Coarse-grained molecular dynamics simulation analysis of the effects of phospholipid and cholesterol on...

Membrane composition is a critical factor for electroporation. Although existing research focuses on pore formation driven by local phospholipid headgroup clusters, the large-scale membrane dynamics post-pore formation remain underexplored. In this study, coarse-grained (CG) molecular dynamics (MD) simulations were employed to investigate the effects of phospholipid headgroups (PC, PE and PS), tail characteristics (DLPC, DPPC, POPC and DOPC) and cholesterol (CHOL) content (0 mol%-50 mol%) on membrane electroporation. The results demonstrate that membrane structural parameters, such as area per lipid, hydrophobic layer thickness and interfacial water penetration depth, significantly influence the electroporation threshold electric field and transmembrane substance flux. Phospholipid headgroups can modulate the area per lipid and hydrophobic layer thickness through their size, hydrogen bonding and charge. Regarding phospholipid tails, increasing their length and unsaturation strengthens the hydrophobic layer, and thereby inhibits electroporation. The incorporation of CHOL into the membrane leads to tighter lipid packing, increased layer thickness and restricted water penetration, all of which elevate the threshold electric field. After electroporation, CHOL reduces transmembrane flux by enhancing line tension, although this inhibitory effect is limited at higher concentrations. The simulation results align well with existing experimental data, suggesting our approach can guide protocol design and highlight membrane composition's critical role in electroporation efficiency.