Polyproline II propensities from GGXGG peptides reveal an anticorrelation with β-sheet scales

There is growing appreciation of the functional relevance of unfolded proteins in biology. However, unfolded states of proteins have proven inaccessible to the usual techniques for high-resolution structural and energetic characterization. Unfolded states are still generally conceived of as statistical coils, based on the pioneering work of Flory [(1969) Statistical Mechanics of Chain Molecules (Wiley, New York)] and Tanford [(1968) Adv. Protein Chem. 23, 121-282]. Recently, several lines of independent evidence have raised doubts about the random coil model and offer support for alternative views. Here, we show that polyproline II conformation is dominant in a host-guest peptide model AcGGXGGNH₂ (X ≠ glycine), in equilibrium predominantly with β-structure. This result is inconsistent with a random coil model and the general view that these peptides are unstructured. By calculating a set of apparent ΔG values from the measured coupling constants of the backbone amides, we can construct a polyproline II scale that correlates negatively with β-sheet scales.