Interaction of Coumarin Phytoestrogens with ERα and ERβ: A Molecular Dynamics Simulation Study

Abstract

Coumarin phytoestrogens, as one of the important classes of phytoestrogens, have been proved to play an important role in various fields of human life. In this study, molecular simulation method including molecular docking and molecular dynamics methods were performed to explore the various effects between four classical coumarin phytoestrogens (coumestrol, 4-methoxycoumestrol, psoralen and isopsoralen), and estrogen receptors (ER_α, ER_β), respectively. The calculated results not only proved that the four coumarin phytoestrogens have weaker affinity than 17β-estradiol to both ER_α, and ER_β, but also pointed out that the selective affinity for ER_β is greater than ER_α. In addition, the binding mode indicated that the formation of hydrogen bond and hydrophobic interaction have an important effect on the stability of the complexes. Further, the calculation and decomposition of binding free energy explored the main contribution interactions to the total free energy.

Keywords: binding free energy; coumarin; estrogen receptor; molecular dynamics simulation; phytoestrogens.

Figure 1

Chemical structure of four coumarin phytoestrogens: (a) coumestrol, (b) 4-methoxycoumestrol, (c) psoralen, (d) isopsoralen as well as (e) 17β-estradiol.

Figure 2

RMSD values of ER-ligand complexes in 100 ns MD simulation (a) in the ER_α system, (b) in the ER_β system.

Figure 3

RMSDvalues of the four coumarin phytoestrogens as well as 17β-estradiol (a) in the ER_α system, (b) in the ER_β system.

Figure 4

RMSF values of ER-ligand complexes in 100 ns MD simulation (a) in the ER_α system, (b) in the ER_β system.

Figure 5

Interaction between ligands and proteins: (a) in the ER_α system; (b) in the ER_β system.

Figure 5

Interaction between ligands and proteins: (a) in the ER_α system; (b) in the ER_β system.

Figure 6

Hydrophobic interaction of complexes, the color from red to blue indicates a decrease in hydrophobic potential.

Figure 6

Hydrophobic interaction of complexes, the color from red to blue indicates a decrease in hydrophobic potential.

Figure 7

Contribution of key amino acids to binding free energy in the ER_α system. Black part: van der Waals and non-polar solvation energy; gray part: electrostatic energy and polar solvation energy. The positive values in the Figure are not conducive to the binding of the ligand to the receptor, and the negative value facilitates the binding of the ligand to the receptor.

Figure 8

Contribution of key amino acids to binding free energy in the ER_β system. Black part: van der Waals and non-polar solvation energy; gray part: electrostatic energy and polar solvation energy. The positive values in the figure are not conducive to the binding of the ligand to the receptor, and the negative value facilitates the binding of the ligand to the receptor.