Molecular Dynamics Simulation of Lipid Oxidation on Cell Membrane Electroporation

Abstract

Experimental studies reveal that nanosecond-pulsed electric fields (nsPEFs) trigger lipid peroxidation. However, how this oxidatively preconditioned state dynamically influences membrane breakdown during subsequent exposures remains a critical blind spot. To resolve this complex interplay, we first quantified how oxidized lipids reshape transmembrane energy landscapes to drive a pre-sensitized membrane state and then mapped spatial causality by colocalizing early pore nucleation sites with oxidized polar domains. Finally, we captured temporal dynamics by tracking non-equilibrium electroporation under complex pulsed waveforms to assess water accumulation. Spatially, we found that the spatial distribution of aldehyde groups showed preferential spatial association with pore-forming sites. Temporally, we found a structural effect. Water molecules that invade the core continuously endure the accumulation of damage from cross fluctuations during the pulse, driving irreversible pore penetration, which is exacerbated with deepening oxidation concentration. Together, these spatial and temporal findings define the transformation of multi-pulse electroporation from a static threshold event to a history-dependent cumulative continuous spectrum, laying a robust physicochemical cornerstone for precision treatment optimization.