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 (ΔΨm) and electroporation; however, research on how this relationship presents in complex membranes with heterogeneous lipid compositions is limited. Here, we use all-atom, double-bilayer MD simulations with explicitly modeled ΔΨm voltages to compare how membranes with homogeneous vs heterogeneous 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 the membrane capacitance, decreasing the ΔΨm for a given transmembrane charge imbalance (δTM) and protecting bilayers against electroporation. These results expand our understanding of how more complex, biologically relevant bilayers respond to electrochemical stress.