Comments by J. C. Spencer

Recent discoveries that Trehalose can prohibit the cause of neurodegenerative challenges including Alzheimer�s disease has become well known but the mechanism has remained unclear until now. The key is preferential hydration on the peptide surface, and trehalose molecules cluster around the peptides. The Tianjin University research in China is published by the American Chemical Society July 2009 and the Journal of Chromatography.

Here is the Abstract and articles:

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[JPCB] Molecular Insight into the Inhibition Effect of Trehalose on the Nucleation and Elongation of Amyloid ?-Peptide Oligomers

2009-7-23
Fu-Feng Liu, Luo Ji, Xiao-Yan Dong and Yan Sun*
Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China
J. Phys. Chem. B, Article ASAP
DOI: 10.1021/jp905580j
Publication Date (Web): July 21, 2009
Copyright � 2009 American Chemical Society
*Corresponding author. Phone: +86 22 27404981. Fax: +86 22 27406590. E-mail: [email protected].

Abstract: Soluble amyloid oligomers are a cytotoxic species in Alzheimer's disease, and the recent discovery that trehalose can prohibit aggregation of amyloid ?-peptide (A?) has received great attention. However, its inhibition mechanism remains unclear. In order to investigate the molecular mechanism of the inhibition effect, molecular dynamics simulations of A?16-22 and A?40 peptides at different trehalose concentrations (0-0.18 mol/L) are performed using an all-atom model. The simulations confirmed that A?16-22 aggregation is prevented by trehalose in a dose-dependent manner, and it is found that the preferential exclusion effect of trehalose is the origin of its inhibition effects. Namely, there is preferential hydration on the peptide surface (3 �), and trehalose molecules cluster around the peptides at a distance of 4-5 �. At high trehalose concentrations, the preferential exclusion of trehalose leads to three sequential effects that prevent the nucleation and elongation of A?16-22 oligomers. First, the secondary structures of A?16-22 monomers are stabilized in the turn, bend or coil, so the ?-sheet-rich structure that is prone to forming peptide oligomers is prevented. Second, the thin hydration layer and trehalose clusters can weaken hydrophobic interactions that lead to A?16-22 aggregation. Third, more direct and indirect H-bonds form between trehalose and A?16-22, which suppress the inter-peptide hydrogen bonding. Analyses of the simulation data for a single A?40 peptide indicate that trehalose can inhibit the nucleation and elongation of A?40 by a similar mechanism with that on A?16-22 oligomerization. The work has thus elucidated the molecular mechanism of trehalose on the inhibition of A? oligomeric aggregation.

http://pubs.acs.org/doi/abs/10.1021/jp905580j

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Journal of Chromatography A - Rational design of affinity peptide ligand by flexible docking simulation

Fufeng Liu, Tianjin University

Rational design of affinity peptide ligand by flexible docking simulation

Journal of Chromatography
2007, 1146: 41�50 3.641
http://dx.doi.org/10.1016/j.chroma.2007.01.130

Rational design of affinity peptide ligands of proteins by flexible docking simulation is performed using the SYBYL program package. This approach involves the use of experimental data to verify a scoring function that can be used to assess the affinity of a peptide for its target protein. The enzyme-linked immunosorbent assay (ELISA) data of several peptides displayed on phage surfaces for insulin and lysozyme, respectively, reported in literature are used for the purpose. It is found that the absolute values of the Dscore calculated from the docking correspond well to the ELISA data that relate to the affinity between the peptides and the target molecule. So, the Dscore function is used to assess the affinity of docked peptides in a pentapeptide library designed on the basis of protein (alpha-amylase) structure. As a result, a pentapeptide with a high Dscore value is selected and a hexapeptide (FHENWS) is built by linking serine to its C-terminal to lengthen the peptide. Molecular surface analysis with the MOLCAD program reveals that electrostatic interactions (including hydrogen bonds) and Van der Waals forces contribute to the affinity of the hexapeptide for alpha-amylase. Chromatographic experiments with the immobilized peptide have given further evidence for this observation. Adsorption isotherm described by the Langmuir equation indicates that the apparent binding constant of alpha-amylase to the immobilized hexapeptide was 2.5�105 L/mol. Finally, high affinity and specificity of the affinity adsorbent is exemplified by the purification of alpha-amylase from crude fermentation broth of Bacillus subtilis.

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