Amphipathic Membrane-Active Peptides Recognize and Stabilize Ruptured Membrane Pores: Exploring Cause and Effect with Coarse-Grained Simulations

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

doi:10.1021/la5038266

Cited by 23 publications

(38 citation statements)

References 69 publications

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“…comparison to the shorter melittin and magainin 2 in membrane pores [73]. We found that the orientations of the three peptides (in α-helical form) were heterogeneous, which contradicts the assumption of perpendicular alignment used to fit the OCD data of Lee et al [86].…”

Section: Our Coarse-grained MD Simulations Have Revealed Important Fecontrasting

confidence: 66%

“…A possible reason for this discrepancy is that the melittin molecules lining the membrane pore are orientationally disordered, while the experiments measure the average projection of peptides in the direction perpendicular to the membrane plane [86]. This type of disordered structure was observed in our recent coarse-grained simulations [73], with pore sizes similar to what was seen in the experiments. Earlier atomistic MD simulations by Sengupta et al [90] also report a so-called "disordered toroidal pore".…”

mentioning

confidence: 54%

“…We have performed coarse-grained MD simulations on a range of amphipathic membrane active peptides, including melittin. Our results indicate that melittin has an affinity to a membrane pore (initially generated electrostatically in the simulations), absorbing to the inner surfaces of the pore and leading to pore stabilization in a concentration dependent manner [73]. We identified that this strong adsorption is driven by the exposure of hydrophobic lipid tails (in the highly curved bilayer of the pore)…”

mentioning

confidence: 74%

“…We found that tp 10 is able to recognize a pre-ruptured membrane pore and stabilize it by diffusing to and aggregating at the pore edge [73]. Here, it is important to note that the reduced cationic residue content in tp10 may allow the peptide to aggregate with high local concentration at the pore edge.…”

mentioning

confidence: 82%

“…We have performed coarse-grained MD simulations on tp10 peptides in contact with a POPC bilayer [73]. We found that tp 10 is able to recognize a pre-ruptured membrane pore and stabilize it by diffusing to and aggregating at the pore edge [73].…”

mentioning

confidence: 99%

See 4 more Smart Citations

Current Understanding of the Mechanisms by which Membrane-Active Peptides Permeate and Disrupt Model Lipid Membranes

Sun

Forsman²,

Woodward

2015

CTMC

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Link to publicationCitation for published version (APA): Sun, D., Forsman, J., & Woodward, C. E. (2016). Current understanding of the mechanisms by which membrane-active peptides permeate and disrupt model lipid membranes. Current Topics in Medicinal Chemistry, 16(2), 170-186. DOI: 10.2174/1568026615666150812121241 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal translocation, but associated with this, is membrane rupture to form large pores, which are subsequently stabilized by peptide adsorption to the pore edges. This disruption to the membrane is presumably responsible for cell death. Amyloidal peptides also show evidence of stable large pore formation, however, the mechanism for pore stabilization appears linked with their ability to form fibrils and prefibrillar aggregates and oligomers. There is some evidence that pores and membrane defects in fact act as nucleation sites for these structures. Where possible we have related the experimental and theoretical work to our own simulation findings in an effort to produce a comprehensive, albeit speculative picture for the mechanisms of action for this important group of peptides. Keywords:Membrane active peptides; anti-microbial peptides; cell-penetrating peptides; amyloid peptides; lipid membrane; pore-formation 3 Graphical AbstractWe review the modes of activity of three classes of membrane active peptides: cell penetrating; antimicrobial, and amyloid peptides.4

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Section: Our Coarse-grained MD Simulations Have Revealed Important Fecontrasting

confidence: 66%

mentioning

confidence: 54%

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confidence: 74%

mentioning

confidence: 82%

mentioning

confidence: 99%

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Current Understanding of the Mechanisms by which Membrane-Active Peptides Permeate and Disrupt Model Lipid Membranes

Sun

Forsman²,

Woodward

2015

CTMC

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Computational prediction of the optimal oligomeric state for membrane‐inserted β‐barrels of protegrin‐1 and related mutants

Lipkin

Lazaridis

2017

Journal of Peptide Science

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Protegrin-1 is a widely studied 18-residue β-hairpin antimicrobial peptide. Evidence suggests that it acts via a β-barrel pore formation mechanism, but the exact number of peptides comprising the pore state is unknown. In this study, we performed molecular dynamics simulations of β-barrels of protegrin and three related mutants (v14v16l, v14v16a, and r4n) in NCNC parallel topology in implicit membrane pores of varying radius and curvature for oligomeric numbers 6–14. We then identified the optimal pore radius and curvature values for all constructs and determined the total effective energy and the translational and rotational entropic losses. These, along with an estimate of membrane deformation free energy from experimental line tension values, provided an estimate of the overall energetics of formation of each pore state. The results indicated that oligomeric numbers 7–13 are generally stable, allowing the possibility of a heterogeneous pore state. The optimal oligomeric state for protegrin is the nonamer, shifting to higher numbers for the mutants. Protegrin, v14v16l, and r4n are stable as membrane-inserted β-barrels, but v14v16a seems much less so because of its decreased hydrophobicity.

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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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Amphipathic Membrane-Active Peptides Recognize and Stabilize Ruptured Membrane Pores: Exploring Cause and Effect with Coarse-Grained Simulations

Cited by 23 publications

References 69 publications

Current Understanding of the Mechanisms by which Membrane-Active Peptides Permeate and Disrupt Model Lipid Membranes

Current Understanding of the Mechanisms by which Membrane-Active Peptides Permeate and Disrupt Model Lipid Membranes

Computational prediction of the optimal oligomeric state for membrane‐inserted β‐barrels of protegrin‐1 and related mutants

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

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