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Implicit Membrane Investigation of the Stability of Antimicrobial Peptide β-Barrels and Arcs

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Abstract

Previous simulations showed that the β-hairpin antimicrobial peptide (AMP) protegrin-1 can form stable octameric β-barrels and tetrameric arcs (half barrels) in both implicit and explicit membranes. Here, we extend this investigation to several AMPs of similar structure: tachyplesin, androctonin, polyphemusin, gomesin, and the retrocyclin θ-defensin. These peptides form short β-hairpins stabilized by 2–3 disulfide bonds. We also examine synthetic β-sheet peptides selected from a combinatorial library for their ability or inability to form pores in lipid membranes. When heptameric, octameric, and decameric β-barrels and tetrameric arcs of these peptides were embedded in pre-formed neutral or anionic lipid pores (i.e., pores in neutral or anionic membranes, respectively), a variety of behaviors and membrane binding energies were observed. Due to the cationic charge of the peptides, more favorable transfer energies and more stable binding were observed in anionic than neutral pores. The synthetic peptides bound very strongly and formed stable barrels and arcs in both neutral and anionic pores. The natural AMPs exhibited unfavorable or marginally favorable binding energy and kinetic stability in neutral pores, consistent with the lower hemolytic activity of some of them compared with protegrin-1. Binding to anionic pores was more favorable, but significant distortions of the barrel or arc structures were sometimes noted. These results are discussed in light of the available experimental data. The diversity of behaviors obtained makes it unlikely that the barrel and arc mechanisms are valid for the entire family of β-hairpin AMPs.

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Acknowledgments

Funding for this research was provided by the National Science Foundation (MCB 1244207). Infrastructure support was provided in part by RCMI grant 2G12RR03060-26A1/8G12MD007603-27 from the National Institutes of Health. No human or animal studies were carried out by the authors for this article. Authors RBL and TL declare that they have no conflict of interest.

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  1. Department of Chemistry, City College of the City University of New York, 160 Convent Ave., New York, NY, 10031, USA

    Richard B. Lipkin & Themis Lazaridis

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Correspondence to Themis Lazaridis.

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Online Resource 1 Average total effective energies (<W>; kcal/mol) and membrane transfer energies (<ΔW>; kcal/mol) of octamer barrels and tetramer arcs of peptides from water to toroidal pores of R o = 10, 12, and 15 Å (k = 15 Å) from 2-ns simulations. Description of the behavior of all octamer β-barrels and tetramer arcs during these simulations.

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Lipkin, R.B., Lazaridis, T. Implicit Membrane Investigation of the Stability of Antimicrobial Peptide β-Barrels and Arcs. J Membrane Biol 248, 469–486 (2015). https://doi.org/10.1007/s00232-014-9759-4

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