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Computational Modeling of Protein Degradation by Biological Nanomachines

生物纳米机器蛋白质降解的计算模型

基本信息

批准号：
1516918
负责人：
George Stan
金额：
$ 59.15万
依托单位：
University of Cincinnati Main Campus
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1516918&HistoricalAwards=false
关键词：
Computational Modeling Protein Degradation Biological

项目摘要

Cell survival is critically dependent on tightly regulated protein degradation mechanisms. Biological nanomachines that mediate protein degradation use repetitive mechanical forces to unfold, translocate (move), and destroy excess or defective proteins. Understanding these mechanisms is of central importance for deciphering the details of essential cellular processes. This project will use computer simulations at multiple scales to elucidate 1) the dependence of protein unfolding and translocation actions on force directionality and 2) the nature of collaboration between components of the biological machines involved in the degradation process. The knowledge gained through this project will advance understanding of the relationship between structure and function in these biological nanomachines and will reveal fundamental principles of protein unfolding and translocation. This project integrates the training of undergraduate and graduate students in computational biophysical chemistry through addressing advanced scientific problems. Increased participation of underrepresented minorities in computational sciences will be promoted through educational and mentoring efforts. This goal will be achieved through the collaboration between the University of Cincinnati and Central State University (CSU), a Historically Black College and University, and will combine outreach activities at CSU with research experience opportunities for underrepresented minorities in the PI's laboratory. The results of this project will be disseminated widely to the general public by the PI, graduate and undergraduate students through publications, conference presentations, the web, and seminars at CSU.This project will elucidate the effect of mechanical anisotropy on unfolding and translocation of multidomain substrate proteins by bacterial Clp ATPases, which are members of the AAA+ superfamily of biological nanomachines. Multiscale models will be developed to probe nanomachine-mediated threading of multidomain constructs of substrate proteins with diverse topology and mechanical stability along specific directions. Computer simulations using these models will be complemented by experiments conducted by collaborators to pinpoint remodeling pathways in restricted and unrestricted geometries. The project will also elucidate the collaboration between Clp ATPase and peptidase components for protein threading. Computer simulations of atomistic and coarse-grained models will be performed to obtain a detailed understanding of allosteric conformational transitions of the peptidase and their role in substrate translocation. These simulations, in conjunction with experimental studies conducted by collaborators, will establish the residue-level interactions that underlie component specialization in these biological machines.

细胞的存活在很大程度上取决于严格调控的蛋白质降解机制。调节蛋白质降解的生物纳米机器使用重复的机械力来展开、移位(移动)和破坏多余或有缺陷的蛋白质。了解这些机制对于破译基本细胞过程的细节至关重要。这个项目将在多个尺度上使用计算机模拟来阐明1)蛋白质展开和移位动作对力的方向性的依赖以及2)参与降解过程的生物机器组件之间的协作性质。通过这个项目获得的知识将促进对这些生物纳米机器结构和功能之间关系的理解，并将揭示蛋白质展开和移位的基本原理。该项目通过解决高级科学问题，整合了计算生物物理化学本科生和研究生的培训。将通过教育和辅导努力促进代表不足的少数群体更多地参与计算科学。这一目标将通过辛辛那提大学和中央州立大学(CSU)之间的合作来实现，中央州立大学(CSU)是一所历史上的黑人学院和大学，将在CSU开展外联活动，并在PI的实验室为代表不足的少数族裔提供研究经验机会。这个项目的结果将通过出版物、会议报告、网络和CSU的研讨会由PI、研究生和本科生广泛传播给公众。这个项目将阐明机械各向异性对细菌CLP ATPase多结构域底物蛋白展开和移位的影响，细菌CLP ATPase是AAA+生物纳米机器超家族的成员。多尺度模型将被开发来探索纳米机器介导的底物蛋白质的多域结构，沿着特定的方向具有不同的拓扑结构和机械稳定性。使用这些模型的计算机模拟将得到合作者进行的实验的补充，以精确定位受限和非受限几何图形中的重塑路径。该项目还将阐明CLP ATPase和多肽酶组件之间的合作，以进行蛋白质穿线。计算机模拟的原子模型和粗粒模型将获得详细的了解变构构象转变的肽酶及其在底物转运中的作用。这些模拟与合作者进行的实验研究将建立残基水平的相互作用，这些相互作用是这些生物机器组件专门化的基础。