Abstract
While it has been known for years that within a protein’s folding/ unfolding transition region the conformational equilibrium can be well approximated by a “two-state” model (1), it is not possible within the context of this “two-state” framework to account for an important and well-established experimental observation. As shown by a number of researchers, the hydrogen-exchange protection factor (PF) patterns of all proteins observed to date show large regional differences (2-12)). If protein folding is “two-state”, all amides that are protected from exchange in the native state show identical protection factors, as they become exposed to solvent through the same folding/unfolding reaction. The heterogeneity observed in the protection-factor patterns suggests that the native state is best characterized as a fluctuating ensemble of conformations that involve local unfolding reactions. In an effort to derive a quantitative description of these fluctuations, we developed the COREX algorithm (13–15), wherein the native state is represented as an ensemble rather than a discrete conformational state. The purpose of this chapter is to present a detailed description of the COREX algorithm, and to show how this ensemble-based description provides a uniform framework for reconciling the cooperative folding/unfolding behavior observed in the transition region with the apparently noncooperative behavior seen under native conditions. This approach also represents a powerful tool for investigating cooperativity and the propagation of mutational effects.
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Hilser, V.J. (2001). Modeling the Native State Ensemble. In: Murphy, K.P. (eds) Protein Structure, Stability, and Folding. Methods in Molecular Biology™, vol 168. Humana Press. https://doi.org/10.1385/1-59259-193-0:093
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DOI: https://doi.org/10.1385/1-59259-193-0:093
Publisher Name: Humana Press
Print ISBN: 978-0-89603-682-6
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