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Cell-inspired, massive electromodulation of friction via transmembrane fields across lipid bilayers

Abstract

Transient electric fields across cell bilayer membranes can lead to electroporation and cell fusion, effects crucial to cell viability whose biological implications have been extensively studied. However, little is known about these behaviours in a materials context. Here we find that transmembrane electric fields can lead to a massive, reversible modulation of the sliding friction between surfaces coated with lipid-bilayer membranes—a 200-fold variation, up to two orders of magnitude greater than that achieved to date. Atomistic simulations reveal that the transverse fields, resembling those at cell membranes, lead to fully reversible electroporation of the confined bilayers and the formation of inter-bilayer bridges analogous to the stalks preceding intermembrane fusion. These increase the interfacial dissipation through reduced hydration at the slip plane, forcing it to revert in part from the low-dissipation, hydrated lipid–headgroup plane to the intra-bilayer, high-dissipation acyl tail interface. Our results demonstrate that lipid bilayers under transmembrane electric fields can have striking materials modification properties.

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Fig. 1: Experimental set-up and characterization of surfaces.
Fig. 2: Normal and shear force profiles between lipid-bearing mica and gold surfaces at different applied potentials on the gold.
Fig. 3: Potential modulation of shear force between DSPC-bearing mica and gold surfaces in situ, and at high salt concentration.
Fig. 4: Atomistic simulation results for lipid bilayers confined between solid slabs of gold and mica.

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Data availability

All data supporting the findings of this study are included within the paper and its Supplementary Information. Source data are provided with this paper. These data are also available from the corresponding authors upon reasonable request.

Code availability

The parameters used in the GROMACS package are available from the corresponding authors. The MATLAB scripts used for MD and experimental data analyses are available from the corresponding authors upon request.

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Acknowledgements

We thank P. Jungwirth for a useful discussion and appreciate useful remarks by M. Kozlov, L. Chernomordik and S. Roke. We thank the European Research Council (advanced grant CartiLube 743016 to J.K.), the McCutchen Foundation (J.K.), the Israel Science Foundation – National Natural Science Foundation of China joint research programme (grant 3618/21 to J.K.), the Weizmann Institute Computing Center for a Cloud Computing grant (to D.J.) and the Israel Science Foundation (grant 1229/20 to J.K.) for financial support. This work was made possible partly through the historic generosity of the Perlman family.

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Y.Z., D.J. and J.K. conceived the project; Y.Z. carried out experiments; D.J. carried out the MD simulations; and R.T. and N.K. helped with experiments. Y.Z., D.J. and J.K. wrote the paper, and all authors commented on the paper.

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Correspondence to Di Jin or Jacob Klein.

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The authors declare no competing interests.

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Nature Materials thanks Susan Perkin and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Schematic of surface force balance (SFB).

Schematic of used SFB setup with principal components labeled. Gold and back-silvered mica surfaces are mounted in cross-cylinder configuration for the interferometric measurements of separation D, enabling measurement of normal inter-surface forces Fn via bending of spring Kn, while friction forces Fs are measured via bending of the shear spring Ks. Multiple beam interference is enabled by the interferometic sandwich consisting of a back-silvered mica facing a reflecting gold surface52. Inserts are the interference fringes from the spectrometer (top right), through the wavelength of which the absolute separation D between surfaces and the mean radius of curvature R are determined, and equivalent electric circuit (bottom left), through which the surface potential of gold is controlled19.

Extended Data Fig. 2 Force profiles to determine mica surface charge density.

Normal force profiles Fn(D)/R (R is the mean radii of curvature, D is the separation between surfaces) between two mica surfaces across purified water with no added salt. Different colors symbolize different pairs of mica surfaces (within each pair the mica sheets are from the same cleaved facet). Representative normal forces profiles are used to determine the mica surface charge density, through fits to the DLVO equation (S2) (black curves), indicating the relevant range of charge densities in the experiments (this range straddles the value used in the MD simulations). The green data points correspond to the value used in fitting normal force profiles between bare gold and mica surfaces (Fig. 1b), to extract the gold surface potential Ψgold (see Methods section 2 for further information).

