Six OH-PBDEs, which have been reported as weak ERα ligands, were selected for mechanism exploration in this work, and their binding interactions with ERα were explored through molecular simulation. The results indicated that both mode of interaction and intensity of interaction may decide the estrogenic and anti-estrogenic activities of the chemicals. Three para-hydroxylated PBDEs display higher binding affinity for ERα, while their different binding sites and orientation in the pocket lead to different estrogenic effect. A strong hydrogen bond net is formed between 4'-OH-BDE-17 with Arg394 and Glu353, while the phenolic hydroxyl of 4'-OH-BDE-49 and 4-OH-BDE-42 only can interact with His524. However, all present comparatively similar alignment as E2 in the pocket, thereby help H12 closing the narrow entrance to the pocket, and allow coactivators to bind. On the contrary, one phenyl ring of the two ortho-hydroxylated PBDEs, 2'-OH-BDE-28 and 6-OH-BDE-47, stretches out and points to the pocket entrance. Such may push away H12, induce a different orientation of H12, and finally adapt the protein conformation into its antagonism status. In addition, steric effect of Br substitution adjacent to the phenolic hydroxyl may result in intensity decrease of the related hydrogen bonds, which alters the activity of OH-PBDEs.
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