Co-operative unfolding of protein domains

How well does the worm-like chain force extension curve fit single-molecule protein unfolding data? Careful analysis of dynamic force spectroscopy data for different proteins[1] suggests that the compliance of a protein is generically larger than that predicted by the worm-like chain model. We propose that the observed excess compliance is due to pre-transitional conformational rearrangements within the protein domain that occur before the more dramatic failure of the domain as a whole. Using a generalization of the formalism introduced by Evans and Ritchie[2], we study protein--unfolding kinetics in our model where these internal conformational rearrangements are represented by a number of interacting Ising-type variables, which cooperatively escape over a barrier to the unfolded state. From this model, we predict a relation between the statistics of the fluctuations of the peak domain--unfolding force and the deviations of the force extension curves from the worm-like chain prediction. We suggest that, by using this approach, one can extract further details on the domain--unfolding pathway from extant force spectroscopy data. \\ $[1]$ D. J. Brockwell (private communication). \\ $[2]$ E. Evans, and K. Ritchie, Biophys. J., {\bf 72} 1541 (1997).