Molecular dynamics simulations of amyloid-ß peptides in heterogeneous environments.

Alzheimer's disease is thought to be caused by the aggregation of amyloid-ß (Aß) 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 Aß (Aß40) peptides and Aß(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 Aß40 forms an α-helix structure and then a ß-hairpin structure at the interface. The ß-hairpin promotes the formation of oligomers with intermolecular ß-sheets. It means that not only the high concentration of Aß40 at the interface but also the structure of Aß40 itself promotes aggregation. In addition, MD simulations of Aß40 on recently-developed GM1-glycan clusters showed that the HHQ (13-15) segment of Aß40 is important for the recognition of GM1-glycan clusters. It was also elucidated that Aß40 forms a helix structure in the C-terminal region on the GM1-glycan 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 Aß at the heterogeneous interfaces and the mechanism of Alzheimer's disease pathogenesis.

Structural Characteristics of Monomeric Aß42 on Fibril in the Early Stage of Secondary Nucleation Process.

Amyloid-ß (Aß) aggregates are believed to be one of the main causes of Alzheimer's disease. Aß peptides form fibrils having cross ß-sheet structures mainly through primary nucleation, secondary nucleation, and elongation. In particular, self-catalyzed secondary nucleation is of great interest. Here, we investigate the adsorption of Aß42 peptides to the Aß42 fibril to reveal a role of adsorption as a part of secondary nucleation. We performed extensive molecular dynamics simulations based on replica exchange with solute tempering 2 (REST2) to two systems: a monomeric Aß42 in solution and a complex of an Aß42 peptide and Aß42 fibril. Results of our simulations show that the Aß42 monomer is extended on the fibril. Furthermore, we find that the hairpin structure of the Aß42 monomer decreases but the helix structure increases by adsorption to the fibril surface. These structural changes are preferable for forming fibril-like aggregates, suggesting that the fibril surface serves as a catalyst in the secondary nucleation process. In addition, the stabilization of the helix structure of the Aß42 monomer on the fibril indicates that the strategy of a secondary nucleation inhibitor design for Aß40 can also be used for Aß42.

Conformational Change of Amyloid-ß 40 in Association with Binding to GM1-Glycan Cluster.

Aggregates of amyloid-ß (Aß) 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 Aß peptide responsible for the onset and development of AD. However, the effect of GM1-glycan cluster on Aß conformations has yet to be clarified. Interactions between Aß 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 Aß40 on a recently developed artificial GM1-glycan cluster. The artificial GM1-glycan cluster facilitates the characterization of interactions between Aß40 and multiple GM1-glycans. We succeeded in observing the binding of Aß40 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 Aß40 for the GM1-glycan cluster recognition. This result is consistent with previous experimental studies regarding the glycan recognition of Aß 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 Aß40 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 Aß40. Our findings suggest that the pathological helix formation of Aß40 is initiated at GM1-glycan moieties rather than lipid ceramide moieties.

Conformational properties of an artificial GM1 glycan cluster based on a metal-ligand complex.

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.