Many-Body Effect of Antimicrobial Peptides: On the Correlation Between Lipid’s Spontaneous Curvature and Pore Formation

Lee, Ming-Tao; Hung, Wei‐Chin; Chen, Fang-Yu; Huang, Huey W.

doi:10.1529/biophysj.105.068080

Cited by 125 publications

(147 citation statements)

References 71 publications

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“…2). This correlation between the membrane thinning and the peptide orientation change has been observed for melittin and other antimicrobial peptides in many different lipid compositions (30)(31)(32). Only the value of P/L* and the degree of thinning varied with peptide and lipid composition.…”

Section: Resultssupporting

confidence: 66%

“…The reconstruction of Br atom distribution clearly shows the lipidic structure of the melittin pore (Fig. 4). [Note that melittin has been studied in a great variety of lipid compositions; the behavior of stable pore formation is similar in all, including the phase transition from the lamellar phase to the R phase (11,24,31,32); there is nothing special about di18:0(9,10Br)PC. ]…”

Section: Resultsmentioning

confidence: 99%

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Process of inducing pores in membranes by melittin

Lee

Sun

Hung

et al. 2013

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

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289

367

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Melittin is a prototype of the ubiquitous antimicrobial peptides that induce pores in membranes. It is commonly used as a molecular device for membrane permeabilization. Even at concentrations in the nanomolar range, melittin can induce transient pores that allow transmembrane conduction of atomic ions but not leakage of glucose or larger molecules. At micromolar concentrations, melittin induces stable pores allowing transmembrane leakage of molecules up to tens of kilodaltons, corresponding to its antimicrobial activities. Despite extensive studies, aspects of the molecular mechanism for pore formation remain unclear. To clarify the mechanism, one must know the states of the melittin-bound membrane before and after the process. By correlating experiments using giant unilamellar vesicles with those of peptide-lipid multilayers, we found that melittin bound on the vesicle translocated and redistributed to both sides of the membrane before the formation of stable pores. Furthermore, stable pores are formed only above a critical peptide-to-lipid ratio. The initial states for transient and stable pores are different, which implies different mechanisms at low and high peptide concentrations. To determine the lipidic structure of the pore, the pores in peptide-lipid multilayers were induced to form a lattice and examined by anomalous X-ray diffraction. The electron density distribution of lipid labels shows that the pore is formed by merging of two interfaces through a hole. The molecular property of melittin is such that it adsorbs strongly to the bilayer interface. Pore formation can be viewed as the bilayer adopting a lipid configuration to accommodate its excessive interfacial area.toroidal pore | oriented circular dichroism | rhombohedral phase M elittin, the major toxin of the bee venom discovered around 1970 (1), produces a variety of effects on nature membranes, including cell lysis (2), antimicrobial activity (3), and voltage-dependent ion conductance (4). A great number of hostdefense antimicrobial peptides (5, 6) discovered in the past three decades have been found to exhibit similar behavior of melittin (3, 7). Among membrane-active peptides, melittin is perhaps the most extensively studied (8-12). It is widely used for cell and liposome lysis and as a model for pore-forming peptides (7, 13). Its whole and partial amino acid sequences have been incorporated in the designs of synthetic proteins to mimic the property of melittin (14, 15). However, its molecular process and mechanism of activities are still in dispute. It is clear that melittin binds to membranes as monomers but acts on the membrane collectively. Even at concentrations as low as a few nanomoles per liter, melittin can induce transient pores that allow transmembrane conduction of atomic ions but not leakage of glucose or larger molecules (4,7,16). In the micromolar range, melittin induces stable pores allowing transmembrane leakage of molecules up to tens of kilodaltons (13,17,18). At even higher concentrations, it can act as a detergent disin...

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Section: Resultssupporting

confidence: 66%

Section: Resultsmentioning

confidence: 99%

Process of inducing pores in membranes by melittin

Lee

Sun

Hung

et al. 2013

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

Self Cite

289

367

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“…38,39 For the sake of completeness, it should be noted that in the present investigation, i) we did not use lipid bilayers but detergent micelles, whose higher curvature and reduced size might likely alter the insertion propensity of the peptide, and ii) the peptide/detergent molar ratio of 1/100 was rather low, if compared to the expected detergent aggregation number in the 50-70 range. 24 Most likely, our samples were characterized by only one peptide per micelle, thus the presented results can be more safely assumed to pertain to the monomeric state of Esc (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18).…”

Section: Resultsmentioning

confidence: 99%

Folded Structure and Insertion Depth of the Frog-Skin Antimicrobial Peptide Esculentin-1b(1–18) in the Presence of Differently Charged Membrane-Mimicking Micelles

