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

ABSTRACT: Aggregates of amyloid-? (A?) 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? peptide responsible for the onset and development of AD. However, the effect of GM1-glycan cluster on A? conformations has yet to be clarified. Interactions between A? 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?40 on a recently developed artificial GM1-glycan cluster. The artificial GM1-glycan cluster facilitates the characterization of interactions between A?40 and multiple GM1-glycans. We succeeded in observing the binding of A?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?40 for the GM1-glycan cluster recognition. This result is consistent with previous experimental studies regarding the glycan recognition of A? 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?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?40. Our findings suggest that the pathological helix formation of A?40 is initiated at GM1-glycan moieties rather than lipid ceramide moieties.

SUBMITTER: Tachi Y 

PROVIDER: S-EPMC6497634 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature