Tau Protein Binding Modes in Alzheimers Disease for Cationic Luminescent Ligands

The bi-thiophene-vinylene-benzothiazole (bTVBT4) ligand developed for Alzheimers disease (AD)-specific detection of amyloid tau has been studied by a combination of several theoretical methods and experimental spectroscopies. With reference to the cryo-EM tau structure of the tau protofilament (Nature 2017, 547, 185), a periodic model system of the fibril was created, and the interactions between this fibril and bTVBT4 were studied with nonbiased molecular dynamics simulations. Several binding sites and binding modes were identified and analyzed, and the results for the most prevailing fibril site and ligand modes are presented. A key validation of the simulation work is provided by the favorable comparison of the theoretical and experimental absorption spectra of bTVBT4 in solution and bound to the protein. It is conclusively shown that the ligand-protein binding occurs at the hydrophobic pocket defined by the residues Ile360, Thr361, and His362. This binding site is not accessible in the Picks disease (PiD) fold, and fluorescence imaging of bTVBT4-stained brain tissue samples from patients diagnosed with AD and PiD provides strong support for the proposed tau binding site.
Funding Agencies|European CommissionEuropean CommissionEuropean Commission Joint Research Centre [765739]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2018-4343, 2016-07213]; Swedish e-Science Research Centre (SeRC); German Research FoundationGerman Research Foundation (DFG) [KO 5423/1-1]; U.S. National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [UO1NS110437]