Methyl dynamics of the amyloid-β peptides Aβ40 and Aβ42

To probe the role of side chain dynamics in Aβ aggregation, we studied the methyl dynamics of native Aβ40 and Aβ42 by measuring cross relaxation rates with interleaved data collection. The methyl groups in the C-terminus are in general more rigid in Aβ42 than in Aβ40, consistent with previous results from backbone 15N dynamics. This lends support to the hypothesis that a rigid C-terminus in Aβ42 may serve as an internal aggregation seed. Interestingly, two methyl groups of V18 located in the central hydrophobic cluster are more mobile in Aβ42 than in Aβ40, most likely due to the paucity of V18 intra-molecular interactions in Aβ42. V18 may then be more available for inter-molecular interactions to form Aβ42 aggregates. Thus, the side chain mobility of the central hydrophobic cluster may play an important role in Aβ aggregation and may contribute to the difference in aggregation propensity between Aβ40 and Aβ42.