Classical molecular dynamics simulation of GB1 peptide (a 16-residue β-hairpin) in different osmotic environments is studied. Urea is used for denaturation of the peptide, and trimethylamine-N-oxide (TMAO) is used to offset the effect of urea. Protein-urea electrostatic interactions are found to play a major role in protein-denaturation. To emphasize on protein protecting action of TMAO against urea, two different models of TMAO are used, viz., the Kast model and the Osmotic model. We observe that the Osmotic model of TMAO gives the best protection to counteract urea's action when used in ratio 1:2 of urea:TMAO (i.e., reverse ratio). This is because the presence of TMAO makes urea-protein electrostatic interactions more unfavorable. Preferential solvation of TMAO molecules by urea (and water) molecules is also observed, which causes depletion in the number of urea molecules in the vicinity of the protein. The calculations of intraprotein hydrogen bonds between different residues of protein further reveal the breaking of backbone hydrogen bonds of residues 2 and 15 in the presence of urea, and the same is preserved in the presence of TMAO. Free energy landscapes show that the narrowest distribution is obtained for the osmotic TMAO model when used in reverse ratio.

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Commonly used denaturants for protein denaturation are conventionally required in high concentrations in order to produce their effects. In this study, a molecular dynamics simulation of a mutated version of the N-terminal domain of a λ-repressor is carried out in the presence of a 10 millimolar (mM) concentration of dodine. Such a small concentration is found to be effective for denaturation of the protein. Both electrostatic and van der Waals interactions (between protein and dodine) play a role in the denaturation process and we observe more denaturation at the terminal helices. Three different molar concentrations of trehalose are used in order to check the counteraction against the action of dodine. This study shows that 0.5 and 1.0 M trehalose are sufficient to counteract the action of dodine. The study also sheds light on the fact that some protein sites are more responsive to unfolding, which is evident from the helical fractions of the terminal helices for different systems. The counteraction of trehalose on dodine-induced protein denaturation is found to be due to the replacement of some of the dodine molecules by trehalose molecules in the solvation shell of the protein. Preferential solvation of dodine molecules by trehalose molecules through hydrogen bonding interactions also plays a vital role in stabilizing the native conformation of the protein in a high trehalose concentration. Replacement of protein-dodine and protein-water hydrogen bonds by protein-trehalose hydrogen bonds is also observed.

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.

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