Oligoarginine vectors for intracellular delivery: Role of arginine side-chain orientation in chain length-dependent destabilization of lipid membranes

Arginine-rich peptides receive increased attention due to their capacity to cross different types of membranes and to transport cargo molecules inside cells. Even though peptide-induced destabilization has been investigated extensively, little is known about the peptide side-chain and backbone orientation with respect to the bilayer that may contribute to a molecular understanding of the peptide-induced membrane perturbations.The main objective of this work is to provide a detailed description of the orientation of arginine peptides in the lipid bilayer of PC and negatively charged PG liposomes using ATR-IR spectroscopy and molecular modeling, and to relate these orientational preferences to lipid bilayer destabilization.Molecular modeling showed that above the transition temperature arginine side-chains are preferentially solvent-directed at the PC/water interface whereas several arginine side-chains are pointing towards the PG hydrophobic core. IR dichroic spectra confirmed the orientation of the arginine side chains perpendicular to the lipid–water interface. IR spectra shows an randomly distributed backbone that seems essential to optimize interactions with the lipid membrane. The observed increase of permeation to a fluorescent dye is related to the peptide induced-formation of gauche bonds in the acyl chains. In the absence of hydrophobic residues, insertion of side-chains that favors phosphate/guanidium interaction is another mechanism of membrane permeabilization that has not been further analyzed so far.

► We investigate the side-chain and backbone orientation of poly-arginine in phospholipid bilayers.
► Above the transition temperature, Arg7 and Arg4, but not Arg1, are found to destabilize PG bilayers.
► Certain side-chains are found to be directed towards the hydrophobic core in PG but not in PC bilayers.
► The interaction results in an increase in gauche conformations of the acyl chains with a general increase of bilayer disorder.