Conformationally Rigid Trifluoromethyl‐Substituted α‐Amino Acid Designed for Peptide Structure Analysis by Solid‐State <sup>19</sup>F NMR Spectroscopy

Mikhailiuk, Pavel K.; Afonin, Sergii; Chernega, Alexander N.; Русанов, Эдуард Б.; Платонов, М. О.; Dubinina, G. G.; Berditsch, Marina; Ulrich, Anne S.; Komarov, Igor V.

doi:10.1002/anie.200600346

Cited by 108 publications

(48 citation statements)

References 21 publications

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“…The solid-state 19 F-NMR approach relies on the designer-made 19 F-labeled amino acid 3-(trifluoromethyl)-bicyclopent-[1.1.1]-1-ylglycine (CF 3 -Bpg), which has a stiff and sterically restrictive side chain [52], [54], [61], [62]. The L - enantiomer has been recently established as a selective NMR label in studies of membrane-bound peptides with simple α-helical or β-pleated conformations [40], [52], [54], [63], [64].…”

Section: Introductionmentioning

confidence: 99%

“…The L - enantiomer has been recently established as a selective NMR label in studies of membrane-bound peptides with simple α-helical or β-pleated conformations [40], [52], [54], [63], [64]. By incorporating D - amino acids into peptides, it has furthermore been possible to modulate their ability to aggregate as β-sheets [39], [65], [66].…”

Section: Introductionmentioning

confidence: 99%

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Structure Analysis and Conformational Transitions of the Cell Penetrating Peptide Transportan 10 in the Membrane-Bound State

Fanghänel

Wadhwani²,

Strandberg³

et al. 2014

PLoS ONE

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Structure analysis of the cell-penetrating peptide transportan 10 (TP10) revealed an exemplary range of different conformations in the membrane-bound state. The bipartite peptide (derived N-terminally from galanin and C-terminally from mastoparan) was found to exhibit prominent characteristics of (i) amphiphilic α-helices, (ii) intrinsically disordered peptides, as well as (iii) β-pleated amyloid fibrils, and these conformational states become interconverted as a function of concentration. We used a complementary approach of solid-state 19F-NMR and circular dichroism in oriented membrane samples to characterize the structural and dynamical behaviour of TP10 in its monomeric and aggregated forms. Nine different positions in the peptide were selectively substituted with either the L - or D -enantiomer of 3-(trifluoromethyl)-bicyclopent-[1.1.1]-1-ylglycine (CF3 -Bpg) as a reporter group for 19F-NMR. Using the L -epimeric analogs, a comprehensive three-dimensional structure analysis was carried out in lipid bilayers at low peptide concentration, where TP10 is monomeric. While the N-terminal region is flexible and intrinsically unstructured within the plane of the lipid bilayer, the C-terminal α-helix is embedded in the membrane with an oblique tilt angle of ∼55° and in accordance with its amphiphilic profile. Incorporation of the sterically obstructive D -CF3 -Bpg reporter group into the helical region leads to a local unfolding of the membrane-bound peptide. At high concentration, these helix-destabilizing C-terminal substitutions promote aggregation into immobile β-sheets, which resemble amyloid fibrils. On the other hand, the obstructive D -CF3 -Bpg substitutions can be accommodated in the flexible N-terminus of TP10 where they do not promote aggregation at high concentration. The cross-talk between the two regions of TP10 thus exerts a delicate balance on its conformational switch, as the presence of the α-helix counteracts the tendency of the unfolded N-terminus to self-assemble into β-pleated fibrils.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structure Analysis and Conformational Transitions of the Cell Penetrating Peptide Transportan 10 in the Membrane-Bound State

Fanghänel

Wadhwani²,

Strandberg³

et al. 2014

PLoS ONE

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“…However, only a few reports on the racemizationfree incorporation of enantiopure fluorinated amino acids into peptides via SPPS have appeared in the literature, including L- 5,5,5,5′,5′,5′-hexafluoroleucine, 1d, 1e, 3 4-fluoro-proline 14 and 3-(trifluoro-methyl)bicyclopent[1.1.1]-1-ylglycine 15 . The reason is two fold.…”

Section: Introductionmentioning

confidence: 99%

Enantioselective synthesis of (2R, 3S)‐ and (2S, 3R)‐4,4,4‐trifluoro‐N‐Fmoc‐O‐tert‐butyl‐threonine and their racemization‐free incorporation into oligopeptides via solid‐phase synthesis

