This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. It is becoming clear that regulation of protein function is often acheived via shifts in the populations of active and inactive conformers. X-ray crystallographic analysis gives only snapshots of possible configurations populated in solution. Taking advantage of our expertises in theoretical and experimental analysis of protein folding and assembly, we seek to use a combined SAXS and theoretical approach to define the structural ensembles present in the functional landscapes of multidomain proteins. This approach extends beyond current simulation analysis of SAXS data to include local and global folding/unfolding transitions that are important in function. Our initial choice in developing this methodology is the enzyme Csk as it is not only an important therapeutic target but also is a system we have characterized in terms of the optimal enzymatic and folding conditions. There is growing evidence that biases in the structural ensemble may play an important role in the regulation of Csk. The methodology developed here is broadly applicable to biological macromolecules and will provide useful information about what ensembles of conformations are consistent with the experimental data as well as the the ubiquitous dynamic reversible folding/assembly processes inherent in biology.
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