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Investigating Dynamic Instability of Microtubules Using MD Simulations

Klaus Schulten, University of Illinois at Urbana-Champaign

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Klaus Schulten, Danielle Chandler, Yanxin Liu, Rafael Bernardi, Till Rudack, Yi Zhang

Microtubules are a major component of the cell cytoskeleton, important for maintaining cell structure, intracellular transport, and cell division. A microtubule consists of two subunits, alpha- and beta-tubulin, which assemble into a tube structure in an alternating fashion. Dynamic instability is an inherent property of microtubules which allows them to stochastically switch between phases of assembly and disassembly, thereby playing a key role in the process of cell division. A class of anticancer drug, named Taxol, works by blocking microtubule disassembly. We propose to investigate dynamic instability of microtubules by employing molecular dynamics simulations. The atomic model of microtubules, bound with different nucleotides, was obtained by integrating structural data from X-ray crystallography and cryo-electron microscopy (cryo-EM).

We seek to explore through the simulations how nucleotide binding and subsequent hydrolysis lead to microtubule assembly and disassembly, respectively, and how the anticancer drug, Taxol, stabilizes microtubules against hydrolysis-induced depolymerization. The results will not only improve our understanding of the fundamental process of cell division, but also shed light on how to stop the unwanted cell division under pathological conditions, such as in cancer cells. The atomic picture of the molecular mechanism of microtubule-stabilizing anticancer agents can help us better understand the ever-increasing drug resistance in chemotherapy, leading to better designs of next generation of anticancer agents.