Folding kinetics of IkB: excursions through the energy landscape

HOFFMAN, RMB; CRAIG PO; DEVRIES, I; KOMIVES E; WOLYNES P

San Francisco, CA, USA

Congreso; Biophysical Society 54th Annual Meeting; 2010

The IkB proteins, inhibitors of the transcription factor NF-kB, are comprised oftandem repeats of a conserved primary structure. The tandem repeats arestabilized as a repeated tertiary structural motif, at least when complexed withNF-kB and DNA. Structural fluctuations in the native state deviate substantiallyfrom a simple repeating pattern, as reported by site-resolved hydrogenexchange rates, NMR chemical shifts and relaxation parameters, andenergetically frustrated intraprotein contacts.Here we have studied the folding of the first four ankyrin repeats of humanIkBalpha and beta, using coarse-grained structural models to extensivelysimulate dynamics under structurally-parameterized Hamiltonians. The foldingreaction coordinate was sampled with biasing potentials and the free energy as afunction of the reaction coordinate was calculated with weighted histogramanalysis. The trajectories were used to assign the thermodynamic changesbetween substates in the folding mechanism. Kinetic models connecting thefolding substates were used to predict experimentally known (un)folding rates.