TY - JOUR
T1 - Molecular dynamics simulations on SDF-1α
T2 - Binding with CXCR4 receptor
AU - Huang, Xiaoqin
AU - Shen, Jianhua
AU - Cui, Meng
AU - Shen, Lingling
AU - Luo, Xiaomin
AU - Ling, Kun
AU - Pei, Gang
AU - Jiang, Hualiang
AU - Chen, Kaixian
N1 - Funding Information:
We extend great thanks to Professor Helmut Grubmüller for his kindly offering the EGO program, to Professor Arthur J. Olson for his provision of the AutoDock 3.0 program, and to Professor S. H. Northrup for his kindness in offering us the MacroDox 3.2.2 program. The authors also wish to thank Dr. Wenbo Zhang of Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, for his helpful discussion. The MD calculations were performed on the ShenWei-I supercomputer at the Shanghai Supercomputer Center. This work was supported by the Ministry of Science and Technology (Grants 1999053907 and 1999054003), the 863 High-Tech Project (Grant 2001AA235131), the National Natural Science Foundation of China (Grants 29725203 and 39825110), Chinese Academy of Sciences (Grant KSCX2-2-02), and the State Key Program of Basic Research of China (Grant 1998051115).
PY - 2003/1/1
Y1 - 2003/1/1
N2 - Insights into the interacting mode of CXCR4 with SDF-1α 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-1α. 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-1α binding complex was generated. Arg188-Glu277 salt bridge plays an important role for both the extracellular domain conformational change and SDF-1α 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-1α, 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-1α binding, which may be possibly associated with signal transduction. Based on the modeling and simulation, a binding mechanism hypothesis between CXCR4 and SDF-1α and its relationship to the signal transduction has been proposed.
AB - Insights into the interacting mode of CXCR4 with SDF-1α 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-1α. 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-1α binding complex was generated. Arg188-Glu277 salt bridge plays an important role for both the extracellular domain conformational change and SDF-1α 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-1α, 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-1α binding, which may be possibly associated with signal transduction. Based on the modeling and simulation, a binding mechanism hypothesis between CXCR4 and SDF-1α and its relationship to the signal transduction has been proposed.
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U2 - 10.1016/S0006-3495(03)74840-1
DO - 10.1016/S0006-3495(03)74840-1
M3 - Article
C2 - 12524273
AN - SCOPUS:0037214576
SN - 0006-3495
VL - 84
SP - 171
EP - 184
JO - Biophysical Journal
JF - Biophysical Journal
IS - 1
ER -