Estimation of activation energy for electroporation and pore growth rate in liquid crystalline and gel phases of lipid bilayers using molecular dynamics simulations

Majhi, Amit Kumar; Kanchi, Subbarao; Venkataraman, V.; Ayappa, K. G.; Maiti, Prabal K.

doi:10.1039/c5sm02029h

Cited by 30 publications

(45 citation statements)

References 75 publications

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“…The nonmonotonous pore formation rates for the fluid-like, equilibrated DPPC bilayer close to and above T m clearly cannot be described by a pure Arrhenius-like behavior, with rates k changing with temperature according to k ∝ exp(− ΔG / k B T ), where ΔG is the activation energy for pore formation ( 39 ) and k B the Boltzmann constant. This was suggested by an earlier MD study that addressed pore opening rates at different temperatures well above T m ( 132 ). ΔG was assumed in this study to be independent of the temperature, which might be a valid assumption well above T m as well as within the gel phase but does not hold true at temperatures close to T m , at which the membrane has significantly different structural properties such as, e.g., long-lasting thin domains that may be coupled to disturbed lipids.…”

Section: Discussionmentioning

confidence: 79%

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Coupling of Membrane Nanodomain Formation and Enhanced Electroporation near Phase Transition

Kirsch

Böckmann

2019

Biophysical Journal

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Biological cells are enveloped by a heterogeneous lipid bilayer that prevents the uncontrolled exchange of substances between the cell interior and its environment. In particular, membranes act as a continuous barrier for salt and macromolecules to ensure proper physiological functions within the cell. However, it has been shown that membrane permeability strongly depends on temperature and, for phospholipid bilayers, displays a maximum at the transition between the gel and fluid phase. Here, extensive molecular dynamics simulations of dipalmitoylphosphatidylcholine bilayers were employed to characterize the membrane structure and dynamics close to phase transition, as well as its stability with respect to an external electric field. Atomistic simulations revealed the dynamic appearance and disappearance of spatially related nanometer-sized thick ordered and thin interdigitating domains in a fluid-like bilayer close to the phase transition temperature (T m). These structures likely represent metastable precursors of the ripple phase that vanished at increased temperatures. Similarly, a two-phase bilayer with coexisting gel and fluid domains featured a thickness minimum at the interface because of splaying and interdigitating lipids. For all systems, application of an external electric field revealed a reduced bilayer stability with respect to pore formation for temperatures close to T m. Pore formation occurred exclusively in thin interdigitating membrane nanodomains. These findings provide a link between the increased membrane permeability and the structural heterogeneity close to phase transition.

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Section: Discussionmentioning

confidence: 79%

“…Also, Majhi et al. did not observe an enhanced electropore formation close to phase transition, possibly related to the enhanced field strengths employed ( 132 ).…”

Section: Discussionmentioning

confidence: 98%

Coupling of Membrane Nanodomain Formation and Enhanced Electroporation near Phase Transition

Kirsch

Böckmann

2019

Biophysical Journal

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“… 20 have demonstrated that the phase state plays the decisive role in the increased critical transmembrane voltage of gel-phase GUVs with respect to fluid-phase GUVs, and not the carbon chain length, due to the large cohesion of the gel-phase lipids. This increased critical transmembrane voltage for electroporation of gel-phase lipids is supported by MD simulations 12 .…”

Section: Introductionmentioning

confidence: 65%

“…To reveal the electroporation mechanisms, electroporation is studied using simplified model systems such as giant unilamellar vesicles (GUVs) 8 – 10 , planar lipid bilayers 11 and different theoretical methods including molecular dynamics (MD) simulations 12 – 14 . GUVs provide the benefit of isolating the function of the membrane from the complex intracellular components involved in a cell, while resembling the size of the cell and curvature of the cell membrane.…”

Section: Introductionmentioning

confidence: 99%

The role of gel-phase domains in electroporation of vesicles

Perrier

Rems

Kreutzer

et al. 2018

Sci Rep

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Transient permeabilisation of the cell membrane is a critical step to introduce drugs or DNA into living cells, yet challenging for both biological research and therapeutic applications. To achieve this, electroporation (or electropermeabilisation) has become a widely used method due to its simplicity to deliver almost any biomolecule to any cell type. Although this method demonstrates promise in the field of drug/gene delivery, the underlying physical mechanisms of the response of the heterogeneous cell membrane to strong electric pulses is still unknown. In this study, we have investigated the role of gel-phase lipids in the electroporation of binary giant unilamellar vesicles (GUVs), composed from DPPC (gel-phase) and DPhPC (fluid-phase) lipids (molar ratio 8:2 and 2:8). We have observed that the exposure to electric pulses leads to expel of fluid-phase lipids and concomitant decrease in GUV size, whereas the gel-phase domains become buckled. Based on experiments on pure fluid-phase and gel-phase GUVs, we have found that fluid-phase lipids can be expelled by electrical forces and the highly viscous gel-phase lipids cannot. Moreover, our analyses suggest that pore formation occurs primarily in fluid-phase domains and that the pore size is similar in all GUVs containing fluid-phase lipids, irrespective of the gel-phase percentage.

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“…All bonds involving the hydrogen atom are constrained using the SHAKE 45 algorithm allowing for a longer time step of 2 fs during the MD simulations. Our previous studies 28,29,[46][47][48][49][50][51] showed that the above mentioned MD protocol produces a very stable MD trajectory for various complex systems.…”

Section: Methodsmentioning

confidence: 98%

pH controlled gating of toxic protein pores by dendrimers

et al. 2016

Self Cite

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Designing effective nanoscale blockers for membrane inserted pores formed by pore forming toxins, which are expressed by several virulent bacterial strains, on a target cell membrane is a challenging and active area of research. Here we demonstrate that PAMAM dendrimers can act as effective pH controlled gating devices once the pore has been formed. We have used fully atomistic molecular dynamics (MD) simulations to characterize the cytolysin A (ClyA) protein pores modified with fifth generation (G5) PAMAM dendrimers. Our results show that the PAMAM dendrimer, in either its protonated (P) or non-protonated (NP) states can spontaneously enter the protein lumen. Protonated dendrimers interact strongly with the negatively charged protein pore lumen. As a consequence, P dendrimers assume a more expanded configuration efficiently blocking the pore when compared with the more compact configuration adopted by the neutral NP dendrimers creating a greater void space for the passage of water and ions. To quantify the effective blockage of the protein pore, we have calculated the pore conductance as well as the residence times by applying a weak force on the ions/water. Ionic currents are reduced by 91% for the P dendrimers and 31% for the NP dendrimers. The preferential binding of Cl(-) counter ions to the P dendrimer creates a zone of high Cl(-) concentration in the vicinity of the internalized dendrimer and a high concentration of K(+) ions in the transmembrane region of the pore lumen. In addition to steric effects, this induced charge segregation for the P dendrimer effectively blocks ionic transport through the pore. Our investigation shows that the bio-compatible PAMAM dendrimers can potentially be used to develop therapeutic protocols based on the pH sensitive gating of pores formed by pore forming toxins to mitigate bacterial infections.

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Estimation of activation energy for electroporation and pore growth rate in liquid crystalline and gel phases of lipid bilayers using molecular dynamics simulations

Cited by 30 publications

References 75 publications

Coupling of Membrane Nanodomain Formation and Enhanced Electroporation near Phase Transition

Coupling of Membrane Nanodomain Formation and Enhanced Electroporation near Phase Transition

The role of gel-phase domains in electroporation of vesicles

pH controlled gating of toxic protein pores by dendrimers

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