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,chi...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 Aβremains unclear.Herein,molecular-scale,sub-nanoscale,and nanoscale chiral-structures were constructed to investigate their chiral effect on the fibrillation of Aβ_(40) 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 Aβ_(40),and the speed-up effect of D-P was slightly stronger than L-P.For sub-nanoscale,both two chiral Zncomplexes(L-Zn and D-Zn)induced the agglomeration of Aβ_(40) without chirality discrimination.For nanoscale,both L-ZnS and DZnS QDs inhibited the fibrillation of Aβ_(40),and the inhibition effect of L-ZnS was notably better than that of D-ZnS.In-situ kinetics experiments of Aβ_(40) co-incubated with two chiral QDs demonstrated that L-ZnS completely prevents the misfolding of Aβ_(40) from unfolded toβ-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 Aβ_(40) 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 Aβ_(40).This work offers a microscopic insight of chiral effect on Aβfibrillation exerted by structures in different-scales,and provides a guidance in precise regulation of protein fibrillation via manipulating chiral structures in different-scales.展开更多
基金supported by the National Natural Science Foundation of China(Nos.21975191(GGB),21805218(GGB),51873168(STL))Natural Science Foundation of Hubei Province(No.2021CFB299(GGB))+1 种基金Fundamental Research Funds for the Central Universities(WUT)(Nos.2021III035JC(GGB),2020III009GX(STL)2020III035GX(GGB)).
文摘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 Aβremains unclear.Herein,molecular-scale,sub-nanoscale,and nanoscale chiral-structures were constructed to investigate their chiral effect on the fibrillation of Aβ_(40) 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 Aβ_(40),and the speed-up effect of D-P was slightly stronger than L-P.For sub-nanoscale,both two chiral Zncomplexes(L-Zn and D-Zn)induced the agglomeration of Aβ_(40) without chirality discrimination.For nanoscale,both L-ZnS and DZnS QDs inhibited the fibrillation of Aβ_(40),and the inhibition effect of L-ZnS was notably better than that of D-ZnS.In-situ kinetics experiments of Aβ_(40) co-incubated with two chiral QDs demonstrated that L-ZnS completely prevents the misfolding of Aβ_(40) from unfolded toβ-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 Aβ_(40) 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 Aβ_(40).This work offers a microscopic insight of chiral effect on Aβfibrillation exerted by structures in different-scales,and provides a guidance in precise regulation of protein fibrillation via manipulating chiral structures in different-scales.
