Conformational flexibility of beta-secretase: molecular dynamics simulation and essential dynamics analysis.
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.
Xiong
Bin
B
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.
Huang
Xiao-Qin
XQ
Shen
Ling-Ling
LL
Shen
Jian-Hua
JH
Luo
Xiao-Min
XM
Shen
Xu
X
Jiang
Hua-Liang
HL
Chen
Kai-Xian
KX
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
D008024:Ligands; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases