Background: An important mechanism of endocrine activity is chemicals entering target cells via transport\nproteins and then interacting with hormone receptors such as the estrogen receptor (ER). a-Fetoprotein (AFP) is a\nmajor transport protein in rodent serum that can bind and sequester estrogens, thus preventing entry to the\ntarget cell and where they could otherwise induce ER-mediated endocrine activity. Recently, we reported rat AFP\nbinding affinities for a large set of structurally diverse chemicals, including 53 binders and 72 non-binders.\nHowever, the lack of three-dimensional (3D) structures of rat AFP hinders further understanding of the structural\ndependence for binding. Therefore, a 3D structure of rat AFP was built using homology modeling in order to\nelucidate rat AFP-ligand binding modes through docking analyses and molecular dynamics (MD) simulations.\nMethods: Homology modeling was first applied to build a 3D structure of rat AFP. Molecular docking and\nMolecular Mechanics-Generalized Born Surface Area (MM-GBSA) scoring were then used to examine potential rat\nAFP ligand binding modes. MD simulations and free energy calculations were performed to refine models of\nbinding modes.\nResults: A rat AFP tertiary structure was first obtained using homology modeling and MD simulations. The rat AFPligand\nbinding modes of 13 structurally diverse, representative binders were calculated using molecular docking,\n(MM-GBSA) ranking and MD simulations. The key residues for rat AFP-ligand binding were postulated through\nanalyzing the binding modes.\nConclusion: The optimized 3D rat AFP structure and associated ligand binding modes shed light on rat AFP-ligand\nbinding interactions that, in turn, provide a means to estimate binding affinity of unknown chemicals. Our results\nwill assist in the evaluation of the endocrine disruption potential of chemicals.
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