Conformational Transitions of Amyloid-β: A Langevin and Generalized Langevin Dynamics Simulation Study.

The dynamics of conformational transitions of the disordered protein, amyloid-β, is studied via Langevin and generalized Langevin dynamics simulations. The transmission coefficient for the unfold-misfold transition of amyloid-β is calculated from multiple independent trajectories that originate at the transition state with different initial velocities and are directly correlated to Kramers and Grote-Hynes theories. For lower values of the frictional coefficient, a well-defined rate constant is obtained, whereas, for higher values, the transmission coefficient decays with time, indicating a breakdown of the Kramers and Grote-Hynes theories and the emergence of a dynamic disorder, which demonstrates the presence of multiple local minima in the misfolding potential energy surface. The calculated free energy profile describes a two-state transition of amyloid-β in the energy landscape. The transition path time distribution computed from these simulations is compared with the related experimental and theoretical results for the unfold-misfold transition of amyloid-β. The high free energy barrier for this transition confirms the misfolding of amyloid-β. These findings offer an insight into the dynamics of the unfold-misfold transition of this protein.