Xiao

Jiang

2007

Biopolymers

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An efficient method for the enantioselective synthesis of (2R, 3S)-and (2S, 3R)-4,4,4-trifluoro-NFmoc-O-tert-butyl-threonine (tfT) on multi-gram scales was developed. Absolute configurations of the two stereoisomers were ascertained by X-ray crystallography. Racemization-free coupling conditions for the incorporation of tfT into oligopeptides were then explored. For solution-phase synthesis, tfT racemization was not an issue under conventional coupling conditions. For solid-phase synthesis, the following conditions were identified to achieve racemization-free synthesis: if tfT (3.0 eq.) was not the first amino acid to be linked to the resin (1.0 eq.), the condition is: 2.7 eq. DIC/3.0 eq. HOBt as the coupling reagent at 0 °C for 20 h; if tfT (3.0 eq.) was the first amino acid to be linked to the resin (1.0 eq.), then 1.0 eq. of CuCl 2 needs to be added to the coupling reagent.

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“…19 F-labeling, we substituted the amino acid at the position to be labeled by CF 3 -Bpg, which was synthesized following Mikhailiuk et al (13). Deviating from above coupling conditions, 1.5 equivalents of Boc-CF 3 -Bpg were coupled overnight using HBTU.…”

Section: Synthesis Of 19 F-labeled Kalata B1mentioning

confidence: 99%

“…1 b). This artificial amino acid has been used in several cases in a-helical membrane-active peptides for determination of their tilt angle with respect to lipid bilayers, where structure and biological activity proved to be unaltered (13,14). Here, we apply the technique for the first time, to our knowledge, on a peptide with a complex fold and were able to analyze its orientation using the known, rigid three-dimensional (3D) structure of kalata B1 (15,16).…”

Section: Introductionmentioning

confidence: 99%

Orientation and Location of the Cyclotide Kalata B1 in Lipid Bilayers Revealed by Solid-State NMR

Grage

Sani

Cheneval

et al. 2017

Biophysical Journal

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Cyclotides are ultra-stable cyclic disulfide-rich peptides from plants. Their biophysical effects and medically interesting activities are related to their membrane-binding properties, with particularly high affinity for phosphatidylethanolamine lipids. In this study we were interested in understanding the molecular details of cyclotide-membrane interactions, specifically with regard to the spatial orientation of the cyclotide kalata B1 from Oldenlandia affinis when embedded in a lipid bilayer. Our experimental approach was based on the use of solid-state 19

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Conformationally Rigid Trifluoromethyl‐Substituted α‐Amino Acid Designed for Peptide Structure Analysis by Solid‐State ¹⁹F NMR Spectroscopy

Cited by 108 publications

References 21 publications

Structure Analysis and Conformational Transitions of the Cell Penetrating Peptide Transportan 10 in the Membrane-Bound State

Structure Analysis and Conformational Transitions of the Cell Penetrating Peptide Transportan 10 in the Membrane-Bound State

Enantioselective synthesis of (2R, 3S)‐ and (2S, 3R)‐4,4,4‐trifluoro‐N‐Fmoc‐O‐tert‐butyl‐threonine and their racemization‐free incorporation into oligopeptides via solid‐phase synthesis

Orientation and Location of the Cyclotide Kalata B1 in Lipid Bilayers Revealed by Solid-State NMR

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Conformationally Rigid Trifluoromethyl‐Substituted α‐Amino Acid Designed for Peptide Structure Analysis by Solid‐State 19F NMR Spectroscopy

Cited by 108 publications

References 21 publications

Structure Analysis and Conformational Transitions of the Cell Penetrating Peptide Transportan 10 in the Membrane-Bound State

Structure Analysis and Conformational Transitions of the Cell Penetrating Peptide Transportan 10 in the Membrane-Bound State

Enantioselective synthesis of (2R, 3S)‐ and (2S, 3R)‐4,4,4‐trifluoro‐N‐Fmoc‐O‐tert‐butyl‐threonine and their racemization‐free incorporation into oligopeptides via solid‐phase synthesis

Orientation and Location of the Cyclotide Kalata B1 in Lipid Bilayers Revealed by Solid-State NMR

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Conformationally Rigid Trifluoromethyl‐Substituted α‐Amino Acid Designed for Peptide Structure Analysis by Solid‐State ¹⁹F NMR Spectroscopy