title: Molecular dynamics simulations of interaction between protein-tyrosine phosphatase 1B and a bidentate inhibitor.
abstract: OBJECTIVE
  To investigate the dynamic properties of protein-tyrosine phosphatase (PTP) 1B and reveal the structural factors responsible for the high inhibitory potency and selectivity of the inhibitor SNA for PTP1B.
  
  
  METHODS
  We performed molecular dynamics (MD) simulations using a long time-scale for both PTP1B and PTP1B complexed with the inhibitor SNA, the most potent and selective PTP1B inhibitor reported to date. The trajectories were analyzed by using principal component analysis.
  
  
  RESULTS
  Trajectory analyses showed that upon binding the ligand, the flexibility of the entire PTP1B molecule decreases. The most notable change is the movement of the WPD-loop. Our simulation results also indicated that electrostatic interactions contribute more to PTP1B-SNA complex conformation than the van der Waals interactions, and that Lys41, Arg47, and Asp48 play important roles in determining the conformation of the inhibitor SNA and in the potency and selectivity of the inhibitor. Of these, Arg47 contributed most. These results were in agreement with previous experimental results.
  
  
  CONCLUSIONS
  The information presented here suggests that potent and selective PTP1B inhibitors can be designed by targeting the surface residues, for example the region containing Lys41, Arg47, and Asp48, instead of the second phosphate binding site (besides the active phosphate binding site).
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, China. gxliu@ecust.edu.cn
authors.forename: Gui-xia
authors.initials: GX
authors.lastname: Liu
authors.forename: Jin-zhi
authors.initials: JZ
authors.lastname: Tan
authors.forename: Chun-ying
authors.initials: CY
authors.lastname: Niu
authors.forename: Jian-hua
authors.initials: JH
authors.lastname: Shen
authors.forename: Xiao-min
authors.initials: XM
authors.lastname: Luo
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.forename: Kai-xian
authors.initials: KX
authors.lastname: Chen
authors.forename: Hua-liang
authors.initials: HL
authors.lastname: Jiang
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D025341:Principal Component Analysis; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases