Conformational preferences of Leu‐enkephalin in reverse micelles as membrane‐mimicking environment

Rudolph‐Böhner, Sabine; Quarzago, Daniela; Czisch, Michael; Ragnarsson, Ulf; Moröder, Luis

doi:10.1002/(sici)1097-0282(199705)41:6<591::aid-bip1>3.3.co;2-m

Cited by 8 publications

(14 citation statements)

References 7 publications

(10 reference statements)

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“…For analogues 20a-c and 21a-b with the D-and L-bicyclo moiety, extended structures were found at these two positions, also independent of the bridgehead stereochemistry. These findings rationalize the design and use of these bicyclic dipeptides in our study to mimic the different conformations reported [35][36][37][38][39][40] on Leu-enkephalin. However, it must be noted that the analogue (21c) with the same D-and L-bicyclo moiety gives a reverse turn structure instead of an extended structure.…”

Section: Conformational Studiessupporting

confidence: 78%

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Parallel synthesis and biological evaluation of different sizes of bicyclo^[2,3]‐Leu‐enkephalin analogues

Gu¹,

Ying²,

Min³

et al. 2005

Biopolymers

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show abstract

Section: Conformational Studiessupporting

confidence: 78%

“…In previous conformational studies [35][36][37][38][39][40] on this endogenous neuropeptide, both turn and extended conformations spanning residues 2-3 were reported. Depending on the configurations of the chiral centers in the bicyclic dipeptides, these dipeptides may be constrained to different conformations.…”

Section: Conformational Studiesmentioning

confidence: 99%

Parallel synthesis and biological evaluation of different sizes of bicyclo^[2,3]‐Leu‐enkephalin analogues

Gu¹,

Ying²,

Min³

et al. 2005

Biopolymers

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“…The conformation of enkephalin is thought to change with the presumed formation of more compact structures in the phospholipid membrane environment as suggested by NMR measurements 5,14-16,18. Therefore it is of interest to observe the changes in the inter-chromophore distance in the presence of SDS micelles.…”

Section: Discussionmentioning

confidence: 99%

Conformational Heterogeneity of a Leucine Enkephalin Analogue in Aqueous Solution and Sodium Dodecyl Sulfate Micelles: Comparison of Time-Resolved FRET and Molecular Dynamics Simulations

2009

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We have undertaken time-resolved Förster resonance energy transfer (FRET) and molecular dynamics simulations to analyze conformations and conformational heterogeneity of an analog of leucine enkephalin in solution and in the presence of SDS micelles. Enkephalins are opioid pentapeptides that interact with opioid receptors in the central nervous system. We used time-correlated single-photon counting to detect energy transfer between the N-terminal tyrosine and a tryptophan residue substituted for phenylalanine at the 4 position. FRET from Tyr to Trp was measured over a temperature range from 5°C to 55°C in aqueous solution. By taking into account Tyr rotamer interconversion rates measured previously, we determined average distances between Tyr and Trp for the two populated rotameric conformations of Tyr. Molecular dynamics simulations (100 ns) support this analysis and indicate extensive conformational heterogeneity. The simulations also predict that the FRET orientational factor is correlated with the Tyr-Trp separation. Failure to account for the correlation between orientation and distance results in errors that appear to be largely offset in YGGWL by a weighting bias inherent in the R−6 dependence of the energy-transfer rate. The Tyr lifetimes decrease upon titration of the peptides with SDS, indicating formation of compact conformations of the peptide in the micelle environment. This result is consistent with the conjecture that the lipid environment may induce formation of bioactive conformations of the peptide.

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“…However, in the presence of trifluoroethanol (TFE) or membrane-mimicking surroundings, they could have structured conformations, since their secondary structural elements can be stabilized by the environmental effects 12, 13, 15, 16. Therefore, the circumstances surrounding such a peptide should be important especially for their conformational definitions 17…”

Section: Introductionmentioning

confidence: 99%

The Importance of Micelle-Bound States for the Bioactivities of Bifunctional Peptide Derivatives for δ/μ Opioid Receptor Agonists and Neurokinin 1 Receptor Antagonists

et al. 2008

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In order to provide new insight into the determining factors of membrane-bound peptide conformation which might play an important role in peptide-receptor docking and further biological behaviors, the dodecylphosphocholine (DPC) micelle-bound conformations of bifunctional peptide derivatives of δ-preferring opioid agonists and NK1 antagonists (1: Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-O-3,5-Bzl(CF3)2; 2: Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-3,5-Bzl(CF3)2; 3: Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-Bzl) were determined based on 2D NMR studies. Although the differences in the primary sequence were limited to the C-terminus, the obtained NMR conformations were unexpectedly different for each compound. Moreover, their biological activities showed different trends in direct relation to the compound-specific conformations in DPC micelles. The important result is that not only were the NK1 antagonist activities different (the pharmacophore located at the C-terminus), but the opioid agonist activities (this pharmacophore was at the structurally preserved N-terminus) also were shifted, suggesting that a general conformational change in the bioactive state was induced due to relatively small and limited structural modifications.

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Conformational preferences of Leu‐enkephalin in reverse micelles as membrane‐mimicking environment

Cited by 8 publications

References 7 publications

Parallel synthesis and biological evaluation of different sizes of bicyclo^[2,3]‐Leu‐enkephalin analogues

Parallel synthesis and biological evaluation of different sizes of bicyclo^[2,3]‐Leu‐enkephalin analogues

Conformational Heterogeneity of a Leucine Enkephalin Analogue in Aqueous Solution and Sodium Dodecyl Sulfate Micelles: Comparison of Time-Resolved FRET and Molecular Dynamics Simulations

The Importance of Micelle-Bound States for the Bioactivities of Bifunctional Peptide Derivatives for δ/μ Opioid Receptor Agonists and Neurokinin 1 Receptor Antagonists

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Conformational preferences of Leu‐enkephalin in reverse micelles as membrane‐mimicking environment

Cited by 8 publications

References 7 publications

Parallel synthesis and biological evaluation of different sizes of bicyclo[2,3]‐Leu‐enkephalin analogues

Parallel synthesis and biological evaluation of different sizes of bicyclo[2,3]‐Leu‐enkephalin analogues

Conformational Heterogeneity of a Leucine Enkephalin Analogue in Aqueous Solution and Sodium Dodecyl Sulfate Micelles: Comparison of Time-Resolved FRET and Molecular Dynamics Simulations

The Importance of Micelle-Bound States for the Bioactivities of Bifunctional Peptide Derivatives for δ/μ Opioid Receptor Agonists and Neurokinin 1 Receptor Antagonists

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Parallel synthesis and biological evaluation of different sizes of bicyclo^[2,3]‐Leu‐enkephalin analogues

Parallel synthesis and biological evaluation of different sizes of bicyclo^[2,3]‐Leu‐enkephalin analogues