Molecular orientation and optimization of membrane dyes based on conjugated oligoelectrolytes

• Published in: Cell reports physical science 2023-06, Vol.4 (6), p.101429, Article 101429
• Main Authors: Zhu, Ji-Yu, Bazan, Guillermo C.
• Format: Article
• Language: English
• Subjects: conjugated oligoelectrolytes; lipid bilayer mimic; structure-activity relationship; water-soluble membrane dyes
• ISSN: 2666-3864; 2666-3864
• DOI: 10.1016/j.xcrp.2023.101429

Conjugated oligoelectrolytes (COEs) are amphiphilic, fluorogenic molecules that spontaneously associate with lipid bilayer membranes and are gaining attention as molecular reporters, particularly for exosome detection by flow cytometry. Questions nonetheless remain on how to best design COEs for optimal performance and on the geometry of lipid bilayer intercalation. In response, we designed a series of oligo-phenylenevinylene COEs with varying lengths and numbers of charged groups to address these uncertainties. Examination of the organization within lipid bilayers through polarized fluorescence microscopy shows that the optical transition moments are perpendicular to the bilayer plane, with the conjugated segment flanked by hydrophobic phospholipid tails. COEs initially form a disorganized layer on the vesicle periphery, reflecting electrostatic association before intercalation. Uptake experiments show that longer dimensions and increased numbers of charges allow for a higher degree of cellular association. Both shorter core length and increased number of charges accelerate the rate needed to achieve emission saturation. [Display omitted] •Membrane-intercalating COEs span the whole lipid bilayer core•Longer COEs and increasing the number of charges improve cell association•Shorter COEs and more highly charged COEs improve the rate of cell staining Zhu and Bazan explore the geometry of membrane-intercalating COEs within lipid bilayers and provide guiding molecular design principles for transmembrane dyes. Structure-activity relationship studies of a homologous series of elongated COEs show how fine-tuning molecular length and charge density can impact both the rate and degree of cellular association.