A Disorder-Induced Domino-Like Destabilization Mechanism Governs the Folding and Functional Dynamics of the Repeat Protein IκBα
(A) The predicted 1D free-energy profiles as a function of the number of structured residues (RC – reaction coordinate). (B) A closer look at the free energy profile close to the denaturation midpoint indicating the presence of two major intermediates (I1 and I2), a minor intermediate (I′) apart from the end states (U and N). The continuous red curve is the tryptophan signal calculated from the 2D structural ensemble while the dashed red curve is the assumed tryptophan signal switch. (C) Population of the major macrostates as a function of temperature. (D) Relaxation rates predicted by the model (continuous and dashed lines) compared with experiments (circles). The predicted rates were matched with the experimental midpoint relaxation rates assuming a single uniform diffusion coefficient of (7e6/N) n2 s−1 where n is the reaction coordinate value and N is the protein length. Triangles correspond to the faster phase observed in simulations.