Characterizing the structural behavior of selected Aβ-42 monomers with different solubilities.

The conformational behavior of the wild-type amyloid β-42 (Aβ-42) monomer and two of its mutants was explored via all-atom replica exchange molecular dynamics simulations in explicit solvent, to identify structural features that may promote or deter early-stage oligomerization. The markers used for this purpose indicate that while the three peptides are relatively flexible they have distinct preferential structures and degree of rigidity. In particular, we found that one mutant that remains in the monomeric state in experiments displays a characteristic N-terminal structure that significantly enhances its rigidity. This finding is consistent with various studies that have detected a reduction in oligomerization frequency and Aβ-related toxicity upon sequence-specific antibody or ligand binding to the N-terminal tail of wild-type monomers, likely leading to the stabilization of this region. In general, our results highlight a potential role of the N-terminal segment on Aβ oligomerization and give insights into specific interactions that may be responsible for promoting the pronounced structural changes observed upon introducing point mutations on the wild-type Aβ-42 peptide.