Computational Investigations of the Biomechanics of Protein-protein Interactions Involved in the Control of Microtubule Disassembly

能量转化为机械功和物理力转化为生化信号是细胞功能的核心，这两个过程都是由蛋白质-蛋白质相互作用介导的。理解来自物理世界的力的作用与细胞和分子构象变化耦合的途径和机制是现代生物学中一个具有挑战性的持续努力。该项目通过在细胞内多个尺度上的计算建模，解决微管和相关蛋白质的行为，这些蛋白质是动态结构（细胞骨架）的组成部分，控制细胞形状并对细胞上的外部物理力做出反应。该项目将阐明控制细胞系统行为的基本原理，细胞系统在传导机械力方面起着至关重要的作用，并可用于设计具有增强稳定性和疲劳性能的仿生材料。该项目将为本科生和研究生提供计算生物物理化学方面的教育和培训，并通过在当地中学推广“科学与技术女生项目”，以及通过为辛辛那提大学“科学与工程女性”项目的新生提供研究体验机会，增加在科学领域代表性不足的群体的参与。该项目的结果将由研究者和学生通过出版物、会议报告和访问当地学校的方式向公众传播。该项目将解决结构疲劳在微管拆卸中的作用。这里提出的计算机模拟将达到研究微管力学行为所需的长时间和长尺度，并将提供伴随晶格中缺陷形成的变化的细节。晶格缺陷是参与微管分解的蛋白质的高亲和力结合位点，并调节本项目实验中解决的宏观弹性行为。该项目还将确定由微管相关蛋白的机械作用引起的微管细丝分解的分子水平变化的起源。纤维和微管相关蛋白复合物的多尺度建模将用于强制分解模拟，以确定微管解聚过程中驱动蛋白在诱导高弯曲中间体中的作用的分子水平信息。在这个项目中，模拟和实验的结合将建立微管切断蛋白质相互作用与切断过程中间步骤的性质之间的联系。

The conversion of energy into mechanical work and the conversion of physical force into biochemical signals lies at the heart of cellular function, and both of these processes are mediated by protein-protein interactions. Understanding the pathways and mechanisms that couple the action of forces from the physical world with changes in cellular and molecular conformations is a challenging ongoing effort in modern biology. This project addresses, through computational modeling at multiple scales within the cell, the behavior of microtubules and associated proteins which are components of the dynamic structure (the cytoskeleton) which controls cell shape and responds to external physical forces on the cell. This project will elucidate underlying principles that govern the behavior of cellular systems with crucial roles in transducing mechanical forces and that can be used to design bio-inspired materials with enhanced stability and fatigue behavior. The project will provide education and training of undergraduate and graduate students in computational biophysical chemistry and increase the participation of groups underrepresented in science through the outreach "Girls in Science and Technology Program" at local middle-schools and through research experience opportunities for freshmen students participating in the "Women in Science and Engineering" program at the University of Cincinnati. The results of the project will be disseminated to the general public by the investigator and students through publications, conference presentations, and visits to local schools. The project will address the role of structural fatigue in microtubule disassembly. The computer simulations proposed here will reach the long time- and length-scales required to investigate the mechanical behavior of microtubules and will supply details about the changes that accompany the formation of defects in the lattice. Lattice defects are high-affinity binding sites for proteins involved in the disassembly of microtubules and modulate the macroscopic elastic behavior addressed experimentally in this project. The project will also determine the origin of molecular-level changes in microtubule filament disassembly induced by the mechanical action of microtubule-associated proteins. Multiscale modeling of filament and microtubule-associated protein complexes will be used in forced disassembly simulations to determine molecular-level information about the role of kinesins in inducing highly curved intermediates during microtubule depolymerization. The combination of simulations and experiments in this project will establish the link between microtubule-severing protein interactions and the nature of intermediate steps of the severing process.