Environment- and Sequence-Dependence of Helical Type in Membrane-Spanning Peptides Composed of β<sup>3</sup>-Amino Acids

Korendovych, Ivan V.; Shandler, Scott J.; Montalvo, Geronda L.; DeGrado, William F.

doi:10.1021/ol201218y

Cited by 17 publications

(11 citation statements)

References 27 publications

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“…The peptide sequences and structures of Trp and AzAla are shown in Figure . AzAla Melittin was synthesized by manual fluorenylmethylcarbonyl (Fmoc) solid phase peptide synthesis at elevated temperatures using our previously optimized protocols for hydrophobic peptides . H‐Rink Amide ChemMatrix resin was used as a solid support.…”

Section: Methodsmentioning

confidence: 99%

“…AzAla Melittin was synthesized by manual fluorenylmethylcarbonyl (Fmoc) solid phase peptide synthesis at elevated temperatures using our previously optimized protocols for hydrophobic peptides. [40][41][42] H-Rink Amide ChemMatrix resin was used as a solid support. Deprotection of resin and Fmoc group was carried out in 5% piperazine for 10 min.…”

Section: Peptide Synthesis and Purificationmentioning

confidence: 99%

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Functional characterization of a melittin analog containing a non‐natural tryptophan analog

et al. 2015

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Tryptophan (Trp) is a naturally occurring amino acid, which exhibits fluorescence emission properties that are dependent on the polarity of the local environment around the Trp side chain. However, this sensitivity also complicates interpretation of fluorescence emission data. A non-natural analogue of tryptophan, β-(1-azulenyl)-L-alanine, exhibits fluorescence insensitive to local solvent polarity and does not impact the structure or characteristics of several peptides examined. In this study we investigated the effect of replacing Trp with β-(1-azulenyl)-L-alanine in the well-known bee-venom peptide melittin. This peptide provides a model framework for investigating the impact of replacing Trp with β-(1-azulenyl)-L- alanine in a functional peptide system that undergoes significant shifts in Trp fluorescence emission upon binding to lipid bilayers. Microbiological methods including assessment of the antimicrobial activity by minimal inhibitory concentration (MIC) assays and bacterial membrane permeability assays indicated little difference between the Trp and the β-(1-azulenyl)-L-alanine-substituted versions of melittin. Circular dichroism spectroscopy showed both that peptides adopted the expected α-helical structures when bound to phospholipid bilayers and electrophysiological analysis indicated that both created membrane disruptions leading to significant conductance increases across model membranes. Both peptides exhibited a marked protection of the respective fluorophores when bound to bilayers indicating a similar membrane-bound topology. As expected, while fluorescence quenching and CD indicate the peptides are stably bound to lipid vesicles, the peptide containing β-(1-azulenyl)-L-alanine exhibited no fluorescence emission shift upon binding while the natural Trp exhibited >10 nm shift in emission spectrum barycenter. Taken together, the β-(1-azulenyl)-L-alanine can serve as a solvent insensitive alternative to Trp that does not have significant impacts on structure or function of membrane interacting peptides.

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Section: Methodsmentioning

confidence: 99%

Section: Peptide Synthesis and Purificationmentioning

confidence: 99%

Functional characterization of a melittin analog containing a non‐natural tryptophan analog

et al. 2015

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“…Many aspects of this example are intriguing, including the observation that some all-β 3 sequences can apparently adopt 12-helical conformations rather than 14-helical conformations (Korendovych, Shandler, Montalvo, & DeGrado, 2011; Raguse, Porter, Weisblum, & Gellman, 2002). The helix–helix interaction mode in this system features a relatively large crossing angle, which means that the helices make contact over only a relatively small region (in contrast to a coiled-coil dimer, in which the helices are nearly parallel).…”

Section: Biological Function From Helical β-Peptidesmentioning

confidence: 99%

α-Helix Mimicry with α/β-Peptides

Johnson¹,

Gellman²

2013

Methods in Enzymology

101

139

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We describe a general strategy for creating peptidic oligomers that have unnatural backbones but nevertheless adopt a conformation very similar to the α-helix. These oligomers contain both α- and β-amino acid residues (α/β-peptides). If the β content reaches 25–30% of the residue total, and the β residues are evenly distributed along the backbone, then substantial resistance to proteolytic degradation is often observed. These α/β-peptides can mimic the informational properties of α-helices involved in protein–protein recognition events, as documented in numerous crystal structures. Thus, these unnatural oligomers can be a source of antagonists of undesirable protein–protein interactions that are mediated by natural α-helices, or agonists of receptors for which the natural polypeptide ligands are α-helical. Successes include mimicry of BH3 domains found in proapoptotic proteins, which leads to ligands for anti-apoptotic Bcl-2 family proteins, and mimicry of the gp41 CHR domain, which leads to inhibition of HIV infection in cell-based assays.

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“…In TFE, the β-CHAMP CD spectrum suggested an equilibrium between 12- and 14-helical structures, consistent with increasing destabilization of the 12-helix with increasing solvent polarity. 21,24 Control β-CHAMP peptides followed the same pattern, showing higher 14-helical content in TFE. 21 Also, when the β-CHAMP mixed with the α IIb TM peptide under conditions in which they formed a 1:1 complex (Figure 2), the spectrum was well described as a mixture of the TM α-helical and the 12-helical form of the β-peptide, strongly suggesting that the β-CHAMP binds its target in a 12-helical conformation.…”

mentioning

confidence: 59%

“…21 Thus, both were considered in the design of the CHAMP peptide. In each case, multiple poses of the poly-hGly backbone were exhaustively sampled to discover the optimal backbone orientation.…”

mentioning

confidence: 99%

Computational Design of a β-Peptide That Targets Transmembrane Helices

et al. 2011

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The design of β-peptide foldamers targeting the transmembrane (TM) domains of complex natural membrane proteins has been a formidable challenge. A series of β-peptides was designed to stably insert in TM orientations in phospholipid bilayers. Their secondary structures and orientation in the phospholipid bilayer was characterized using biophysical methods. Computational methods were then devised to design a β-peptide that targeted a TM helix of the integrin αIIbβ3. The designed peptide (β-CHAMP) interacts with the isolated target TM domain of the protein, and activates the intact integrin in vitro.

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Environment- and Sequence-Dependence of Helical Type in Membrane-Spanning Peptides Composed of β³-Amino Acids

Cited by 17 publications

References 27 publications

Functional characterization of a melittin analog containing a non‐natural tryptophan analog

Functional characterization of a melittin analog containing a non‐natural tryptophan analog

α-Helix Mimicry with α/β-Peptides

Computational Design of a β-Peptide That Targets Transmembrane Helices

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Environment- and Sequence-Dependence of Helical Type in Membrane-Spanning Peptides Composed of β3-Amino Acids

Cited by 17 publications

References 27 publications

Functional characterization of a melittin analog containing a non‐natural tryptophan analog

Functional characterization of a melittin analog containing a non‐natural tryptophan analog

α-Helix Mimicry with α/β-Peptides

Computational Design of a β-Peptide That Targets Transmembrane Helices

Contact Info

Product

Resources

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Environment- and Sequence-Dependence of Helical Type in Membrane-Spanning Peptides Composed of β³-Amino Acids