Exposure of biological cells to short, high-voltage electrical pulses induces structural changes in their membranes, leading to an increase in membrane permeability and allowing transmembrane transport of molecules that are otherwise unable to cross the membrane. This phenomenon is termed electroporation and is used in various applications in medicine, biology and biotechnology. Our mechanistic understanding of electroporation has considerably improved through the use of molecular dynamics (MD) simulations. MD enables simulations of the movement of atoms and molecules within the studied system and offers a visualization of processes at the molecular level. MD simulations have revealed that the increase in membrane permeability can be attributed to the formation of aqueous pores formed under the influence of a strong electric field in the membrane lipid bilayer, or even in the voltage sensors of certain voltage-gated ion channels (VGICs). The latter play a crucial role in the generation of electrical signals called action potentials in muscle and neuronal cells. This opens the question on whether electroporation is favoured in lipid domains or VGICs and how susceptible VGICs are to damage due to electroporation. In this thesis we thus used atomistic MD simulations to compare how fast an electric field can form pores in different lipid bilayers and VGICs. We first simulated a 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC) bilayer that represents the simplest model of a cell membrane and is commonly used for studying electroporation with MD simulations. We studied electroporation in two POPC bilayers of different sizes and found that the rate of pore formation depends on the bilayer size, with pores forming faster in the larger bilayer. This finding was considered in the following step, where we simulated electroporation of a bilayer composed of 15 different types of lipids, modeling a realistic lipid domain within a mammalian cell membrane. This bilayer was designed based on results from a previous study and represented a lipid domain that has the highest propensity for electroporation. The time required to form pores in these lipid bilayers was then compared with the time required for electroporation of two clinically relevant VGICs, NaV1.5 and CaV1.1. The sodium channel NaV1.5 is predominantly expressed in cardiac muscle cells, while the calcium channel CaV1.1 is predominantly expressed in skeletal muscles. Our results showed that electroporation of VGICs occurs on average at lower electric field strength than electroporation of lipid bilayers. At a given electric field strength, formation of pores within the voltage sensors of VGICs occurs faster compared to pores within lipid bilayers. This means that electroporation of the studied VGICs, NaV1.5 and CaV1.1, is energetically favorable compared to lipid bilayer electroporation. Consequently, our results suggest that the likeness of electroporation-induced damage to these VGICs is very high. Such damage may affect the ability of muscle and neuronal cells to trigger action potentials and alter the shape of these action potentials after electroporation. The findings of this study are particularly important for optimizing electroporation-based treatments, such as cardiac ablation for treatment of heart arrhythimias, ablation of brain tumours, and nucleic acid delivery into skeletal and cardiac muscle for gene therapy.
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