Properties of lipid electropores II: Comparison of continuum-level modeling of pore conductance to molecular dynamics simulations

Rems, Lea; Tarek, Mounir; Casciola, Maura; Miklavčič, Damijan

doi:10.1016/j.bioelechem.2016.03.005

Cited by 24 publications

(8 citation statements)

References 86 publications

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“…Both complex pores were less conductive to Na + compared to Clions. Similar result has been observed for lipid pores, where the selectivity could be explained by lower bulk mobility of Na + ions and their binding to lipid headgroups, which affects the electrostatic environment inside the pore (55).…”

Section: Complex Pores Can Conduct Ions Preferentially In One Directionsupporting

confidence: 82%

Pulsed electric fields create pores in the voltage sensors of voltage-gated ion channels

Rems

Kasimova

Testa

et al. 2019

Preprint

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Pulsed electric fields are increasingly used in medicine to transiently increase the cell membrane permeability via electroporation, in order to deliver therapeutic molecules into the cell. One type of events that contributes to this increase in membrane permeability is the formation of pores in the membrane lipid bilayer. However, electrophysiological measurements suggest that membrane proteins are affected as well, particularly voltagegated ion channels (VGICs). The molecular mechanisms by which the electric field could affects these molecules remain unidentified. In this study we used molecular dynamics (MD) simulations to unravel the molecular events that take place in different VGICs when exposing them to electric fields mimicking electroporation conditions. We show that electric fields induce pores in the voltage-sensor domains (VSDs) of different VGICs, and that these pores form more easily in some channels than in others. We demonstrate that poration is more likely in VSDs that are more hydrated and are electrostatically more favorable for the entry of ions. We further show that pores in VSDs can expand into so-called complex pores, which become stabilized by lipid head-groups. Our results suggest that such complex pores are considerably more stable than conventional lipid pores and their formation can lead to severe unfolding of VSDs from the channel. We anticipate that such VSDs become dysfunctional and unable to respond to changes in transmembrane voltage, which is in agreement with previous electrophyiological measurements showing a decrease in the voltage-dependent transmembrane ionic currents following pulse treatment. Finally, we discuss the possibility of activation of VGICs by submicrosecond-duration pulses. Overall our study reveals a new mechanism of electroporation through membranes containing voltage-gated ion channels. Statement of SignificancePulsed electric fields are often used for treatment of excitable cells, e.g., for gene delivery into skeletal muscles, ablation of the heart muscle or brain tumors. Voltage-gated ion channels (VGICs) underlie generation and propagation of action potentials in these cells, and consequently are essential for their proper function. Our study reveals the molecular mechanisms by which pulsed electric fields directly affect VGICs and addresses questions that have been previously opened by electrophysiologists. We analyze VGICs' characteristics, which make them prone for electroporation, including hydration and electrostatic properties. This analysis is easily transferable to other membrane proteins thus opening directions for future investigations. Finally, we propose a mechanism for long-lived membrane permeability following pulse treatment, which to date remains poorly understood.

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Section: Complex Pores Can Conduct Ions Preferentially In One Directionsupporting

confidence: 82%

Pulsed electric fields create pores in the voltage sensors of voltage-gated ion channels

Rems

Kasimova

Testa

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Both complex pores were less conductive to Na + compared to Cl − ions. A similar preference for Cl − ions has been observed in lipid pores, in which this selectivity could be explained by lower bulk mobility of Na + ions and their binding to lipid headgroups, which also affects the electrostatic environment inside the pore and induces an electroosmotic flow in the direction of Cl − ion movement ( 56 ).…”

Section: Resultsmentioning

confidence: 60%

Pulsed Electric Fields Can Create Pores in the Voltage Sensors of Voltage-Gated Ion Channels

