Speaker
Description
Electroporation is widely used in medicine to increase cell membrane permeability, enabling delivery of therapeutic molecules and nonthermal tissue ablation. While molecular dynamics simulations (MD) have revealed that electroporation can be associated with formation of pores in both lipid domains and voltage-gated ion channels (VGICs), the relative likelihood of these events in actual cell plasma membranes remains unclear. This gap exists because MD simulations consider only small membrane patches under conditions that do not reflect the complex dynamics of transmembrane voltage during cellular electroporation, where initial pores cause membrane discharge that limits subsequent pore formation. To address this, we conducted atomistic MD simulations comparing poration rates between simple POPC bilayers, bilayers containing NaV1.5, CaV1.1, or CaV1.3 channels, and a complex lipid bilayer designed to represent highly poratable cell plasma membrane domains. Our results show that the tested VGICs are more susceptible to poration than POPC bilayers, forming complex pores stabilized by both lipid head-groups and amino-acid residues in their voltage-sensor domains. This enhanced susceptibility is particularly significant for medical applications targeting excitable tissues, as these channels are crucial for cardiac and skeletal muscle function. The formation of complex pores leads to unfolding of voltage-sensor domains, providing a molecular mechanism for the experimentally observed reduction in voltage-dependent ionic currents following pulse treatment. These findings advance our understanding of cellular electroporation mechanisms and have important implications for optimizing electroporation protocols in medical applications.
