Computational studies of peptide-induced membrane pore formation

Lipkin, R.; Lazaridis, Themis

doi:10.1098/rstb.2016.0219

Cited by 54 publications

(71 citation statements)

References 223 publications

(251 reference statements)

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“…In an effort to examine the membrane uptake mechanism, which takes place across complex lipid bilayers on the order of minutes, some approximations can be made. Coarse grained (CG) models of the membrane, such as the MARTINI force field [266], which represents lipid, water and peptide with "beads" corresponding to multiple atoms [267], or implicit solvent models, such as IMM1 [268] can accelerate MD simulations such that longer timescales can be sampled. Furthermore, the increase in computational speed allows the examination of larger systems comprising complex bilayers with multiple lipid species such as cardiolipin [269] or cholesterol [263].…”

Section: Computer Simulationsmentioning

confidence: 99%

“…Snorkeling to the opposite layer of the membrane then facilitates its transport across the bilayer after which melittin adsorbs in a parallel orientation on the bottom layer. The peptide distribution to both sides of the bilayer can then induce curving of both layers to merge and form a toroidal pore [257,268]. This picture is a short summary of the recent advances in elucidating melittin mechanism and is not complete because there are contradictory reports that support [268,336] or dispute [332] pore formation.…”

Section: Melittinmentioning

confidence: 99%

“…The peptide distribution to both sides of the bilayer can then induce curving of both layers to merge and form a toroidal pore [257,268]. This picture is a short summary of the recent advances in elucidating melittin mechanism and is not complete because there are contradictory reports that support [268,336] or dispute [332] pore formation. However, some consistently observed phenomena point us toward understanding not only melittin mechanism and but also the mechanism of other amphipathic peptides.…”

Section: Melittinmentioning

confidence: 99%

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Membrane Active Peptides and Their Biophysical Characterization

Avcı

Akbulut

Özkırımlı

2018

Preprint

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In the last 20 years, an increasing number of studies have been reported on membrane active peptides, which exert their biological activity by interacting with the cell membrane either to disrupt it and lead to cell lysis or to translocate through it to deliver cargos into the cell and reach their target. These peptides are attractive alternatives to currently used pharmaceuticals. Antimicrobial peptides (AMPs) and peptides designed for drug and gene delivery currently in the drug pipeline suggest that these membrane active peptides will soon constitute a significant percentage of the drug market. Here, we focus on two most prominent classes of membrane active peptides; AMPs and cell-penetrating peptides (CPPs). AMPs are a group of membrane active peptides that disrupt the membrane integrity or inhibit the cellular functions of bacteria, virus and fungi. CPPs are another group of membrane active peptides that mainly function as cargo-carriers even though they may also show antimicrobial activity to some extent. Biophysical techniques to understand how they interact with the membrane have shed light on the peptide-membrane interaction at various levels of detail. Structural investigation of membrane active peptides in the presence of the membrane provides important clues on the effect of the membrane environment on peptide conformations. Advances in live imaging techniques have allowed examination of peptide action at a single cell or single molecule level. In addition to these experimental biophysical techniques, molecular dynamics simulations provided clues on the peptide-lipid interactions and dynamics of the cell entry process at atomic detail. In this review, we summarize the recent advances in experimental and computational investigation of membrane active peptides with particular emphasis on two amphipathic membrane active peptides, the AMP melittin and the CPP pVEC.

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Section: Computer Simulationsmentioning

confidence: 99%

Section: Melittinmentioning

confidence: 99%

Section: Melittinmentioning

confidence: 99%

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Membrane Active Peptides and Their Biophysical Characterization

Avcı

Akbulut

Özkırımlı

2018

Preprint

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“…This review does not cover simulations to study the interactions of venom peptides with ion channels, which have been covered elsewhere . Also, AMPs isolated from sources other than venom are not discussed and the reader is referred to some of the many available reviews on AMPs . Finally, challenges and limitations that are common to all biomolecular simulations such as the choice of force field, the use of enhanced sampling methods and the problem of sampling errors and convergence are only discussed in the context of how they affect the accuracy and reliability of venom peptide–membrane simulations.…”

Section: Introductionmentioning

confidence: 99%

Molecular simulations of venom peptide‐membrane interactions: Progress and challenges

Deplazes

2018

Peptide Science

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Because of their wide range of biological activities venom peptides are a valuable source of lead molecules for the development of pharmaceuticals, pharmacological tools and insecticides. Many venom peptides work by modulating the activity of ion channels and receptors or by irreversibly damaging cell membranes. In many cases, the mechanism of action is intrinsically linked to the ability of the peptide to bind to or partition into membranes. Thus, understanding the biological activity of these venom peptides requires characterizing their membrane binding properties. This review presents an overview of the recent developments and challenges in using biomolecular simulations to study venom peptide‐membrane interactions. The review is focused on (i) gating modifier peptides that target voltage‐gated ion channels, (ii) venom peptides that inhibit mechanosensitive ion channels, and (iii) pore‐forming venom peptides. The methods and approaches used to study venom peptide‐membrane interactions are discussed with a particular focus on the challenges specific to these systems and the type of questions that can (and cannot) be addressed using state‐of‐the‐art simulation techniques. The review concludes with an outlook on future aims and directions in the field.

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“…The effectiveness with which theoretical and experimental data converge on ways of understanding membrane biology was noted during the meeting. Lipkin & Lazaridis [13] discuss such computational approaches to gain an understanding of the interactions of pore-forming peptides with membranes, which (again) suggests a structural role for lipids in pore-forming assemblies. These studies are of relevance for understanding the possible pore-forming activity of b-amyloid in Alzheimer's disease.…”

mentioning

confidence: 99%