title: Molecular dynamics simulations on SDF-1alpha: binding with CXCR4 receptor.
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.
authors.affiliation: 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.
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Huang
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shen
authors.forename: Meng
authors.initials: M
authors.lastname: Cui
authors.forename: Lingling
authors.initials: L
authors.lastname: Shen
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Luo
authors.forename: Kun
authors.initials: K
authors.lastname: Ling
authors.forename: Gang
authors.initials: G
authors.lastname: Pei
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D001483:Base Sequence; D001665:Binding Sites; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000737:chemistry*; D003198:Computer Simulation; D003450:Cryoglobulins; D005110:Extracellular Space / Q000737:chemistry; D006860:Hydrogen Bonding; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D009038:Motion; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D019718:Receptors, CXCR4 / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013499:Surface Properties
chemical_list: D000596:Amino Acids; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D003450:Cryoglobulins; D019718:Receptors, CXCR4; C018090:macromolecular insoluble cold globulin