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Molecular Dynamics Simulations on SDF-1: Binding with CXCR4 Receptor

Xiaoqin Huang^*,, Jianhua Shen^*, Meng Cui^*, Lingling Shen^*, Xiaomin Luo^*, Kun Ling, Gang Pei, Hualiang Jiang^* and Kaixian Chen^*

^* Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, P. R. China; and Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032, P. R. China

Correspondence: Address reprint requests to Prof. Hualiang Jiang, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai 200031, P.R. China. Tel.: +86-21-64318401; Fax: +86-21-64318401; E-mail: jiang{at}iris3.simm.ac.cn, or hljiang{at}mail.shcnc.ac.cn. Prof. Gang Pei, E-mail: gpei{at}sibs.ac.cn. Dr. Jianhua Shen, E-mail: jhshen{at}mail.shcnc.ac.cn

Insights into the interacting mode of CXCR4 with SDF-1 are crucial in understanding the structural and functional characteristics of CXCR4 receptor. In this paper a computational pipeline, integrating protein structure prediction, molecular dynamics simulations, automated molecular docking, and Brownian dynamics simulations were employed to investigate the dynamic and energetic aspects of CXCR4 associating with SDF-1. The entire simulation revealed the surface distribution feature of electrostatic potentials and conformational "open-close" process of the receptor. The possible binding conformation of CXCR4 was identified, and the CXCR4—SDF-1 binding complex was generated. Arg188-Glu277 salt bridge plays an important role for both the extracellular domain conformational change and SDF-1 binding. Two binding sites were mapped at the extracellular domain (Site 1) and inside the transmembrane domain (Site 2), which are composed of conserved residues. Sites 1 and 2 contribute 60% and 40% to the binding affinity with SDF-1, respectively. The binding model is in agreement with most of the experimental data. Transmembrane VI has more significant motion in the harmonious conformational transition of CXCR4 during SDF-1 binding, which may be possibly associated with signal transduction. Based on the modeling and simulation, a binding mechanism hypothesis between CXCR4 and SDF-1 and its relationship to the signal transduction has been proposed.

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