Incorporation of Antimicrobial Peptides into Membranes: A Combined Liquid-State NMR and Molecular Dynamics Study of Alamethicin in DMPC/DHPC Bicelles

Dittmer, Jens; Thøgersen, Lea; Underhaug, Jarl; Bertelsen, Kresten; Vosegaard, Thomas; Pedersen, J. G. A.; Schiøtt, Birgit; Tajkhorshid, Emad; Skrydstrup, Troels; Nielsen, Niels Chr.

doi:10.1021/jp811494p

Cited by 66 publications

(63 citation statements)

References 51 publications

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“…The second peptide, alamethicin, is produced by the fungus Trichoderma viride [30], [31] and displays antibiotic properties similarly to novicidin. This peptide presumably forms a barrel-stave type arrangement at high concentration when added to neutral and charged lipid bilayers [18], [30], [32]–[39]. The results support these two different proposed modes of action for the two peptides and reveal details of the AMP's paths to membrane disruption and pore formation through characterization of the low-P:L states.…”

Section: Introductionsupporting

confidence: 58%

Mechanisms of Peptide-Induced Pore Formation in Lipid Bilayers Investigated by Oriented 31P Solid-State NMR Spectroscopy

et al. 2012

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There is a considerable interest in understanding the function of antimicrobial peptides (AMPs), but the details of their mode of action is not fully understood. This motivates extensive efforts in determining structural and mechanistic parameters for AMP’s interaction with lipid membranes. In this study we show that oriented-sample 31P solid-state NMR spectroscopy can be used to probe the membrane perturbations and -disruption by AMPs. For two AMPs, alamethicin and novicidin, we observe that the majority of the lipids remain in a planar bilayer conformation but that a number of lipids are involved in the peptide anchoring. These lipids display reduced dynamics. Our study supports previous studies showing that alamethicin adopts a transmembrane arrangement without significant disturbance of the surrounding lipids, while novicidin forms toroidal pores at high concentrations leading to more extensive membrane disturbance.

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Section: Introductionsupporting

confidence: 58%

Mechanisms of Peptide-Induced Pore Formation in Lipid Bilayers Investigated by Oriented 31P Solid-State NMR Spectroscopy

et al. 2012

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“…The monolayer structure and small curvature radius of micelles can cause peptides and proteins to adopt incorrectly folded conformations or to aggregate (118). Recently, discoidal micelles or bicelles have been used in NMR spectroscopy of both membrane peptides and proteins (112, 118–122). Generally, bicelles are formed by long-chain phospholipids (DMPC, DMPG) and amphiphilic molecules such as CHAPSO, or a short-chain lipid, such as DHPC.…”

Section: Bacterial Membrane Composition and Membrane Mimicking Sysmentioning

confidence: 99%

On the Role of NMR Spectroscopy for Characterization of Antimicrobial Peptides

Porcelli

Ramamoorthy

Bárány

et al. 2013

Methods in Molecular Biology

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Summary Antimicrobial peptides (AMPs) provide a primordial source of immunity, conferring upon eukaryotic cells resistance against bacteria, protozoa, and viruses. Despite a few examples of anionic peptides, AMPs are usually relatively short positively charged polypeptides, consisting of a dozen to about a hundred amino acids, and exhibiting amphipathic character. Despite significant differences in their primary and secondary structures, all AMPs discovered to date share the ability to interact with cellular membranes, thereby affecting bilayer stability, disrupting membrane organization, and/or forming well-defined pores. AMPs selectively target infectious agents without being susceptible to any of the common pathways by which these acquire resistance, thereby making AMPs prime candidates to provide therapeutic alternatives to conventional drugs. However, the mechanisms of AMP actions are still a matter of intense debate. The structure-function paradigm suggests that a better understanding of how AMPs elicit their biological functions could result from atomic resolution studies of peptide-lipid interactions. In contrast, more strict thermodynamic views preclude any roles for three-dimensional structures. Indeed, the design of selective AMPs based soley on structural parameters has been challenging. In this chapter, we will focus on selected AMPs for which studies on the corresponding AMP-lipid interactions have helped reach an understanding of how AMP effects are mediated. We will emphasize the roles of both liquid- and solid-state NMR spectroscopy for elucidating the mechanisms of action of AMPs.

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“…23 Dittmer et al reported a combined NMRÀMD study of alamethicinÀ lipid interactions. 24 Sengupta et al observed significant amounts of disorder in toroidal pore structures in another MD study of AMPs. 25 Jean-Francois et al 26 also investigated the roles of electrostatic effects on AMP action.…”

Section: ' Introductionmentioning

confidence: 97%

Spontaneous Buckling of Lipid Bilayer and Vesicle Budding Induced by Antimicrobial Peptide Magainin 2: A Coarse-Grained Simulation Study

Woo

Wallqvist

2011

J. Phys. Chem. B

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Molecular mechanisms of the action of antimicrobial peptides on bacterial membranes were studied by large scale coarse-grained simulations of magainin 2-dipalmitoylphosphatidylcholine/palmitoyloleoylphosphatidylglycerol (DPPC/POPG) mixed bilayer systems with spatial extents up to 0.1 μm containing up to 1600 peptides. Equilibrium simulations exhibit disordered toroidal pores stabilized by peptides. However, when a layer of peptides is placed near the lipid head groups on one side of the bilayer only, their incorporation leads to a spontaneous buckling of the bilayer. This buckling is followed by the formation of a quasi-spherical vesicular bud connected to the bilayer by a narrow neck. The mean curvature of the budding region is consistent with what is expected based on the dependence of the area per lipid on the peptide-to-lipid ratio in equilibrium simulations. Our simulations suggest that the incorporation of antimicrobial peptides on the exterior surface of a vesicle or a bacterial cell leads to buckling and vesicle budding, presumably accompanied by nucleations of giant transient pores of sizes that are much larger than indicated by equilibrium measurements and simulations.

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Incorporation of Antimicrobial Peptides into Membranes: A Combined Liquid-State NMR and Molecular Dynamics Study of Alamethicin in DMPC/DHPC Bicelles

Cited by 66 publications

References 51 publications

Mechanisms of Peptide-Induced Pore Formation in Lipid Bilayers Investigated by Oriented 31P Solid-State NMR Spectroscopy

Mechanisms of Peptide-Induced Pore Formation in Lipid Bilayers Investigated by Oriented 31P Solid-State NMR Spectroscopy

On the Role of NMR Spectroscopy for Characterization of Antimicrobial Peptides

Spontaneous Buckling of Lipid Bilayer and Vesicle Budding Induced by Antimicrobial Peptide Magainin 2: A Coarse-Grained Simulation Study

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