Competing interactions for antimicrobial selectivity based on charge complementarity

AbstractAntimicrobial peptides (AMPs) are an evolutionary conserved component of the innate immune system and possible templates for the development of new antibiotics. An important property of antimicrobial peptides is their ability to discriminate bacterial from eucaryotic cells which is attributed to the difference in lipid composition of the outer leaflet of the plasma membrane between the two types of cells. Whereas eucaryotic cells usually expose zwitterionic lipids, procaryotic cells expose also anionic lipids which bind the cationic antimicrobial peptides electrostatically. An example is the antimicrobial peptide NK-2 which is highly cationic and favors binding to anionic membranes. In the present study, the difference in binding affinity of NK-2 for palmitoyl-oleoyl-phosphatidyl-glycerol (POPG) and palmitoyl-oleoyl-phosphatidyl-choline (POPC) is studied using molecular dynamics simulations in conjunction with a coarse grained model and thermodynamic integration, by computing the change in free energy and its components upon the transfer of NK-2 from POPC to POPG. The transfer is indeed found to be highly favorable. Interestingly, the favorable contribution from the electrostatic interaction between the peptide and the anionic lipids is overcompensated by an unfavorable contribution from the change in lipid–cation interactions due to the release of counterions from the lipids. The increase in entropy due to the release of the cations is compensated by other entropic components. The largest favorable contribution arises from the solvation of the counterions. Overall the interaction between NK-2 and POPG is not determined by a single driving force but a subtle balance of competing interactions