Oligomerization of the antimicrobial peptide Protegrin-5 in a membrane-mimicking environment. Structural studies by high-resolution NMR spectroscopy

Usachev, Konstantin S.; Kolosova, Olga; Klochkova, Evelina; Yulmetov, Aydar; Аганов, А. В.; Клочков, В. В.

doi:10.1007/s00249-016-1167-5

Cited by 17 publications

(12 citation statements)

References 52 publications

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“…Solid-state NMR provided some evidence that protegrin may form β-barrels containing 8–10 monomers in NCCN parallel topology 25 (see Topology below). However, solution NMR in detergents showed NCCN antiparallel topology for protegrin-1 26 , protegrin-3 27 , and protegrin-5 28 . The same solid-state NMR study also showed that 75% of the hairpins have homodimerized N and C strands in an anionic membrane, implying that the β-barrel state is the dominant component of a heterogeneous mixture.…”

Section: Introductionmentioning

confidence: 96%

Transmembrane Pore Structures of β-Hairpin Antimicrobial Peptides by All-Atom Simulations

2017

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Protegrin-1 is an 18-residue β-hairpin antimicrobial peptide (AMP) that has been suggested to form transmembrane β-barrels in biological membranes. However, alternative structures have also been proposed. Here, we performed multimicrosecond, all-atom molecular dynamics simulations of various protegrin-1 oligomers on the membrane surface and in transmembrane topologies. The membrane surface simulations indicated that protegrin dimers are stable, while trimers and tetramers break down. Tetrameric arcs remained stably inserted in lipid membranes, but the pore water was displaced by lipid molecules. Unsheared protegrin β-barrels opened into β-sheets that surrounded stable aqueous pores, whereas tilted barrels with sheared hydrogen bonding patterns were stable in most topologies. A third type of observed pore consisted of multiple small oligomers surrounding a small, partially lipidic pore. We also considered the β-hairpin AMP tachyplesin, which showed less tendency to oligomerize than protegrin: the octameric bundle resulted in small pores surrounded by 6 peptides as monomers and dimers, with some peptides returning to the membrane surface. The results imply that multiple configurations of protegrin oligomers may produce aqueous pores and illustrate the relationship between topology and putative steps in protegrin-1’s pore formation. However, the long-term stability of these structures needs to be assessed further.

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Section: Introductionmentioning

confidence: 96%

Transmembrane Pore Structures of β-Hairpin Antimicrobial Peptides by All-Atom Simulations

2017

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“…Whereas molecules whose interactions are with proteinaceous receptors can be made inefficient by one or a few changes in amino acid sequence, polypeptides that act by disrupting the lipid bilayer physicochemical properties are less likely to become inactivated by resistance (Rollins-Smith et al 2002). Indeed the amphipathic nature of AMPs has been found essential and can be achieved by helical (Sansom 1991;Bechinger 1997), cyclic (Cao et al 2018Laurencin et al 2018;Tsutsumi et al 2018;Zhao et al 2018), and/or β-sheet arrangements (Hong and Su 2011; Rautenbach et al 2016a, b;Sychev et al 2017;Usachev et al 2017). Thus the insights gained from the studies of cationic amphipathic antimicrobial peptides have stimulated the design of a number of small amphipathic molecules (Arnusch et al 2012;Ghosh et al 2014), pseudopeptides (Porter et al 2002;Patch and Barron 2003;Kuroda and DeGrado 2005;Violette et al 2006;Makovitzki et al 2008;Scott et al 2008;Rotem and Mor 2009;Palermo and Kuroda 2010;Laurencin et al 2018), and polymers (Rank et al 2017) with potent antimicrobial properties.…”

Section: Introductionmentioning

confidence: 99%

The Mechanisms of Action of Cationic Antimicrobial Peptides Refined by Novel Concepts from Biophysical Investigations

