Computational Insights into Membrane Disruption by Cell-Penetrating Peptides

Cell-penetrating
peptides (CPPs) can translocate into cells without
inducing cytotoxicity. The internalization process implies several
steps at different time scales ranging from microseconds to minutes.
We combine adaptive Steered Molecular Dynamics (aSMD) with conventional
Molecular Dynamics (cMD) to observe nonequilibrium and equilibrium
states to study the early mechanisms of peptide–bilayer interaction
leading to CPPs internalization. We define three membrane compositions
representing bilayer sections, neutral lipids (i.e., upper leaflet),
neutral lipids with cholesterol (i.e., hydrophobic core), and neutral/negatively
charged lipids with cholesterol (i.e., lower leaflet) to study the
energy barriers and disruption mechanisms of Arg9, MAP, and TP2, representing
cationic, amphiphilic, and hydrophobic CPPs, respectively. Cholesterol
and negatively charged lipids increase the energetic barriers for
the peptide–bilayer crossing. TP2 interacts with the bilayer
by hydrophobic insertion, while Arg9 disrupts the bilayer by forming
transient or stable pores. MAP has shown both behaviors. Collectively,
these findings underscore the significance of innovative computational
approaches in studying membrane-disruptive peptides and, more specifically,
in harnessing their potential for cell penetration.