucleation in biomembrane rupture. New J Phys 13:095010. https://doi.org/10.1088/1367-2630/13/9/095010
Evans E, Heinrich V, Ludwig F, Rawicz W (2003) Dynamic tension spectroscopy and strength of biomembranes. Biophys J 85:2342–2350. https://doi.org/10.1016/S0006-3495(03)74658-X
Fuertes G, García-Sáez AJ, Esteban-Martín S, Giménez D, Sánchez-Muñoz OL, Schwille P, Salgado J (2010) Pores formed by Baxα5 relax to a smaller size and keep at equilibrium. Biophys J 99:2917–2925. https://doi.org/10.1016/j.bpj.2010.08.068
Fuertes G, Giménez D, Esteban-Martín S, Sánchez-Muñoz OL, Salgado J (2011) A lipocentric view of peptide-induced pores. Eur Biophys J 40:399–415. https://doi.org/10.1007/s00249-011-0693-4
Galimzyanov TR, Molotkovsky RJ, Bozdaganyan ME, Cohen FS, Pohl P, Akimov SA (2015) Elastic membrane deformations govern interleaflet coupling of lipid-ordered domains. Phys Rev Lett 115:088101. https://doi.org/10.1103/physrevlett.115.088101
García-Sáez AJ, Chiantia S, Salgado J, Schwille P (2007) Pore formation by a Bax-derived peptide: effect on the line tension of the membrane probed by AFM. Biophys J 93:103–112. https://doi.org/10.1529/biophysj.106.100370
Glaser RW, Leikin SL, Chernomordik LV, Pastushenko VF, Sokirko AI (1988) Reversible electrical breakdown of lipid bilayers: formation and evolution of pores. Biochim Biophys Acta 940:275–287
Green DR, Reed JC (1998) Mitochondria and Apoptosis. Science 281:1309–1312. https://doi.org/10.1126/science.281.5381.1309
Guha S, Ghimire J, Wu E, Wimley WC (2019) Mechanistic landscape of membrane-permeabilizing peptides. Chem Rev 119(9):6040–6085. https://doi.org/10.1021/acs.chemrev.8b00520
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. https://doi.org/10.1021/ja053129n
Gurtovenko AA, Anwar J, Vattulainen I (2010) Defect-mediated trafficking across cell membranes: insights fromin silicomodeling. Chem Rev 110:6077–6103. https://doi.org/10.1021/cr1000783
Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ (1981) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch 391:85–100. https://doi.org/10.1007/BF00656997
Hamm M, Kozlov MM (2000) Elastic energy of tilt and bending of fluid membranes. Eur Phys J E 3:323–335. https://doi.org/10.1007/s101890070003
Haney, E.F., Straus, S.K., Hancock, R.E.W., 2019. Reassessing the Host Defense Peptide Landscape. Frontiers in Chemistry 7. https://doi.org/10.3389/fchem.2019.00043
Helfrich W (1973) Elastic properties of lipid bilayers: theory and possible experiments. Z Naturforsch C 28:693–703
Hovakeemian SG, Liu R, Gellman SH, Heerklotz H (2015) Correlating antimicrobial activity and model membrane leakage induced by nylon-3 polymers and detergents. Soft Matter 11:6840–6851. https://doi.org/10.1039/c5sm01521a
Huang HW, Charron NE (2017) Understanding membrane-active antimicrobial peptides. Quart Rev Biophys 50:e10. https://doi.org/10.1017/s0033583517000087
Huang HW, Chen F-Y, Lee M-T (2004) Molecular mechanism of Peptide-induced pores in membranes. Phys Rev Lett 92:198304
Karal MAS, Yamazaki M (2015) Communication: activation energy of tension-induced pore formation in lipid membranes. J. Chem. Phys 143:081103. https://doi.org/10.1063/1.4930108
Karal MAS, Alam JM, Takahashi T, Levadny V, Yamazaki M (2015) Stretch-activated pore of the antimicrobial peptide, Magainin 2. Langmuir 31:3391–3401. https://doi.org/10.1021/la503318z
Karal MAS, Levadnyy V, Yamazaki M (2016) Analysis of constant tension-induced rupture of lipid membranes using activation energy. Phys Chem Chem Phys 18:13487–13495. https://doi.org/10.1039/c6cp01184e
Karatekin E, Sandre O, Guitouni H, Borghi N, Puech P-H, Brochard-Wyart F (2003) Cascades of transient pores in giant vesicles: line tension and transport. Biophys J 84:1734–1749. https://doi.org/10.1016/S0006-3495(03)74981-9
Kelly GJ, Kia AF-A, Hassan F, O’Grady S, Morgan MP, Creaven BS, McClean S, Harmey JH, Devocelle M (2016) Polymeric prodrug combination to exploit the therapeutic potential of antimicrobial peptides against cancer cells. Org Biomol Chem 14:9278–9286. https://doi.org/10.1039/C6OB01815G
