Modeling peptide binding to anionic membrane pores

He, Yi; Prieto, Lidia; Lazaridis, Themis

doi:10.1002/jcc.23282

Cited by 19 publications

(39 citation statements)

References 81 publications

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“…Due to the fairly small size of the system, the effect of imposing proper structural restraints and then removing them in separate steps (see Figure 2) is relatively small (∼1 kcal/mol); the exception is observed at a low anionic lipid fraction, in which case the binding is weak, and thus it is important to properly treat the conformational flexibility of the peptide by following the protocol in Figure 2. The differential solvation PMF protocol used in previous work 34,40,41,60 (⟨ΔΔW slv ⟩ men column in Table 1) gives somewhat similar results to both BAR and the (un)binding PMF, although with notably larger statistical uncertainties (also see Figure S3 in the Supporting Information).…”

Section: Journal Of Chemical Theory and Computationsupporting

confidence: 70%

Free Energy Calculations for the Peripheral Binding of Proteins/Peptides to an Anionic Membrane. 1. Implicit Membrane Models

Zhang

Yethiraj

Cui

2014

J. Chem. Theory Comput.

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The binding of peptides and proteins to the surface of complex lipid membranes is important in many biological processes such as cell signaling and membrane remodeling. Computational studies can aid experiments by identifying physical interactions and structural motifs that determine the binding affinity and specificity. However, previous studies focused on either qualitative behaviors of protein/membrane interactions or the binding affinity of small peptides. Motivated by this observation, we set out to develop computational protocols for bimolecular binding to charged membranes that are applicable to both peptides and large proteins. In this work, we explore a method based on an implicit membrane/solvent model (generalized Born with a simple switching in combination with the Gouy-Chapman-Stern model for a charged interface), which we expect to lead to useful results when the binding does not implicate significant membrane deformation and local demixing of lipids. We show that the binding free energy can be efficiently computed following a thermodynamic cycle similar to protein-ligand binding calculations, especially when a Bennett acceptance ratio based protocol is used to consider both the membrane bound and solution conformational ensembles. Test calculations on a series of peptides show that our computational approach leads to binding affinities in encouraging agreement with experimental data, including for the challenging example of the bringing of flexible MARCKS-ED peptides to membranes. The calculations highlight that for a membrane with a significant fraction of anionic lipids, it is essential to include the effect of ion adsorption using the Stern model, which significantly modifies the effective surface charge. This implicit membrane model based computational protocol helps lay the groundwork for more systematic analysis of protein/peptide binding to membranes of complex shape and composition.

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Section: Journal Of Chemical Theory and Computationsupporting

confidence: 70%

Free Energy Calculations for the Peripheral Binding of Proteins/Peptides to an Anionic Membrane. 1. Implicit Membrane Models

Zhang

Yethiraj

Cui

2014

J. Chem. Theory Comput.

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“…(57) Other factors besides membrane affinity, such as membrane penetration depth or hydrophobic matching, may influence membrane disruption by peptides. (58–60)…”

Section: Discussionmentioning

confidence: 99%

Lipid Composition-Dependent Membrane Fragmentation and Pore-Forming Mechanisms of Membrane Disruption by Pexiganan (MSI-78)

et al. 2013

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The potency and selectivity of many antimicrobial peptides (AMPs) are correlated with their ability to interact with and disrupt the bacterial cell membrane. In vitro experiments using model membranes have been used to determine the mechanism of membrane disruption of AMPs. Since the mechanism of action of an AMP depends on the ability of the model membrane to accurately mimic the cell membrane, it is important to understand the effect of membrane composition. Anionic lipids which are present in the outer membrane of prokaryotes but are less common in eukaryotic membranes are usually considered key for the bacterial selectivity of AMPs. We show by fluorescence measurements of peptide-induced membrane permeabilization that the presence of anionic lipids at high concentrations can actually inhibit membrane disruption by the AMP MSI-78 (pexiganan), a representative of a large class of highly cationic AMPs. Paramagnetic quenching studies suggest MSI-78 is in a surface-associated inactive mode in anionic SDS micelles, but is in a deeply buried and presumably more active mode in zwitterionic DPC micelles. Furthermore, a switch in mechanism occurs with lipid composition. Membrane fragmentation with MSI-78 is observable in mixed vesicles containing both anionic and zwitterionic lipids but not in vesicles composed of a single lipid of either type. These findings suggest membrane affinity and membrane permeabilization are not always correlated, and additional effects can be seen as the complexity of the model membranes is increased that may be more reflective of the actual cellular environment.

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“…Three different models for peptidemembrane interaction are commonly used: barrel-stave, toroidal and carpet models [9][10][11]. It was suggested that collective behaviour of peptides can play a role in the bacterial membrane destruction [12][13][14][15][16][17][18][19]. For instance, using 31 P oriented solid-state NMR experiments it was found that at high peptide concentration alamethicin adopts a transmembrane conformation while the novicidin forms a toroidal pore in the membrane [16].…”

Section: Introductionmentioning

confidence: 98%

The cooperative behaviour of antimicrobial peptides in model membranes

Wang

Mura

Zhou

et al. 2014

Biochimica et Biophysica Acta (BBA) - Biomembranes

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A systematic analysis of the hypothesis of the antimicrobial peptides' (AMPs) cooperative action is performed by means of full atomistic molecular dynamics simulations accompanied by circular dichroism experiments. Several AMPs from the aurein family (2.5,2.6, 3.1), have a similar sequence in the first ten amino acids, are investigated in different environments including aqueous solution, trifluoroethanol (TFE), palmitoyloleoylphosphatidylethanolamine (POPE), and palmitoyloleoylphosphatidylglycerol (POPG) lipid bilayers. It is found that the cooperative effect is stronger in aqueous solution and weaker in TFE. Moreover, in the presence of membranes, the cooperative effect plays an important role in the peptide/lipid bilayer interaction. The action of AMPs is a competition of the hydrophobic interactions between the side chains of the peptides and the hydrophobic region of lipid molecules, as well as the intra peptide interaction. The aureins 2.5-COOH and 2.6-COOH form a hydrophobic aggregate to minimize the interaction between the hydrophobic group and the water. Once that the peptides reach the water/lipid interface the hydrophobic aggregate becomes smaller and the peptides start to penetrate into the membrane. In contrast, aurein 3.1-COOH forms only a transient aggregate which disintegrates once the peptides reached the membrane, and it shows no cooperativity in membrane penetration.

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Modeling peptide binding to anionic membrane pores

Cited by 19 publications

References 81 publications

Free Energy Calculations for the Peripheral Binding of Proteins/Peptides to an Anionic Membrane. 1. Implicit Membrane Models

Free Energy Calculations for the Peripheral Binding of Proteins/Peptides to an Anionic Membrane. 1. Implicit Membrane Models

Lipid Composition-Dependent Membrane Fragmentation and Pore-Forming Mechanisms of Membrane Disruption by Pexiganan (MSI-78)

The cooperative behaviour of antimicrobial peptides in model membranes

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