The effects of lipid-drug interaction are crucial in understanding the efficacy, efficiency, and toxicity of drugs. The interaction of amphipathic molecules with membranes is related to several cellular processes such as signaling, ion conductance, energy conversion and action of local anesthetics. In this study, we employ fluorescence anisotropy, isothermal titration calorimetry (ITC), equilibrium dialysis, and molecular dynamics (MD) simulations to characterize the interaction of small amphipathic molecules with membranes. Further, the effects of membrane curvature and fluidity on drug-lipid interactions have not been fully elucidated at the molecular level. Here we study the interactions of the drug dibucaine with small unilamellar vesicles (SUVs) of different sizes prepared with lipid 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), to determine the underlying thermodynamical and physiological properties of drug-membrane interaction as a function of curvature. Specifically, we determine free energy, enthalpy, entropy, binding constant, and anisotropy of drug-membrane interaction. We used fluorescent dye, 1,6-diphenyl-1,3,5-hexatriene (DPH) embedded into lipid bilayer to study the changes in membrane fluidity upon binding of dibucaine. We use ITC and equilibrium dialysis to characterize the thermodynamics of drug binding to membrane with different curvature. We use molecular dynamic (MD) simulations to understand the detailed molecular picture of drug binding to membrane with different curvature. We find that binding of amphipathic drug to highly curved vesicle is ehthalpically driven, as evident by the heat released measured by ITC. On the other hand, binding of drug to a flat membrane is entropically driven as evident by increase in membrane fluidity measured by fluorescence anisotropy. These studies suggest that it might be possible to rationally design or modify a drug to preferentially target flat or curved membranes.

Thermodynamical investigation of drug-dipid interaction

244th National Meeting (2012)

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