How is the interaction of a chloride channel blocker with phospholipids influenced by divalent metal ions? Effect of unsaturation on the lipid side chain.

• Binding interaction of 9-methylanthroate (9MA) with lipids DMPC and POPC. • Effect of different divalent cations (Ca2+, Mg2+, Zn2+) on the binding interaction. • Degree of penetration of the cations on 9MA-DMPC assembly is Ca2+ < Mg2+ < Zn2+. • Unsaturation on the lipid side chain plays a key role for dissimilar metal effect. The present study reveals the effect of various divalent ions (Ca2+, Mg2+and Zn2+) on the binding interaction of a prospective chloride channel blocker, 9-methylanthroate (9MA), with liposome membranes, namely, dimyristoylphosphatidylcholine (DMPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). The liposome membranes DMPC and POPC differ in the unsaturation of the side-chain. The drug (9MA) is found to experience a greater degree of partitioning into the POPC lipid bilayer (containing unsaturated side-chain) in comparison to DMPC (containing saturated side-chain). The stronger 9MA-POPC binding interaction is found to be only nominally perturbed by the presence of metal salts. On the contrary, the 9MA-DMPC binding interaction is found to be significantly perturbed by the presence of metal salts and is manifested on the environment-responsive spectroscopic properties of the drug. The steady-state and picosecond-resolved fluorescence spectroscopic results reveal the effect of metal ions on DMPC bilayer to follow the trend Ca2+ < Mg2+ < Zn2+. This is also quantified by evaluating the partition coefficient of the drug into DMPC lipid in the presence of various divalent ions which is found to follow the same sequence. The degree of penetration of these cations has been rationalized on the basis of adsorption of cations on DMPC headgroup region resulting in dehydration of the headgroup along with shrinking of it. [ABSTRACT FROM AUTHOR]