Extended Data Fig. 3 Characterization of mica and gold surfaces and lipid surface assemblies: A) AFM micrographs. B) DLS size distribution of lipid vesicles. C) Cyclic voltammetry of gold surface. D) Table of effective moduli of mica and gold surfaces.

Characterization of surfaces and lipid assemblies: A) AFM micrographs of POPC bilayers on mica and DSPC liposomes on gold: A(i): POPC-covered mica surface; and A(ii): DSPC liposomes-covered gold surface, with corresponding height profiles. Respective liposomes had a similar morphology whether on mica or on gold: POPC liposomes ruptures on mica surface and DSPC liposomes maintain the integrity on gold surface. B) Size distribution of DSPC liposomes at different time points after extrusion (dark blue for day 0, red for day 3). Day 0 denotes measurements done within ca. 3 hours) of extrusion. The results shows that the extruded liposomes are stable to aggregation or coarsening for at least 3 days. Data are presented as mean values +/- SD (based on 3 independent measurements). C) Cyclic voltammetry of the prepared gold surface in the SFB studies, measured in 1 mM KClO4 solution. The peaks marked by the black arrows in the upper panel correspond to the oxidation of gold surface; to avoid such oxidation, the working range is limited to the ideally polarized zone (lower panel), where the current is attributed to the charging of electric double layers. In practice the limits were between -0.3 V and + 0.2 V. D) Values of effective modulus K of compressed mica and gold surfaces. The mean radius a of the flattened contact area between the surfaces was measured from the fringe-tip flattening at 2 different independent contact points at known loads Fn. The modulus was evaluated from the Hertzian expression K = FnR/a3 (where R ≈ 1 cm is the mean radius of curvature measured separately at each contact point) and its mean value K = 3.06 × 109 Pa is used (see also Methods section 4).

Extended Data Fig. 4 Water defects in lipid layers.

Water defects following washing. The area fraction of water defects is estimated from AFM scans (top panels) of POPC bilayers on mica surfaces using image segmentation (middle panels) where the number of pixels with a value corresponding to the darkest shade is counted and divided by the total number of pixels of the image. The area fraction of water defects are respectively 15.8% and 9.8% for the scans on the left and right. From such scans we estimate an average water defect area ratio p ≈ 0.13 (that is ca. 13% water defect area ratio). The number of water molecules per POPC molecule nw is then evaluated using the following equation: \({n}_{{\rm{w}}}={n}_{{\rm{w}}}(\,p=0)+\frac{p}{(1-p)}apl\,{H}_{0}{\rho }_{{\rm{w}}}/({{m}}_{{\rm{H}}2{\rm{O}}}{N}_{{\rm{Avogadro}}})\), where \({n}_{{\rm{w}}}\left(\,p=0\right)=12,{apl}=0.62\,{{\rm{nm}}}^{2}\) is the area per lipid evaluated from the equilibrium state of the \({n}_{{\rm{w}}}=12\) double-bilayer simulation under zero electric field, H0 = 5 nm is the thickness of a monolayer, \({\rho }_{{\rm{w}}}\) is the water density. p = 0.13 corresponds to a mean hydration level of 20 water/lipid. Bottom: depth profiles corresponding to the cross-section indicated in the scan image.

Extended Data Fig. 5 Additional normal and shear force profiles (augmenting Fig. 2 in main text).

