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http://dx.doi.org/10.1007/s10059-009-0086-z

Interaction Models of Substrate Peptides and β-Secretase Studied by NMR Spectroscopy and Molecular Dynamics Simulation  

Lee, Jee-Young (Bio/Molecular Informatics Center, Department of Bioscience and Biotechnology, Konkuk University)
Lee, Sung-Ah (Bio/Molecular Informatics Center, Department of Bioscience and Biotechnology, Konkuk University)
Kim, Jin-Kyoung (Bio/Molecular Informatics Center, Department of Bioscience and Biotechnology, Konkuk University)
Chae, Chi-Bom (Institute of Biomedical Science and Technology, Konkuk University)
Kim, Yangmee (Bio/Molecular Informatics Center, Department of Bioscience and Biotechnology, Konkuk University)
Publication Information
Molecules and Cells / v.27, no.6, 2009 , pp. 651-656 More about this Journal
Abstract
The formation of ${\beta}$-amyloid peptide ($A{\beta}$) is initiated from cleavage of amyloid precursor protein (APP) by a family of protease, ${\alpha}$-, ${\beta}$-, and ${\gamma}$-secretase. Sub W, a substrate peptide, consists of 10 amino acids, which are adjacent to the ${\beta}$-cleavage site of wild-type APP, and Sub M is Swedish mutant with double mutations on the left side of the ${\beta}$-cleavage site of APP. Sub W is a normal product of the metabolism of APP in the secretary pathway. Sub M is known to increase the efficiency of ${\beta}$-secretase activity, resulting in a more specific binding model compared to Sub W. Three-dimensional structures of Sub W and Sub M were studied by CD and NMR spectroscopy in water solution. On the basis of these structures, interaction models of ${\beta}$-secretase and substrate peptides were determined by molecular dynamics simulation. Four hydrogen bonds and one water-mediated interaction were formed in the docking models. In particular, the hydrogen bonding network of Sub M-BACE formed spread over the broad region of the active site of ${\beta}$-secretase (P5-P3'), and the side chain of P2- Asn formed a hydrogen bond specifically with the side chain of Arg235. These are more favorable to the cleavage of Sub M by ${\beta}$-secretase than Sub W. The two substrate peptides showed different tendency to bind to ${\beta}$-secretase and this information may useful for drug development to treat and prevent Alzheimer's disease.
Keywords
${\beta}$-secretase; Alzheimer's disease; amyloid precursor protein; molecular dynamics simulation; NMR; Swedish mutant;
Citations & Related Records
Times Cited By KSCI : 2  (Citation Analysis)
Times Cited By Web Of Science : 4  (Related Records In Web of Science)
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