Average orientation of a fluoroaromatic molecule in lipid bilayers from DFT-informed NMR measurements of ¹H–¹⁹F dipolar couplings

Abstract

An NMR approach is described for determining the orientational preference of bioactive fluoroaromatic molecules within lipid bilayers, by combining measurements of 19F chemical shift anisotropy with the detection of 1H–19F dipolar couplings.

Drug orientations within statin-loaded lipoprotein nanoparticles by 19F solid-state NMR

“…Statins embedded in the rHDL lipid bilayer will undergo anisotropic motions that scale the 19 F chemical shift anisotropy in a predictable way that depends on the drug's orientation in the planar matrix. 11 Molecules rotate about a principal axis that runs parallel with the bilayer normal and the NMR line shape is sensitive to the orientations of the 19 F chemical shift tensor elements d 11 , d 22 and d 33 relative to this axis, as defined by angles a and b (Fig. 1C).…”

“…S1, ESI †), as seen for other fluorophenyl compounds. 11 Additional random motional fluctuations of the molecule about the two axes perpendicular to the main axis must also be considered in the analysis, as must internal rotations of the fluoroaromatic ring (Fig. 1C).…”