Homology modeling, molecular docking, and molecular dynamics simulations elucidated alpha-fetoprotein binding modes.

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Shen J, Zhang W, Fang H, Perkins R, Tong W, Hong H

Homology modeling, molecular docking, and molecular dynamics simulations elucidated alpha-fetoprotein binding modes.

BMC Bioinformatics. 2013;14 Suppl 14:S6. doi: 10.1186/1471-2105-14-S14-S6. Epub 2013 Oct 9.

PubMed ID

24266910 [ View in PubMed

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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). alpha-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. CONCLUSION: 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.

DrugBank Data that Cites this Article

Drug Carriers

Drug	Carrier	Kind	Organism	Pharmacological Action	Actions
Dioxybenzone	Alpha-fetoprotein	Protein	Rat	Unknown	Binder	Details