Molecular details on the intermediate states of melittin action on a cell membrane

https://doi.org/10.1016/j.bbamem.2018.09.007Get rights and content
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Highlights

  • Intermediate states during the melittin-induced membrane poration are observed.

  • Melittin-induced extraction of lipids occurs exclusively from the outer leaflet.

  • Asymmetry in membranes lowers the free energy barrier for melittin insertion.

Abstract

Antimicrobial peptides (AMPs) provide a promising solution to the serious threat of multidrug-resistant bacteria or superbugs to public healthcare, due to their unique disruption to bacterial membrane such as perforation. Unfortunately, the underlying action mechanism of AMPs, especially the possible transition between the membrane binding and perforation states of peptides (i.e., the classical two-state model), is still largely unknown. Herein, by combining experimental techniques with pertinent membrane models and molecular dynamic (MD) simulations, new insights into the intermediate states of the AMP melittin-membrane interaction process are obtained. Specifically, it is demonstrated that, after the initial binding, the accumulated melittin on the bilayer triggers vigorous fluctuation of the membrane and even extracts some lipid molecules exclusively from the deformed outer leaflet of the bilayer. Such a distinctive mass removal manner and the resultant local asymmetry in lipid number between the two leaflets change the mechanical status of the membrane and in turn reduce the free energy barrier for the melittin insertion. Finally, the formation of the transmembrane pores is facilitated significantly. These findings provide new insights into the complicated antimicrobial mechanisms of AMPs.

Keywords

Antimicrobial peptide
Melittin
Cell membrane
Perforation mechanism
Molecular dynamic simulations

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