Membrane association and selectivity of the antimicrobial peptide NK‐2: a molecular dynamics simulation study

Pimthon, Jutarat; Willumeit‐Römer, Regine; Lendlein, Andreas; Hofmann, Dieter

doi:10.1002/psc.1165

Cited by 18 publications

(19 citation statements)

References 62 publications

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“…A decrease in order parameters and hence a peptide‐induced disorder have been observed for arginine‐rich peptides and for NK‐2 using simulations and PGLa peptide using NMR . This decrease in order was ascribed to the membrane thinning effect induced by binding of these antimicrobial peptides parallel to the membrane surface similar to the effect produced by binding of detergents .…”

Section: Resultsmentioning

confidence: 88%

A novel chimeric peptide with antimicrobial activity

2015

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Beta-lactamase-mediated bacterial drug resistance exacerbates the prognosis of infectious diseases, which are sometimes treated with co-administration of beta-lactam type antibiotics and beta-lactamase inhibitors. Antimicrobial peptides are promising broad-spectrum alternatives to conventional antibiotics in this era of evolving bacterial resistance. Peptides based on the Ala46-Tyr51 beta-hairpin loop of beta-lactamase inhibitory protein (BLIP) have been previously shown to inhibit beta-lactamase. Here, our goal was to modify this peptide for improved beta-lactamase inhibition and cellular uptake. Motivated by the cell-penetrating pVEC sequence, which includes a hydrophobic stretch at its N-terminus, our approach involved the addition of LLIIL residues to the inhibitory peptide N-terminus to facilitate uptake. Activity measurements of the peptide based on the 45-53 loop of BLIP for enhanced inhibition verified that the peptide was a competitive beta-lactamase inhibitor with a K(i) value of 58 μM. Incubation of beta-lactam-resistant cells with peptide decreased the number of viable cells, while it had no effect on beta-lactamase-free cells, indicating that this peptide had antimicrobial activity via beta-lactamase inhibition. To elucidate the molecular mechanism by which this peptide moves across the membrane, steered molecular dynamics simulations were carried out. We propose that addition of hydrophobic residues to the N-terminus of the peptide affords a promising strategy in the design of novel antimicrobial peptides not only against beta-lactamase but also for other intracellular targets.

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Section: Resultsmentioning

confidence: 88%

A novel chimeric peptide with antimicrobial activity

2015

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“…Simulations can provide information on the peptide–lipid interactions that initiate and facilitate the peptide binding/insertion process. Atomistic simulations can identify electrostatic interactions between the anionic membrane groups and the cationic peptide positively residues that are involved in the initial peptide–membrane contact [ 289 , 290 ]. They can also provide valuable information on the mechanism of peptide–lipid interaction toward differentiating between different working models [ 41 ].…”

Section: Computer Simulationsmentioning

confidence: 99%

Membrane Active Peptides and Their Biophysical Characterization

2018

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In the last 20 years, an increasing number of studies have been reported on membrane active peptides. These peptides 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. Membrane active peptides are attractive alternatives to currently used pharmaceuticals and the number of antimicrobial peptides (AMPs) and peptides designed for drug and gene delivery in the drug pipeline is increasing. Here, we focus on two most prominent classes of membrane active peptides; AMPs and cell-penetrating peptides (CPPs). Antimicrobial peptides are a group of membrane active peptides that disrupt the membrane integrity or inhibit the cellular functions of bacteria, virus, and fungi. Cell penetrating peptides are another group of membrane active peptides that mainly function as cargo-carriers even though they may also show antimicrobial activity. Biophysical techniques shed light on peptide–membrane interactions at higher resolution due to the advances in optics, image processing, and computational resources. 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. Live imaging techniques allow examination of peptide action at a single cell or single molecule level. In addition to these experimental biophysical techniques, molecular dynamics simulations provide 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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“…For Grampositive membrane only DPPG was used. The ratios of peptide to lipid molecules for both analyses with Grampositive and -negative were of 1 with studies of molecular dynamics realized by Pimthon and co-workers [24]. All hydrogen atoms were added using the AutoDock Tool.…”

Section: In Silico Membrane Interactionsmentioning

confidence: 99%

The Use of MALDI-TOF-MS and In Silico Studies for Determination of Antimicrobial Peptides’ Affinity to Bacterial Cells

Mandal

Migliolo²,

Franco³

2012

J. Am. Soc. Mass Spectrom.

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Several methods have been proposed for determining the binding affinity of antimicrobial peptides (AMPs) to bacterial cells. Here the utilization of MALDI-TOF-MS was proposed as a reliable and efficient method for high throughput AMP screening. The major advantage of the technique consists of finding AMPs that are selective and specific to a wide range of Gramnegative and -positive bacteria, providing a simple reliable screening tool to determine the potential candidates for broad spectrum antimicrobial drugs. As a prototype, amp-1 and -2 were used, showing highest activity toward Gram-negative and -positive membranes respectively. In addition, in silico molecular docking studies with both peptides were carried out for the membranes. In silico results indicated that both peptides presented affinity for DPPG and DPPE phospholipids, constructed in order to emulate an in vivo membrane bilayer. As a result, amp-1 showed a higher complementary surface for Gram-negative while amp-2 showed higher affinity to Gram-positive membranes, corroborating MS analyses. In summary, results here obtained suggested that in vitro methodology using MALDI-TOF-MS in addition to theoretical studies may be able to improve AMP screening quality.

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Membrane association and selectivity of the antimicrobial peptide NK‐2: a molecular dynamics simulation study

Cited by 18 publications

References 62 publications

A novel chimeric peptide with antimicrobial activity

A novel chimeric peptide with antimicrobial activity

Membrane Active Peptides and Their Biophysical Characterization

The Use of MALDI-TOF-MS and In Silico Studies for Determination of Antimicrobial Peptides’ Affinity to Bacterial Cells

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