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首页> 外文期刊>International Journal of Molecular Sciences >Modeling the Colchicum autumnale Tubulin and a Comparison of Its Interaction with Colchicine to Human Tubulin
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Modeling the Colchicum autumnale Tubulin and a Comparison of Its Interaction with Colchicine to Human Tubulin

机译：秋水仙秋水仙碱微管蛋白的建模及其与秋水仙碱与人微管蛋白相互作用的比较

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摘要

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 .
机译：微管蛋白是许多小分子天然化合物的靶标，这些化合物会改变微管动力学，并导致细胞周期停滞和凋亡。这些化合物之一是秋水仙碱，秋水仙（Colchicum autumnale）生产的一种植物生物碱。秋季梭状芽胞杆菌产生强力的细胞毒素秋水仙碱并表达其靶蛋白，但它对秋水仙碱的细胞毒性作用具有免疫力，迄今尚不清楚这种抗药性的机制。在本文中，调查了秋茄中秋水仙碱抗性的分子机制，并将其与人微管蛋白进行了比较。为此，创建了秋季梭状芽孢杆菌α-β微管蛋白异二聚体的同源性模型，并进行了分子动力学（MD）模拟和分子力学泊松–玻耳兹曼计算（MM / PBSA），以确定秋水仙碱对微管蛋白的结合亲和力。使用我们的分子方法，表明与人微管蛋白相比，秋茄微管蛋白中的秋水仙碱结合位点含有少量氨基酸取代。然而，这些取代诱导对微管蛋白的结合亲和力显着降低，并且随后其结构的构象变化更少。提示这种小的构象变化不足以深刻地破坏微管动力学，这解释了秋天梭菌对秋水仙碱的高抗性。

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