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Issue 1, 2017
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A computational study of self-assembled hexapeptide inhibitors against amyloid-β (Aβ) aggregation

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Abstract

The fibrillation and deposition of amyloid-β (Aβ) peptides in human brains are pathologically linked to Alzheimer's disease (AD). Development of different inhibitors (peptides, organic molecules, and nanoparticles) to prevent Aβ aggregation becomes a promising therapeutic strategy for AD treatment. We recently propose a “like-interacts-like” design principle to computationally design/screen and experimentally validate a new set of hexapeptide inhibitors with completely different sequences from the Aβ sequence. These hexapeptide inhibitors inhibit Aβ aggregation and reduce Aβ-induced cytotoxicity. However, inhibitory mechanisms of these hexapeptides and the underlying interactions between hexapeptides and Aβ remain unclear. Herein we apply multi-scale computational methods (quantum-chemical calculations, molecular docking and explicit-solvent molecular dynamic simulation) to explore the structure, dynamics, and interaction between 3 identified hexapeptides (CTLWWG, GTVWWG, and CTIYWG) and different Aβ-derived fragments and an Aβ17–42 pentamer. When interacting with 6 Aβ-derived fragments, 3 hexapeptide inhibitors show stronger interactions with two lysine-included fragments (16KLVFFA21 and 27NKGAII33) than other fragments, indicating different sequence-specific interactions with Aβ. When interacting with the Aβ17–42 pentamer, the 3 peptides show similar binding modes and interaction mechanisms by preferentially binding to the edge of the Aβ17–42 pentamer to potentially block the Aβ elongation pathway. This work provides structural-based binding information on further modification and optimization of these peptide inhibitors to experimentally enhance their inhibitory abilities against Aβ aggregation.

Graphical abstract: A computational study of self-assembled hexapeptide inhibitors against amyloid-β (Aβ) aggregation

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Publication details

The article was received on 27 Oct 2016, accepted on 22 Nov 2016 and first published on 23 Nov 2016


Article type: Paper
DOI: 10.1039/C6CP07341G
Citation: Phys. Chem. Chem. Phys., 2017,19, 155-166
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    A computational study of self-assembled hexapeptide inhibitors against amyloid-β (Aβ) aggregation

    Y. Qiao, M. Zhang, Y. Liang, J. Zheng and G. Liang, Phys. Chem. Chem. Phys., 2017, 19, 155
    DOI: 10.1039/C6CP07341G

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