Solution NMR Studies of Aβ Monomer Dynamics

Chunyu      Wang

Abstract

Aβ is widely recognized as a key molecule in Alzheimers disease, causing neurotoxicity through Aβ aggregates, Aβ oligomers and fibrils. Aβ40 and Aβ42, composed of 40 and 42 residues, respectively, are the major Aβ species in human brain. Aβ42 aggregates much faster than Aβ40 but the mechanism of such difference in aggregation propensity is poorly understood. Using NMR spin relaxation, we have shown that Aβ40 and Aβ42 monomers have different dynamics in both backbone and sidechain on the ps-ns time scale. Aβ42 is more rigid in C-terminus in both backbone and sidechain while Aβ40 has more rigid methyl groups in the central hydrophobic cluster (CHC: Aβ17-21). These observations are consistent with differences in the major conformations of Aβ40 and Aβ42 monomers derived from replica exchange MD (REMD). To further demonstrate the relevance of dynamics in aggregation mechanism, a perturbation was introduced to Aβ42 in the form of M35 oxidation. After M35 side chain oxidation to sulfoxide, Aβ42 experiences Aβ40-like changes in dynamics. At the same time, M35 oxidation causes dramatic reduction in Aβ42 aggregation rate. These data have thus established an important role for protein dynamics in the mechanism of Aβ aggregation.

Keywords: Amyloid β-peptide, solution, NMR, dynamics, aggregation, Alzheimer's disease, M35 oxidation, amyloid -peptide, solution NMR, A Monomer Dynamics, neurotoxicity, fibrils, C-terminus, central hydrophobic cluster, REMD, Translational Diffusion Coefficient, Analytical Ultracentrifugation (AUC), Paramagnetic Relaxation Enhancement (PRE), MD Simulation Link, A mutants, AD drug discovery, FAD, X-ray crystallography, 2D HSQC spectra, HFIP, NOE values, Lipari-Szabo model-free formalismAmyloid β-peptide, solution, NMR, dynamics, aggregation, Alzheimer's disease, M35 oxidation, amyloid -peptide, solution NMR, A Monomer Dynamics, neurotoxicity, fibrils, C-terminus, central hydrophobic cluster, REMD, Translational Diffusion Coefficient, Analytical Ultracentrifugation (AUC), Paramagnetic Relaxation Enhancement (PRE), MD Simulation Link, A mutants, AD drug discovery, FAD, X-ray crystallography, 2D HSQC spectra, HFIP, NOE values, Lipari-Szabo model-free formalism