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

• Published in: International journal of molecular sciences Vol. 18; no. 8; p. 1676
• Main Authors: Spasevska, Ivana, Ayoub, Ahmed T, Winter, Philip, Preto, Jordane, Wong, Gane K-S, Dumontet, Charles, Tuszynski, Jack A
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 02-08-2017; MDPI
• Subjects: Affinity; Apoptosis; binding site; Binding sites; C. autumnale; Cell cycle; Colchicine; Colchicine - chemistry; Colchicine - metabolism; Colchicum - chemistry; Colchicum - genetics; Colchicum - metabolism; Computer simulation; Cytotoxicity; High resistance; Homology; Humans; Microtubules; Models, Molecular; Molecular biology; Molecular dynamics; molecular modeling; Molecular modelling; Plant Proteins - genetics; Plant Proteins - metabolism; Tubulin; Tubulin - chemistry; Tubulin - genetics; Tubulin - metabolism; tubulin; colchicine; molecular modeling; C. autumnale; cytotoxicity; binding site
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms18081676

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
. While
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
are investigated and compared to human tubulin. To this end, homology models for
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
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
.