Electrostatics of cell membrane recognition: Structure and activity of neutral and cationic rigid push-pull rods in isoelectric, anionic, and polarized lipid bilayer membranes
N. Sakai et al., Electrostatics of cell membrane recognition: Structure and activity of neutral and cationic rigid push-pull rods in isoelectric, anionic, and polarized lipid bilayer membranes, J AM CHEM S, 123(11), 2001, pp. 2517-2524
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.