(570d) N-Terminal Hypothesis for Alzheimer’s Disease: Analyzing Dimers of a ? peptide and its Protective and Causative Mutants
The structure of homozygous and heterozygous dimers of wild-type AÎ²1-42, and its causative (A2V) and protective (A2T) variants are analyzed. To study the role of N-terminus in the interactions between AÎ² dimers, we constrain the central hydrophobic region and C-terminus to the known structure of AÎ² fibers, while leaving the N-terminus free and examine the structural differences between these dimers. Furthermore, we performed unconstrained simulations of AÎ² dimers to understand their association and the resulting structures.Â To analyze these dimers we examined the number of contacts and distances between the N-termini, and contact (2D heat) maps of their conformational landscape. Aggregation kinetics and long term potentiation of the three variants are also measured and compared in the presence and absence of monoclonal antibody, bapineuzumab, which targets N-terminal residues 1-5 of AÎ² with high affinity.