To probe the role of side chain dynamics in A beta aggregation, we studied the methyl dynamics of native A beta 40 and A beta 42 by measuring cross relaxation rates with interleaved data collection. The methyl groups in the C-terminus are in general more rigid in A beta 42 than in A beta 40, consistent with previous results from backbone N-15 dynamics. This lends support to the hypothesis that a rigid C-terminus in A beta 42 may serve as an internal aggregation seed. Interestingly, two methyl groups of V18 located in the central hydrophobic cluster are more mobile in A beta 42 than in A beta 40, most likely due to the paucity of V18 intra-molecular interactions in A beta 40. V18 may then be more available for inter-molecular interactions to form A beta 42 aggregates. Thus, the side chain mobility of the central hydrophobic cluster may play an important role in A beta aggregation and may contribute to the difference in aggregation propensity between A beta 40 and A beta 42. (c) 2007 Elsevier Inc. All rights reserved.