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Molecular basis of small-molecule binding to α-synuclein

Paul Robustelli, Alain Ibanez-de-Opakua, Cecily Campbell-Bezat, Fabrizio Giordanetto, Stefan Becker, Markus Zweckstetter, Albert C. Pan, David E. Shaw
doi: https://doi.org/10.1101/2021.01.22.426549
Paul Robustelli
1D. E. Shaw Research, New York, NY 10036, USA
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Alain Ibanez-de-Opakua
2German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany
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Cecily Campbell-Bezat
1D. E. Shaw Research, New York, NY 10036, USA
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Fabrizio Giordanetto
1D. E. Shaw Research, New York, NY 10036, USA
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Stefan Becker
3Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany
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Markus Zweckstetter
2German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany
3Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany
4DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), 37073 Göttingen, Germany
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  • For correspondence: Albert.Pan@DEShawResearch.com Markus.Zweckstetter@dzne.de David.Shaw@DEShawResearch.com
Albert C. Pan
1D. E. Shaw Research, New York, NY 10036, USA
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  • For correspondence: Albert.Pan@DEShawResearch.com Markus.Zweckstetter@dzne.de David.Shaw@DEShawResearch.com
David E. Shaw
1D. E. Shaw Research, New York, NY 10036, USA
5Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA
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  • For correspondence: Albert.Pan@DEShawResearch.com Markus.Zweckstetter@dzne.de David.Shaw@DEShawResearch.com
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Abstract

Intrinsically disordered proteins (IDPs) are implicated in many human diseases. They have generally not been amenable to conventional structure-based drug design, however, because their intrinsic conformational variability has precluded an atomic-level understanding of their binding to small molecules. Here we present long-timescale, atomic-level molecular dynamics (MD) simulations of monomeric α-synuclein (an IDP whose aggregation is associated with Parkinson’s disease) binding the small-molecule drug fasudil in which the observed protein-ligand interactions were found to be in good agreement with previously reported NMR chemical shift data. In our simulations, fasudil, when bound, favored certain charge-charge and π-stacking interactions near the C terminus of α-synuclein, but tended not to form these interactions simultaneously, rather breaking one of these interactions and forming another nearby (a mechanism we term dynamic shuttling). Further simulations with small molecules chosen to modify these interactions yielded binding affinities and key structural features of binding consistent with subsequent NMR experiments, suggesting the potential for MD-based strategies to facilitate the rational design of small molecules that bind with disordered proteins.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted January 24, 2021.
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Molecular basis of small-molecule binding to α-synuclein
Paul Robustelli, Alain Ibanez-de-Opakua, Cecily Campbell-Bezat, Fabrizio Giordanetto, Stefan Becker, Markus Zweckstetter, Albert C. Pan, David E. Shaw
bioRxiv 2021.01.22.426549; doi: https://doi.org/10.1101/2021.01.22.426549
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Molecular basis of small-molecule binding to α-synuclein
Paul Robustelli, Alain Ibanez-de-Opakua, Cecily Campbell-Bezat, Fabrizio Giordanetto, Stefan Becker, Markus Zweckstetter, Albert C. Pan, David E. Shaw
bioRxiv 2021.01.22.426549; doi: https://doi.org/10.1101/2021.01.22.426549

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