Effect of Strain Rate on Single Tau, Dimerized Tau and Tau-Microtubule Interface: A Molecular Dynamics Simulation Study.

Microtubule-associated protein (MAP) tau is a cross-linking molecule that provides structural stability to axonal microtubules (MT). It is considered a potential biomarker for Alzheimer's disease (AD), dementia, and other neurological disorders. It is also a signature protein for Traumatic Brain Injury (TBI) assessment. In the case of TBI, extreme dynamic mechanical energies can be felt by the axonal cytoskeletal members. As such, fundamental understandings of the responses of single tau protein, polymerized tau protein, and tau-microtubule interfaces under high-rate mechanical forces are important. This study attempts to determine the high-strain rate mechanical behavior of single tau, dimerized tau, and tau-MT interface using molecular dynamics (MD) simulation. The results show that a single tau protein is a highly stretchable soft polymer. During deformation, first, it significantly unfolds against van der Waals and electrostatic bonds. Then it stretches against strong covalent bonds. We found that tau acts as a viscoelastic material, and its stiffness increases with the strain rate. The unfolding stiffness can be ~50-500 MPa, while pure stretching stiffness can be >2 GPa. The dimerized tau model exhibits similar behavior under similar strain rates, and tau sliding from another tau is not observed until it is stretched to >7 times of original length, depending on the strain rate. The tau-MT interface simulations show that very high strain and strain rates are required to separate tau from MT suggesting Tau-MT bonding is stronger than MT subunit bonding between themselves. The dimerized tau-MT interface simulations suggest that tau-tau bonding is stronger than tau-MT bonding. In summary, this study focuses on the structural response of individual cytoskeletal components, namely microtubule (MT) and tau protein. Furthermore, we consider not only the individual response of a component, but also their interaction with each other (such as tau with tau or tau with MT). This study will eventually pave the way to build a bottom-up multiscale brain model and analyze TBI more comprehensively.