Computational protocol: 3D Models of MBP, a Biologically Active Metabolite of Bisphenol A, in Human Estrogen Receptor α and Estrogen Receptor β

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Protocol publication

[…] Human ERα was downloaded from the Protein Data Bank [PDB] as a template for docking of MBP and BPA. ChemDraw 3D was used to create PDB files for MBP and BPA, which were docked to human ERα [PDB:1G50] with AutoDock 4 , and AutoDock Vina . The grid was centered over the estrogen binding site in human ERα. AutoDock 4 was run using the Lamarckian Genetic Algorithm for 250 trials of 5 million energy evaluations. AutoDock Vina was run with a setting of 20 for exhaustiveness and poses for the 100 lowest energies were collected.The crystal structure of ERβ complexed with E2 [PDB:3OLS] was selected for docking MBP and BPA. As was found in other ERβ structures in the PDB, 3OLS lacks coordinates for five amino acids corresponding to residues 416–420. To model the missing amino acids, we used the Homology option in Insight II and the 1G50 structure for human ERα as a template. A PDB file of the complete ERβ with E2 was refined with Discover 3 with the CVFF force field and a distant dependent dielectric constant of 2 for 50 iterations. We docked MBP and BPA into this PDB file of human ERβ with AutoDock 4 and AutoDockVina with the settings used previously for human ERα.The lowest energy complexes of MBP and BPA in ERα and ERβ, as calculated by AutoDock 4 and AutoDock Vina, were refined with the Discover 3 software in Insight II. For this energy minimization step, Discover 3 was used with the CVFF force field and a distant dependent dielectric constant of 2 for 10,000 iterations. During this refinement step, both the amino acids on the ERs and MBP and BPA rearrange their positions so as to lower the Gibbs free energy of the complex. [...] We used X-Score , and DSX [DrugScore eXtended] to estimate the relative binding energy of MBP and BPA in the various configurations in ERα and ERβ. X-Score uses an empirical scoring function to estimate the affinity of a ligand for a protein. DSX uses a knowledge-based scoring function based on the DrugScore formalism to estimate the affinity of a ligand for a protein. In comparing the score of two ligands for a protein, the ligand with the larger negative score has the higher affinity. […]

Pipeline specifications

Software tools ChemDraw, AutoDock, AutoDock Vina, DSX
Applications Drug design, Protein interaction analysis
Organisms Homo sapiens
Diseases Spinocerebellar Ataxias
Chemicals Estradiol, Estrogens