Molecular Dynamics

Molecular Dynamics Study of Electroporation in Cholesterol-Containing Bilayers

The permeabilization of a lipid bilayer by applying a transverse electric field, a phenomenon called electroporation, is the basis of diverse medical techniques such as electrochemotherapy. Furthermore, cholesterol is a unique lipid component in biological membranes and is known to determine most of their structural properties. As a consequence, it is clear that the effect of cholesterol in the bilayer electroporation process is fundamental for its technical application to natural cell membranes. Here, MD simulations of DOPC bilayers with different contents of cholesterol have been performed, and for each case the electroporating field threshold E0 has been calculated and the properties of the membrane have been analyzed. It has been found that the condensing action of cholesterol increases the cohesive nature of the host membrane, and as a consequence, cholesterol-containing membranes require a stronger electric field to be electroporated than the pure case. In particular, we found that membrane cohesion sharply increases at Chol contents above 10 mol %, in accordance to the sudden increment of E0 above this Chol fraction. Thus, our model is able to capture not only the structural effects that cholesterol induces in equilibrium biological membranes but also those that show up when an external electric field is applied. The complete sequence of pore formation has been analyzed. First, a water fluctuation penetrates the membrane and forms a very thin cone of water molecules. If this water filament progresses, it may eventually reach the anodic leaflet, forming a thin hydrophobic pore. After a while, the lipids around the pore rotate and cover the water filament with their hydrophilic head groups, forming a hydrophilic pore that rapidly widens. Although this sequence is common to all simulated systems, some distinct features are noticed between cholesterol-free and cholesterol-containing membranes. In the former case, the occurrence of water fluctuations is much higher and once a fluctuation sufficiently penetrates the membrane, the formation of the hydrophobic and hydrophilic pores is almost simultaneous. The hydrophobic pore only lasts a few hundreds of picoseconds since DOPC molecules quickly rotate to stabilize the pore. Instead, for cholesterol-containing membranes, the kinetics of pore formation is much slower. First, the fluctuations are less probable than for the pure case. Second, when a large enough fluctuation is formed, it takes more time (even a few nanoseconds) to traverse the membrane and connect the two leaflets. Third, once the hydrophobic pore has been formed, cholesterol and DOPC molecules rotate to form the hydrophilic pore. . Summarizing, we have contributed to a detailed understanding of the role of cholesterol in electroporation phenomenon. Our ultimate goal has been to obtain a better model to elucidate the molecular processes that occur during the application of the electric field to cells or biological tissues, and how one of the most important components of the cell membrane (cholesterol) can affect the electroporation process.

Snapshots for the pore dynamics in a DOPC bilayer subjected to an applied electric field Eap ) E0 ) 325 mV/nm (a) initial configuration; (b) 9520 ps; (c) 9550 ps; (d) 9750 ps. Water molecules are plotted with red and white sticks; DOPC phosphate groups, with yellow beads. In the initial configuration, DOPC molecules are plotted using blue sticks. Periodic boundary conditions are applied in the xy plane.

Snapshots for the pore dynamics in a DOPC bilayer with 40 mol % Chol, subjected to an applied electric field Eap ) E0 ) 750 mV/nm: (a) initial configuration; (b) 5850 ps; (c) 7800 ps; (d) 8850 ps. Water molecules are plotted with red and white sticks; DOPC phosphate groups and Chol hydroxyl groups, with yellow and green beads, respectively. In the initial configuration, DOPC and Chol molecules are plotted using blue and green sticks, respectively. Periodic boundary conditions are applied in the xy plane.

Contacto: Departamento de Computación - Facultad de Ciencias Exactas y Naturales - Universidad de Buenos Aires
Pabellón I - Ciudad Universitaria - (C1428EGA) - Buenos Aires - Argentina
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Molecular Dynamics

Molecular Dynamics Study of Electroporation in Cholesterol-Containing Bilayers