Characterization of the unfolded state of repeat proteins.

The unfolded state ensemble of proteins has been described as a structurally featureless state. While this approach is supported by the fact that many unfolded proteins follow the scaling law behavior of a random coil, there is evidence that the unfolded states of various proteins are stabilized by native or non-native interactions. Recently, the existence of extensive non-native structure was reported for a repeat protein, which resulted in a scaling law exponent that is significantly smaller than that of a random polymer [Cortajarena et al., J. Mol. Biol. 382(1), 203-212 (2008)]. It was concluded that the high compactness of this protein stems from a significant fraction of interacting PP(II) helical segments in the unfolded state. In this study, we aim at providing possible molecular understanding of this anomalous compactness of the unfolded state and to investigate its origin. Using a hierarchy of computational models, we ask whether in general the unfolded state of a repeat protein is likely to be intrinsically more compact than the unfolded state of globular proteins, or whether this phenomenon depends mostly on the occurrence of a specific sequence that promotes PP(II) conformations. Our results suggest that the formation of the PP(II) conformation is indeed essential, yet the recurring sequence of repeat proteins promotes the interactions between these PP(II) segments and the formation of non-native interactions in the unfolded state.