A stochastic chemo-mechanical model for microtubule dynamics on the dimer level: hydrolysis, catastrophes, and regulation

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Microtubules are filamentous proteins in the cytoskeleton with a complex dynamical polymerization behavior involving so-called catastrophe and rescue events, which is essential for their biological function, for example during mitosis. This research project is focused on the development and analysis of a stochastic chemo-mechanical model for microtubule dynamics on the dimer level. Hydrolysis of tubulin dimers gives rise to mechanical forces within the microtubule, which are released in catastrophe events, where the microtubule enters a phase of rapid depolymerization and tubulin dimer bending becomes apparent. The theoretical and simulation model will couple these mechanical forces to the chemical kinetics of addition and removal of dimers and, in particular, further hydrolysis events within the microtubule. This latter aspect has not been addressed in the literature so far. Within the chemo-mechanical simulation model, at each time step, the microtubule will be mechanically relaxed and polymerization and hydrolysis events are performed stochastically according to their kinetic rates, which are modulated by mechanical forces. Parameters of the theoretical model will be constrained by available experimental data, for example, for polymerization and depolymerization velocities. Regarding the microtubule mechanics, we will implement and compare the allosteric model, where hydrolysis gives rise to bending of individual tubulin dimers and the lattice model, where hydrolysis weakens the stabilizing lateral bonds between intrinsically bent tubulin dimers. Regarding the chemical kinetics of hydrolysis, we will implement and compare both random hydrolysis order and a vectorial hydrolysis scheme. In particular, we will investigate to what extend the coupling between mechanics and hydrolysis can provide a microscopic model for the initiation of catastrophes, i.e., the transition into a rapid depolymerization phase. Finally, we will use the chemo-mechanical microtubule model to develop theoretical models for the function of microtubule regulating proteins such as stathmin or XMAP215; stathmin is an important microtubule growth inhibitor, whereas XMAP215 increases the MT growth rate. There is evidence, that both proteins couple to the local curvature and, thus, also to the mechanics of the microtubule.