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Different Positron Emission Tomography Tau Tracers Bind to Multiple Binding Sites on the Tau Fibril: Insight from Computational Modeling
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.ORCID iD: 0000-0003-0185-5724
KTH, School of Biotechnology (BIO), Centres, Albanova VinnExcellence Center for Protein Technology, ProNova. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry.ORCID iD: 0000-0002-1763-9383
2018 (English)In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 9, no 7, p. 1757-1767Article in journal (Refereed) Published
Abstract [en]

Using the recently reported cryo-EM structure for the tau fibril [Fitzpatrick et al. (2017) Nature 547, 185-190], which is a potential target concerning Alzheimer's disease, we present the first molecular modeling studies on its interaction with various positron emission tomography (PET) tracers. Experimentally, based on the binding assay studies, at least three different high affinity binding sites have been reported for tracers in the tau fibril. Herein, through integrated modeling using molecular docking, molecular dynamics, and binding free energy calculations, we provide insight into the binding patterns of various tracers to the tau fibril. We suggest that there are four different high affinity binding sites available for many of the studied tracers showing varying binding affinity to different binding sites. Thus, PBB3 binds most strongly to site 4, and interestingly, this site is not a preferable site for any other tracers. For THIC5351, our data show that it strongly binds to sites 3 and 1, the former one being more preferable. We also find that MK6240 and T807 bind to site 1 specifically. The modeling data also give some insight into whether a tracer bound to a specific site can be replaced by others or not. For example, the displacement of T807 by PBB3 as reported experimentally can also be explained and attributed to the larger binding affinity of the latter compound in all binding sites. The binding free energy results explain very well the small binding affinity of THK523 compared to all the aryl quinoline moieties containing THK tracers. The ability of certain tau tracers, like FDDNP and THK523, to bind to amyloid fibrils has also been investigated. Furthermore, such off-target interaction of tau tracers with amyloid beta fibrils has been validated using a quantum mechanical fragmentation approach.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018. Vol. 9, no 7, p. 1757-1767
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:kth:diva-232912DOI: 10.1021/acschemneuro.8b00093ISI: 000439531400024PubMedID: 29630333Scopus ID: 2-s2.0-85050285842OAI: oai:DiVA.org:kth-232912DiVA, id: diva2:1237316
Note

QC 20180808

Available from: 2018-08-08 Created: 2018-08-08 Last updated: 2018-11-13Bibliographically approved

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Natarajan Arul, MuruganÅgren, Hans

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Theoretical Chemistry and BiologyAlbanova VinnExcellence Center for Protein Technology, ProNovaChemistry
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