Glycopeptides related to beta-endorphin adopt helical amphipathic conformations in the presence of lipid bilayers.
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 (K(D)) 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).
Dhanasekaran
Muthu
M
The Carl S. Marvel Laboratories, Department of Chemistry, The University of Arizona, 1306 East University Blvd., Tucson, Arizona 85721, USA.
Palian
Michael M
MM
Alves
Isabel
I
Yeomans
Larisa
L
Keyari
Charles M
CM
Davis
Peg
P
Bilsky
Edward J
EJ
Egleton
Richard D
RD
Yamamura
Henry I
HI
Jacobsen
Neil E
NE
Tollin
Gordon
G
Hruby
Victor J
VJ
Porreca
Frank
F
Polt
Robin
R
D000595:Amino Acid Sequence; D001812:Blood-Brain Barrier; D002942:Circular Dichroism; D006020:Glycopeptides / Q000737:chemistry* / Q000493:pharmacokinetics; D008051:Lipid Bilayers / Q000737:chemistry*; D008823:Micelles; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011138:Polytetrafluoroethylene / Q000737:chemistry; D017433:Protein Structure, Secondary; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D020349:Surface Plasmon Resonance; D014867:Water / Q000737:chemistry; D001615:beta-Endorphin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics
D006020:Glycopeptides; D008051:Lipid Bilayers; D008823:Micelles; D014867:Water; D012967:Sodium Dodecyl Sulfate; D001615:beta-Endorphin; D011138:Polytetrafluoroethylene