Structural and Kinetic Molecular Dynamics Study of Electroporation in Cholesterol-Containing Bilayers

Abstract

We present a numerical study of pore formation in lipid bilayers containing cholesterol (Chol) and subjected to a transverse electric field. Molecular dynamics simulations of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DOPC) membranes reveal the formation of a pore when an electric field of 325 mV/nm is applied. The minimum electric field needed for membrane permeabilization strongly increases with the addition of cholesterol above 10 mol %, reaching 750 mV/nm for 40 mol % Chol. Analysis of simulations of DOPC/Chol bilayers suggests this is caused by a substantial increment of membrane cohesion. Simulations also show that pore formation kinetics is much slower at high Chol contents.

Effects of Dimethyl Sulfoxide on Lipid Membrane Electroporation

“…As reported in Ref. 9, cholesterol, by means of its condensing and ordering effect, increases the compactness of the bilayer, thus increasing the strength of the electric field required to porate it. A similar effect has been recently found in MD simulations when using lipid molecules with acyl chains and/or linkages (ester or ether) that favor membrane stability, 17 or for the addition of archaeal lipids in DPPC bilayers.…”

“…Mainly, the electroporation threshold (the minimum electric field required to porate the membrane) is determined by the membrane physical properties: more stable, compact and condensed bilayers require higher applied electric fields in order to be porated. 9,17,18 MD simulations also show that in the absence of any applied electric field, DMSO triggers a similar chain of events by promoting water defects that initiate hydrophobic water columns that later develop into stable hydrophilic membrane pores. 5,[10][11][12] Because the physical (electroporation) and chemical (DMSO-induced) methods follow a similar sequence for pore formation, the combination of both acting simultaneously is expected to lead to pore formation under more favorable conditions.…”

“…9,17,18 Here, the electroporation threshold E 0 was computed following a similar procedure to that in Ref. 9.…”

“…9,17,18 Here, the electroporation threshold E 0 was computed following a similar procedure to that in Ref. 9. Each membrane simulation was run independently for 25 ns in triplicate, and a transverse electric field, E, was fixed in the MD simulation protocol.…”

“…2,3 Membrane pores can also be chemically induced by the use of particular membrane-fluidizing compounds such us dimethyl sulfoxide (DMSO, (CH 3 ) 2 SO), a small amphiphilic molecule that has been shown to enhance cell permeability through the formation of water pores. 4,5 Recently, molecular dynamics (MD) simulations have been used to elucidate the molecular mechanisms leading to pore formation in simple lipid bilayers by both the application of an external electric field [6][7][8][9][10] and the effects of DMSO. 5,[10][11][12] According to the simulations, the molecular mechanism of electroporation occurs in different stages.…”