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The Interaction of Flavonols with Membrane Components: Potential Effect on Antioxidant Activity

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Abstract

Flavonols are the most widely distributed class of dietary flavonoids with a wide range of pharmacological properties due to their potent lipid peroxidation inhibition activity. The permeability and orientation of these compounds in lipid bilayers can provide an understanding of their antioxidant and lipid-peroxidation inhibition activity based on their structures at the molecular level. For this purpose, we studied antioxidant activity and atomic-scale molecular dynamics simulations of 3-hydroxyflavone (fisetin), 5-hydroxyflavone (apigenin) and 3,5-hydroxyflavone (morin) in palmitoyloleylphosphatidylcholine (POPC) membrane models with 0 mol% and 40 mol% cholesterol concentration. In pure POPC bilayer with 0 mol% cholesterol concentration, the flavonols penetrated into bilayer with lowest free energy profiles, however, incorporation of 40% cholesterol concentration reduced the permeability of the flavonols. Higher cholesterol concentrations in the POPC lipid bilayer resulted in an increase of the bilayer thickness and corresponding decrease in the area per lipid which rationalizes the reduced partitioning of flavonols due to cholesterol. In the presence of cholesterol, the flavonols reside at the polar interfacial region of the lipid bilayer to form higher H-bonding interactions with cholesterol molecules in addition to water and lipid oxygens. Among all the selected flavonols, morin showed the highest affinity which was driven by the hydrophobic effect as also depicted by ITC (Isothermal titration calorimetry) experiments and thus, more efficient antioxidant in scavenging superoxide, nitric oxide radicals as well as lipid peroxyl radicals. Furthermore, our simulations also confirmed that the permeability of compounds is sensitive towards the cholesterol content in the membrane.

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Acknowledgements

We sincerely thank Indian Institute of Technology Delhi HPC facility for computational resources.

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Authors and Affiliations

  1. Materials Science and Engineering, Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar, Gujarat, India

    Sarmistha Saha

  2. Department of Physiology and Pharmacology “Vittorio Erspamer, Sapienza University of Rome, Rome, Italy

    Emiliano Panieri & Luciano Saso

  3. Faculty of Pharmacy, Ankara University, Ankara, Turkey

    Sibel Suzen

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  1. Sarmistha Saha
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Correspondence to Sarmistha Saha.

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232_2019_105_MOESM1_ESM.jpg

Supplementary material 1 Planar chemical structures of the compounds: (A) fisetin, (B) apigenin and (C) morin. The 2-D chemical structures were obtained by ChemDraw 12.0 and the 3-D structures were obtained by the program PyMOL. (JPEG 85 kb)

232_2019_105_MOESM2_ESM.jpg

Supplementary material 2 Snapshots of MD simulations at 25 and 50 ns in the POPC lipid bilayer characteristic to the location (a, b) fisetin, (c, d) apigenin and (e, f) morin, respectively. (JPEG 333 kb)

232_2019_105_MOESM3_ESM.jpg

Supplementary material 3 Snapshots of MD simulations at 25 and 50 ns in the POPC lipid bilayer with 40% cholesterol characteristic to the location (a, b) fisetin, (c, d) apigenin and (e, f) morin, respectively.(JPEG 325 kb)

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Saha, S., Panieri, E., Suzen, S. et al. The Interaction of Flavonols with Membrane Components: Potential Effect on Antioxidant Activity. J Membrane Biol 253, 57–71 (2020). https://doi.org/10.1007/s00232-019-00105-1

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