Rationalizing the membrane interactions of cationic amphipathic antimicrobial peptides by their molecular shape

Bechinger, Burkhard

doi:10.1016/j.cocis.2009.02.004

Cited by 91 publications

(110 citation statements)

References 98 publications

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“…3). The solid-state data therefore favor a mechanism where, under the experimental conditions of the present study, the membrane packing is locally destabilized by the insertion of amphipathic molecules rather than models where the helices adopt transmembrane alignments (39). Therefore, the nature of the molecules, such as charge and hydrophobic volume, strongly contribute to the variety of actions observed and the lipid polymorphism induced.…”

Section: Discussionmentioning

confidence: 86%

“…Therefore, the nature of the molecules, such as charge and hydrophobic volume, strongly contribute to the variety of actions observed and the lipid polymorphism induced. In addition, this type of supramolecular polypeptide-lipid assemblies can exhibit many different morphologies that are best described by phase diagrams (3,39) where lysis, wormhole-(40) and carpet-model (41), or regions where the bilayer is unaffected or even stabilized, correspond to different regions in the diagram. The ''phase boundaries'' depend on lipid composition, temperature, salt, pH, and other environmental parameters, and thereby reflect the variable environments encountered by the peptides when interacting with the membranes of different species (39,42).…”

Section: Discussionmentioning

confidence: 99%

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Membrane structure and conformational changes of the antibiotic heterodimeric peptide distinctin by solid-state NMR spectroscopy

Resende

Moraes

Munhoz

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The heterodimeric antimicrobial peptide distinctin is composed of 2 linear peptide chains of 22-and 25-aa residues that are connected by a single intermolecular S-S bond. This heterodimer has been considered to be a unique example of a previously unrecorded class of bioactive peptides. Here the 2 distinctin chains were prepared by chemical peptide synthesis in quantitative amounts and labeled with 15 N, as well as 15 N and 2 H, at selected residues, respectively, and the heterodimer was formed by oxidation. CD spectroscopy indicates a high content of helical secondary structures when associated with POPC/POPG 3:1 vesicles or in membrane-mimetic environments. The propensity for helix formation follows the order heterodimer >chain 2 >chain 1, suggesting that peptidepeptide and peptide-lipid interactions both help in stabilizing this secondary structure. In a subsequent step the peptides were reconstituted into oriented phospholipid bilayers and investigated by 2 H and proton-decoupled 15 N solid-state NMR spectroscopy. Whereas chain 2 stably inserts into the membrane at orientations close to perfectly parallel to the membrane surface in the presence or absence of chain 1, the latter adopts a more tilted alignment, which further increases in the heterodimer. The data suggest that membrane interactions result in considerable conformational rearrangements of the heterodimer. Therefore, chain 2 stably anchors the heterodimer in the membrane, whereas chain 1 interacts more loosely with the bilayer. These structural observations are consistent with the antimicrobial activities when the individual chains are compared to the dimer. amphipathic alpha-helix ͉ membrane insertion ͉ membrane protein structure determination ͉ peptide-peptide interactions ͉ synergistic activity A s more and more pathogens develop resistance against many commonly used antibiotics, urgent actions are needed to counteract this resistance and new bactericidal and fungicidal compounds have to be developed. Both plants and animals produce, store, and secrete antibiotic peptides in exposed tissues, or synthesize such compounds upon induction, and indeed many antibiotic peptides have been isolated from natural sources (1, 2). The availability of these molecules establishes a defense system that can be set into action immediately when infections occur, and several antimicrobial peptides have been found to also exhibit virucidal and tumorcidal activities (reviewed in refs. 3 and 4). The lack of sequence homology, the activity of chiral analogues, the amphipathic properties, and biophysical measurements all suggest that the bacterial membranes rather than chiral receptors are the targets of many of these peptides (1, 3), although more recent findings suggest that at least some of them also have internal targets after crossing the membrane (5, 6).The heterodimeric peptide distinctin has been isolated from Phyllomedusa distincta, a frog living in the southeast Atlantic forests of Brazil (7). The distinctin is composed of 2 linear peptide chains, one of 22-an...

