Investigation of the Structure of Full-Length Tau Proteins with Coarse-Grained and All-Atom Molecular Dynamics Simulations.

Tau proteins not only have many important biological functions but also are associated with several neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease (AD). However, it is still a challenge to identify the atomic structure of full-length tau proteins due to their lengthy and disordered characteristics and the factor that there are no crystal structures of full-length tau proteins available. We performed multi- and large-scale molecular dynamics simulations of the full-length tau monomer (the 2N4R isoform and 441 residues) in aqueous solution under biological conditions with coarse-grained and all-atom force fields. The obtained atomic structures produced radii of gyration and chemical shifts that are in excellent agreement with those of experiment. The generated monomer structure ensemble would be very useful for further studying the oligomerization mechanism and discovering tau oligomerization inhibitors, which are important events in AD drug development.