title: Homology modeling, molecular docking, and molecular dynamics simulations elucidated α-fetoprotein binding modes.
abstract: BACKGROUND
  An important mechanism of endocrine activity is chemicals entering target cells via transport proteins and then interacting with hormone receptors such as the estrogen receptor (ER). α-Fetoprotein (AFP) is a major transport protein in rodent serum that can bind and sequester estrogens, thus preventing entry to the target cell and where they could otherwise induce ER-mediated endocrine activity. Recently, we reported rat AFP binding affinities for a large set of structurally diverse chemicals, including 53 binders and 72 non-binders. However, the lack of three-dimensional (3D) structures of rat AFP hinders further understanding of the structural dependence for binding. Therefore, a 3D structure of rat AFP was built using homology modeling in order to elucidate rat AFP-ligand binding modes through docking analyses and molecular dynamics (MD) simulations.
  
  
  METHODS
  Homology modeling was first applied to build a 3D structure of rat AFP. Molecular docking and Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) scoring were then used to examine potential rat AFP ligand binding modes. MD simulations and free energy calculations were performed to refine models of binding modes.
  
  
  RESULTS
  A rat AFP tertiary structure was first obtained using homology modeling and MD simulations. The rat AFP-ligand binding modes of 13 structurally diverse, representative binders were calculated using molecular docking, (MM-GBSA) ranking and MD simulations. The key residues for rat AFP-ligand binding were postulated through analyzing the binding modes.
  
  
  CONCLUSIONS
  The optimized 3D rat AFP structure and associated ligand binding modes shed light on rat AFP-ligand binding interactions that, in turn, provide a means to estimate binding affinity of unknown chemicals. Our results will assist in the evaluation of the endocrine disruption potential of chemicals.
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.forename: Wenqian
authors.initials: W
authors.lastname: Zhang
authors.forename: Hong
authors.initials: H
authors.lastname: Fang
authors.forename: Roger
authors.initials: R
authors.lastname: Perkins
authors.forename: Weida
authors.initials: W
authors.lastname: Tong
authors.forename: Huixiao
authors.initials: H
authors.lastname: Hong
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D011817:Rabbits; D051381:Rats; D016415:Sequence Alignment; D000509:alpha-Fetoproteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: C483800:Afp protein, rat; D008024:Ligands; D000509:alpha-Fetoproteins