Solution NMR Studies of Aβ Monomer Dynamics

A beta is widely recognized as Akey molecule in Alzheimer's disease, causing neurotoxicity through A beta aggregates, A beta oligomers and fibrils. A beta 40 and A beta 42, composed of 40 and 42 residues, respectively, are the major A beta species in human brain. A beta 42 aggregates much faster than A beta 40 but the mechanism of such difference in aggregation propensity is poorly understood. Using NMR spin relaxation, we have shown that A beta 40 and A beta 42 monomers have different dynamics in both backbone and sidechain on the ps-ns time scale. A beta 42 is more rigid in C-terminus in both backbone and sidechain while A beta 40 has more rigid methyl groups in the central hydrophobic cluster (CHC: A beta 17-21). These observations are consistent with differences in the major conformations of A beta 40 and A beta 42 monomers derived from replicAexchange MD (REMD). To further demonstrate the relevance of dynamics in aggregation mechanism, Aperturbation was introduced to A beta 42 in the form of M35 oxidation. After M35 side chain oxidation to sulfoxide, A beta 42 experiences A beta 40-like changes in dynamics. At the same time, M35 oxidation causes dramatic reduction in A beta 42 aggregation rate. These data have thus established an important role for protein dynamics in the mechanism of A beta aggregation.