Abstract
The interaction of antimicrobial peptides (AMPs) with the inner membrane of Gram-negative bacteria is a key determinant of their abilities to exert diverse bactericidal effects. Here we present a molecular level understanding of the initial target membrane interaction for two cationic α-helical AMPs that share structural similarities but have a ten-fold difference in antibacterial potency towards Gram-negative bacteria. The binding and insertion from solution of pleurocidin or magainin 2 to membranes representing the inner membrane of Gram-negative bacteria, comprising a mixture of 128 anionic and 384 zwitterionic lipids, is monitored over 100 ns in all atom molecular dynamics simulations. The effects of the membrane interaction on both the peptide and lipid constituents are considered and compared with new and published experimental data obtained in the steady state. While both magainin 2 and pleurocidin are capable of disrupting bacterial membranes, the greater potency of pleurocidin is linked to its ability to penetrate within the bacterial cell. We show that pleurocidin displays much greater conformational flexibility when compared with magainin 2, resists self-association at the membrane surface and penetrates further into the hydrophobic core of the lipid bilayer. Conformational flexibility is therefore revealed as a key feature required of apparently α-helical cationic AMPs for enhanced antibacterial potency.
Highlights
Molecular level information that explains bactericidal potency has the potential to identify the bactericidal strategies with the greatest likelihood of success and scope for peptide improvement
According to their cationic and amphipathic nature, most antimicrobial peptides (AMPs) are expected to interact with bacterial membranes and, whether bacterial death is caused by this interaction or interactions with intracellular machinery, the outcome of the AMP-membrane interaction is likely a key determinant of antibacterial potency
The present study is concerned with testing whether molecular dynamics (MD) simulations could faithfully reproduce such features of peptide-membrane interactions, where differences in the membrane active behavior and conformation have been observed between pleurocidin and magainin 2 in the steady state, and provide molecular level information that would explain why and/or how these structurally related peptides operate in such a different manner to kill Gram-negative bacteria and better understand the much greater potency of pleurocidin
Summary
Molecular level information that explains bactericidal potency has the potential to identify the bactericidal strategies with the greatest likelihood of success and scope for peptide improvement. Our attention has been drawn to two cationic amphipathic peptides, pleurocidin (from Pleuronectes americanus) and magainin 2 (from Xenopus laevis), that seemingly share a number of physico-chemical properties, adopting near identical secondary structures in traditional membrane mimetic media[17] These peptides have a ten-fold difference in potency towards Gram-negative bacteria such as Escherichia coli and Pseudomonas aeruginosa, as determined in vitro, and have profoundly different effects on the target cells[4,17]. Pleurocidin impacted on a large number of intracellular biological processes indicating a multifaceted antibacterial strategy and suggesting that the greater potency of pleurocidin is due to its greater ability to penetrate the inner membrane of Gram-negative bacteria This previous work suggests that there may be subtle differences in how these two AMPs interact with the plasma membrane of Gram-negative bacteria. The MD simulations and experimental data showed good agreement and together reveal features of the membrane interaction of pleurocidin, in particular its conformational flexibility, that contribute to its greater potency when compared with magainin 2
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