Journal of Molecular Modeling

, Volume 19, Issue 12, pp 5225–5235 | Cite as

Molecular docking of thiamine reveals similarity in binding properties between the prion protein and other thiamine-binding proteins

  • Nataraj S. Pagadala
  • Trent C. Bjorndahl
  • Nikolay Blinov
  • Andriy Kovalenko
  • David S. Wishart
Original Paper


Prion-induced diseases are a global health concern. The lack of effective therapy and 100 % mortality rates for such diseases have made the prion protein an important target for drug discovery. Previous NMR experimental work revealed that thiamine and its derivatives bind the prion protein in a pocket near the N-terminal loop of helix 1, and conserved intermolecular interactions were noted between thiamine and other thiamine-binding proteins. Furthermore, water-mediated interactions were observed in all of the X-ray crystallographic structures of thiamine-binding proteins, but were not observed in the thiamine–prion NMR study. To better understand the potential role of water in thiamine–prion binding, a docking study was employed using structural X-ray solvent. Before energy minimization, docked thiamine assumed a “V” shape similar to some of the known thiamine-dependent proteins. Following minimization with NMR-derived restraints, the “F” conformation was observed. Our findings confirmed that water is involved in ligand stabilization and phosphate group interaction. The resulting refined structure of thiamine bound to the prion protein allowed the 4-aminopyrimidine ring of thiamine to π-stack with Tyr150, and facilitated hydrogen bonding between Asp147 and the amino group of 4-aminopyrimidine. Investigation of the π-stacking interaction through mutation of the tyrosine residue further revealed its importance in ligand placement. The resulting refined structure is in good agreement with previous experimental restraints, and is consistent with the pharmacophore model of thiamine-binding proteins.


Prion protein Thiamine Water interaction Pi stacking 



The authors wish to acknowledge the financial support of the Alberta Prion Research Institute (APRI), Alberta Innovates Bio-Solutions, the National Research Council of Canada (NRC-NINT), and the Canadian Institutes of Health Research (CIHR).

Supplementary material

894_2013_1979_MOESM1_ESM.doc (4.2 mb)
ESM 1 (DOC 4.16 MB)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Nataraj S. Pagadala
    • 1
  • Trent C. Bjorndahl
    • 2
  • Nikolay Blinov
    • 3
    • 4
  • Andriy Kovalenko
    • 4
    • 3
  • David S. Wishart
    • 2
    • 4
  1. 1.Department of Electrical and Computer EngineeringUniversity of AlbertaEdmontonCanada
  2. 2.Departments of Biological Sciences and Computing ScienceUniversity of AlbertaEdmontonCanada
  3. 3.Department of Mechanical EngineeringUniversity of AlbertaEdmontonCanada
  4. 4.National Institute for NanotechnologyEdmontonCanada

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