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

参与微管解体控制的蛋白质-蛋白质相互作用的生物力学的计算研究

• 批准号: 1412183
• 负责人: Ruxandra Dima
• 金额: $ 54.67万
• 依托单位: University of Cincinnati Main Campus
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1412183&HistoricalAwards=false
• 关键词: Computational; Investigations; Biomechanics; Protein; protein

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.

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，而这两个过程都是由蛋白质-蛋白质相互作用调节的。在现代生物学中，理解将来自物理世界的力的作用与细胞和分子构象的变化相结合的路径和机制是一项具有挑战性的持续努力。这个项目通过在细胞内的多个尺度上的计算建模来研究微管和相关蛋白质的行为，这些微管和相关蛋白质是控制细胞形状并对细胞上的外部物理力做出反应的动态结构(细胞骨架)的组成部分。该项目将阐明控制细胞系统行为的基本原理，这些系统在传递机械力方面具有关键作用，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“女科学和技术方案”以及通过为参加辛辛那提大学“科学和工程女性”方案的大一学生提供研究经验机会，增加科学界代表性不足的群体的参与。该项目的结果将由调查员和学生通过出版物、会议报告和对当地学校的访问向公众传播。该项目将解决结构疲劳在微管分解中的作用。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度尺度，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部位，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来源。丝状和微管相关蛋白复合体的多尺度模拟将被用于强制拆解模拟，以确定关于在微管解聚过程中驱动蛋白在诱导高度弯曲的中间体中所起作用的分子水平的信息。这个项目中的模拟和实验的结合将建立微管-切断蛋白质相互作用和切断过程的中间步骤的性质之间的联系。