Insights into the Interaction between Polyphenols and β-Lactoglobulin through Molecular Docking, MD Simulation, and QM/MM Approaches

[Image: see text] In this work, we have explored the interaction of three different polyphenols with the food protein β-lactoglobulin. Antioxidant activities of polyphenols are influenced by complexation with the protein. However, studies have shown that polyphenols after complexation with the protein can be more beneficial due to enhanced antioxidant activities. We have carried out molecular docking, molecular dynamics (MD) simulation, and quantum mechanics/molecular mechanics (QM/MM) studies on the three different protein–polyphenol complexes. We have found from molecular docking studies that apigenin binds in the internal cavity, luteolin binds at the mouth of the cavity, and eriodictyol binds outside the cavity of the protein. Docking studies have also provided binding free energy and inhibition constant values that showed that eriodictyol and apigenin exhibit better binding interactions with the protein than luteolin. For eriodictyol and luteolin, van der Waals, hydrophobic, and hydrogen bonding interactions are the main interacting forces, whereas for apigenin, hydrophobic and van der Waals interactions play major roles. We have calculated the root mean square deviation (RMSD), root mean square fluctuations (RMSF), solvent-accessible surface area (SASA), interaction energies, and hydrogen bonds of the protein–polyphenol complexes. Results show that the protein–eriodictyol complex is more stable than the other complexes. We have performed ONIOM calculations to study the antioxidant properties of the polyphenols. We have found that apigenin and luteolin act as better antioxidants than eriodictyol does on complexation with the protein, which is consistent with the results obtained from MD simulations.