Early stages of interactions of cell-penetrating peptide penetratin with a DPPC bilayer

Cell-penetrating-peptides (CPPs) can deliver themselves together with a macromolecular cargo into cells and, hence, have promising applications in drug delivery. The detailed physical mechanisms that underlie and determine their cellular uptake remain unknown. We used molecular dynamics (MD) simulations to study the interaction of a well-known CPP, namely penetratin, with a zwitterionic di-palmitoyl-phosphatidyl-choline (DPPC) bilayer. Our study shows that the arginine and lysine residues play a crucial role in peptide-membrane binding through charge-pair and hydrogen bond interactions. We also characterize peptide conformation and show that it remains helical near the N-terminus but can fold into a variety of other conformations in the residues close to the C-terminus. The response of membrane to the peptide is also investigated.