Elsevier

Molecules and Cells

Volume 27, Issue 6, June 2009, Pages 651-656
Molecules and Cells

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

https://doi.org/10.1007/s10059-009-0086-zGet rights and content
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The formation of β-amyloid peptide (Aβ) is initiated from cleavage of amyloid precursor protein (APP) by a family of protease, α-, β-, and γ-secretase. Sub W, a substrate peptide, consists of 10 amino acids, which are adjacent to the β-cleavage site of wild-type APP, and Sub M is Swedish mutant with double mutations on the left side of the β-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 β-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 β-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 β-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 β-secretase than Sub W. The two substrate peptides showed different tendency to bind to β-secretase and this information may useful for drug development to treat and prevent Alzheimer’s disease.

Keywords

p-secretase
Alzheimer’s disease
amyloid precursor protein
molecular dynamics simulation
NMR
Swedish mutant

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