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Presentationsmolecular-mechanical model of dynamic microtubuleCenter for theoretical problems of physico-chemical pharmacology, RAS, ul. Kosygina 4, Moscow, 119991 Russia; Physics Department, Lomonosov Moscow State University, ul. Lenisnkie gory, 1-2, Moscow, 119991, Russia, Tel.: (495)938-25-33, fax: (495)938-25-33, Email: nikita_gb@mail.ru 1University of Pennsylvania, USA, 19104, Philadelphia, 3400 Civic Center Microtubules are intracellular polymers of tubulin, essential for transport, motility, division and maintaining intracellular organization. Mircrotubules are dynamically unstable, i.e. they spontaneously switch between phases of polymerization and depolymerization under fixed media conditions (either in cytoplasm or in experimental solution). Despite the key role of dynamic instability in a number of cellular processes and a long history of experimental and theoretical research, molecular mechanisms of this phenomenon remain unclear. We have built a molecular-mechanical model, regarding microtubule as an ensemble of interacting solid particles, whose motions are described with Brownian dynamics equations. Association of new particles from solution and hydrolysis of tubulin-bound guanosine triphosphates in the microtubule body are modeled with a Monte-Carlo approach. Our model is superior to previous models of dynamic microtubules by the level of detail and the number of experimental observations that it can describe within the same set of parameters. We have applied this model to the analysis of the mechanism of transition from polymerization to depolymerization, conventionally called “catastrophe”. According to published experimental reports, the probability of microtubule catastrophe increases as the microtubule polymerizes, suggesting that polymerization is a multi-step process. That effect has been named microtubule “aging”. With the help of our model we tested two previously proposed hypotheses about the nature of microtubule “aging” process, and found that none of them is consistent with our simulations. As a result of our analysis we have put forward a new alternative explanation of the mechanism of microtubule catastrophe, based on the accumulation of multiple reversible short-lived destabilizing molecular events at the microtubule tip, such as formation of curled protofilaments. Our theoretical data point out to new potential ways of regulation of microtubule dynamics by associated proteins in live cells.
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