TY - JOUR

T1 - Tau Protein Binding Modes in Alzheimer’s Disease for Cationic Luminescent Ligands

AU - Todarwal, Yogesh

AU - Gustafsson, Camilla

AU - Nguyen Thi Minh, Nghia

AU - Ertzgaard, Ingrid

AU - Klingstedt, Therése

AU - Ghetti, Bernardino

AU - Vidal, Ruben

AU - König, Carolin

AU - Lindgren, Mikael

AU - Nilsson, K. Peter R.

AU - Linares, Mathieu

AU - Norman, Patrick

N1 - Funding Information: Financial support is acknowledged from the European Commission (Grant No. 765739), the Swedish Research Council (Grant Nos. 2018-4343 and 2016-07213), the Swedish e-Science Research Centre (SeRC), the German Research Foundation (Project No. KO 5423/1-1), and the U.S. National Institutes of Health (Grant No. UO1NS110437) as well as computational resources provided by the Swedish National Infrastructure for Computing (SNIC).

PY - 2021/10/28

Y1 - 2021/10/28

N2 - The bi-thiophene-vinylene-benzothiazole (bTVBT4) ligand developed for Alzheimer's 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 Pick's 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.

AB - The bi-thiophene-vinylene-benzothiazole (bTVBT4) ligand developed for Alzheimer's 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 Pick's 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.

UR - http://www.scopus.com/inward/record.url?scp=85118107439&partnerID=8YFLogxK

U2 - 10.1021/acs.jpcb.1c06019

DO - 10.1021/acs.jpcb.1c06019

M3 - Article

VL - 125

SP - 11628

EP - 11636

JO - The Journal of Physical Chemistry B

JF - The Journal of Physical Chemistry B

SN - 1520-5207

IS - 42

ER -