Evaluating the Impact of Phosphorylation on the Dynamics of the Tau Protein Proline-Rich Region

The proline-rich region of the tubulin-associated unit (TAU) protein is of substantial interest in understanding neurodegenerative diseases due to its interaction with bridging integrator 1 (BIN1). The associated gene <i>BIN1</i> is substantially associated with the development of Alzheimer's disease. Previous studies have underlined the importance of the conformation of the proline-rich region of TAU and the effect of its phosphorylation. In this study, we investigate the change in compactness between a four times phosphorylated TAU fragment (210-240) compared to the unphosphorylated (non-P) form using computational means. We apply our Ensemble Reconstruction from Fragments (ERF) approach to create two unbiased conformational ensembles from which a reweighted ensemble is derived that agrees with observables from nuclear magnetic resonance experiments. The resulting shift of the radius of gyration indicates a preference for relatively compact conformations for the non-P form, while the restraints derived from the experimental data do not substantially influence the compactness of the phosphorylated peptide.