BINDING OF BASIC PEPTIDES TO MEMBRANES PRODUCES LATERAL DOMAINS ENRICHED IN THE ACIDIC LIPIDS PHOSPHATIDYLSERINE AND PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE - AN ELECTROSTATIC MODEL AND EXPERIMENTAL RESULTS

Direct fluorescence digital imaging microscopy observations demonstrat e that a basic peptide corresponding to the effector region of the myr istoylated alanine-rich C kinase substrate (MARCKS) self-assembles int o membrane domains enriched in the acidic phospholipids phosphatidylse rine (PS) and phosphatidylinositol 4,5-bisphosphate (PIP2). We show he re that pentalysine, which corresponds to the first five residues of t he MARCKS effector region peptide and binds to membranes through elect rostatic interactions, also forms domains enriched in PS and PIP2. We present a simple model of domain formation that represents the decreas e in the free energy of the system as the sum of two contributions: th e free energy of mixing of neutral and acidic lipids and the electrost atic free energy. The first contribution is always positive and oppose s domain formation, whereas the second contribution may become negativ e and, at low ionic strength, overcome the first contribution. Our mod el, based on Gouy-Chapman-Stern theory, makes four predictions: 1) mul tivalent basic ligands, for which the membrane binding is a steep func tion of the mole fraction of acidic lipid, form domains enriched in ac idic lipids; domains break up at high concentrations of either 2) basi c ligand or 3) monovalent salt; and 4) if multivalent anionic lipids ( e.g., PIP2) are present in trace concentrations in the membrane, they partition strongly into the domains. These predictions agree qualitati vely with experimental data obtained with pentalysine and spermine, an other basic ligand.