title: A computational study of self-assembled hexapeptide inhibitors against amyloid-β (Aβ) aggregation.
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 (16KLVFFA21and27NKGAII33) 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.
authors.affiliation: Key Laboratory of Biorheological Science and Technology Ministry of Education, Bioengineering college, Chongqing University, Chongqing 400044, P. R. China. gzliang@cqu.edu.cn.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: Department of Chemical and Biomolecular Engineering, The University of Akron, Akron, Ohio 44325, USA.
authors.forename: Mingzhen
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Biorheological Science and Technology Ministry of Education, Bioengineering college, Chongqing University, Chongqing 400044, P. R. China. gzliang@cqu.edu.cn.
authors.forename: Ya'nan
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Chemical and Biomolecular Engineering, The University of Akron, Akron, Ohio 44325, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Key Laboratory of Biorheological Science and Technology Ministry of Education, Bioengineering college, Chongqing University, Chongqing 400044, P. R. China. gzliang@cqu.edu.cn.
authors.forename: Guizhao
authors.initials: G
authors.lastname: Liang
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D011789:Quantum Theory
chemical_list: D016229:Amyloid beta-Peptides; D009842:Oligopeptides