title: The orientation and dynamics of estradiol and estradiol oleate in lipid membranes and HDL disc models.
abstract: Estradiol (E2) and E2 oleate associate with high-density lipoproteins (HDLs). Their orientation in HDLs is unknown. We studied the orientation of E2 and E2 oleate in membranes and reconstituted HDLs, finding that E2 and E2 oleate are membrane-associated and highly mobile. Our combination of NMR measurements, molecular dynamics simulation, and analytic theory identifies three major conformations where the long axis of E2 assumes a parallel, perpendicular, or antiparallel orientation relative to the membrane's z-direction. The perpendicular orientation is preferred, and furthermore, in this orientation, E2 strongly favors a particular roll angle, facing the membrane with carbons 6, 7, 15, and 16, whereas carbons 1, 2, 11, and 12 point toward the aqueous phase. In contrast, the long axis of E2 oleate is almost exclusively oriented at an angle of ∼60° to the z-direction. In such an orientation, the oleoyl chain is firmly inserted into the membrane. Thus, both E2 and E2 oleate have a preference for interface localization in the membrane. These orientations were also found in HDL discs, suggesting that only lipid-E2 interactions determine the localization of the molecule. The structural mapping of E2 and E2 oleate may provide a design platform for specific E2-HDL-targeted pharmacological therapies.
authors.affiliation: Institute of Medical Physics and Biophysics, University of Leipzig, Leipzig, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Vogel
authors.affiliation: Institute of Medical Physics and Biophysics, University of Leipzig, Leipzig, Germany.
authors.forename: Holger A
authors.initials: HA
authors.lastname: Scheidt
authors.affiliation: Wabash College, Crawfordsville, Indiana.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Feller
authors.affiliation: National Institute for Health and Welfare, Public Health Genomics Unit and Institute for Molecular Medicine Finland, Helsinki, Finland.
authors.forename: Jari
authors.initials: J
authors.lastname: Metso
authors.affiliation: Turku Positron Emission Tomography Centre, University of Turku, Turku, Finland.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Badeau
authors.affiliation: Folkälsan Research Center, Biomedicum and Heart and Lung Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: Matti J
authors.initials: MJ
authors.lastname: Tikkanen
authors.affiliation: Laboratory of Organic Chemistry, University of Helsinki, Helsinki, Finland.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Wähälä
authors.affiliation: National Institute for Health and Welfare, Public Health Genomics Unit and Institute for Molecular Medicine Finland, Helsinki, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Jauhiainen
authors.affiliation: Institute of Medical Physics and Biophysics, University of Leipzig, Leipzig, Germany; Department of Chemical Sciences, Tata Institute of Fundamental Research, Mumbai, India. Electronic address: daniel.huster@medizin.uni-leipzig.de.
authors.forename: Daniel
authors.initials: D
authors.lastname: Huster
mesh_terms: D004958:Estradiol / Q000737:chemistry*; D008075:Lipoproteins, HDL / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D019301:Oleic Acid / Q000737:chemistry
chemical_list: D008075:Lipoproteins, HDL; D008081:Liposomes; D019301:Oleic Acid; D004958:Estradiol