Antimicrobial Bombinin-like Peptide 3 Selectively Recognizes and Inserts into Bacterial Biomimetic Bilayers in Multiple Steps

Annaval, Thibault; Ramos‐Martín, Francisco; Herrera‐León, Claudia; Adélaïde, Morgane; Antonietti, Viviane; Buchoux, Sébastien; Sonnet, Pascal; Sarazin, Catherine; D’Amelio, Nicola

doi:10.1021/acs.jmedchem.1c00310

Cited by 6 publications

(5 citation statements)

References 110 publications

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“…While these experimental data demonstrate some level of self‐association, they tend to exclude the formation of alpha‐helical multimers in solution. Despite the relatively high concentration used, it should be pointed out that negatively charged bilayers, such as the membranes of cancer cells, can attract efficiently positively charged peptides making their local concentration much higher as in MD simulations [93]. For this reason, while the formation of stable tetramers in solution can be ruled out, dimers could form on the surface of membranes aiding the penetration of HB43 into cancer cells, as suggested by our simulations.…”

Section: Resultsmentioning

confidence: 66%

The impact of phosphatidylserine exposure on cancer cell membranes on the activity of the anticancer peptide HB43

et al. 2021

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HB43 (FAKLLAKLAKKLL) is a synthetic peptide active against cell lines derived from breast, colon, melanoma, lung, prostate, and cervical cancers. Despite its remarkable spectrum of activity, the mechanism of action at the molecular level has never been investigated, preventing further optimization of its selectivity. The alternation of charged and hydrophobic residues suggests amphipathicity, but the formation of alpha-helical structure seems discouraged by its short length and the large number of positively charged residues. Using different biophysical and in silico approaches we show that HB43 is completely unstructured in solution but assumes alpha-helical conformation in the presence of DPC micelles and liposomes exposing phosphatidylserine (PS) used as mimics of cancer cell membranes. Membrane permeabilization assays demonstrate that the interaction leads to the preferential destabilization of PS-containing vesicles with respect to PC-containing ones, here used as noncancerous cell mimics. ssNMR reveals that HB43 is able to fluidify the internal structure of cancer-cell mimicking liposomes while MD simulations show its internalization in such bilayers. This is achieved by the formation of specific interactions between the lysine side chains and the carboxylate group of phosphatidylserine and/or the phosphate oxygen atoms of targeted phospholipids, which could catalyze the formation of the alpha helix required for internalization. With the aim of better understanding the peptide biocompatibility and the additional antibacterial activity, the interaction with noncancerous cell mimicking liposomes exposing phosphatidylcholine (PC) and bacterial mimicking bilayers exposing phosphatidylglycerol (PG) is also described.

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Section: Resultsmentioning

confidence: 66%

The impact of phosphatidylserine exposure on cancer cell membranes on the activity of the anticancer peptide HB43

et al. 2021

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“…Notably, a less structured C-terminal segment has recently been reported in the literature for another AMP. 64 On the other hand, due to their stronger binding to phospholipid chains, the central helical residues are inserted deeper in the membrane, resulting in enhanced stability in their conformation compared to the residues at the termini.…”

Section: Discussionmentioning

confidence: 99%

Insights into Molecular Interactions between a GAPDH-Related Fish Antimicrobial Peptide, Analogs Thereof, and Bacterial Membranes

Cashman-Kadri,

Lagüe,

Subirade

et al. 2024

Biochemistry

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Interactions between SJGAP (skipjack tuna GAPDH-related antimicrobial peptide) and four analogs thereof with model bacterial membranes were studied using Fouriertransform infrared spectroscopy (FTIR) and molecular dynamics (MD) simulations. MD trajectory analyses showed that the Nterminal segment of the peptide analogs has many contacts with the polar heads of membrane phospholipids, while the central α helix interacts strongly with the hydrophobic core of the membranes. The peptides also had a marked influence on the wave numbers associated with the phase transition of phospholipids organized as liposomes in both the interface and aliphatic chain regions of the infrared spectra, supporting the interactions observed in the MD trajectories. In addition, interesting links were found between peptide interactions with the aliphatic chains of membrane phospholipids, as determined by FTIR and from the MD trajectories, and the membrane permeabilization capacity of these peptide analogs, as previously demonstrated. To summarize, the combined experimental and computational efforts have provided insights into crucial aspects of the interactions between the investigated peptides and bacterial membranes. This work thus makes an original contribution to our understanding of the molecular interactions underlying the antimicrobial activity of these GAPDH-related antimicrobial peptides from Scombridae.

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“…Molecular dynamics (MD) simulations have been shown to be an extremely useful tool for in silico investigations of the biophysical properties of antimicrobial peptides at a molecular level [17][18][19]. MD simulations have previously been used to explore several different individual stages of the mechanism of action of AMPs, such as their mechanism of insertion into lipid bilayers [20,21], their position and interactions once they are fully inserted into the bilayer [12,19], and their configuration when associated with a membrane pore structure [22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Insight into the Early Stages of Toroidal Pore Formation by the Antimicrobial Peptide Smp24

Bertelsen,

Lacey,

Nichol

et al. 2023

Pharmaceutics

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The antimicrobial peptide Smp24, originally derived from the venom of Scorpio maurus palmatus, is a promising candidate for further drug development. However, before doing so, greater insight into the mechanism of action is needed to construct a reliable structure–activity relationship. The aim of this study was to specifically investigate the critical early stages of peptide-induced membrane disruption. Single-channel current traces were obtained via planar patch-clamp electrophysiology, with multiple types of pore-forming events observed, unlike those expected from the traditional, more rigid mechanistic models. To better understand the molecular-level structures of the peptide-pore assemblies underlying these observed conductance events, molecular dynamics simulations were used to investigate the peptide structure and orientation both before and during pore formation. The transition of the peptides to transmembrane-like states within disordered toroidal pores occurred due to a peptide-induced bilayer-leaflet asymmetry, explaining why pore stabilization does not always follow pore nucleation in the experimental observations. To fully grasp the structure–activity relationship of antimicrobial peptides, a more nuanced view of the complex and dynamic mechanistic behaviour must be adopted.

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Antimicrobial Bombinin-like Peptide 3 Selectively Recognizes and Inserts into Bacterial Biomimetic Bilayers in Multiple Steps

Cited by 6 publications

References 110 publications

The impact of phosphatidylserine exposure on cancer cell membranes on the activity of the anticancer peptide HB43

The impact of phosphatidylserine exposure on cancer cell membranes on the activity of the anticancer peptide HB43

Insights into Molecular Interactions between a GAPDH-Related Fish Antimicrobial Peptide, Analogs Thereof, and Bacterial Membranes

Mechanistic Insight into the Early Stages of Toroidal Pore Formation by the Antimicrobial Peptide Smp24

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