Conformational Change of Amyloid-β40 in Association with Binding to GM1-Glycan Cluster

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