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Permanent link (DOI): https://doi.org/10.7939/R30R9MH5F

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Modeling the Colchicum autumnale Tubulin and a Comparison of Its Interaction with Colchicine to Human Tubulin Open Access

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Author or creator
Spasevska, Ivana
Ayoub, Ahmed T
Winter, Philip
Preto, Jordane
Wong, Gane K-S
Dumonte, Charles
Tuszynski, Jack A
Additional contributors
Subject/Keyword
tubulin
colchicine
C. autumnale
binding site
cytotoxicity
molecular modeling
Type of item
Journal Article (Published)
Language
English
Place
Time
Description
Tubulin is the target for many small-molecule natural compounds, which alter microtubules dynamics, and lead to cell cycle arrest and apoptosis. One of these compounds is colchicine, a plant alkaloid produced by Colchicum autumnale. While C. autumnale produces a potent cytotoxin, colchicine, and expresses its target protein, it is immune to colchicine’s cytotoxic action and the mechanism of this resistance is hitherto unknown. In the present paper, the molecular mechanisms responsible for colchicine resistance in C. autumnale are investigated and compared to human tubulin. To this end, homology models for C. autumnale α-β tubulin heterodimer are created and molecular dynamics (MD) simulations together with molecular mechanics Poisson–Boltzmann calculations (MM/PBSA) are performed to determine colchicine’s binding affinity for tubulin. Using our molecular approach, it is shown that the colchicine-binding site in C. autumnale tubulin contains a small number of amino acid substitutions compared to human tubulin. However, these substitutions induce significant reduction in the binding affinity for tubulin, and subsequently fewer conformational changes in its structure result. It is suggested that such small conformational changes are insufficient to profoundly disrupt microtubule dynamics, which explains the high resistance to colchicine by C. autumnale
Date created
2017/08/02
DOI
doi:10.7939/R30R9MH5F
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Attribution 4.0 International
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File title: Modeling the Colchicum autumnale Tubulin and a Comparison of Its Interaction with Colchicine to Human Tubulin
File author: Ivana Spasevska, Ahmed T. Ayoub, Philip Winter, Jordane Preto, Gane K.-S. Wong, Charles Dumontet and Jack A. Tuszynski
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