Cell-penetrating peptides (CPPs) are relatively short, charged, or amphipathic peptides that facilitate the translocation of cargo across cellular membranes. One such peptide is penetratin, a 16-amino-acid cationic CPP. It exhibits minimal interaction with zwitterionic lipid bilayers but strongly interacts with anionic membranes. We investigated the interactions of unmodified penetratin (Pen1) and its capped analogue (Pen2) using a combination of spectroscopic, calorimetric, tensiometric, and molecular dynamics (MD) approaches with models of bacterial (anionic) and human cell membranes. Both Pen variants have a +7 charge; Pen2 shows greater structural stability, enhanced helical propensity, and deeper membrane insertion (as evidenced by circular dichroism and fluorescence spectroscopy, and surface pressure measurements). In bacterial membranes, Pen1 binds exothermically, while Pen2 exhibits a two-stage process: an initial entropy-driven endothermic binding followed by exothermic interaction. End-group capping promotes more stable and compact peptide conformations, facilitates water shedding, and increases membrane hydrogen bonding.
Thompson et al. (Fri,) studied this question.