Molecular Dynamics Simulation and Analysis of the Antimicrobial Peptide–Lipid Bilayer Interactions

Arasteh, Shima; Bagheri, Mojtaba

doi:10.1007/978-1-4939-6737-7_8

Cited by 9 publications

(5 citation statements)

References 36 publications

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“…By analyzing the detailed information obtained from the atomistic models, it has been possible to explain different experimental observations on the AS-48 bactericidal bioactivity. Moreover, most of the results are also in close agreement with experiments and simulations performed with other antimicrobial systems. − …”

Section: Introductionsupporting

confidence: 82%

The Role of Key Amino Acids in the Antimicrobial Mechanism of a Bacteriocin Model Revealed by Molecular Simulations

Cruz

Ramos

Martínez‐Salazar

et al. 2021

J. Chem. Inf. Model.

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The AS-48 bacteriocin is a potent antimicrobial polypeptide with enhanced stability due to its circular sequence of peptidic bonds. The mechanism of biological action is still not well understood in spite of both the elucidation of the molecular structure some years ago and several experiments performed that yielded valuable information about the AS-48 bacterial membrane poration activity. In this work, we present a computational study at an atomistic scale to analyze the membrane disruption mechanism. The process is based on the two-stage model: (1) peptide binding to the bilayer surface and (2) membrane poration due to the surface tension exerted by the peptide. Indeed, the induced membrane tension mechanism is able to explain stable formation of pores leading to membrane disruption. The atomistic detail obtained from the simulations allows one to envisage the contribution of the different amino acids during the poration process. Clustering of cationic residues and hydrophobic interactions between peptide and lipids seem to be essential ingredients in the process. GLU amino acids have shown to enhance the membrane disrupting ability of the bacteriocin. TRP24–TRP24 interactions make also an important contribution in the initial stages of the poration mechanism. The detailed atomistic information obtained from the simulations can serve to better understand bacteriocin structural characteristics to design more potent antimicrobial therapies.

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Section: Introductionsupporting

confidence: 82%

The Role of Key Amino Acids in the Antimicrobial Mechanism of a Bacteriocin Model Revealed by Molecular Simulations

Cruz

Ramos

Martínez‐Salazar

et al. 2021

J. Chem. Inf. Model.

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“…The peptides were solvated in a cubic box filled with ∼17 000 TIP3P water molecules. A proper number of Na + and Cl – counterions were added to the system for the total charge neutralization . The energy minimization was achieved to remove any steric clashes.…”

Section: Methodsmentioning

confidence: 99%

“…A proper number of Na + and Cl − counterions were added to the system for the total charge neutralization. 26 The energy minimization was achieved to remove any steric clashes. The system was coupled to the V-rescale and Berendsen thermostats (coupling time of 0.1 and 1.0 ps, respectively), equilibrated at 300 K and 1 atm, and was followed by 200 ns MD production with the time step of 2 fs and recorded frame of 2 ps.…”

Section: ■ Introductionmentioning

confidence: 99%

Palmitoylation of Membrane-Penetrating Magainin Derivatives Reinforces Necroptosis in A549 Cells Dependent on Peptide Conformational Propensities

Behzadi

Arasteh

Bagheri

2020

ACS Appl. Mater. Interfaces

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Anticancer lipopeptides (ACLPs) are considered promising alternatives to combat resistant cancer cells, but the influence of peptide conformational propensity alone on their selectivity and mechanism remains obscure. In this study, we developed N-palmitoylated MK5E (P1MK5E) and MEK5 (P1MEK5) that have the same composition of 23 residues undergoing the pH-dependent structural alterations but differ in the conformational tendency of their amino acid composites. Nonlipidated peptides were readily accumulated in the A549 cell nucleus by the direct membrane translocation and the heparan sulfate-mediated endocytosis than the lipid-raftdependent pathway. The increased hydrophobicity favored the amino acid-positiondependent folding of P1MK5E and P1MEK5, respectively, toward the α-helical coiledcoil nanofibrils and amyloidlike β-protofibrils. At the close concentrations (∼7.5 μM) to the toxic effects of doxorubicin (DOX), P1MK5E exhibited (i) an increased anticancer toxicity through a time-dependent S-phase arrest, (ii) enhanced plasma membrane permeability, and (iii) dose-dependent changes in the cell death characteristic features in the A549 cells relative to P1MEK5 that was almost inactive at ∼75 μM. These observations were in accordance with the TNF-α-mediated necroptotic signaling in the c-MYC/PARP1-overexpressed A549 cells exposed to P1MK5E and accompanied by the ultrastructure of plasma membrane protrusions, extensive endoplasmic reticulum (ER) membrane expansion, mitochondrial swelling, and the formation of distinct cytoplasmic vacuolation. The structural results and the bioactivity behaviors, herein, declared the significance of α-helical propensity in the peptide sequence and the nanostructure morphologies of self-assembling ACLPs upon the selectivity and enhanced anticancer effectiveness, which notably holds promise in the design and development of efficient therapeutics for cancer.

