Abstract
Antimicrobial peptides (AMPs), produced by a wide range of organisms, have attracted attention due to their potential use as novel antibiotics. The majority of these peptides are cationic and are thought to function by permeabilizing the bacterial membrane, either by making pores or by dissolving it (‘carpet’ model). A key hypothesis in the literature is that antimicrobial and hemolytic activity correlate with binding affinity to anionic and zwitterionic membranes, respectively. Here we test this hypothesis by using binding free energy data collected from the literature and theoretical binding energies calculated from implicit membrane models for 53 helical AMPs. We indeed find a correlation between binding energy and biological activity, depending on membrane anionic content: antibacterial activity correlates best with transfer energy to membranes with anionic lipid fraction higher than 30% and hemolytic activity correlates best with transfer energy to a 10% anionic membrane. However, the correlations are weak, with correlation coefficient up to 0.4. Weak correlations of the biological activities have also been found with other physical descriptors of the peptides, such as surface area occupation, which correlates significantly with antibacterial activity; insertion depth, which correlates significantly with hemolytic activity; and structural fluctuation, which correlates significantly with both activities. The membrane surface coverage by many peptides at the MIC is estimated to be much lower than would be required for the ‘carpet’ mechanism. Those peptides that are active at low surface coverage tend to be those identified in the literature as pore-forming. The transfer energy from planar membrane to cylindrical and toroidal pores was also calculated for these peptides. The transfer energy to toroidal pores is negative in almost all cases while that to cylindrical pores is more favorable in neutral than in anionic membranes. The transfer energy to pores correlates with the deviation from predictions of the ‘carpet’ model.
Highlights
Antimicrobial peptides (AMPs) are found in a wide variety of organisms such as plants, insects, and vertebrates, providing a host-defense mechanism against invading microbial species [1,2,3,4]
We found that the surface charge difference between bacterial and eukaryotic membranes is an important determinant of peptide selectivity: antibacterial activity correlates best with transfer energy to a membrane containing over 30% anionic lipid; hemolytic activity correlates best with transfer energy to a membrane containing 10% anionic lipid
Using experimental data and theoretical calculations we tested the hypothesis that antimicrobial and hemolytic activity correlate with the binding energy to the corresponding membranes
Summary
Antimicrobial peptides (AMPs) are found in a wide variety of organisms such as plants, insects, and vertebrates, providing a host-defense mechanism against invading microbial species [1,2,3,4]. These peptides usually exhibit selectivity against prokaryotic pathogen cells over the host cells [5,6,7]. Some AMPs have been found to have intracellular targets, but the majority are thought to kill bacteria by disrupting the cell membrane [11,12,13,14] either by pore formation [15] or by detergent-like disintegration (the ‘carpet’ model)[16]. Understanding the process of translocation and pore formation could have wide-ranging implications
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