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Membrane structure and conformational changes of the antibiotic heterodimeric peptide distinctin by solid-state NMR spectroscopy

Resende

Moraes

Munhoz

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…However, DOPE accumulated in the vicinity of peptide K only in the curved system, which is unexpected because with its small head group and bulky tails, DOPE typically partitions into areas of negative curvature. This surprising result can be understood considering that the conical shape of DOPE is well-suited to the space requirements of the adsorbed peptide: it fills the space underneath the peptide while offering enough room in between the lipid head groups for the peptide (67).…”

Section: Peptide K Promotes Positive Curvature In Coarse-grained MD Smentioning

confidence: 99%

A Coiled-Coil Peptide Shaping Lipid Bilayers upon Fusion

Rabe

Aisenbrey

Pluháčková

et al. 2016

Biophysical Journal

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A system based on two designed peptides, namely the cationic peptide K, (KIAALKE) 3 , and its complementary anionic counterpart called peptide E, (EIAALEK) 3 , has been used as a minimal model for membrane fusion, inspired by SNARE proteins. Although the fact that docking of separate vesicle populations via the formation of a dimeric E/K coiled-coil complex can be rationalized, the reasons for the peptides promoting fusion of vesicles cannot be fully explained. Therefore it is of significant interest to determine how the peptides aid in overcoming energetic barriers during lipid rearrangements leading to fusion. In this study, investigations of the peptides' interactions with neutral PC/PE/cholesterol membranes by fluorescence spectroscopy show that tryptophan-labeled K* binds to the membrane (K K*~6 .2 10 3 M À1 ), whereas E* remains fully water-solvated. 15 N-NMR spectroscopy, depth-dependent fluorescence quenching, CD-spectroscopy experiments, and MD simulations indicate a helix orientation of K* parallel to the membrane surface. Solid-state 31 P-NMR of oriented lipid membranes was used to study the impact of peptide incorporation on lipid headgroup alignment. The membrane-immersed K* is found to locally alter the bilayer curvature, accompanied by a change of headgroup orientation relative to the membrane normal and of the lipid composition in the vicinity of the bound peptide. The NMR results were supported by molecular dynamics simulations, which showed that K reorganizes the membrane composition in its vicinity, induces positive membrane curvature, and enhances the lipid tail protrusion probability. These effects are known to be fusion relevant. The combined results support the hypothesis for a twofold role of K in the mechanism of membrane fusion: 1) to bring opposing membranes into close proximity via coiled-coil formation and 2) to destabilize both membranes thereby promoting fusion.

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“…To target bacterial membranes as their prime interaction site, peptide folding into helices or pleated sheets in the vicinity of model membranes has been reported to be crucial for understanding the structuredependent mode of action for a number of short peptides [34,35]. The conformational transitions for CS-1a and CS-2a, from unordered in buffer to a-helical in PC/PG LUVs, indicate the importance of hydrophobic moment for acquiring helical structure, which, in turn, is also related to antibacterial activity.…”

Section: Discussionmentioning

confidence: 99%

Comparative mode of action of novel hybrid peptide CS‐1a and its rearranged amphipathic analogue CS‐2a

et al. 2012

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Cell selective, naturally occurring, host defence cationic peptides present a good template for the design of novel peptides with the aim of achieving a short length with improved antimicrobial potency and selectivity. A novel, short peptide CS-1a (14 residues) was derived using a sequence hybridization approach on sarcotoxin I (39 residues) and cecropin B (35 residues). The sequence of CS-1a was rearranged to enhance amphipathicity with the help of a Schiffer-Edmundson diagram to obtain CS-2a. Both peptides showed good antibacterial activity in the concentration range 4-16 lgÁmL À1 against susceptible as well as drug-resistant bacterial strains, including the clinically relevant pathogens Acenatobacter sp. and methicillin-resistant Staphylococcus aureus. The major thrust of these peptides is their nonhaemolytic activity against human red blood cells up to a high concentration of 512 lgÁmL À1. Compared to CS-1a, amphipathic peptide CS-2a showed a more pronounced a-helical conformation, along with a better membrane insertion depth in bacterial mimic 1,2-dipalmitoylsn-glycero-3-phosphocholine/1,2-dipalmitoyl-sn-glycero-3-phospho-(1′-rac-glycerol) small unilamellar vesicles. With equivalent lipid-binding affinity, the two peptides assumed different pathways of membrane disruption, as demonstrated by calcein leakage and the results of transmission electron microscopy on model bacterial mimic large unilamellar vesicles. Extending the work from model membranes to intact Escherichia coli cells, differences in membrane perturbation were visible in microscopic images of peptide-treated E. coli. The present study describes two novel short peptides with potent activity, cell selectivity and divergent modes of action that will aid in the future design of peptides with better therapeutic potential.

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Rationalizing the membrane interactions of cationic amphipathic antimicrobial peptides by their molecular shape

Cited by 91 publications

References 98 publications

Membrane structure and conformational changes of the antibiotic heterodimeric peptide distinctin by solid-state NMR spectroscopy

Membrane structure and conformational changes of the antibiotic heterodimeric peptide distinctin by solid-state NMR spectroscopy

A Coiled-Coil Peptide Shaping Lipid Bilayers upon Fusion

Comparative mode of action of novel hybrid peptide CS‐1a and its rearranged amphipathic analogue CS‐2a

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