The overall goal of the proposed work is to provide a quantitative biophysical description of the protein folding and binding kinetics and thermodynamics of members of the kB family as they interact with members of the NFKB family. Integration with the Wolynes project will correlate theory and experiment to develop a deeper understanding of how the protein structure determines its biophysical properties. Integration with the Dyson project will cross the time-scale boundaries from NMR time scale dynamics to longer time scales probed by H/D exchange and smFRET. Integration with the Hoffmann and Ghosh projects will provide a link between biophysical properties and function. A focus of the project is the intrinsic disorder of iKBa AR5-AR6-C-terminal EST-containing region and its role in establishing functional control of NFKB signaling.