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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
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Special Emphasis Panel (ZRG1-BCMB-D (40))
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University of California San Diego
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Wolynes, Peter G (2015) Evolution, energy landscapes and the paradoxes of protein folding. Biochimie 119:218-30
Potoyan, Davit A; Wolynes, Peter G (2014) On the dephasing of genetic oscillators. Proc Natl Acad Sci U S A 111:2391-6
Alverdi, Vera; Hetrick, Byron; Joseph, Simpson et al. (2014) Direct observation of a transient ternary complex during I?B?-mediated dissociation of NF-?B from DNA. Proc Natl Acad Sci U S A 111:225-30
Tao, Zhihua; Fusco, Amanda; Huang, De-Bin et al. (2014) p100/I?B? sequesters and inhibits NF-?B through kappaBsome formation. Proc Natl Acad Sci U S A 111:15946-51
Schafer, N P; Kim, B L; Zheng, W et al. (2014) Learning To Fold Proteins Using Energy Landscape Theory. Isr J Chem 54:1311-1337
Dembinski, Holly; Wismer, Kevin; Balasubramaniam, Deepa et al. (2014) Predicted disorder-to-order transition mutations in I?B? disrupt function. Phys Chem Chem Phys 16:6480-5
Alves, Bryce N; Tsui, Rachel; Almaden, Jonathan et al. (2014) I?B? is a key regulator of B cell expansion by providing negative feedback on cRel and RelA in a stimulus-specific manner. J Immunol 192:3121-32
Ferreiro, Diego U; Komives, Elizabeth A; Wolynes, Peter G (2014) Frustration in biomolecules. Q Rev Biophys 47:285-363
Kim, Bobby L; Schafer, Nicholas P; Wolynes, Peter G (2014) Predictive energy landscapes for folding ?-helical transmembrane proteins. Proc Natl Acad Sci U S A 111:11031-6
Cervantes, Carla F; Handley, Lindsey D; Sue, Shih-Che et al. (2013) Long-range effects and functional consequences of stabilizing mutations in the ankyrin repeat domain of IýýBýý. J Mol Biol 425:902-13

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