Dresden 2017 – wissenschaftliches Programm
CPP 16.4: Poster
Montag, 20. März 2017, 18:30–21:00, P1C
Dynamics of Seeded Aβ40-Fibril Growth from Atomistic Molecular Dynamics Simulations: Kinetic Trapping and Reduced Water Mobility in the Locking Step — •Nadine Schwierz1, Christina V. Frost2, Phillip L. Geissler1, and Martin Zacharias2 — 1Chemistry Department, University of California, Berkeley, California 94720, United States — 2Physik Department, Technische Universität München, 85748 Garching, Germany
Filamentous β-amyloid aggregates are crucial for the pathology of Alzheimer's disease. Despite the tremendous biomedical importance, the molecular pathway of growth propagation is not completely understood and remains challenging to investigate by simulations due to the long time scales involved. Here, we apply extensive all-atom molecular dynamics simulations in explicit water to obtain free energy profiles and kinetic information from position-dependent diffusion profiles for different Aβ fibril growth processes. Our approach provides insight into the molecular steps and allows close agreement with experimental binding free energies and macroscopic growth rates. Water plays a decisive role, and solvent entropy is identified as the main driving force for assembly. Fibril growth is disfavored energetically due to cancellation of direct peptide-peptide interactions and solvation effects. The kinetics of growth is consistent with the characteristic dock/lock mechanism, and docking is at least 2 orders of magnitude faster. In the locking step, the dynamics is much slower due to kinetically trapped conformations and the reduced mobility of hydration water.