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

二聚体水平微管动力学的随机化学机械模型：水解、灾难和调节

基本信息

批准号：
277689029
负责人：
Professor Dr. Jan Kierfeld
金额：
--
依托单位：
Forschungsgruppen Theorie der Kondensierten Materie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2015
资助国家：
德国
起止时间：
2014-12-31 至 2021-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/277689029?language=en
关键词：
stochastic chemo mechanical model microtubule

项目摘要

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.

微管是细胞骨架中的丝状蛋白质，具有复杂的动力学聚合行为，涉及所谓的灾难和救援事件，这对于其生物学功能至关重要，例如在有丝分裂过程中。该研究项目的重点是对二聚体水平上微管动力学的随机化学机械模型的开发和分析。微管蛋白二聚体的水解产生了微管内的机械力，这些力在灾难事件中释放出来，在灾难事件中，微管进入快速解聚的相，而微管蛋白二聚体弯曲变得显而易见。理论和仿真模型将这些机械力与化学动力学融为一体，并在微管内添加二聚体，尤其是在微管内的进一步的水解事件。到目前为止，文献尚未解决后一个方面。在化学机械模拟模型中，在每个时间步骤中，微管将是机械放松的，聚合和水解事件将根据其动力学速率随机进行，并由机械力调节。理论模型的参数将受到可用的实验数据的约束，例如聚合和解聚速度。关于微管力学，我们将实施和比较变构模型，其中水解导致单个小管蛋白二聚体和晶格模型的弯曲，其中水解削弱了本质上弯曲的小管蛋白二聚体之间的稳定侧向键。关于水解的化学动力学，我们将实施和比较随机水解顺序和矢量水解方案。特别是，我们将调查如何扩展力学和水解之间的耦合，可以为灾难引发的显微镜模型，即将过渡到快速分解阶段。最后，我们将使用化学机械微管模型来开发用于调节蛋白质（例如Stathmin或XMAP215）功能功能的理论模型。 Stathmin是重要的微管生长抑制剂，而XMAP215增加了MT的生长速度。有证据表明，这两种蛋白质都将其与局部曲率融为一体，从而将其与微管的力学相结合。