Sökning: onr:"swepub:oai:DiVA.org:kth-299162" >
Cryptic Sites in Ta...
Cryptic Sites in Tau Fibrils Explain the Preferential Binding of the AV-1451 PET Tracer toward Alzheimer's Tauopathy
-
- Natarajan Arul, Murugan (författare)
- KTH,Teoretisk kemi och biologi,KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, S-10691 Stockholm, Sweden.
-
- Nordberg, Agneta (författare)
- Karolinska Institutet,Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, S-14186 Stockholm, Sweden.;Karolinska Univ Hosp, Aging Brain, Theme Aging, S-14186 Stockholm, Sweden.
-
- Ågren, Hans (författare)
- Uppsala universitet,Institutionen för fysik och astronomi,Henan Univ, Coll Chem & Chem Engn, Kaifeng 475004, Henan, Peoples R China.,Röntgenfysik
-
(creator_code:org_t)
- 2021-06-21
- 2021
- Engelska.
-
Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 12:13, s. 2437-2447
- Relaterad länk:
-
https://doi.org/10.1...
-
visa fler...
-
https://pubs.acs.org...
-
https://uu.diva-port... (primary) (Raw object)
-
https://urn.kb.se/re...
-
https://doi.org/10.1...
-
http://kipublication...
-
https://urn.kb.se/re...
-
visa färre...
Abstract
Ämnesord
Stäng
- Tauopathies are a subclass of neurodegenerative diseases characterized by an accumulation of microtubule binding tau fibrils in brain regions. Diseases such as Alzheimer's (AD), chronic traumatic encephalopathy (CTE), Pick's disease (PiD), and corticobasal degeneration (CBD) belong to this subclass. Development of tracers which can visualize and discriminate between different tauopathies is of clinical importance in the diagnosis of various tauopathies. Currently, several tau tracers are available for in vivo imaging using a positron emission tomography (PET) technique. Among these tracers, PBB3 is reported to bind to various types of tau fibrils with comparable binding affinities. In contrast, tau tracer AV-1451 is reported to bind to specific types of tau fibrils (in particular to AD-associated and CTE) with higher binding affinity and only show nonspecific or weaker binding toward tau fibrils dominant with 3R isoforms (associated with PiD). The tau fibrils associated with different tauopathies can adopt different microstructures with different binding site microenvironments. By using detailed studies of the binding profiles of tau tracers for different types of tau fibrils, it may be possible to design tracers with high selectivity toward a specific tauopathy. The microstructures for the tau fibrils from patients with AD, PiD, and CTE have recently been demonstrated by cryogenic electron microscopy (cryo-EM) measurements allowing structure-based in silico simulations. In the present study, we have performed a multiscale computational study involving molecular docking, molecular dynamics, free energy calculations, and QM fragmentation calculations to understand the binding profiles of tau tracer AV-1451 and its potential use for diagnosis of AD, CTE, and PiD tauopathies. Our computational study reveals that different affinity binding sites exist for AV-1451 in the tau fibrils associated with different tauopathies. The binding affinity of this tracer toward different tau fibrils goes in this order: PiD > AD > CTE. The interaction energies for different tau fibril-tracer complexes using the QM fragmentation scheme also showed the same trend. However, by carrying out molecular dynamics simulations for the AD-derived tau fibrils in organic solvents, we found additional high affinity binding sites for AV-1451. The AV-1451 binding profile in these cryptic sites correctly explains the preferential binding of this tracer toward the AD fibrils when compared with the PiD fibrils. This study clearly demonstrates having a cryo-EM structure is still not sufficient for the structure-based tracer discovery for certain targets, as they may have "potential but hidden" high affinity binding sites, and we need additional strategies to identify them.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Nyckelord
- Tau imaging
- neurofibrillary tangles
- multiscale modeling
- Alzheimer's disease
- Pick's disease
- chronic traumatic encephalopathy
- QM fragmentation scheme
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
Hitta via bibliotek
Till lärosätets databas