posted on 2024-02-26, 08:04authored bySon V. Nguyen, Lev Levintov, Roy P. Planalp, Harish Vashisth
The Szeto-Schiller
(SS) peptides are a subclass of cell-penetrating
peptides that can specifically target mitochondria and mediate conditions
caused by mitochondrial dysfunction. In this work, we constructed
an iron-chelating SS peptide and studied its interaction with a mitochondrial-mimicking
membrane using atomistic molecular dynamics (MD) simulations. We report
that the peptide/membrane interaction is thermodynamically favorable,
and the localization of the peptide to the membrane is driven by electrostatic
interactions between the cationic residues and the anionic phospholipid
headgroups. The insertion of the peptide into the membrane is driven
by hydrophobic interactions between the aromatic side chains in the
peptide and the lipid acyl tails. We also probed the translocation
of the peptide across the membrane by applying nonequilibrium steered
MD simulations and resolved the translocation pathway, free energy
profile, and metastable states. We explored four distinct orientations
of the peptide along the translocation pathway and found that one
orientation was energetically more favorable than the other orientations.
We tested a significantly slower pulling velocity on the most thermodynamically
favorable system and compared metastable states during peptide translocation.
We found that the peptide can optimize hydrophobic interactions with
the membrane by having aromatic side chains interacting with the lipid
acyl tails instead of forming π–π interactions
with each other. The mechanistic insights emerging from our work will
potentially facilitate improved peptide design with enhanced activity.