The NFKB signaling system mediates both transient inflammatory responses that involve highly dynamic control of transcription, and longer-term immunological responses and development that involve precise dose response control mechanisms (14, 29). All are critical to human health, as demonstrated by NFKB involvement in inflammatory disease and in lymphocytic malignancies (37). These fundamentally different functions are achieved by the interplay of distinct family members of transcriptional activators and inhibitor proteins, whose biophysical properties determine their half-life control, interaction specificity, and dynamic and dose response behavior. A predictive understanding of the functioning of the NFKB signaling system in physiology and pathology remains unrealized, primarily due to a lack of information about the fundamental regulatory mechanisms and associated molecular specificities of key NFKB and IKB family members, and our inability to integrate diverse information and link it to specific physiological functions of cells and animal model systems. The present proposal aims to address these deficiencies. It complements the other projects of the Programand involves highly integrated studies, leveraging the molecular biophysical insights about protein folding, degradation and molecular interaction, to develop a predictive understanding of cellular signaling processes in inflammation and immune responses. This is achieved through the integrated approaches of biochemistry, mathematical modeling, cell biology, and animal physiology.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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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
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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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