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PMID: 12524273 Published · ppublish English Evaluation Study Journal Article Research Support, Non-U.S. Gov't Validation Study

Molecular dynamics simulations on SDF-1alpha: binding with CXCR4 receptor.

Biophysical journal ·Vol. 84 ·No. 1 ·2003-01-00 ·Pages 171-84

Huang X, Shen J, Cui M, Shen L, Luo X, Ling K, Pei G, Jiang H, Chen K

Abstract

Insights into the interacting mode of CXCR4 with SDF-1alpha 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-1alpha. 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-1alpha binding complex was generated. Arg188-Glu277 salt bridge plays an important role for both the extracellular domain conformational change and SDF-1alpha 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 approximately 60% and 40% to the binding affinity with SDF-1alpha, 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-1alpha binding, which may be possibly associated with signal transduction. Based on the modeling and simulation, a binding mechanism hypothesis between CXCR4 and SDF-1alpha and its relationship to the signal transduction has been proposed.

MeSH Terms
Algorithms Amino Acid Sequence Amino Acids/chemistry Base Sequence Binding Sites Chemokine CXCL12 Chemokines, CXC/chemistry Computer Simulation Cryoglobulins Extracellular Space/chemistry Hydrogen Bonding Kinetics Models, Chemical Models, Molecular Molecular Conformation Motion Protein Conformation Protein Folding Protein Structure, Tertiary Receptors, CXCR4/chemistry Structure-Activity Relationship Surface Properties
Chemicals
Amino Acids Chemokine CXCL12 Chemokines, CXC Cryoglobulins Receptors, CXCR4 macromolecular insoluble cold globulin
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Huang Xiaoqin
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, P R China.
Shen Jianhua
Cui Meng
Shen Lingling
Luo Xiaomin
Ling Kun
Pei Gang
Jiang Hualiang
Chen Kaixian
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Article Info
Journal
Biophysical journal
Abbr.
Biophys J
ISSN
0006-3495
DOI
10.1016/S0006-3495(03)74840-1
Published
2003-01-00
Pages
171-84
Language
English
Region
United States
NLM ID
0370626
PMCID
PMC1302601
Subset
IM
External Links
PubMed source DOI: 10.1016/S0006-3495(03)74840-1 PMC Full Text View journal details
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