Amyloid fibrils of Amyloid-β (Aβ) protein consists of a structured hydrophobic core and a disordered N-terminal domain (residues 1–16). The disordered domain is believed to be important for regulating aggregation propensity and the flexibility of this domain is likely essential for aggregation control. We probed the dynamics of the mature fibrils comprising Aβ (1-40) in the 3-fold symmetric polymorph at selected side chains of the N-terminal domain, using 2H solid-state NMR methods. Based on the line shape and relaxation data, we proposed the two-state model, in which the free state of the domain undergoes a diffusive motion and this motion is quenched in the bound state, likely due to transient intra and inter-molecular interactions. At 37oC, freezing of the dynamics is observed progressively along the sequence. As the temperature is lowered, the fraction of the bound state exhibits sigmoidal behavior. The determination of the rate constant of the N-terminal domain motion at 37 oC is also approached from another angle using 2H NMR R1rho , quadrupolar CPMG relaxation measurements, and quadrupolar CEST measurements. The experiments are complementary in terms of probing somewhat different time scales of motions. The results indicate a more complex scenario with at least two mobile states of the N-terminal domain undergoing global diffusive motions and conformational exchange processes. In addition to the wild-type Aβ, we probed variants with mutations in the β-bend region, which can be responsible for the early onset of the disease, such as E22Δ and D23N mutants. Additionally, we have investigated several naturally occurring post-translational modifications in the N-terminal domain, such as ΔE3, isoaspartate-D7, and phosphorylated-S8 variants. The differential dynamics of the N-terminal in these variants may point to aggregation control pathways.

Dynamics of the disordered N-terminal domain of amyloid-β(1-40) fibrils using deuterium solid-state NMR, application to wild-type Aβ, β-bend mutants, and post-translational modifications

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.