Dynamical Rigidity Percolation in Microtubule Bundles

微管束中的动态刚性渗透

• 批准号: 1207624
• 负责人: Daniel Cox
• 金额: $ 51万
• 依托单位: University of California-Davis
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1207624&HistoricalAwards=false
• 关键词: Dynamical; Rigidity; Percolation; Microtubule; Bundles

TECHNICAL SUMMARYThis award supports theoretical and computational research and education at the interface of the mathematical sciences and biology. The coupled microtubule-tau bundles of the neuronal axon are a remarkable active material, functionally stable over decades even as the component proteins are constantly renewed. Using mechanisms proposed for tau removal in late stages of Alzheimer's Disease, which are initiated by oligomerization of the a-beta peptide, the PIs will develop a coarse grained theory of the mechanical failure of this system as the tau proteins are depleted via: (i) tau fragmentation induced by a-beta oligomer triggered protease production; (ii) tau charging (phosphorylation) through a-beta triggered kinase production; (iii) aggregation which robs tau monomers from the bundles. The kinetics of these processes should produce different time courses for tau removal and hence allow insight into mechanical failure mechanisms. The taus will be modeled as springs. The PIs will carry out explicit molecular dynamics simulations on likely tau oligomer structures to determine the relevant spring forces. The compressed tau springs hold off mechanical collapse induced by at least two sources: (i) depletion forces between microtubules induced by intercalating molecules, which have a higher translational entropy when the microtubules collapse together; (ii) surface tension from the outer membrane/actin filament cytoskeleton. The PIs will develop force models for the taus and microtubule depletion forces, and input them to a 2-dimensional percolation model for the mechanical rigidity. The sequential "spring removal" can be mapped to the kinetics of the tau degradation to predict time courses for cell mechanics experiments conducted under exposure to a-beta oligomers. The PIs will also explore a fully three-dimensional model, which allows for tilting of the microtubules, which might be important for allowing the microtubules to experience the depletion attraction. Finally, the PIs will attempt to develop algorithms to scale the time behavior at high laboratory concentrations for the damaging A-beta oligomers of Alzheimer's disease to physiologically relevant concentrations. The use of mechanical approaches to the study of intracellular properties is relatively new, as experimental approaches are only recently catching up to theoretical potential. The PIs will support both graduate students and advanced undergraduates to work on these problems; they will receive interdisciplinary education in the physical and biological sciences, and will have access to state of the art GPU based computing facilities augmented by this award. NON-TECHNICAL SUMMARYThis award supports theoretical and computational research and education at the interface of the mathematical sciences and biology. The PIs will develop computer-based models for the mechanical properties of the proteins inside the long shafts, or axons, of nerve cells. Specifically, they will simulate the long protein filaments, known as microtubules, which are interlinked by protein springs, tau proteins, to find how the stiffness of the system is degraded when the tau proteins are removed. This happens in the time course of Alzheimer's disease, but the precise manner in which the tau removal occurs is a matter of ongoing investigation. By developing simulations of the mechanical properties of these protein bundles, which include the dynamical behavior of the tau proteins and the microtubules, the PIs can account for the different paths by which tau proteins can be degraded in Alzheimer's disease. Including forces driving microtubules together due to other molecules inside the nerve cells and the "balloon skin" of the nerve cell external membrane, the PIs hope to provide experimentally testable predictions to identify the key processes of nerve cell degradation and death in Alzheimer's disease. Tau proteins are interesting systems in their own right: unlike proteins such as hemoglobin which adopt unique shapes in the human body, tau proteins are intrinsically unstructured yet clearly important to nerve cell function. As an input to larger scale mechanical models, the PIs will simulate the mechanical properties of individual and paired tau proteins. The insights gained may provide inspiration for new approaches to active, self-healing composite materials outside of living systems. Since the microtubule/tau bundles remain mechanically stable and functional over decades of time in healthy, disease free individuals, they are remarkable model systems for such smart, active materials.

技术摘要奖在数学科学和生物学的界面上支持理论和计算研究和教育。神经元轴突的耦合微管-TAU束是一种显着的活性材料，即使不断更新组件蛋白在数十年中，在功能上稳定。 Using mechanisms proposed for tau removal in late stages of Alzheimer's Disease, which are initiated by oligomerization of the a-beta peptide, the PIs will develop a coarse grained theory of the mechanical failure of this system as the tau proteins are depleted via: (i) tau fragmentation induced by a-beta oligomer triggered protease production; （ii）通过A-beta触发激酶产生的Tau充电（磷酸化）； （iii）聚集，从捆绑包中抢劫tau单体。 这些过程的动力学应产生不同的时间课程，以进行tau去除，从而可以深入了解机械故障机制。 Taus将被建模为弹簧。 PI将对可能的tau低聚物结构进行明确的分子动力学模拟，以确定相关的弹簧力。 压缩的tau弹簧阻止了至少两个来源诱导的机械塌陷：（i）通过插入分子诱导的微管之间的耗尽力，当微管一起塌陷时，它们具有较高的翻译熵； （ii）外膜/肌动蛋白细胞骨骼的表面张力。 PI将开发用于TAU和微管耗竭力的力模型，并将其输入到机械刚性的二维渗透模型中。 可以将顺序的“弹簧去除”映射到Tau降解的动力学，以预测暴露于A-Beta低聚物的细胞力学实验的时间课程。 PI还将探索一个完全三维模型，该模型允许微管的倾斜，这对于允许微管体验耗尽的吸引力可能很重要。最后，PI将尝试开发算法以在高实验室浓度下扩展时间行为，以使阿尔茨海默氏病的A-beta低聚物损害与生理相关的浓度。使用机械方法来研究细胞内特性是相对较新的，因为实验方法直到最近才能遵循理论上的潜力。 PI将支持研究生和高级本科生解决这些问题；他们将在物理和生物科学中接受跨学科教育，并可以访问该奖项增强基于GPU的计算机设施。非技术摘要这一奖项支持数学科学和生物学界面的理论和计算研究和教育。 PI将开发基于计算机的模型，以用于神经细胞内长轴或轴突内部蛋白质的机械性能。具体而言，它们将模拟长蛋白丝（称为微管），它们与蛋白质弹簧，tau蛋白相互联系，以找到当去除tau蛋白时如何降解系统的刚度。 这发生在阿尔茨海默氏病的时间过程中，但是发生tau的确切方式是正在进行的调查问题。 通过开发这些蛋白束的机械性能的模拟，其中包括tau蛋白和微管的动力学行为，PIS可以解释可在阿尔茨海默氏病中降解tau蛋白的不同路径。包括由于神经细胞内部的其他分子和神经细胞外膜外膜的“气球皮肤”而驱动微管的力，PIS希望提供可实验测试的预测，以确定阿尔茨海默氏病中神经细胞降解和死亡的关键过程。 tau蛋白本身就是有趣的系统：与蛋白质（如血红蛋白）不同的是在人体中采用独特形状的蛋白质，tau蛋白质本质上是非结构化的，但对于神经细胞功能显然很重要。 作为大规模机械模型的输入，PI将模拟单个和配对的tau蛋白的机械性能。 获得的见解可能会为活跃的自我修复复合材料的新方法提供灵感。 由于在健康，无疾病的个体中，微管/tau束在机械上保持稳定和功能性，因此它们是这种智能活性材料的非凡模型系统。