Manzo¹,

Casu²,

Rinaldi³

et al. 2014

J. Nat. Prod.

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Antimicrobial peptides (AMPs) are effectors of the innate immunity of most organisms. Their role in the defense against pathogen attack and their high selectivity for bacterial cells make them attractive for the development of a new class of antimicrobial drugs. The N-terminal fragment of the frog-skin peptide esculentin-1b (Esc(1-18)) has shown broad spectrum antimicrobial activity.Similarly to most cationic AMPs, it is supposed to act by binding to and damaging the negatively charged plasma-membrane of bacteria. Differently from many other AMPs, Esc(1-18) activity is preserved in biological fluids such as serum. In this work, a structural investigation was performed through NMR spectroscopy. The 3D structure was obtained in the presence of either zwitterionic or negatively charged micelles as membrane models for eukaryotic and prokaryotic membranes, respectively. Esc(1-18) showed a higher affinity for and deeper insertion into the latter, and adopted an amphipathic helical structure characterized by a kink at the residue G8. These findings were confirmed by measuring penetration into lipid monolayers. The presence of negatively charged lipids in the bilayer appears to be necessary for Esc(1-18) to bind, fold in the right threedimensional structure and, ultimately, to exert its biological role as an AMP. 3The lack of a new class of antibiotics is an urgent problem, as many important pathogens are rapidly developing resistance to most of the clinically usable antibiotics. 1,2 Clinical impact of antibiotic resistance is immense, with increasing length of hospital stay, costs and mortality. 3,4 Antimicrobial peptides (AMPs) have attracted the interest of the scientific community as promising candidates for the development of a new class of antimicrobial drugs. They are part of the innate immune system of the majority of the multicellular organisms, and are typically characterized by a wide spectrum of antimicrobial activity, from Gram-negative to Gram-positive bacteria, fungi, protozoa and enveloped viruses. [5][6][7] Despite amino acid sequence homology is not high, AMPs share some common features. They are relatively short (< 60 residues), cationic, have a large content (≥ 50%) of hydrophobic residues and adopt an amphipathic three-dimensional folding when interacting with pathogens" membranes. 6 Generally, AMPs destroy or permeate the microbial plasma-membrane. The membrane is formed through evolutionarily well conserved biosynthetic processes and represents a non-selective target, making modifications by the microorganisms difficult and, thus, resistance onset is unlikely. 8 Several recent articles have reviewed in detail the different modes of action postulated for AMPs. [9][10][11] The amphipathic conformation adopted by the AMP, with the hydrophilic residues interacting with the polar head groups of the phospholipids and the water molecules, and the hydrophobic residues being protected from water contacts by inserting into the lipid bilayer core, is considered essential for it to exert the antimicro...

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“…This model assumes that the pore walls are formed not only by peptide ␣-helices but also by head-groups of the bilayer-forming phospholipids. Recently, the correlation between the pore forming potency of peptides and the SC of the lipid as a support for the toroidal model was questioned, based on similar correlations exhibited by melittin and alamethicin (49). Therefore, it was of importance to obtain additional lines of evidence for the toroidal pore formation in the case of colicin E1.…”

mentioning

confidence: 99%

Lipid Dependence of the Channel Properties of a Colicin E1-Lipid Toroidal Pore

Sobko

Kotova

Antonenko

et al. 2006

Journal of Biological Chemistry

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Colicin E1 belongs to a group of bacteriocins whose cytotoxicity toward Escherichia coli is exerted through formation of ion channels that depolarize the cytoplasmic membrane. The lipid dependence of colicin single-channel conductance demonstrated intimate involvement of lipid in the structure of this channel. The colicin formed "small" conductance 60-picosiemens (pS) channels, with properties similar to those previously characterized, in 1,2-dieicosenoyl-snglycero-3-phosphocholine (C20) or thinner membranes, whereas it formed a novel "large" conductance 600-pS state in thicker 1,2-dierucoyl-sn-glycero-3-phosphocholine (C22) bilayers. Both channel states were anion-selective and voltage-gated and displayed a requirement for acidic pH. Lipids having negative spontaneous curvature inhibited the formation of both channels but increased the ratio of open 600 pS to 60 pS conductance states. Different diameters of small and large channels, 12 and 16 Å , were determined from the dependence of single-channel conductance on the size of nonelectrolyte solute probes. Colicin-induced lipid "flip-flop" and the decrease in anion selectivity of the channel in the presence of negatively charged lipids implied a significant contribution of lipid to the structure of the channel, most readily described as toroidal organization of lipid and protein to form the channel pore.The lipid environment of membrane proteins that defines the local distribution of polarity, dielectric constant, and steric geometry has a central role in the determination of protein structure and function. For ion channels, lipids impose the following constraints: (i) structure-function is sensitive to the matching of hydrophobic thickness of the protein and lipid bilayer (1-10); (ii) opening of channels (e.g. mechano-sensitive, can be dependent on bilayer tension) (11), which manifests itself in a dependence on acyl chain length (12); (iii) spontaneous curvature (SC) 2 of lipids linked to the lateral pressure of the bilayer can modulate ion channel activity (13), as demonstrated for the KcsA channel (14) and mechano-sensitive MscL channels (12, 15); and (iv) many channel proteins require anionic lipids for function (16 -19).Channel-forming proteins can require specific lipids, presumably because of a combination of charge and curvature parameters, to form active channels (e.g. anionic lipid bound between the transmembrane ␣-helices and necessary for gating of the KcsA channel (20, 21)). The lantibiotic nisin provides a well defined example of lipid participation in peptide pore formation, in which the peptidoglycan precursor lipid II is an intrinsic component of the pore formed by this antimicrobial peptide (22). The proposed structure of this pore contains 5-8 nisin molecules and an identical number of lipid II molecules (23). Participation of lipid in the formation of a channel wall was hypothesized for cholesteroldependent cytolysins (24,25).Colicins are plasmid-encoded bacteriocins that are cytotoxic to Escherichia coli and related strains. Their modes of ...

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Many-Body Effect of Antimicrobial Peptides: On the Correlation Between Lipid’s Spontaneous Curvature and Pore Formation

Cited by 125 publications

References 71 publications

Process of inducing pores in membranes by melittin

Process of inducing pores in membranes by melittin

Folded Structure and Insertion Depth of the Frog-Skin Antimicrobial Peptide Esculentin-1b(1–18) in the Presence of Differently Charged Membrane-Mimicking Micelles

Lipid Dependence of the Channel Properties of a Colicin E1-Lipid Toroidal Pore

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