FOLDING AND BINDING OF IKBA/NF-KB COMPLEXES

IKBA/NF-KB 复合物的折叠和结合

• 批准号: 7096435
• 负责人: Peter Guy Wolynes
• 金额: $ 21.62万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7096435
• 关键词: I kappa B beta; biological signal transduction; biophysics; chemical kinetics; computer program /software; computer simulation; computer system design /evaluation; model design /development; molecular dynamics; nuclear factor kappa beta; protein binding; protein folding; protein protein interaction; protein sequence; protein structure function; proteomics

The NF-KB/lKBalpha system is an essential cell signaling system and is representative of a family of protein-protein interactions in the cell. The function of this system provides a challenge to the main structure-function paradigm in biophysics because parts of both partners are incompletely structured when the molecules are isolated. Thus there are major implications for many areas of proteomics, which also involve natively unfolded proteins. Specific recognition of IKBalpha by NF-KB involves collaborative folding and binding between the two proteins. We will investigate computationally the kinetics of this process, because this collaborative folding/binding event may be an example of the proposed "fly-casting mechanism" previously suggested by us as a possible reason for utilization of unfolded proteins in biological systems. These studies will combine energy landscape theory with simulations using a variety of model energy functions. This system is a particularly auspicious choice for such a study because a very extensive model of the in vivo kinetics has already been established and tested in the Hoffmann laboratory. Thus the evolutionary and functional significance of "fly-casting" can be assessed. Our theoretical predictions will be tested by laboratory investigations of the Ghosh, Komives and Dyson groups. The collaborative folding/binding found here raises more general issues concerned with experimental and theoretical characterization of the structure of proteins with dispersed ensembles of structures. Developing computer algorithms for dealing with this circumstance, based on replica methods and energy landscape theories, is another focus of our theoretical work. Developing approaches to predict binding modes for such floppy proteins using sequence information alone is another goal. Finally the basic biophysics that drives the association of partially folded partners will be addressed using the simulation models we generate. Studying the underlying forces in molecular detail may give insight into the specificity patterns exhibited by this family of proteins, which participate in many different signaling events relevant to physiological responses. The NF-KB/lKBalpha system has been implicated in several diseases ranging from osteoporosis to septic shock. Controlling folding/binding in this system may provide a new strategy for drug intervention, although our emphasis is on the basic science of the problem.

核因子-KB/1KBalpha系统是一种重要的细胞信号系统，是一类蛋白质-蛋白质家族的代表 细胞内的相互作用。该系统的功能对系统的主体结构--功能提出了挑战 生物物理学中的范例，因为双方的部分都不完全结构化，当 分子是孤立的。因此，这对蛋白质组学的许多领域都有重大影响，这些领域还包括 天然未折叠的蛋白质。核因子-KB对IKBalpha的特异性识别涉及协同折叠和 这两种蛋白质之间的结合。我们将通过计算来研究这一过程的动力学，因为 这种协作折叠/装订事件可能是所提议的“飞投机制”的一个例子 我们以前提出的在生物系统中使用未折叠蛋白质的一个可能原因。 这些研究将把能源景观理论与使用各种能源模型的模拟相结合 功能。对于这种研究来说，这个系统是一个特别幸运的选择，因为一个非常广泛的模型 体内动力学已经在霍夫曼实验室建立和测试。因此，进化的 “飞铸”的功能意义是可以评估的。我们的理论预测将得到以下检验 对Ghosh、Komives和Dyson组的实验室调查。发现了协同折叠/装订 这里提出了与结构的实验和理论表征有关的更一般的问题 具有分散的结构集合的蛋白质。开发处理这一问题的计算机算法 基于复制方法和能量景观理论的环境是我们理论研究的另一个焦点 工作。利用序列信息预测这类软盘蛋白结合模式的研究进展 独自一人是另一个目标。最后，推动部分折叠伙伴联系的基本生物物理学将 使用我们生成的模拟模型来处理。在分子细节上研究潜在的力 可以洞察这一蛋白家族所表现出的特异性模式，这些蛋白参与了许多 与生理反应相关的不同信号事件。核因子-KB/1KBalpha系统已被牵连 治疗从骨质疏松症到败血症休克等多种疾病。在该系统中控制折叠/装订可以 为药物干预提供一种新的策略，尽管我们的重点是该问题的基础科学。