Hydrophobicity, hydrophobic moment and angle subtended by charged residues modulate antibacterial and haemolytic activity of amphipathic helical peptides

Dathe, Margitta; Wieprecht, Torsten; Nikolenko, Heike; Handel, Liselotte; Maloy, W L; MacDonald, Dorothy; Beyermann, Michael; Bienert, Michael

doi:10.1016/s0014-5793(97)00055-0

Cited by 375 publications

(297 citation statements)

References 32 publications

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“…These motifs offer a major stability to the protein structure. Nevertheless, the antimicrobial activity is modulated by physicochemical properties, such hydrophobicity, An SVM Model Based on Physicochemical Properties to Predict Antimicrobial Activity 61 cationicity and amphipathicity [1,5]. We propose that the combination of these features can be used to predict antimicrobial activity through supervised machine learning.…”

Section: Resultsmentioning

confidence: 99%

“…AMPs are a very diverse and abundant group, being divided in several classes, but some of them share some physicochemical characteristics, some studies propose that they are non essential, but the determinant for activity is the tertiary structure [4], however, other studies show that the physicochemical characteristics modulate the antimicrobial activity [5]. Some classes of AMP have a special structural feature, a cysteine knot motif with three disulfide linkages in their structures, which provides a major stability to the structure.…”

Section: Introductionmentioning

confidence: 99%

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An SVM Model Based on Physicochemical Properties to Predict Antimicrobial Activity from Protein Sequences with Cysteine Knot Motifs

Porto

Fernandes

Franco

2010

Lecture Notes in Computer Science

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Abstract. The cysteine knot motifs are widely spread in several classes of peptides including those with antimicrobial functions. These motifs offer a major stability to the protein structure. Nevertheless, the antimicrobial activity is modulated by physicochemical properties. In this paper, we create a model of support vector machine to predict antimicrobial activity from sequences with similar motifs, based on physicochemical properties: net charge, ratio between hydrophobic and charged residues, average hydrophobicity and hydrophobic moment. The support vector machine model was trained with 146 antimicrobial peptides with six cysteines from the antimicrobial peptides database and an equal number of random sequences predicted as transmembrane proteins. The polynomial kernel shows the best accuracy (77.4%) on 10-fold cross validation. Testing in a blind dataset, we observe an accuracy of 83.02%. Through this model, proteins of varied size with a cysteine knot motif can be predicted with good reliability.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An SVM Model Based on Physicochemical Properties to Predict Antimicrobial Activity from Protein Sequences with Cysteine Knot Motifs

Porto

Fernandes

Franco

2010

Lecture Notes in Computer Science

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“…Free energies of transfer ΔG of the peptides were determined from mole-fraction partition coefficients K x using ΔG = −RTlnK x , where K x is given by (8) where f p is the fraction of peptide bound. K x was determined by least-squares fitting of eq.…”

Section: Discussionmentioning

confidence: 99%

Folding Amphipathic Helices Into Membranes: Amphiphilicity Trumps Hydrophobicity

Fernández-Vidal

Jayasinghe

Ladokhin

et al. 2007

Journal of Molecular Biology

159

147

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High amphiphilicity is a hallmark of interfacial helices in membrane proteins and membrane-active peptides, such as toxins and antimicrobial peptides. Although there is general agreement that amphiphilicity is important for membrane-interface binding, an unanswered question is its importance relative to simple hydrophobicity-driven partitioning. We have examined this fundamental question using measurements of the interfacial partitioning of a family of seventeenresidue amidated-acetylated peptides into both neutral and anionic lipid vesicles. Composed only of Ala, Leu, and Gln residues, the amino acid sequences of the peptides were varied to change peptide amphiphilicity without changing total hydrophobicity. We found that peptide helicity in water and interface increased linearly with hydrophobic moment, as did the favorable peptide partitioning free energy. This observation provides simple tools for designing amphipathic helical peptides. Finally, our results show that helical amphiphilicity is far more important for interfacial binding than simple hydrophobicity. Keywordsantimicrobial peptides; toxins; membrane proteins; peptide secondary structure; hydrophobic momentThe amphipathic (or amphiphilic) helix is an important structural motif in proteins. Its most common representation shows polar residues along the length of one-half of a helix surface and non-polar residues along the opposite surface (Figure 1). This polar-nonpolar asymmetry, characterized mathematically by the so-called hydrophobic moment1 (μ H ), makes the amphipathic helix ideally suited for binding to membrane interfaces with the polar surface facing the aqueous phase and the less polar surface facing the membrane interior. This arrangement is often seen in membrane proteins 2,3 where amphipathic helices apparently provide structural stability. But they are also important functionally. For example, amphipathic helices play important functional roles in both ligand-gated 4 ( Figure 1) and voltage-gated Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public AccessAuthor Manuscript J Mol Biol. Author manuscript; available in PMC 2008 July 13. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript K + channels 5 and in the insertion of disulfide bonds into Escherichia coli periplasmic proteins by the DsbB-DsbA complex 6 . Because of its tendency to partition into membrane interfaces ( Figure 1) and subsequently permeabilize membranes, the amphipathic helix is a common starting motif for designing or re-engineering antimicrobial peptides 7-12 . Helix amphiphilicity has been ...

