Electrostatics of cell membrane recognition: Structure and activity of neutral and cationic rigid push-pull rods in isoelectric, anionic, and polarized lipid bilayer membranes

Design, synthesis, and structural and functional studies of rigid-rod ionop hores of different axial electrostatic asymmetry are reported. The employed design strategy emphasized presence of(a) a rigid scaffold to minimize the conformational complexity, (b) a unimolecular ion-conducting pathway to mi nimize the suprastructural complexity and monitor the function, (c) an exte nded fluorophore to monitor structure, (d) variable axial rod dipole, and ( e) variable terminal charges to create axial asymmetry. Studies in isoelect ric, anionic, and polarized bilayer membranes confirmed a general increase in activity of uncharged rigid push-pull rods in polarized bilayers. The si milarly increased activity of cationic rigid push-pull rods with an electro static asymmetry comparable to that of cr-helical bee toxin melittin (posit ive charge near negative axial dipole terminus) is shown by fluorescence-de pth quenching experiments to originate from the stabilization of, transmemb rane rod orientation by the membrane potential. The reduced activity of rig id push-pull rods having an electrostatic asymmetry comparable to that in o r-helical natural antibiotics (a positive charge near the positive axial di pole terminus) is shown by structural studies to originate from rod "ejecti on" by membrane potentials comparable to that found in mammalian plasma mem branes. This structural evidence for cell membrane recognition by asymmetri c rods is unprecedented and of possible practical importance with regard to antibiotic resistance.