Disrupting Amyloid Filaments of Tau by Means of Electric Fields.

The tau protein is a major component of neurofibrillary tangles, one of the hallmarks of Alzheimer's disease, which is the most common neurodegenerative disorder in the elderly. Experimental and computational studies have shed light on the fibrillar morphologies of tau and the kinetics of self-assembly, but little is known about the structural stability of the fibrils in the presence of external electric fields. We investigated the behavior of cross-β filaments of tau under the effect of an oscillating external electric field by means of multiple molecular dynamics simulations. Two models of the aqueous solvent were used: explicit water and implicit solvent based on the continuum dielectric. The simulations started from tau filaments with two different topologies determined by cryogenic electron microscopy of patient samples: the so-called straight filament (SF) and paired helical filament (PHF). Two values of the electric field strength and oscillation frequencies of 0.1, 1, or 10 GHz were employed. In all simulations, tau segment 340-KSEKLDFKDRV-350, which includes seven charged side chains, showed pronounced flexibility, which was exacerbated at high field strength. A larger loss of β-strand content was observed for the SF than for the PHF topology. Moreover, the SF assembly dissociated into two protofilaments in the presence of the external field, which was not observed for the more stable PHF topology. The loss of β-sheet structure was highest at the frequency of 1 GHz and smallest at 10 GHz in the explicit water simulations, while mixed decays of β-sheet content were obtained with the implicit solvent.