College of Psychology: Faculty Articles

Title

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

Document Type

Article

Publication Date

11-1-2012

Keywords

Chemotherapy, Nanopores, Paclitaxel, Tubulin, Yew Tree

Publication Title

Pharmaceutical Research

ISSN

0724-8741

Volume

29

Issue/No.

11

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.

DOI

10.1007/s11095-012-0829-y