Activity of synthetic ion channels is influenced by cation-pi interactions with phospholipid headgroups

Abstract

A suite of synthetic hydraphile ion channels has been used to probe the possibility of cation-pi interactions between the channel and the phospholipid bilayer. The hydraphiles selected for this study contained either no sidearm, aliphatic sidearms or aromatic sidearms that varied in electron-richness. An ion selective electrode (ISE) method was used to evaluate the ion transport ability of these hydraphiles across synthetic bilayers. Transport was dependent on sidearm identity. Ion transport activity for the aromatic sidechained compounds was greatest when the sidearms were electron rich and vesicles were prepared from 100% DOPC (trimethylammonium cation headgroup, overall neutral). When the lipid headgroups were made more negative by changing the composition from DOPC to 70 : 30 (w/w) DOPC : DOPA, transport by the aromatic-sidechained channels was reduced. Fluorescence studies showed that when the lipid composition changed, the headgroups experienced a different polarity, suggesting reorientation. The data are in accord with a stabilizing cation-pi interaction between the aromatic sidearm of the hydraphile channel and the ammonium phospholipid headgroup.

Fig. 1

Fractional sodium ion release from liposomes ([lipid] 0.4 mM) mediated by 12 μM of compounds 2-7 as determined by ISE methods.

Fig. 2

Dependence of Na⁺ release at 1500 s from liposomes mediated by compounds 1-7. Filled bars: liposomes prepared from pure DOPC. Open bars: liposomes prepared from 70 : 30 (w/w) DOPC : DOPA.

Fig. 3

Hammett substituent constant dependence of Na⁺ release at 1500 s from liposomes mediated by compounds 2, 4, 5, and 6. The transport data show a reasonable correlation with the electronic effect.

Fig. 4

Fluorescence spectra for dansyl channel 7 in (bottom line) buffer, in pure DOPC liposomes, and (top line) 70 : 30 (w/w) DOPC : DOPA liposomes.

Fig. 5

Ribbon structure of the KcsA potassium channel with Phe (yellow), Tyr (pink), Trp (blue) depicted as space filling models. This image was constructed using Protein Explorer from the crystallographic coordinates 1BL8 of the KcsA channel from Streptomyces lividans as determined by Doyle et al.