Electroporation is a well-established technique that induces transient pores in cell membranes through intense electric fields. While previous studies have focused primarily on lipid bilayers, the role of membrane proteins in electroporation remains poorly understood. This study investigates the impact of high-intensity electric fields on the TRPV4 ion channel using molecular dynamics simulations to elucidate protein involvement in electroporation processes. The research examines two conformational states of human TRPV4 (hTRPV4, closed and inactivated) embedded in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine lipid bilayers in a hydrated system under electric (E-)field exposure of 50, 70, and 80 MV/m. A novel algorithm was developed to precisely identify and analyze two distinct water populations: interfacial water near membrane surfaces and channel-confined water within the TRPV4 channel. Key findings reveal fundamentally different responses between these water populations. These findings provide new mechanistic insights into protein-mediated electroporation, highlighting its potential role in electroporation-driven membrane permeabilization, and suggest opportunities for developing targeted therapeutic strategies that exploit the presence and functional state of specific transmembrane proteins in membrane permeabilization processes.
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