Multistep Molecular Dynamics Simulations Identify the Highly Cooperative Activity of Melittin in Recognizing and Stabilizing Membrane Pores

Sun, Delin; Forsman, Jan; Woodward, Clifford E.

doi:10.1021/acs.langmuir.5b01995

Cited by 45 publications

(38 citation statements)

References 63 publications

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“…Another study calculated PMFs for protegrin's orientation within membrane bilayers, finding a significant tilt angle at the optimal orientation [172]. The free energy of melittin binding and reorientation in phospholipid bilayers has also been calculated [95,173,174], as well as (b) Coarse-grained modelling CG modelling of AMP pore formation can offer unique insights, as it allows longer simulation times and larger systems than all-atom modelling. Most CG studies so far have used the MARTINI model [102,107], but models that employ coarser graining have also appeared [176].…”

Section: (A) All-atom Modellingmentioning

confidence: 99%

Computational studies of peptide-induced membrane pore formation

Lipkin

Lazaridis

2017

Phil. Trans. R. Soc. B

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A variety of peptides induce pores in biological membranes; the most common ones are naturally produced antimicrobial peptides (AMPs), which are small, usually cationic, and defend diverse organisms against biological threats. Because it is not possible to observe these pores directly on a molecular scale, the structure of AMP-induced pores and the exact sequence of steps leading to their formation remain uncertain. Hence, these questions have been investigated via molecular modelling. In this article, we review computational studies of AMP pore formation using all-atom, coarse-grained, and implicit solvent models; evaluate the results obtained and suggest future research directions to further elucidate the pore formation mechanism of AMPs.This article is part of the themed issue 'Membrane pores: from structure and assembly, to medicine and technology'.

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Section: (A) All-atom Modellingmentioning

confidence: 99%

Computational studies of peptide-induced membrane pore formation

Lipkin

Lazaridis

2017

Phil. Trans. R. Soc. B

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“…Accordingly, it was proposed that the enhanced activity of melittin was due to the electrostatic repulsion between melittin and DPTAP, thus causing a disfavored interfacial location of the peptide and a deeper insertion in the membrane, and thereby resulting in bilayer fragmentation. Similarly, intermelittin electrostatic repulsion was also proposed as a trigger for the change in peptide location 75 .…”

Section: Electrostatic Effect On Lipid Extractionmentioning

confidence: 99%

Role of the Cationic C-Terminal Segment of Melittin on Membrane Fragmentation

2016

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The widespread distribution of cationic antimicrobial peptides capable of membrane fragmentation in nature underlines their importance to living organisms. In the present work, we determined the impact of the electrostatic interactions associated with the cationic Cterminal segment of melittin, a 26-amino acid peptide from bee venom (net charge +6), on its binding to model membranes and on the resulting fragmentation. In order to detail the role played by the C-terminal charges, we prepared a melittin analogue for which the 4 cationic amino acids in positions 21 to 24 were substituted with the polar residue citrulline, providing a peptide with the same length and amphiphilicity but with a lower net charge (+2). We compared the peptide bilayer affinity and the membrane fragmentation for bilayers prepared from dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)/1,2-dipalmitoyl-sn-glycero-3-phospho-L-serine (DPPS) mixtures. It is shown that neutralization of the C-terminal considerably increased melittin affinity for zwitterionic membranes. The unfavorable contribution associated with transferring the cationic C-terminal in a less polar environment was reduced, leaving the hydrophobic interactions, which drive the peptide insertion in bilayers, with limited counterbalancing interactions. The presence of negatively charged lipids (DPPS) in bilayers increased melittin binding by introducing attractive electrostatic interactions, the augmentation being, as expected, greater for native melittin than for its citrullinated analogue. The membrane fragmentation power of the peptide was shown to be controlled by electrostatic interactions and could be modulated by the charge carried by both the membrane and the lytic peptide. The analysis of the lipid composition of the extracted fragments from DPPC/DPPS bilayers revealed no lipid specificity. It is proposed that extended phase separations are more susceptible to lead to the extraction of a lipid species in a specific manner than a specific lipid-peptide affinity. The present work on the lipid extraction by melittin and citrullinated melittin with model membranes emphasizes the complex relation between the affinity, the lipid extraction/membrane fragmentation, and the lipid specificity.

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“…40 It was also shown recently that a lipid flip-flop can be a possible pathway to generate a single transmembrane peptide. 34 …”

Section: Resultsmentioning

confidence: 99%

Coarse-grained simulations of hemolytic peptide δ-lysin interacting with a POPC bilayer

King

Bennett

Almeida

et al. 2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

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δ-lysin, secreted by a Gram-positive bacterium Staphylococcus aureus, is a 26-residue membrane active peptide that shares many common features with antimicrobial peptides (AMPs). However, it possesses a few unique features that differentiate itself from typical AMPs. In particular, δ-lysin has zero net charge, even though it has many charged residues, and it preferentially lyses eukaryotic cells over bacterial cells. Here, we present the results of coarse-grained molecular dynamics simulations of δ-lysin interacting with a zwitterionic membrane over a wide range of peptide concentrations. When the peptides concentration is low, spontaneous dimerization of peptides is observed on the membrane surface, but deep insertion of peptides or pore formation was not observed. However, the calculated free energy of peptide insertion suggests that a small fraction of peptides is likely to be present inside the membrane at the peptide concentrations typically seen in dye efflux experiments. When the simulations with multiple peptides are carried out with a single pre-inserted transmembrane peptide, spontaneous pore formation occurs with a peptide-to-lipid ratio (P/L) as low as P/L = 1:42. Inter-peptide salt bridges among the transmembrane peptides seem to play a role in creating compact pores with very low level of hydration. More importantly, the transmembrane peptides making up the pore are constantly pushed to the opposite side of the membrane when the mass imbalance between the two sides of membrane is significant. Thus, the pore is very dynamic, allowing multiple peptides to translocate across the membrane simultaneously.

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Multistep Molecular Dynamics Simulations Identify the Highly Cooperative Activity of Melittin in Recognizing and Stabilizing Membrane Pores

Cited by 45 publications

References 63 publications

Computational studies of peptide-induced membrane pore formation

Computational studies of peptide-induced membrane pore formation

Role of the Cationic C-Terminal Segment of Melittin on Membrane Fragmentation

Coarse-grained simulations of hemolytic peptide δ-lysin interacting with a POPC bilayer

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