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Research Article

Chiral effect on Aβ fibrillation from molecular-scale to nanoscale

Guanbin Gao1,§( ), Guowei Zhu1,§, Liangchong Yu1, Zijun Zhang1, Ting Zhang1, Xinglin Liu1, Cheng Zhang1, Lin Zhou1, Taolei Sun2( )
State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, Wuhan 430070, China
School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan 430070, China

§ Guanbin Gao and Guowei Zhu contributed equally to this work.

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Graphical Abstract

Three types of chiral structures differed in the scale (including molecular-scale, sub-nanoscale, and nanoscale) were constructed to reveal the chiral effect on amyloid-beta (Aβ) fibrillation exerted by structures in different scales. The molecular-scale and sub-nanoscale chiral structures could accelerate the fibrillation with chirality discrimination and induce the agglomeration of Aβ40, respectively. Only the nanoscale chiral ZnS quantum dots (QDs) could inhibit Aβ fibrillation with chirality discrimination. This work provides new insights in further understanding the mechanism of biological disorders including Alzheimer’s disease.

Abstract

β-Amyloid (Aβ) peptide fibrillation, one of the characteristic hallmarks of Alzheimer’s disease, is determined by many interfacial physical-chemical factors, e.g., charge, hydrophobicity, etc. Despite extensive research, chiral effect in different-scales on the fibrillation process of Aβ remains unclear. Herein, molecular-scale, sub-nanoscale, and nanoscale chiral-structures were constructed to investigate their chiral effect on the fibrillation of Aβ40 peptides. Chiral structures from molecular-scale to nanoscale were obtained from the different periods of the chemosynthesis process of chiral ZnS quantum-dots (QDs), confirmed by real-time monitoring of circular dichroism spectra. For molecular-scale, both L-penicillamine (L-P) and D-P ligands accelerated the fibrillation of Aβ40, and the speed-up effect of D-P was slightly stronger than L-P. For sub-nanoscale, both two chiral Zn-complexes (L-Zn and D-Zn) induced the agglomeration of Aβ40 without chirality discrimination. For nanoscale, both L-ZnS and D-ZnS QDs inhibited the fibrillation of Aβ40, and the inhibition effect of L-ZnS was notably better than that of D-ZnS. In-situ kinetics experiments of Aβ40 co-incubated with two chiral QDs demonstrated that L-ZnS completely prevents the misfolding of Aβ40 from unfolded to β-sheet, while D-ZnS cannot achieve this. Further site-replacement experiments and simulation results revealed the underlying molecular mechanisms of the different inhibition efficiency of chiral ZnS QDs on Aβ40 fibrillation, which mainly attribute to the stereoselectivity interaction between the chiral ligands of ZnS QDs and electro-positive amino acid residues (R5, K16, and K28) of Aβ40. This work offers a microscopic insight of chiral effect on Aβ fibrillation exerted by structures in different-scales, and provides a guidance in precise regulation of protein fibrillation via manipulating chiral structures in different-scales.

Keywords

chiralitymolecular-scalesub-nanoscalenanoscaleAβ40fibrillation

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Nano Research
Volume 15 Issue 7,
July 2022
Pages 6721-6729
DOI: 10.1007/s12274-022-4303-9
Cite this article:
Gao G, Zhu G, Yu L, et al. Chiral effect on Aβ fibrillation from molecular-scale to nanoscale. Nano Research, 2022, 15(7): 6721-6729. https://doi.org/10.1007/s12274-022-4303-9
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Received: 25 January 2022
Revised: 07 March 2022
Accepted: 07 March 2022
Published: 28 April 2022
© Tsinghua University Press 2022
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