Aisenbrey¹,

Marquette²,

Bechinger³

2019

Advances in Experimental Medicine and Biology

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Even 30 years after the discovery of magainins, biophysical and structural investigations on how these peptides interact with membranes can still bear surprises and add new interesting detail to how these peptides exert their antimicrobial action. Early on, using oriented solid-state NMR spectroscopy, it was found that the amphipathic helices formed by magainins are active when being oriented parallel to the membrane surface. More recent investigations indicate that this in-planar alignment is also found when PGLa and magainin in combination exert synergistic pore-forming activities, where studies on the mechanism of synergistic interaction are ongoing. In a related manner, the investigation of dimeric antimicrobial peptide sequences has become an interesting topic of research which bears promise to refine our views how antimicrobial action occurs. The molecular shape concept has been introduced to explain the effects of lipids and peptides on membrane morphology, locally and globally, and in particular of cationic amphipathic helices that partition into the membrane interface. This concept has been extended in this review to include more recent ideas on soft membranes that can adapt to external stimuli including membrane-disruptive molecules. In this manner, the lipids can change their shape in the presence of low peptide concentrations, thereby maintaining the bilayer properties. At higher peptide concentrations, phase transitions occur which lead to the formation of pores and membrane lytic processes. In the context of the molecular shape concept, the properties of lipopeptides, including surfactins, are shortly presented, and comparisons with the hydrophobic alamethicin sequence are made. Keywords (separated by "-") Magainin-PGLa-Cecropin-LL37-Surfacting alamethicin-Membrane topology-Membrane pore-Membrane macroscopic phase-SMART model-Carpet model-Toroidal pore-Peptide-lipid interactions-Molecular shape concept

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“…In contrast, molecules that specifically target proteinaceous receptors can be made inefficient by mutagenesis of one or a few sites, and it is much less likely that bacteria develop resistance to compounds whose primary target is the destruction of the physico-chemical properties of the lipid membrane [ 15 ]. Membrane-active peptides exhibit a wide range of structural features some being helical in their bilayer-associated state [ 16 , 17 ], others forming cyclic [ 18 , 19 , 20 , 21 ] and/or β-sheet arrangements [ 22 , 23 , 24 , 25 , 26 ]. Indeed, following the insights gained from the studies of cationic amphipathic antimicrobial peptides a number of small amphipathic molecules [ 27 , 28 ], pseudopeptides [ 21 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ], and polymers [ 37 ] have been designed and investigated, and found to also exhibit potent antimicrobial activities.…”

Section: Introductionmentioning

confidence: 99%

Biophysical Investigations Elucidating the Mechanisms of Action of Antimicrobial Peptides and Their Synergism

Marquette

Bechinger

2018

Biomolecules

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Biophysical and structural investigations are presented with a focus on the membrane lipid interactions of cationic linear antibiotic peptides such as magainin, PGLa, LL37, and melittin. Observations made with these peptides are distinct as seen from data obtained with the hydrophobic peptide alamethicin. The cationic amphipathic peptides predominantly adopt membrane alignments parallel to the bilayer surface; thus the distribution of polar and non-polar side chains of the amphipathic helices mirror the environmental changes at the membrane interface. Such a membrane partitioning of an amphipathic helix has been shown to cause considerable disruptions in the lipid packing arrangements, transient openings at low peptide concentration, and membrane disintegration at higher peptide-to-lipid ratios. The manifold supramolecular arrangements adopted by lipids and peptides are represented by the ‘soft membranes adapt and respond, also transiently’ (SMART) model. Whereas molecular dynamics simulations provide atomistic views on lipid membranes in the presence of antimicrobial peptides, the biophysical investigations reveal interesting details on a molecular and supramolecular level, and recent microscopic imaging experiments delineate interesting sequences of events when bacterial cells are exposed to such peptides. Finally, biophysical studies that aim to reveal the mechanisms of synergistic interactions of magainin 2 and PGLa are presented, including unpublished isothermal titration calorimetry (ITC), circular dichroism (CD) and dynamic light scattering (DLS) measurements that suggest that the peptides are involved in liposome agglutination by mediating intermembrane interactions. A number of structural events are presented in schematic models that relate to the antimicrobial and synergistic mechanism of amphipathic peptides when they are aligned parallel to the membrane surface.

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Oligomerization of the antimicrobial peptide Protegrin-5 in a membrane-mimicking environment. Structural studies by high-resolution NMR spectroscopy

Cited by 17 publications

References 52 publications

Transmembrane Pore Structures of β-Hairpin Antimicrobial Peptides by All-Atom Simulations

Transmembrane Pore Structures of β-Hairpin Antimicrobial Peptides by All-Atom Simulations

The Mechanisms of Action of Cationic Antimicrobial Peptides Refined by Novel Concepts from Biophysical Investigations

Biophysical Investigations Elucidating the Mechanisms of Action of Antimicrobial Peptides and Their Synergism

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