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“…Molecular dynamics (MD) simulation has been widely considered as a practical approach to enhance the atomic-level understanding of the antimicrobial mechanism and valuable structural information of AMPs, which is a challenging goal to be achieved through experimental methods. − MD simulations have been extensively implemented in the studies of membrane selectivity, structural characteristics of the peptide embedded into the lipid bilayer, the key residues, and the effect of peptide concentration on the antimicrobial mechanism. For example, Mehrnejad et al performed conventional MD simulations on pleurocidin and a series of different bilayer membranes to elucidate the cellular and molecular mechanism for the membrane selectivity of the pleurocidin peptide .…”

Section: Introductionmentioning

confidence: 99%

Influence of Different Aromatic Hydrophobic Residues on the Antimicrobial Activity and Membrane Selectivity of BRBR-NH₂ Tetrapeptide

et al. 2020

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The ultrashort linear antimicrobial tetrapeptide BRBR-NH 2 with an unnatural residue biphenylalanine (B) has potent and rapid antimethicillin-resistant Staphylococcus aureus (MRSA) activity but lacks hemolytic activity. The anti-MRSA activity of BRBR-NH 2 is 8-fold more potent than that of WRWR-NH 2 and 16-fold more potent than that of FRFR-NH 2 . However, how to influence their antimicrobial activities and mechanisms through the substitution of different aromatic hydrophobic residues is still unclear. In this work, to study the effects of varying hydrophobic interactions and membrane selectivities of BRBR-NH 2 , we performed multiple long-time (1000 ns) molecular dynamics (MD) simulations to investigate the interactions of a red blood cell (RBC) membrane and a Gram-positive bacterial cell membrane with three different tetrapeptides (BRBR-NH 2 , WRWR-NH 2 , and FRFR-NH 2 ) under different ratios of peptides and lipids and also explored the changes in the membrane and structural characteristics of peptides. The binding energy results show that BRBR-NH 2 interacts weakly with the RBC membrane, while not all BRBR-NH 2 can be adsorbed to the RBC membrane surface. The MD simulation results produced significant local membrane thinning of multiBRBR-NH 2 peptides in the Gram-positive bacterial cell membrane. An in-depth analysis of structural features and peptide−membrane interactions suggests that the aggregation of BRBR-NH 2 on the membrane surface plays a crucial role in the destruction of the cell membrane. Taken together with the observed local membrane thinning, the in-depth analysis demonstrated that the interactions between the lipid bilayer and the BRBR-NH 2 aggregation surface result in a local disturbance of the membrane structure. It can be concluded that the high anti-MRSA activity of BRBR-NH 2 is attributed to the aggregation of BRBR-NH 2 on the membrane surface. On the other hand, WRWR-NH 2 and FRFR-NH 2 peptides tend to bind with the membrane surface in a monomeric form and cover the membrane surface in a carpet-like manner. Therefore, these results provide an advanced microscopic understanding of how hydrophobic interactions or hydrophobic residues affect the antimicrobial activity and mechanism of antimicrobial peptides (AMPs).

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Molecular Dynamics Simulation and Analysis of the Antimicrobial Peptide–Lipid Bilayer Interactions

Cited by 9 publications

References 36 publications

The Role of Key Amino Acids in the Antimicrobial Mechanism of a Bacteriocin Model Revealed by Molecular Simulations

The Role of Key Amino Acids in the Antimicrobial Mechanism of a Bacteriocin Model Revealed by Molecular Simulations

Palmitoylation of Membrane-Penetrating Magainin Derivatives Reinforces Necroptosis in A549 Cells Dependent on Peptide Conformational Propensities

Influence of Different Aromatic Hydrophobic Residues on the Antimicrobial Activity and Membrane Selectivity of BRBR-NH₂ Tetrapeptide

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Molecular Dynamics Simulation and Analysis of the Antimicrobial Peptide–Lipid Bilayer Interactions

Cited by 9 publications

References 36 publications

The Role of Key Amino Acids in the Antimicrobial Mechanism of a Bacteriocin Model Revealed by Molecular Simulations

The Role of Key Amino Acids in the Antimicrobial Mechanism of a Bacteriocin Model Revealed by Molecular Simulations

Palmitoylation of Membrane-Penetrating Magainin Derivatives Reinforces Necroptosis in A549 Cells Dependent on Peptide Conformational Propensities

Influence of Different Aromatic Hydrophobic Residues on the Antimicrobial Activity and Membrane Selectivity of BRBR-NH2 Tetrapeptide

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Influence of Different Aromatic Hydrophobic Residues on the Antimicrobial Activity and Membrane Selectivity of BRBR-NH₂ Tetrapeptide