Kirsch SA, Böckmann RA (2016) Membrane pore formation in atomistic and coarse-grained simulations. Biochim Biophys Acta 1858:2266–2277. https://doi.org/10.1016/j.bbamem.2015.12.031
Kotnik T, Frey W, Sack M, Meglič SH, Peterka M, Miklavčič D (2015) Electroporation-based applications in biotechnology. Trends Biotechnol 33:480–488. https://doi.org/10.1016/j.tibtech.2015.06.002
Ladokhin AS, Wimley WC, White SH (1995) Leakage of membrane vesicle contents: determination of mechanism using fluorescence requenching. Biophys J 69:1964–1971. https://doi.org/10.1016/S0006-3495(95)80066-4
Lee M-T, Chen F-Y, Huang HW (2004) Energetics of pore formation induced by membrane active peptides. Biochemistry 43:3590–3599. https://doi.org/10.1021/bi036153r
Leontiadou H, Mark AE, Marrink SJ (2004) Molecular dynamics simulations of hydrophilic pores in lipid bilayers. Biophys J 86:2156–2164. https://doi.org/10.1016/S0006-3495(04)74275-7
Levadny V, Tsuboi T, Belaya M, Yamazaki M (2013) Rate constant of tension-induced pore formation in lipid membranes. Langmuir 29:3848–3852. https://doi.org/10.1021/la304662p
Levine ZA (2017) Lipid electropore lifetime in molecular models. In: Miklavčič D (ed) Handbook of electroporation. Springer, Cham, pp 113–131. https://doi.org/10.1007/978-3-319-32886-7_86
Levine ZA, Vernier PT (2010) Life cycle of an electropore: field-dependent and field-independent steps in pore creation and annihilation. J Membr Biol 236:27–36. https://doi.org/10.1007/s00232-010-9277-y
Litster JD (1975) Stability of lipid bilayers and red blood cell membranes. Phys Lett A 53:193–194. https://doi.org/10.1016/0375-9601(75)90402-8
Lopez J, Tait SWG (2015) Mitochondrial apoptosis: killing cancer using the enemy within. Br J Cancer 112:957–962. https://doi.org/10.1038/bjc.2015.85
Mader JS, Hoskin DW (2006) Cationic antimicrobial peptides as novel cytotoxic agents for cancer treatment. Expert Opin Investig Drugs 15:933–946. https://doi.org/10.1517/13543784.15.8.933
Marrink SJ, Lindahl E, Edholm O, Mark AE (2001) Simulation of the spontaneous aggregation of phospholipids into bilayers. J Am Chem Soc 123:8638–8639. https://doi.org/10.1021/ja0159618
Marrink SJ, de Vries AH, Tieleman DP (2009) Lipids on the move: simulations of membrane pores, domains, stalks and curves. Biochim Biophys Acta 1788:149–168. https://doi.org/10.1016/j.bbamem.2008.10.006
Melikov KC, Frolov VA, Shcherbakov A, Samsonov AV, Chizmadzhev YA, Chernomordik LV (2001) Voltage-induced nonconductive pre-pores and metastable single pores in unmodified planar lipid bilayer. Biophys J 80:1829–1836. https://doi.org/10.1016/s0006-3495(01)76153-x
Miklavčič D (ed) (2017) Handbook of Electroporation. Springer International Publishing, Cham. https://doi.org/10.1007/978-3-319-32886-7
Neale C, Pomès R (2016) Sampling errors in free energy simulations of small molecules in lipid bilayers. Biochim et Biophys Acta 1858:2539–2548. https://doi.org/10.1016/j.bbamem.2016.03.006
Neu JC, Krassowska W (1999) Asymptotic model of electroporation. Phys Rev E 59:3471–3482. https://doi.org/10.1103/PhysRevE.59.3471
Paula S, Volkov AG, Hoek ANV, Haines TH, Deamer DW (1996) Permeation of protons, potassium ions, and small polar molecules through phospholipid bilayers as a function of membrane thickness. Biophys J 70:339–348. https://doi.org/10.1016/s0006-3495(96)79575-9
Portet T, Dimova R (2010) A new method for measuring edge tensions and stability of lipid bilayers: effect of membrane composition. Biophys J 99:3264–3273. https://doi.org/10.1016/j.bpj.2010.09.032
Puech P-H, Borghi N, Karatekin E, Brochard-Wyart F (2003) Line thermodynamics: adsorption at a membrane edge. Phys Rev Lett 90:128304
Raaymakers C, Verbrugghe E, Hernot S, Hellebuyck T, Betti C, Peleman C, Claeys M, Bert W, Caveliers V, Ballet S, Martel A, Pasmans F, Roelants K (2017) Antimicrobial peptides in frog poisons constitute a molecular toxin delivery system against predators. Nat Commun 8:1495. https://doi.org/10.1038/s41467-017-01710-1
Rathinakumar, R., Wimley, W.C., 2010. High-throughput discovery of broad-spectrum peptide antibiotics. FASEB J. https://doi.org/10.1096/fj.10-157040
