FOLDING AND BINDING OF IKBA/NF-KB COMPLEXES

NF-κ B/κ B α系统是一种重要的细胞信号传导系统，是蛋白质-蛋白质相互作用家族的代表。 细胞内的相互作用。该系统的功能对系统的主要结构-功能提出了挑战 生物物理学中的范例，因为双方的部分是不完全结构时， 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， 天然未折叠蛋白质。NF-κ B对IKB α的特异性识别涉及协同折叠， 两种蛋白质之间的结合。我们将通过计算研究这一过程的动力学，因为 这种协作折叠/装订事件可以是所提出的“飞投机制”的一个例子。 这是我们先前提出的在生物系统中利用未折叠蛋白质的可能原因。 这些研究将联合收割机能源景观理论与使用各种模型能源的模拟相结合 功能协调发展的这个系统对于这样的研究来说是一个特别有利的选择，因为一个非常广泛的模型， 体内动力学已经在Hoffmann实验室建立和测试。因此， 并且可以评估“飞抛”的功能意义。我们的理论预测将通过 Ghosh、Komives和Dyson小组的实验室研究。发现的协同折叠/绑定 这里提出了更普遍的问题与实验和理论表征的结构 具有分散的整体结构的蛋白质。开发计算机算法来处理这个问题 环境，基于复制方法和能源景观理论，是我们理论的另一个焦点， 工作开发利用序列信息预测这种松软蛋白质结合模式的方法 孤独是另一个目标。最后，驱动部分折叠伴侣结合的基本生物物理学将 使用我们生成的模拟模型来解决。从分子细节上研究潜在的力 可以深入了解这个蛋白质家族所表现出的特异性模式，这些蛋白质参与许多 与生理反应相关的不同信号事件。NF-κ B/κ B α系统与 从骨质疏松症到感染性休克的多种疾病中。在该系统中控制折叠/装订可以 为药物干预提供一个新的策略，尽管我们的重点是问题的基础科学。

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.