Effects of induced tension and electrostatic interactions on the mechanisms of antimicrobial peptide translocation across lipid bilayer

Including electrostatic interactions into dissipative particle dynamics simulations, we can study the process of the translocation of cationic antimicrobial peptides across lipid bilayer membranes when their head groups are either negatively charged or neutral. Two translocation mechanisms are predicted. Bilayer thinning and tension increase caused by the binding of peptide to the zwitterionic lipid membrane surface is one mechanism. By this mechanism, peptide translocation only occurs when the peptide concentration exceeds a critical value and is a stochastic and rare event. The translocation completes via a two-state pathway: a perpendicular insertion state and a final parallel adsorption state. The penetration of the peptide into the bilayer also promotes the flip-flop of lipids. If some lipids of the bilayer are negatively charged, the electrostatic attraction between peptides and acidic phospholipids in the distal leaflet of the bilayer is another mechanism. In this case, the peptide translocation completes via a three-state pathway: initial parallel adsorption state, perpendicular insertion state, and a final parallel adsorption state. The critical peptide concentration is smaller and translocation is faster and more reliable than that of the first mechanism. In both mechanisms, an intermediate metastable peptide insertion state is composed of only one peptide and a few lipids.