Rems

Kasimova

Testa

et al. 2020

Biophysical Journal

Self Cite

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Pulsed electric fields are increasingly used in medicine to transiently increase the cell membrane permeability via electroporation to deliver therapeutic molecules into the cell. One type of event that contributes to this increase in membrane permeability is the formation of pores in the membrane lipid bilayer. However, electrophysiological measurements suggest that membrane proteins are affected as well, particularly voltage-gated ion channels (VGICs). The molecular mechanisms by which the electric field could affects these molecules remain unidentified. In this study, we used molecular dynamics simulations to unravel the molecular events that take place in different VGICs when exposing them to electric fields mimicking electroporation conditions. We show that electric fields can induce pores in the voltage-sensor domains (VSDs) of different VGICs and that these pores form more easily in some channels than in others. We demonstrate that poration is more likely in VSDs that are more hydrated and are electrostatically more favorable for the entry of ions. We further show that pores in VSDs can expand into so-called complex pores, which become stabilized by lipid headgroups. Our results suggest that such complex pores are considerably more stable than conventional lipid pores, and their formation can lead to severe unfolding of VSDs from the channel. We anticipate that such VSDs become dysfunctional and unable to respond to changes in transmembrane voltage, which is in agreement with previous electrophysiological measurements showing a decrease in the voltage-dependent transmembrane ionic currents after pulse treatment. Finally, we discuss the possibility of activation of VGICs by submicrosecond-duration pulses. Overall, our study reveals a new, to our knowledge, mechanism of electroporation through membranes containing VGICs.

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“…A discussion of the modeling procedures and results would be beyond the scope of this manuscript. However, the reader can find more information on molecular dynamic simulations of pore formation in membranes in chapters of the book on “Advanced Electroporation Techniques in Biology and Medicine” [Tarek and Delemotte, ; Vernier, ] and in references [Bennett et al, ; Son et al, ; Rems et al, ].…”

Section: Primary Effects Of Ultrashort Pulses On Cellsmentioning

confidence: 99%

From the basic science of biological effects of ultrashort electrical pulses to medical therapies

Schoenbach

2018

Bioelectromagnetics

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This article is based on my presentation at the D'Arsonval Ceremony at the Joint Annual Meeting of the Bioelectromagnetics Society and the European BioElectromagnetics Association in Hangzhou, China, in June of 2017. It describes the pathway from the first studies on the effects of intense, nanosecond pulses on biological cells to the development of medical therapies based on these effects. The motivation for the initial studies of the effects of high voltage, nanosecond pulses on mammalian cells was based on a simple electrical circuit model, which predicted that such pulses allow us to affect not just the plasma membrane but also the subcellular structures. The first experimental study that confirmed this hypothesis was published in 2001 in the Bioelectromagnetics journal. It was followed by a large number of publications that showed that such ultrashort pulses affect cell functions, such as programmed cell death, and, at lower intensity, calcium mobilization from intracellular structures. These basic studies were leading to novel cancer treatments, treatments of cardiac arrhythmia, and advanced wound healing. Further, by reducing the pulse duration into the picosecond range, antenna-based neural stimulation seems to be possible. This manuscript gives an overview of the progress in this field of research in the decade after the initial bioelectric studies with high-voltage, nanosecond pulses, particularly the research performed at the Frank Reidy Research Center for Bioelectrics. It also tells you about my journey and that of my colleagues at the Center for Bioelectrics into and through this fascinating bioelectromagnetics research area. Bioelectromagnetics. 39:257-276, 2018. © 2018 Wiley Periodicals, Inc.

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Properties of lipid electropores II: Comparison of continuum-level modeling of pore conductance to molecular dynamics simulations

Cited by 24 publications

References 86 publications

Pulsed electric fields create pores in the voltage sensors of voltage-gated ion channels

Pulsed electric fields create pores in the voltage sensors of voltage-gated ion channels

Pulsed Electric Fields Can Create Pores in the Voltage Sensors of Voltage-Gated Ion Channels

From the basic science of biological effects of ultrashort electrical pulses to medical therapies

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