The molecular mechanism of bisphenol A (BPA) as an endocrine disruptor by interacting with nuclear receptors: insights from molecular dynamics (MD) simulations

Abstract

Bisphenol A (BPA) can interact with nuclear receptors and affect the normal function of nuclear receptors in very low doses, which causes BPA to be one of the most controversial endocrine disruptors. However, the detailed molecular mechanism about how BPA interferes the normal function of nuclear receptors is still undiscovered. Herein, molecular dynamics simulations were performed to explore the detailed interaction mechanism between BPA with three typical nuclear receptors, including hERα, hERRγ and hPPARγ. The simulation results and calculated binding free energies indicate that BPA can bind to these three nuclear receptors. The binding affinities of BPA were slightly lower than that of E2 to these three receptors. The simulation results proved that the binding process was mainly driven by direct hydrogen bond and hydrophobic interactions. In addition, structural analysis suggested that BPA could interact with these nuclear receptors by mimicking the action of natural hormone and keeping the nuclear receptors in active conformations. The present work provided the structural evidence to recognize BPA as an endocrine disruptor and would be important guidance for seeking safer substitutions of BPA.

Fig 1. The chemical structure of the ligands.

a) bisphenol A; b) 17β-estradiol (E2).

Fig 2. Monitoring of the equilibration of the MD trajectories of the four complexes.

a) Time evolution of the RMSD of all protein backbone atoms (C, CA, N); b) Time evolution of the RMSD of Cα atoms of the protein; c) Time evolution of the RMSD of the Cα atoms of residues around 5 Å of the ligand; d) Time evolution of the RMSD of heavy atoms for the ligands.

Fig 3. Conformation change of H6, β1 and β2 of hERRγ (residues 317–341).

a) The initial structure of the protein with BPA shown in yellow sticks; b) The conformations of the studied regions at different times; c) The poses of BPA in the binding pocket at different times; d) Time revolution of the RMSD of backbone atoms of residues 317–341.

Fig 4. The RMSFs of Cα atoms relative to the initial structure.

Fig 5. Cartoon representations of the active and inactive conformation of hERα.

a) The active state of the protein with H12 in red cartoon and coactivator in green cartoon; b) The inactive state of the protein with H12 (red) covered the shallow groove which would be occupied by the coactivator.

Fig 6. The distances between H11 and H12 of the four systems throughout the 100 ns molecular dynamics simulations.

Fig 7. Enthalpy evolution against the last 15 ns of the four systems.

Fig 8. Intermolecular ligand-receptor per-residue interaction spectrum of the four complexes.

Fig 9. Polar and nonpolar energy contributions of the identified key residues to the complex binding.

Fig 10. The binding pose of E2 and BPA in the binding site at 100 ns.

a) Binding mode of E2; b) Binding mode of BPA. The ligands are shown in yellow ball and sticks. hERα is shown in slate cartoon. Hydrogen bonds formed between the ligand and receptors are indicated as red dashed lines.

Fig 11. The interaction between BPA and hERRγ.

Protein is shown in cartoon colored slate. Key residues are shown in green sticks. BPA is shown in yellow ball and stick. Direct hydrogen bond is indicated as red dashes.

Fig 12. Direct interactions between BPA and hPPARγ.

a) Superimposition of the initial structure (cyan) to the 100ns structure (green) of hPPARγ-BPA complex with BPA shown in sticks; b) Movement of BPA in the binding pocket at different times; c) Sticks representation of the interaction between BPA (yellow) and hPPARγ (green).