Interaction of amphiphilic coumarin with DPPC/DPPS lipid bilayer: effects of concentration and alkyl tail length.

Poornima Kalyanram, Huilin Ma, Shena Marshall, Christina Goudreau, Ana Cartaya, Tyler Zimmermann, Istvan Stadler, Shikha Nangia, Anju Gupta

Physical chemistry chemical physics : PCCP 2020 Jul 21

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In this work, interactions between amphiphilic amino methyl coum arin and dipalmitoyl-sn-glycero-3-phosphocholine/dipalmitoyl-sn-glycero-3-phosphoserine (DPPC/DPPS) lipid bilayer were investigated. A combination of experimental techniques (zeta potential, fluorescence spectroscopy, and differential scanning calorimetry) along with molecular dynamics simulations was employed to examine the influence of alkyl tail length and concentration of the amphiphilic coumarin on the lipid bilayer. Alkyl tails comprising 5(C5), 9(C9), and 12(C12) carbon atoms were conjugated to amino methyl coum arin via a single-step process. The binding and insertion mechanisms of the amphiphilic coumarins were studied in increasing concentrations for short-tailed (C5) and long-tailed (C12) coumarins. The simulation results show that C5 coumarin molecules penetrate the lipid bilayer, but owing to the short alkyl tail, they interact primarily with the lipid head groups resulting in lipid bilayer thinning; however, at high concentrations, the C5 coumarins undergo continuous insertion-ejection from the outer leaflet of the lipid bilayer. In contrast, C12 coumarins interact favorably with the hydrophobic lipid tails and lack the ejection-reinsertion behavior. Instead, the C12 coumarin molecules undergo flip-flops between the outer and inner leaflets of the lipid bilayer. At high concentrations, the high-frequency flip-flops lead to lipid destabilization, causing the lipid bilayer to rupture. The simulation results are in excellent agreement with the toxicity of amphiphilic coumarin activity in cancer cells. The efficacy of amphiphilic coumarins in liposomal lipid bilayers demonstrates the promise of these molecules as a tool in the treatment of cancer.

Citation

Poornima Kalyanram, Huilin Ma, Shena Marshall, Christina Goudreau, Ana Cartaya, Tyler Zimmermann, Istvan Stadler, Shikha Nangia, Anju Gupta. Interaction of amphiphilic coumarin with DPPC/DPPS lipid bilayer: effects of concentration and alkyl tail length. Physical chemistry chemical physics : PCCP. 2020 Jul 21;22(27):15197-15207