Mitochondria-Targeted Peptides and Bilayer Composition Modulate Membrane Electroporation Under Elevated Electrochemical Stress

Several studies have used molecular dynamics (MD) simulations to examine the relationship between transmembrane potentials (ΔΨ_m ) and electroporation; however, research on how this relationship presents in complex membranes with heterogenous lipid compositions is limited. Here we use all-atom, double-bilayer MD simulations with explicitly-modeled ΔΨ_m voltages to compare how membranes with homogenous vs. heterogenous lipid compositions respond to varying degrees of electrochemical stress. These two bilayer systems were also exposed to a mitochondria-targeted peptide named Elamipretide which has been shown experimentally to modulate membrane electrostatics. Additionally, we used Computational Electrophysiology (CompEL) MD simulations to analyze how lipid composition and peptide exposure influence rates of passive transmembrane ion flux during electroporation events. The addition of cardiolipin (CL) and Elamipretide increased membrane capacitance, decreasing the ΔΨ_m for a given transmembrane charge imbalance (δ_TM ) and protecting bilayers against electroporation. These results expand our understanding of how more complex, biologically-relevant bilayers respond to electrochemical stress.