Effect of Post-translational Modifications and Mutations on Amyloid-β fibrils Dynamics at N-terminus

Abstract We investigate the variability in the dynamics of the disordered N-terminal domain of amyloid-β fibrils (Aβ), comprising residues 1–16 of Aβ1–40, due to post-translational modifications and mutations in the β-bend regions known to modulate aggregation properties. Using 2H static solid-state NMR approaches, we compare the dynamics in the wild-type Aβ fibrils in the threefold symmetric polymorph with the fibrils from three post-translational modification sequences: isoaspartate-D7, the phosphorylation of S8, and an N-terminal truncation ΔE3. Additional comparisons are made with the mutants in the β-bend region (residues 21–23) corresponding to the familial Osaka E22Δ deletion and D23N Iowa mutation. We also include the aggregates induced by Zn2+ ions. The dynamics are probed at the F4 and G9 positions. The main motional model involves two free states undergoing diffusion and conformational exchanges with the bound state in which the diffusion is quenched because of transient interactions involving fibril core and other intrastrand contacts. The fraction of the bound state increases in a sigmoidal fashion with a decrease in temperature. There is clear variability in the dynamics: the phosphorylation of S8 variant is the most rigid at the G9 site in line with structural studies, the ΔE3 fibrils are more flexible at the G9 site in line with the morphological fragmentation pattern, the Zn-induced aggregates are the most mobile, and the two β-bend mutants have the strongest changes at the F4 site toward higher rigidity. Overall, the changes underlie the potential role of conformational ensembles in setting the stage for aggregation-prone states.