Hesperidin and naringin are predominant flavonoids in citrus fruits and exert various biological activities. However, mechanism of these activities has not been completely investigated at cellular and molecular levels. For this reason, we aim to systematically elucidate molecular interactions between citrus flavonoids, hesperidin and naringin, and model lipid membranes composed of dimyristoylphosphatidylcholine (DMPC) using combinatorial experimental biophysical techniques, attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy, differential scanning calorimetry (DSC), atomic force microscopy (AFM) and field emission scanning electron microscopy (FE-SEM) as a function of citrus flavonoid concentrations, and computational study. ATR-FTIR showed that both flavonoids significantly increase the fluidity of DMPC membranes with the increase in the bandwidth values of the CH2 antisymmetric stretching vibration. While hesperidin exhibits weakly disordering effect in hydrophobic region, naringin has an ordering effect in this region. Both flavonoids induce alterations in the arrangement of polar heads of lipids. DSC revealed that naringin significantly influences the cooperativity and thermotropic phase behavior of DMPC compared to hesperidin. Furthermore, microscopic observations are in cooperation with the spectroscopic and calorimetric results indicating that naringin is more effective than hesperidin in terms of inducing changes in the membrane organization. Density functional theory (DFT) study demonstrated that both DMPC − Hesperidin and DMPC − Naringin systems form strong hydrogen bonding via PO2− moieties. Methodologies showed that small structural differences can influence the membrane bilayers distinctly. Consequently, this study implies that variations in structural and dynamical properties of lipid membranes can be critical for processes involving the inhibition of lipid peroxidation and antioxidant mechanism.
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