Rems L (2017) Lipid Pores: Molecular and Continuum Models. In: Miklavćić D (ed) Handbook of Electroporation. Springer International Publishing, Cham, pp 3–23. https://doi.org/10.1007/978-3-319-32886-7_76
Robertson J (1960) The molecular structure and contact relationships of cell membranes. Prog Biophys Mol Biol 10:343–418
Sachs JN, Crozier PS, Woolf TB (2004) Atomistic simulations of biologically realistic transmembrane potential gradients. J. Chem. Phys. 121:10847–10851. https://doi.org/10.1063/1.1826056
Sandre O, Moreaux L, Brochard-Wyart F (1999) Dynamics of transient pores in stretched vesicles. Proc Natl Acad Sci USA 96:10591–10596. https://doi.org/10.1073/pnas.96.19.10591
Shinoda W (2016) Permeability across lipid membranes. Biochim Biophys Acta 1858:2254–2265. https://doi.org/10.1016/j.bbamem.2016.03.032
Singer SJ (2004) Some early history of membrane molecular biology. Annu Rev Physiol 66:1–27. https://doi.org/10.1146/annurev.physiol.66.032902.131835
Singer SJ, Nicolson GL (1972) The fluid mosaic model of the structure of cell membranes. Science 175:720–731
Tarek M (2005) Membrane Electroporation: a Molecular Dynamics Simulation. Biophys J 88:4045–4053. https://doi.org/10.1529/biophysj.104.050617
Taupin C, Dvolaitzky M, Sauterey C (1975) Osmotic pressure-induced pores in phospholipid vesicles. Biochemistry 14:4771–4775
Tieleman DP (2004) The molecular basis of electroporation. BMC Biochem 5:10. https://doi.org/10.1186/1471-2091-5-10
Tieleman DP, Leontiadou H, Mark AE, Marrink S-J (2003) Simulation of pore formation in lipid bilayers by mechanical stress and electric fields. J Am Chem Soc 125:6382–6383. https://doi.org/10.1021/ja029504i
Tokman M, Lee JH, Levine ZA, Ho M-C, Colvin ME, Vernier PT (2013) Electric field-driven water dipoles: nanoscale architecture of electroporation. PLoS ONE 8:e61111. https://doi.org/10.1371/journal.pone.0061111
Tolpekina TV, den Otter WK, Briels WJ (2004) Nucleation free energy of pore formation in an amphiphilic bilayer studied by molecular dynamics simulations. J Chem Phys 121:12060–12066. https://doi.org/10.1063/1.1815296
Tsong TY (1991) Electroporation of cell membranes. Biophys J 60:297–306. https://doi.org/10.1016/s0006-3495(91)82054-9
Unsay JD, Cosentino K, Sporbeck K, García-Sáez AJ (2017) Pro-apoptotic cBid and Bax exhibit distinct membrane remodeling activities: an AFM study. Biochim Biophys Acta 1859:17–27. https://doi.org/10.1016/j.bbamem.2016.10.007
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. https://doi.org/10.1021/jp077148q
Wang Y, Zhao T, Wei D, Strandberg E, Ulrich AS, Ulmschneider JP (2014) How reliable are molecular dynamics simulations of membrane active antimicrobial peptides? Biochim Biophys Acta 1838:2280–2288. https://doi.org/10.1016/j.bbamem.2014.04.009
Wang G, Li X, Wang Z (2015) APD3: the antimicrobial peptide database as a tool for research and education. Nucleic Acids Res 44:D1087–D1093. https://doi.org/10.1093/nar/gkv1278
Weaver JC, Chizmadzhev YA (1996) Theory of electroporation: a review. Bioelectrochem Bioenerg 41:135–160. https://doi.org/10.1016/s0302-4598(96)05062-3
Wohlert J, den Otter WK, Edholm O, Briels WJ (2006) Free energy of a trans-membrane pore calculated from atomistic molecular dynamics simulations. J Chem Phys 124:154905. https://doi.org/10.1063/1.2171965
Zhelev DV, Needham D (1993) Tension-stabilized pores in giant vesicles: determination of pore size and pore line tension. Biochim Biophys Acta 1147:89–104. https://doi.org/10.1016/0005-2736(93)90319-u
Ziegler MJ, Vernier PT (2008) Interface water dynamics and porating electric fields for phospholipid bilayers. J. Phys. Chem. B 112:13588–13596. https://doi.org/10.1021/jp8027726
Acknowledgements
JS acknowledges support from the Spanish MINECO (BFU2016-76805-P and BFU2017-91559-EXP, financed in part by the European Social Fund—ESF).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Cunill-Semanat, E., Salgado, J. Spontaneous and Stress-Induced Pore Formation in Membranes: Theory, Experiments and Simulations. J Membrane Biol 252, 241–260 (2019). https://doi.org/10.1007/s00232-019-00083-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00232-019-00083-4