Reorientational Dynamics of Amyloid-β from NMR Spin Relaxation and Molecular Simulation

Amyloid-beta (Abeta) aggregation is a hallmark of Alzheimer's disease. As an intrinsically disordered protein, Abeta undergoes extensive dynamics on multiple length and time scales. Access to a comprehensive picture of the reorientational dynamics in Abeta requires therefore the combination of complementary techniques. Here, we integrate 15N spin relaxation rates at three magnetic fields with microseconds-long molecular dynamics simulation, ensemble-based hydrodynamic calculations, and previously published nanosecond fluorescence correlation spectroscopy to investigate the reorientational dynamics of Abeta1-40 (Abeta40) at single-residue resolution. The integrative analysis shows that librational and dihedral angle fluctuations occurring at fast and intermediate time scales are not sufficient to decorrelate orientational memory in Abeta40. Instead, slow segmental motions occurring at 5 ns are detected throughout the Abeta40 sequence and reach up to 10 ns for selected residues. We propose that the modulation of time scales of reorientational dynamics with respect to intra- and intermolecular diffusion plays an important role in disease-related Abeta aggregation.