Pharmaceutical Research

, Volume 29, Issue 11, pp 3007–3021 | Cite as

Modeling the Yew Tree Tubulin and a Comparison of its Interaction with Paclitaxel to Human Tubulin

  • Jack A. Tuszynski
  • Travis J. A. Craddock
  • Jonathan Y. Mane
  • Khaled Barakat
  • Chih-Yuan Tseng
  • Melissa Gajewski
  • Philip Winter
  • Laleh Alisaraie
  • Jordan Patterson
  • Eric Carpenter
  • Weiwei Wang
  • Michael K. Deyholos
  • Linji Li
  • Xiao Sun
  • Yong Zhang
  • Gane Ka-Shu Wong
Research Paper
First Online:
Received:
Accepted:

ABSTRACT

Purpose

To explore possible ways in which yew tree tubulin is naturally resistant to paclitaxel. While the yew produces a potent cytotoxin, paclitaxel, it is immune to paclitaxel’s cytotoxic action.

Methods

Tubulin sequence data for plant species were obtained from Alberta 1000 Plants Initiative. Sequences were assembled with Trinity de novo assembly program and tubulin identified. Homology modeling using MODELLER software was done to generate structures for yew tubulin. Molecular dynamics simulations and molecular mechanics Poisson–Boltzmann calculations were performed with the Amber package to determine binding affinity of paclitaxel to yew tubulin. ClustalW2 program and PHYLIP package were used to perform phylogenetic analysis on plant tubulin sequences.

Results

We specifically analyzed several important regions in tubulin structure: the high-affinity paclitaxel binding site, as well as the intermediate binding site and microtubule nanopores. Our analysis indicates that the high-affinity binding site contains several substitutions compared to human tubulin, all of which reduce the binding energy of paclitaxel.

Conclusions

The yew has achieved a significant reduction of paclitaxel’s affinity for its tubulin by utilizing several specific residue changes in the binding pocket for paclitaxel.

KEY WORDS

chemotherapy nanopores paclitaxel tubulin yew tree 

ABBREVIATIONS

1KP

1000 plants initiative

BLAST

basic local alignment search tool

MD

molecular dynamics

MM-PBSA

molecular mechanics Poisson–Boltzmann surface area

MT

microtubule

NDGA

nordihydroguaiaretic acid

ORF

open reading frames

PDB

protein data bank

PTX

paclitaxel

RMSD

root mean square deviation

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Notes

ACKNOWLEDGMENTS AND DISCLOSURES

J.A.T. acknowledges support for this research from the Alberta Cancer Foundation, Alberta Advanced Education and Technology, the Allard Foundation, the Canadian Breast Cancer Foundation, and the National Sciences and Engineering Research Council of Canada (NSERC Canada). T.J.A.C. acknowledges funding support for this research from NSERC Canada. G.K.S.W. acknowledges Alberta Advanced Education and Technology, Genome Alberta, Alberta Innovates Tech Futures iCORE, Musea Ventures, and BGI-Shenzhen for the funding of the Alberta 1000 Plants Initiative.

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Jack A. Tuszynski
    • 1
    • 2
    • 7
  • Travis J. A. Craddock
    • 2
    • 3
  • Jonathan Y. Mane
    • 1
  • Khaled Barakat
    • 2
    • 4
  • Chih-Yuan Tseng
    • 1
  • Melissa Gajewski
    • 1
  • Philip Winter
    • 1
  • Laleh Alisaraie
    • 1
  • Jordan Patterson
    • 3
  • Eric Carpenter
    • 5
  • Weiwei Wang
    • 3
  • Michael K. Deyholos
    • 5
  • Linji Li
    • 6
  • Xiao Sun
    • 6
  • Yong Zhang
    • 6
  • Gane Ka-Shu Wong
    • 3
    • 5
    • 8
  1. 1.Department of OncologyUniversity of AlbertaEdmontonCanada
  2. 2.Department of PhysicsUniversity of AlbertaEdmontonCanada
  3. 3.Department of MedicineUniversity of AlbertaEdmontonCanada
  4. 4.Department of Engineering Mathematics & PhysicsFayoum UniversityFayoumEgypt
  5. 5.Department of Biological SciencesUniversity of AlbertaEdmontonCanada
  6. 6.Guangdong Provincial Engineer Laboratory of Proteomics BGI-ShenzhenYantian District, ShenzhenChina
  7. 7.Department of Oncology, Division of Experimental OncologyCross Cancer Institute 11560 University Ave.EdmontonCanada
  8. 8.BGI-ShenzhenShenzhenChina

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