Glycopeptides related to β-endorphin adopt helical amphipathic conformations in the presence of lipid bilayers

Muthu Dhanasekaran, Michael M. Palian, Isabel Alves, Larisa Yeomans, Charles M. Keyari, Peg Davis, Edward J. Bilsky, Richard D. Egleton, Henry I. Yamamura, Neil E. Jacobsen, Gordon Tollin, Victor J Hruby, Frank Porreca, Robin L Polt

Research output: Contribution to journalArticle

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Abstract

A series of glycosylated endorphin analogues designed to penetrate the blood-brain barrier (BBB) have been studied by circular dichroism and by 2D-NMR in the presence of water; TFE/water; SDS micelles; and in the presence of both neutral and anionic bicelles. In water, the glycopeptides showed only nascent helix behavior and random coil conformations. Chemical shift indices and nuclear Overhauser effects (NOE) confirmed helices in the presence of membrane mimics. NOE volumes provided distance constraints for molecular dynamics calculations used to provide detailed backbone conformations. In all cases, the glycopeptides were largely helical in the presence of membrane bilayer models (micelles or bicelles). Plasmon waveguide resonance (PWR) studies showed hen egg phosphatidyl choline (PC) bilayers produce amphipathic helices laying parallel to the membrane surface, with dissociation constants (KD) in the low nanomolar to micromolar concentration range. Two low-energy states are suggested for the glycosylated endorphin analogues, a flexible aqueous state and a restricted membrane bound state. Strong interactions between the glycopeptide amphipaths and membranes are crucial for penetration of the BBB via an endocytotic mechanism (transcytosis).

Original languageEnglish (US)
Pages (from-to)5435-5448
Number of pages14
JournalJournal of the American Chemical Society
Volume127
Issue number15
DOIs
StatePublished - Apr 20 2005

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Endorphins
Lipid bilayers
Glycopeptides
Lipid Bilayers
Conformations
Membranes
Micelles
Blood-Brain Barrier
Water
Transcytosis
Polytetrafluoroethylene
Chemical shift
Dichroism
Molecular Dynamics Simulation
Circular Dichroism
Phosphatidylcholines
Electron energy levels
Ovum
Molecular dynamics
Waveguides

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Glycopeptides related to β-endorphin adopt helical amphipathic conformations in the presence of lipid bilayers. / Dhanasekaran, Muthu; Palian, Michael M.; Alves, Isabel; Yeomans, Larisa; Keyari, Charles M.; Davis, Peg; Bilsky, Edward J.; Egleton, Richard D.; Yamamura, Henry I.; Jacobsen, Neil E.; Tollin, Gordon; Hruby, Victor J; Porreca, Frank; Polt, Robin L.

In: Journal of the American Chemical Society, Vol. 127, No. 15, 20.04.2005, p. 5435-5448.

Research output: Contribution to journalArticle

Dhanasekaran, M, Palian, MM, Alves, I, Yeomans, L, Keyari, CM, Davis, P, Bilsky, EJ, Egleton, RD, Yamamura, HI, Jacobsen, NE, Tollin, G, Hruby, VJ, Porreca, F & Polt, RL 2005, 'Glycopeptides related to β-endorphin adopt helical amphipathic conformations in the presence of lipid bilayers', Journal of the American Chemical Society, vol. 127, no. 15, pp. 5435-5448. https://doi.org/10.1021/ja0432158
Dhanasekaran, Muthu ; Palian, Michael M. ; Alves, Isabel ; Yeomans, Larisa ; Keyari, Charles M. ; Davis, Peg ; Bilsky, Edward J. ; Egleton, Richard D. ; Yamamura, Henry I. ; Jacobsen, Neil E. ; Tollin, Gordon ; Hruby, Victor J ; Porreca, Frank ; Polt, Robin L. / Glycopeptides related to β-endorphin adopt helical amphipathic conformations in the presence of lipid bilayers. In: Journal of the American Chemical Society. 2005 ; Vol. 127, No. 15. pp. 5435-5448.
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