Molecular Dynamics Simulations of the Tau R3-R4 Domain Monomer in the Bulk Solution and at the Surface of a Lipid Bilayer Model.

ABSTRACT

The aggregation of the tau protein plays a significant role in Alzheimer's disease, and the tau R3-R4 domain spanning residues 306-378 was shown to form the amyloid fibril core of a full-length tau. The conformations of the tau R3-R4 monomer in the bulk solution and at the surface of membranes are unknown. In this study, we address these questions by means of atomistic molecular dynamics. The simulations in the bulk solution show a very heterogeneous ensemble of conformations with low ß and helical contents. The tau R3-R4 monomer has the propensity to form transient ß-hairpins within the R3 repeat and between the R3 and R4 repeats and parallel ß-sheets spanning the R3 and R4 repeats. The simulations also show that the surface of the membrane does not induce ß-sheet insertion and leads to an ensemble of structures very different from those in the bulk solution. They also reveal the dynamical properties of the membrane-bound state of the tau R3-R4 monomer, enabling insertion of the residues 306-318 and 376-378.