Additional normal and frictional force profiles similar to those in Fig. 2 measured in repeat experiments with freshly prepared surfaces, indicating the close reproducibility and repeatability of the data. (A) Normal force profiles between POPC-bilayers coated gold and mica surfaces. The dotted line separates the repulsive regime (Fn/R > 0, shown in log-linear scale) and the attractive regime (Fn/R < 0, shown in linear-linear scale). The dashed vertical line shows the ‘hard-wall’separation at Dhw = 9.0 ± 0.4 nm. The two surfaces ‘jump’ (J) into contact at 200 mV applied potentials, as marked by the arrow, due to the Euler instability at ∂Fn/∂D > Kn. (B) Repulsive normal force profiles between DSPC-liposomes coated surfaces. The ‘hard-wall’ separation (Dhw = 19.3 ± 1.2 nm) indicates two flattened DSPC-liposomes. (C) The friction profiles corresponding to (A), measured at DDhw, showing the friction coefficient changing between (1.21 ± 0.22) × 10−3 and 0.11. (D) Friction Fs as a function of normal load Fn, corresponding to (B), showing the change of friction coefficient between (1.12 ± 0.39) × 10−3 and 0.099.

Extended Data Fig. 6 Electroporation of DSPC bilayers.

The electroporation simulations with DSPC lipid membranes were repeated using the same protocols as presented in the text and Methods, and in more detail in ref. 24, for POPC. The initial gel-phase DSPC membrane structure was acquired from the opensource data published by ref. 77, where the lipid tails are properly tilted and equilibrated to give the correct packing. The given structure was then quadrupled in size to give 144 DSPC lipids/monolayer and the hydration level was correspondingly adjusted to nw = 12 and nw = 20, representing defectless membranes and membranes with elevated hydration levels due to defects, as discussed in the manuscript. The initial electroporation was introduced by applying a 0.8–1.0 V/nm electric field, and then reduced to 0.10 V/nm and equilibrated for 60 ns until the pores stabilize. This demonstrates that gel-phase DSPC membranes undergo electroporation very similarly to the liquid-phase POPC membranes as in Fig. 4b.

Extended Data Fig. 7 Reversibility of friction changes on toggling potentials. A, B, C): Reproducibility of friction vs. load profiles as potential is toggled. D) Reversibility of friction during sliding on potential toggling.

Illustrating the reversibility of the friction change on potential toggling. A, B and C. For POPC A and DSPC B, the typical friction vs. load profiles are measured under controlled potentials applied to the gold surface, which are toggled over several cycles, as shown by different symbols as indicated in the legends. The potentials are shown by colors: dark blue for applied potential of -0.3 V, red for applied potential of 0.2 V. The results of A and B are summarized in C, showing the sequential change of applied potentials (red-shaded band: Ψapp = 200 mV, high field; blue-shaded band Ψapp = -300 mV, low field), under which the friction coefficients are measured. The results shows 4 cycles of reversible change in POPC friction-load profiles (empty and filled squares), and 5 cycles in DSPC friction-load profiles (empty and full circles). D. Illustrating the reversibility over several cycles of the transition of shear force Fs(t) between DSPC-bearing mica and gold surfaces in situ (that is during sliding), achieved by potential-modulation during sliding under fixed load (see Fig. 3a in main text): Upper trace I is the back-and-forth lateral motion applied to the upper mica surface, while lower trace II shows shear force Fs(t) transmitted to the lower surface mounted on the locked normal spring. At arrows in trace II the potential changes from Ψapp = 200 mV (high field) to -300 mV (negligible field) and back again. Since any normal motion is eliminated by the spring-locking (Fig. 3a in main text), the reversible changes in Fs are due only to field-induced changes in the boundary layer rather than to any change in compressive load, and are fully reversible over at least 5 consecutive cycles.

Extended Data Fig. 8 Change in friction as function of transverse electric field across bilayers.

Friction coefficient μ as a function of electric field (estimated as described in Methods, section 5), indicating the sharp increase for both POPC and DSPC surface coatings, attributed to the electric fields exceeding the threshold values for poration (which are seen to depend, as expected, on whether the lipids are in their liquid or gel phase (POPC and DSPC respectively). Different symbols are data from repeat experiments. Solid lines are used to guide the eye. Data are presented as mean values +/- SD (based on 3 independent measurements).

