The NF-KB/lKBalpha system is an essential cell signaling system and is representative of a family of protein-proteininteractions in the cell. The function of this system provides a challenge to the main structure-functionparadigm in biophysics because parts of both partners are incompletely structured when themolecules are isolated. Thus there are major implications for many areas of proteomics, which also involvenatively unfolded proteins. Specific recognition of IKBalpha by NF-KB involves collaborative folding andbinding between the two proteins. We will investigate computationally the kinetics of this process, becausethis 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 energyfunctions. This system is a particularly auspicious choice for such a study because a very extensive model ofthe in vivo kinetics has already been established and tested in the Hoffmann laboratory. Thus the evolutionaryand functional significance of 'fly-casting' can be assessed. Our theoretical predictions will be tested bylaboratory investigations of the Ghosh, Komives and Dyson groups. The collaborative folding/binding foundhere raises more general issues concerned with experimental and theoretical characterization of the structureof proteins with dispersed ensembles of structures. Developing computer algorithms for dealing with thiscircumstance, based on replica methods and energy landscape theories, is another focus of our theoreticalwork. Developing approaches to predict binding modes for such floppy proteins using sequence informationalone is another goal. Finally the basic biophysics that drives the association of partially folded partners willbe addressed using the simulation models we generate. Studying the underlying forces in molecular detailmay give insight into the specificity patterns exhibited by this family of proteins, which participate in manydifferent signaling events relevant to physiological responses. The NF-KB/lKBalpha system has been implicatedin several diseases ranging from osteoporosis to septic shock. Controlling folding/binding in this system mayprovide a new strategy for drug intervention, although our emphasis is on the basic science of the problem.
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