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“…the L/K molar ratio) and charge periodicity [11,[18][19][20][21]. The lytic activities of these peptides vary according to the L/K ratio [22,23] and a specific sequence is not required to get an adequate polar/apolar topology and a strong membranolytic activity, matching those of the stronger natural toxins [20,24].In homologous series of such LK peptides, the observed lytic activities on zwitterionic liposomes and erythrocytes are similar having an optimum at a length of 15 residues, i.e. there is a delicate balance between hydrophobicity and charge repulsion (two antagonistic forces) [14,22,25].…”

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confidence: 99%

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confidence: 99%

The antibiotic activity of cationic linear amphipathic peptides: lessons from the action of leucine/lysine copolymers on bacteria of the class Mollicutes

Béven

Castano

Dufourcq

et al. 2003

European Journal of Biochemistry

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Peptides composed of leucyl and lysyl residues (ÔLK peptidesÕ) with different compositions and sequences were compared for their antibacterial activities using cell wall-less bacteria of the class Mollicutes (acholeplasmas, mycoplasmas and spiroplasmas) as targets. The antibacterial activity of the amphipathic a-helical peptides varied with their size, 15 residues being the optimal length, independent of the membrane hydrophobic core thickness and the amount of cholesterol. The 15-residue ideally amphipathic a helix with a +5 positive net charge (KLLKLLLKLLLKLLK) had the strongest antibacterial activity, similar to that of melittin. In contrast, scrambled peptides devoid of amphipathy and the less hydrophobic b-sheeted peptides [(LK) n K], even those 15-residue long, were far less potent than the helical ones. Furthermore, the growth inhibitory activity of the peptides was correlated with their ability to abolish membrane potential. These data are fully consistent with a predominantly flat orientation of LK peptides at the lipid/ water interface and strongly supports that these peptides and probably the linear polycationic amphipathic defence peptides act on bacterial membranes in four main steps according to the ÔcarpetÕ model: (a) interfacial partitioning with accumulation of monomers on the target membrane (limiting step); (b) peptide structural changes (conformation, aggregation, and orientation) induced by interactions with the lipid bilayer (as already shown with liposomes and erythrocytes); (c) plasma membrane permeabilization/ depolarization via a detergent-like effect; and (d) rapid bacterial cell death if the extent of depolarization is maintained above a critical threshold.Keywords: amphipathic peptides; antibacterial activity; bacterial cell death; membrane depolarization; mollicutes.The amphipathic a helix concept helps in understanding the behaviour of very different classes of proteins and peptides, especially those acting on membranes [1][2][3][4]. This concept, which has been useful in the field of peptidic cytotoxins to develop new analogues, and to better understand their mode of action [5][6][7], is still the basis for the rational design of new antimicrobial compounds, i.e. analogues or chimeras of natural products [8], or radically new molecules [9,10].The need to understand their mode of action and improve their efficacy and/or selectivity towards microorganisms led to the synthesis of new active peptides, made possible largely by the progress in solid state synthesis. As a result, a large wealth of information was obtained on many natural peptides endowed with cytotoxic (including antimicrobial) activity. However, answers are still missing regarding: (a) the requirements for optimized activity and selectivity; and (b) the mechanisms of action, especially in bacterial cells. In an effort of rationalization, a minimalistic approach was initiated by the pioneering work of De Grado and Lear [11] using residue substitutions or designing simplified sequences [2,[12][13][14]. Using the very mini...

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Hydrophobicity, hydrophobic moment and angle subtended by charged residues modulate antibacterial and haemolytic activity of amphipathic helical peptides

Cited by 375 publications

References 32 publications

An SVM Model Based on Physicochemical Properties to Predict Antimicrobial Activity from Protein Sequences with Cysteine Knot Motifs

An SVM Model Based on Physicochemical Properties to Predict Antimicrobial Activity from Protein Sequences with Cysteine Knot Motifs

Folding Amphipathic Helices Into Membranes: Amphiphilicity Trumps Hydrophobicity

The antibiotic activity of cationic linear amphipathic peptides: lessons from the action of leucine/lysine copolymers on bacteria of the class Mollicutes

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