Extended Data Fig. 9 Shear stress between compressed sliding bilayers as function of hydration.

Demonstrating directly how slight interfacial dehydration contributes to strongly increased sliding friction by comparing the shear stress in three cases between POPC bilayers sliding at 1 m/s and normal stress 10 atm. a) Blue trace: shear stress as a function of time between bilayers at hydration level nw = 12 in the absence of an E-field, when the two layers are planar with no pores, showing a low frictional stress. b) Red trace: the same nw = 12 case following application of a field E = 0.1 V/nm, where electroporation results in sequestration of water in the pores leading to dehydration at the lipid headgroup/headgroup interface, as shown in Fig. 4e, f, and resulting much higher frictional stress. c) Yellow trace: bilayers at a reduced hydration level nw = 11 in the absence of an E-field, where the two layers are planar with no pores, and the mean spacing between dipoles exposed by opposing bilayers is very similar to that in the porated nw = 12 case25 (trace (b)); the shear stress is similar (within ca. 20%) to the red trace data (b) for the porated nw = 12 case. This shows directly that dehydration resulting from electroporation leads to friction similar that between planar non-porated bilayers at slightly lower hydration levels. The planar, unporated nw = 11 bilayers (trace (c)) were slightly expanded25 (by 3% laterally in x and in y directions) to account for the undulations at the slip-plane of the porated nw = 12 layers indicated in Fig. 4e. We remark that the magnitude of the shear stresses is in all cases much larger than that measured experimentally (Figs. 2, 3) as the sliding velocity (1 m/s) in the MD experiments is orders of magnitude larger than in the SFB25 (for comparison with the experimental data see extrapolation to low velocities as in ref. 25). Details concerning evaluation of the nw values are given in ref. 25.

Extended Data Fig. 10 Comparing stalk structure and field-induced bridge structure between bilayers.

Comparison of the ‘bridge’ structure formed between the electroporated membranes and a stalk structure. a) Structure of the all-atom double POPC bilayers at nw = 20, E = 0.1 V/nm condition where the solid confining surfaces and water molecules are not shown for clarity, and only the headgroup P (gold) and N (blue) atoms and the carbon atoms (cyan) of the tails are shown. Each monolayer contains 128 lipids. b) Structure a with only the tail carbon atoms shown. c) A structure of coarse-grained MARTINI 2.2 P POPC double bilayers with 256 lipids/monolayer, where a stalk is artificially facilitated using a reaction coordinate as described in ref. 38. Only tail carbons are shown. The inter-membrane hydrophobic structure observed under the nw = 20, E = 0.1 V/nm condition, which termed ‘bridge’ in the manuscript, is seen to be essentially identical to the ‘stalk’ known from the literature, where a cylindrical lipid core forms and inter-connects the membranes. In the case of the ‘bridge’ between the porated membranes, the existence of the pores (stabilized with headgroups exposed to the inter-membrane water phase) is indicated by the headgroup atoms in structure a), and does not affect the property of the bridge structure in terms of the connectivity with each of the two membranes. The circular cross section of the bridge or stalk is seen more explicitly in Movie S2 where the carbon tails only are shown.

Supplementary information

Supplementary Video 1

Demonstrating reversibility of poration on switching field off.

Supplementary Video 2

Demonstrating structure of inter-bilayer stalk.

Source data

Source Data Fig. 1

Original data for plot in Fig. 1b and two height profiles in Fig. 1c,d.

Source Data Fig. 2

Original dataset for the plots.

Source Data Fig. 3

Original dataset for real-time traces (Fig. 3a(i),(ii)) and for plots (Fig. 3b–d).

Source Data Fig. 4

Original dataset for Fig. 4d,e.

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Zhang, Y., Jin, D., Tivony, R. et al. Cell-inspired, massive electromodulation of friction via transmembrane fields across lipid bilayers. Nat. Mater. (2024). https://doi.org/10.1038/s41563-024-01926-9

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