Adsorption of cationic and amphipathic cell-penetrating peptides to porated membranes

Abstract

Cell-penetrating peptides (CPPs) are short peptide sequences that can translocate to the inside of most mammalian cells and transport molecular cargoes through lipid membranes. While initially most identified CPPs were of a cationic nature, recently, certain amphipathic sequences peptides have been developed that exhibit cell-penetrating properties. Since CPPs were first discovered, their translocation mechanism has been subject to intese debate. In this regard, computational methods can help us analyze a wide range of parameters, and extract precise data for each case, in order to better understand their translocation mechanism. In the present work, we develop a molecular theory that allows to investigate the adsorption and insertion of cationic andamphipathic CPPs on membranes bearing hydrophilic pores. This method accounts for size, shape, conformation, protonation state and charge distribution of the peptides, as well as the interactions between hydrophobic peptides and the membrane; this method also describes the state of protonation of acidic membrane lipids. We present a systematic investigation of the effect of different peptides and its concentration,membrane composition, pore size, salt concentration and pH on the extent of peptide adsorption and insertion into the pores.