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

Amyloid-beta (A beta) aggregation is a hallmark of Alzheimers disease. As an intrinsically disordered protein, A ss undergoes extensive dynamics on multiple length and time scales. Access to a comprehensive picture of the reorientational dynamics in A beta requires therefore the combination of complementary techniques. Here, we integrate N-15 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 A beta 1-40 (A beta 40) 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 A beta 40. Instead, slow segmental motions occurring at similar to 5 ns are detected throughout the A beta 40 sequence and reach up to similar 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 A beta aggregation.