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

BMC Bioinformatics

Proceedings

Weida Tong¹  Jie Shen¹  Wenqian Zhang¹  Huixiao Hong¹  Roger Perkins¹  Hong Fang² 

[1] Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, 72079, Jefferson, AR, USA;Office of Scientific Coordination, National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, 72079, Jefferson, AR, USA;

关键词: Molecular Dynamic Simulation;    Protein Data Bank;    Molecular Docking;    Root Mean Square Deviation;    Homology Modeling;   

DOI  :  10.1186/1471-2105-14-S14-S6

来源: Springer

【 摘 要 】

BackgroundAn 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.MethodsHomology 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.ResultsA 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.ConclusionThe 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.

【 授权许可】

Unknown   
© Shen et al; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.