Computer simulations of anionic unsaturated lipid bilayer - A suitable model to study membrane interactions with a cell-penetrating peptide

Unsaturated phosphatidylserine (PS) bilayers are widely used in experimental studies of peptides and proteins in charged membranes. Atomic-scale details of peptide-membrane interactions may be assessed via molecular dynamics (MD) simulations. Unfortunately, a wide application of computational techniques to such systems is limited because of serious technical problems related to correct treatment of long-range electrostatic effects. Here we present a new model of full-atom hydrated PS bilayer. It consists of 128 molecules of 1,2-dioleoyl-snglycero-3-phosphoserine (DOPS), 128 Na+ counterions, and explicit waters. The system was subjected to 15-ns MD simulations with different algorithms of electrostatics treatment (cutoff function and particle mesh Ewald summation (PME)). As a result, an optimal PME-based MD-protocol was elaborated. It provides a good agreement between the macroscopic averages calculated for the equilibrium part of the MD trajectory and those available from experiments. The model of the DOPS bilayer was used to study interactions with penetratin (pAntp). pAntp is a 16-residue peptide that is capable of passing through cell membranes and negatively charged phospholipid vesicles without their leakage. Unfortunately, the mechanism of penetration is still insufficiently understood. During the simulations, a free adsorption of pAntp on the water-lipid interface was observed. The membrane binding of pAntp, was accompanied by distortion of its initial a-helical conformation. The critical roles of individual amino acid residues and surface charge of the DOPS bilayer were delineated. It was shown that the peptide-induced perturbation of the membrane had a local character.