Pick’s Tau Fibril Shows Multiple Distinct PET Probe Binding Sites: Insights from Computational Modelling
In recent years, it has been realized that the tau protein is a key player in multiple neurodegenerative diseases. Positron emission tomography (PET) radiotracers that bind to tau filaments in Alzheimer’s disease (AD) are in common use, but PET tracers binding to tau filaments of rarer, age-related...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/1/349 |
| _version_ | 1797542793297526784 |
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| author | Sushil K. Mishra Yoshiki Yamaguchi Makoto Higuchi Naruhiko Sahara |
| author_facet | Sushil K. Mishra Yoshiki Yamaguchi Makoto Higuchi Naruhiko Sahara |
| author_sort | Sushil K. Mishra |
| collection | DOAJ |
| description | In recent years, it has been realized that the tau protein is a key player in multiple neurodegenerative diseases. Positron emission tomography (PET) radiotracers that bind to tau filaments in Alzheimer’s disease (AD) are in common use, but PET tracers binding to tau filaments of rarer, age-related dementias, such as Pick’s disease, have not been widely explored. To design disease-specific and tau-selective PET tracers, it is important to determine where and how PET tracers bind to tau filaments. In this paper, we present the first molecular modelling study on PET probe binding to the structured core of tau filaments from a patient with Pick’s disease (Tau<sup>PiD</sup>). We have used docking, molecular dynamics simulations, binding-affinity and tunnel calculations to explore Tau<sup>PiD</sup> binding sites, binding modes, and binding energies of PET probes (AV-1451, MK-6240, PBB3, PM-PBB3, THK-5351 and PiB) with Tau<sup>PiD</sup>. The probes bind to Tau<sup>PiD</sup> at multiple surface binding sites as well as in a cavity binding site. The probes show unique surface binding patterns, and, out of them all, PM-PBB3 proves to bind the strongest. The findings suggest that our computational workflow of structural and dynamic details of the tau filaments has potential for the rational design of Tau<sup>PiD</sup> specific PET tracers. |
| first_indexed | 2024-03-10T13:36:32Z |
| format | Article |
| id | doaj.art-263c29b6458741c98aa16f9bdd9a9496 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T13:36:32Z |
| publishDate | 2020-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-263c29b6458741c98aa16f9bdd9a94962023-11-21T07:28:03ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-12-0122134910.3390/ijms22010349Pick’s Tau Fibril Shows Multiple Distinct PET Probe Binding Sites: Insights from Computational ModellingSushil K. Mishra0Yoshiki Yamaguchi1Makoto Higuchi2Naruhiko Sahara3Advance Glycoscience Research Cluster, National University of Ireland Galway, H91 W2TY Galway, IrelandFaculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi 981-8558, JapanNational Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, JapanNational Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, JapanIn recent years, it has been realized that the tau protein is a key player in multiple neurodegenerative diseases. Positron emission tomography (PET) radiotracers that bind to tau filaments in Alzheimer’s disease (AD) are in common use, but PET tracers binding to tau filaments of rarer, age-related dementias, such as Pick’s disease, have not been widely explored. To design disease-specific and tau-selective PET tracers, it is important to determine where and how PET tracers bind to tau filaments. In this paper, we present the first molecular modelling study on PET probe binding to the structured core of tau filaments from a patient with Pick’s disease (Tau<sup>PiD</sup>). We have used docking, molecular dynamics simulations, binding-affinity and tunnel calculations to explore Tau<sup>PiD</sup> binding sites, binding modes, and binding energies of PET probes (AV-1451, MK-6240, PBB3, PM-PBB3, THK-5351 and PiB) with Tau<sup>PiD</sup>. The probes bind to Tau<sup>PiD</sup> at multiple surface binding sites as well as in a cavity binding site. The probes show unique surface binding patterns, and, out of them all, PM-PBB3 proves to bind the strongest. The findings suggest that our computational workflow of structural and dynamic details of the tau filaments has potential for the rational design of Tau<sup>PiD</sup> specific PET tracers.https://www.mdpi.com/1422-0067/22/1/349dockingMM/GBSA calculationpositron emission tomography (PET) imagingtauPET tracers |
| spellingShingle | Sushil K. Mishra Yoshiki Yamaguchi Makoto Higuchi Naruhiko Sahara Pick’s Tau Fibril Shows Multiple Distinct PET Probe Binding Sites: Insights from Computational Modelling International Journal of Molecular Sciences docking MM/GBSA calculation positron emission tomography (PET) imaging tau PET tracers |
| title | Pick’s Tau Fibril Shows Multiple Distinct PET Probe Binding Sites: Insights from Computational Modelling |
| title_full | Pick’s Tau Fibril Shows Multiple Distinct PET Probe Binding Sites: Insights from Computational Modelling |
| title_fullStr | Pick’s Tau Fibril Shows Multiple Distinct PET Probe Binding Sites: Insights from Computational Modelling |
| title_full_unstemmed | Pick’s Tau Fibril Shows Multiple Distinct PET Probe Binding Sites: Insights from Computational Modelling |
| title_short | Pick’s Tau Fibril Shows Multiple Distinct PET Probe Binding Sites: Insights from Computational Modelling |
| title_sort | pick s tau fibril shows multiple distinct pet probe binding sites insights from computational modelling |
| topic | docking MM/GBSA calculation positron emission tomography (PET) imaging tau PET tracers |
| url | https://www.mdpi.com/1422-0067/22/1/349 |
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