Aggregates of amyloid- β (A β ) peptide are well known to be the causative substance of Alzheimer’s disease (AD). Recent studies showed that monosialotetrahexosylganglioside (GM1) clusters induce the pathological aggregation of A β peptide responsible for the onset and development of AD. However, the effect of GM1-glycan cluster on A β conformations has yet to be clarified. Interactions between A β peptide and GM1-glycan cluster is important for the earliest stage of the toxic aggregation on GM1 cluster. Here, we performed all-atom molecular dynamics (MD) simulations of A β 40 on a recently developed artificial GM1-glycan cluster. The artificial GM1-glycan cluster facilitates the characterization of interactions between A β 40 and multiple GM1-glycans. We succeeded in observing the binding of A β 40 to the GM1-glycan cluster in all of our MD simulations. Results obtained from these MD simulations indicate the importance of HHQ (13-15) segment of A β 40 for the GM1-glycan cluster recognition. This result is consistent with previous experimental studies regarding the glycan recognition of A β peptide. The recognition mechanism of HHQ (13-15) segment is mainly explained by non-specific stacking interactions between side-chains of histidine and rings of sugar residues, in which the HHQ regime forms coil and bend structures. Moreover, we found that A β 40 exhibits helix structures at C-terminal side on the GM1-glycan cluster. The helix formation is the initial stage of the pathological aggregation at ceramide moieties of GM1 cluster. The binding of Lys28 to Neu triggers the helix formation at C-terminus side because the formation of a salt bridge between Lys28 and Neu leads to change of intrachain interactions of A β 40. Our findings suggest that the pathological helix formation of A β 40 is initiated at GM1-glycan moieties rather than lipid ceramide moieties.
Edited by Akio Kitao Alzheimer's disease is thought to be caused by the aggregation of amyloid-β (Aβ) peptides. Their aggregation is accelerated at hydrophilic/hydrophobic interfaces such as the air-water interface and the surface of monosialotetrahexosylganglioside (GM1) clusters on neuronal cell membranes. In this review, we present recent studies of full-length Aβ (Aβ40) peptides and Aβ(16-22) fragments in such heterogeneous environments by molecular dynamics (MD) simulations. These peptides have both hydrophilic and hydrophobic amino-acid residues and tend to exist at the hydrophilic/hydrophobic interface. Therefore, the peptide concentration increases at the interface, which is one of the factors that promote aggregation. Furthermore, it was found that Aβ40 forms an α-helix structure and then a β-hairpin structure at the interface. The β-hairpin promotes the formation of oligomers with intermolecular β-sheets. It means that not only the high concentration of Aβ40 at the interface but also the structure of Aβ40 itself promotes aggregation. In addition, MD simulations of Aβ40 on recently-developed GM1-glycan clusters showed that the HHQ (13-15) segment of Aβ40 is important for the recognition of GM1glycan clusters. It was also elucidated that Aβ40 forms a helix structure in the C-terminal region on the GM1glycan cluster. This result suggests that the helix formation, which is the first step in the conformational changes toward pathological aggregation, is initiated at the GM1-glycan moieties rather than at the lipid-ceramide moieties. These studies will enhance the physicochemical understanding of the structural changes of Aβ at the heterogeneous interfaces and the mechanism of Alzheimer's disease pathogenesis.
An artificial glycan cluster, in which 24 monosialotetrahexosylganglioside (GM1) glycans are transplanted to the interface of a metal-ligand complex, was recently proposed to investigate the interaction between GM1 glycan clusters and amyloidogenic proteins by NMR analysis. In this study, all-atom molecular dynamics simulations were performed to characterize the conformational properties of the artificial GM1 glycan cluster. We found that more than 65% of GM1 glycans are clustered by interchain hydrogen bonds. Interchain hydrogen bonds are mainly formed between Neu5Ac and Gal’. Pentamers were most frequently observed in the metal-ligand complex. GM1 glycans are tilted and hydrophobically interact with ligand moieties. The hydrophobic surface of the metal-ligand complex increases intrachain hydrogen bonds in each conformation of the GM1 glycans. The increase of intrachain hydrogen bonds stabilizes the local minimum conformations of the GM1 glycan in comparison with the monomeric one. Interchain hydrogen bonding between glycans and glycan-ligand hydrophobic interactions also contribute to this conformational stabilization. Our results provide the physicochemical properties of the new artificial GM1 glycan cluster under the thermal fluctuations for understanding its protein recognition and designing the drug material for amyloidogenic proteins.
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