title: Conformational flexibility of beta-secretase: molecular dynamics simulation and essential dynamics analysis.
abstract: OBJECTIVE
  Based on the structural analysis to reveal the mechanism of ligand binding to beta-secretase and the specificity of each binding sub-site.
  
  
  METHODS
  Molecular dynamics was used to simulate on the ligand free beta-secretase and ligand bound beta-secretase. The trajectories were analyzed using the essential dynamics, and the significant conformational change was illustrated employing the DynDom program.
  
  
  RESULTS
  The essential dynamics and DynDom analyses clearly showed that the beta-secretase experienced a large conformational change upon the substrate or inhibitor binding. The flap structure adopted a swing motion, gradually covering the active site to facilitate the ligand binding process. Residues Ser86 and Ile87 served as the hinge point. Inhibitor-enzyme interaction analysis revealed that residues at P2, P1, and P1' positions of the inhibitor were very important for the binding, and residues at P2' and P3' positions may be modified to improve the binding specificity. S3 subsite of the enzyme still had space to modify the inhibitors in increasing the binding affinity.
  
  
  CONCLUSIONS
  The information presented here is valuable and could be used to identify small molecular inhibitors of beta-secretase.
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Xiong
authors.forename: Xiao-Qin
authors.initials: XQ
authors.lastname: Huang
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Shen
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: Hua-Liang
authors.initials: HL
authors.lastname: Jiang
authors.forename: Kai-Xian
authors.initials: KX
authors.lastname: Chen
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D003198:Computer Simulation; D010450:Endopeptidases; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D008024:Ligands; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases