Binding of a Pyrene-based Fluorescent Amyloid Ligand to Transthyretin: A Combined Crystallographic and Molecular Dynamics Study

Research output: Contribution to journalArticleResearchpeer review

Authors

  • Thi Minh Nghia Nguyen
  • Afshan Begum
  • Jun Zhang
  • Petter Leira
  • Yogesh Todarwal
  • Mathieu Linares
  • Patrick Norman
  • Dean Derbyshire
  • Eleonore von Castelmur
  • Mikael Lindgren
  • Per Hammarström
  • Carolin König

External Research Organisations

  • Linkoping University
  • Norwegian University of Science and Technology (NTNU)
  • Royal Institute of Technology (KTH)
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Details

Original languageEnglish
Pages (from-to)6628–6635
Number of pages8
JournalThe Journal of Physical Chemistry Part B: Biophysics, Biomaterials, Liquids, Soft Matter
Volume127
Issue number30
Early online date21 Jul 2023
Publication statusPublished - 3 Aug 2023

Abstract

Misfolding and aggregation of transthyretin (TTR) cause several amyloid diseases. Besides being an amyloidogenic protein, TTR has an affinity for bicyclic small-molecule ligands in its thyroxine (T4) binding site. One class of TTR ligands are trans-stilbenes. The trans-stilbene scaffold is also widely applied for amyloid fibril-specific ligands used as fluorescence probes and as positron emission tomography tracers for amyloid detection and diagnosis of amyloidosis. We have shown that native tetrameric TTR binds to amyloid ligands based on the trans-stilbene scaffold providing a platform for the determination of high-resolution structures of these important molecules bound to protein. In this study, we provide spectroscopic evidence of binding and X-ray crystallographic structure data on tetrameric TTR complex with the fluorescent salicylic acid-based pyrene amyloid ligand (Py1SA), an analogue of the Congo red analogue X-34. The ambiguous electron density from the X-ray diffraction, however, did not permit Py1SA placement with enough confidence likely due to partial ligand occupancy. Instead, the preferred orientation of the Py1SA ligand in the binding pocket was determined by molecular dynamics and umbrella sampling approaches. We find a distinct preference for the binding modes with the salicylic acid group pointing into the pocket and the pyrene moiety outward to the opening of the T4 binding site. Our work provides insight into TTR binding mode preference for trans-stilbene salicylic acid derivatives as well as a framework for determining structures of TTR-ligand complexes.

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Cite this

Binding of a Pyrene-based Fluorescent Amyloid Ligand to Transthyretin: A Combined Crystallographic and Molecular Dynamics Study. / Nguyen, Thi Minh Nghia; Begum, Afshan; Zhang, Jun et al.
In: The Journal of Physical Chemistry Part B: Biophysics, Biomaterials, Liquids, Soft Matter, Vol. 127, No. 30, 03.08.2023, p. 6628–6635.

Research output: Contribution to journalArticleResearchpeer review

Nguyen, TMN, Begum, A, Zhang, J, Leira, P, Todarwal, Y, Linares, M, Norman, P, Derbyshire, D, von Castelmur, E, Lindgren, M, Hammarström, P & König, C 2023, 'Binding of a Pyrene-based Fluorescent Amyloid Ligand to Transthyretin: A Combined Crystallographic and Molecular Dynamics Study', The Journal of Physical Chemistry Part B: Biophysics, Biomaterials, Liquids, Soft Matter, vol. 127, no. 30, pp. 6628–6635. https://doi.org/10.1021/acs.jpcb.3c02147
Nguyen, T. M. N., Begum, A., Zhang, J., Leira, P., Todarwal, Y., Linares, M., Norman, P., Derbyshire, D., von Castelmur, E., Lindgren, M., Hammarström, P., & König, C. (2023). Binding of a Pyrene-based Fluorescent Amyloid Ligand to Transthyretin: A Combined Crystallographic and Molecular Dynamics Study. The Journal of Physical Chemistry Part B: Biophysics, Biomaterials, Liquids, Soft Matter, 127(30), 6628–6635. https://doi.org/10.1021/acs.jpcb.3c02147
Nguyen TMN, Begum A, Zhang J, Leira P, Todarwal Y, Linares M et al. Binding of a Pyrene-based Fluorescent Amyloid Ligand to Transthyretin: A Combined Crystallographic and Molecular Dynamics Study. The Journal of Physical Chemistry Part B: Biophysics, Biomaterials, Liquids, Soft Matter. 2023 Aug 3;127(30):6628–6635. Epub 2023 Jul 21. doi: 10.1021/acs.jpcb.3c02147
Nguyen, Thi Minh Nghia ; Begum, Afshan ; Zhang, Jun et al. / Binding of a Pyrene-based Fluorescent Amyloid Ligand to Transthyretin : A Combined Crystallographic and Molecular Dynamics Study. In: The Journal of Physical Chemistry Part B: Biophysics, Biomaterials, Liquids, Soft Matter. 2023 ; Vol. 127, No. 30. pp. 6628–6635.
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title = "Binding of a Pyrene-based Fluorescent Amyloid Ligand to Transthyretin: A Combined Crystallographic and Molecular Dynamics Study",
abstract = "Misfolding and aggregation of transthyretin (TTR) cause several amyloid diseases. Besides being an amyloidogenic protein, TTR has an affinity for bicyclic small-molecule ligands in its thyroxine (T4) binding site. One class of TTR ligands are trans-stilbenes. The trans-stilbene scaffold is also widely applied for amyloid fibril-specific ligands used as fluorescence probes and as positron emission tomography tracers for amyloid detection and diagnosis of amyloidosis. We have shown that native tetrameric TTR binds to amyloid ligands based on the trans-stilbene scaffold providing a platform for the determination of high-resolution structures of these important molecules bound to protein. In this study, we provide spectroscopic evidence of binding and X-ray crystallographic structure data on tetrameric TTR complex with the fluorescent salicylic acid-based pyrene amyloid ligand (Py1SA), an analogue of the Congo red analogue X-34. The ambiguous electron density from the X-ray diffraction, however, did not permit Py1SA placement with enough confidence likely due to partial ligand occupancy. Instead, the preferred orientation of the Py1SA ligand in the binding pocket was determined by molecular dynamics and umbrella sampling approaches. We find a distinct preference for the binding modes with the salicylic acid group pointing into the pocket and the pyrene moiety outward to the opening of the T4 binding site. Our work provides insight into TTR binding mode preference for trans-stilbene salicylic acid derivatives as well as a framework for determining structures of TTR-ligand complexes.",
author = "Nguyen, {Thi Minh Nghia} and Afshan Begum and Jun Zhang and Petter Leira and Yogesh Todarwal and Mathieu Linares and Patrick Norman and Dean Derbyshire and {von Castelmur}, Eleonore and Mikael Lindgren and Per Hammarstr{\"o}m and Carolin K{\"o}nig",
note = "The authors acknowledge funding by the German Research Foundation (DFG) through the Emmy Noether Young Group Leader Programme (CK, project KO 5423/1-1), the Swedish e-Science Research Centre (SeRC, MaL, PN), the Swedish Research Council (PN, Grant No. 2018-4343; PH, Grant No. 2019-04405), the Swedish Brain Foundation (PH, Grant No. ALZ2019-0004 and ALZ2022-0004), and Gustaf V and Drottning Victorias Stiftelse (PH). Computing resources were provided by the Swedish National Infrastructure for Computing (SNIC), and biophysical instrumentation was used at ProLinC core facility.",
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T2 - A Combined Crystallographic and Molecular Dynamics Study

AU - Nguyen, Thi Minh Nghia

AU - Begum, Afshan

AU - Zhang, Jun

AU - Leira, Petter

AU - Todarwal, Yogesh

AU - Linares, Mathieu

AU - Norman, Patrick

AU - Derbyshire, Dean

AU - von Castelmur, Eleonore

AU - Lindgren, Mikael

AU - Hammarström, Per

AU - König, Carolin

N1 - The authors acknowledge funding by the German Research Foundation (DFG) through the Emmy Noether Young Group Leader Programme (CK, project KO 5423/1-1), the Swedish e-Science Research Centre (SeRC, MaL, PN), the Swedish Research Council (PN, Grant No. 2018-4343; PH, Grant No. 2019-04405), the Swedish Brain Foundation (PH, Grant No. ALZ2019-0004 and ALZ2022-0004), and Gustaf V and Drottning Victorias Stiftelse (PH). Computing resources were provided by the Swedish National Infrastructure for Computing (SNIC), and biophysical instrumentation was used at ProLinC core facility.

PY - 2023/8/3

Y1 - 2023/8/3

N2 - Misfolding and aggregation of transthyretin (TTR) cause several amyloid diseases. Besides being an amyloidogenic protein, TTR has an affinity for bicyclic small-molecule ligands in its thyroxine (T4) binding site. One class of TTR ligands are trans-stilbenes. The trans-stilbene scaffold is also widely applied for amyloid fibril-specific ligands used as fluorescence probes and as positron emission tomography tracers for amyloid detection and diagnosis of amyloidosis. We have shown that native tetrameric TTR binds to amyloid ligands based on the trans-stilbene scaffold providing a platform for the determination of high-resolution structures of these important molecules bound to protein. In this study, we provide spectroscopic evidence of binding and X-ray crystallographic structure data on tetrameric TTR complex with the fluorescent salicylic acid-based pyrene amyloid ligand (Py1SA), an analogue of the Congo red analogue X-34. The ambiguous electron density from the X-ray diffraction, however, did not permit Py1SA placement with enough confidence likely due to partial ligand occupancy. Instead, the preferred orientation of the Py1SA ligand in the binding pocket was determined by molecular dynamics and umbrella sampling approaches. We find a distinct preference for the binding modes with the salicylic acid group pointing into the pocket and the pyrene moiety outward to the opening of the T4 binding site. Our work provides insight into TTR binding mode preference for trans-stilbene salicylic acid derivatives as well as a framework for determining structures of TTR-ligand complexes.

AB - Misfolding and aggregation of transthyretin (TTR) cause several amyloid diseases. Besides being an amyloidogenic protein, TTR has an affinity for bicyclic small-molecule ligands in its thyroxine (T4) binding site. One class of TTR ligands are trans-stilbenes. The trans-stilbene scaffold is also widely applied for amyloid fibril-specific ligands used as fluorescence probes and as positron emission tomography tracers for amyloid detection and diagnosis of amyloidosis. We have shown that native tetrameric TTR binds to amyloid ligands based on the trans-stilbene scaffold providing a platform for the determination of high-resolution structures of these important molecules bound to protein. In this study, we provide spectroscopic evidence of binding and X-ray crystallographic structure data on tetrameric TTR complex with the fluorescent salicylic acid-based pyrene amyloid ligand (Py1SA), an analogue of the Congo red analogue X-34. The ambiguous electron density from the X-ray diffraction, however, did not permit Py1SA placement with enough confidence likely due to partial ligand occupancy. Instead, the preferred orientation of the Py1SA ligand in the binding pocket was determined by molecular dynamics and umbrella sampling approaches. We find a distinct preference for the binding modes with the salicylic acid group pointing into the pocket and the pyrene moiety outward to the opening of the T4 binding site. Our work provides insight into TTR binding mode preference for trans-stilbene salicylic acid derivatives as well as a framework for determining structures of TTR-ligand complexes.

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DO - 10.1021/acs.jpcb.3c02147

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JO - The Journal of Physical Chemistry Part B: Biophysics, Biomaterials, Liquids, Soft Matter

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