PolyQ peptides teeter between polyproline II (PPII) and beta-sheet conformations. In tandem polyQ-polyP peptides, the polyP segment tips the balance toward PPII, increasing the threshold number of Gln residues needed for fibrillation. To investigate the mechanism of cis-inhibition by flanking polyP segments on polyQ fibrillation, we examined short polyQ, polyP, and tandem polyQ-polyP peptides. These polyQ peptides have only three glutamines and cannot form beta-sheet fibrils. We demonstrate that polyQ-polyP peptides form small, soluble oligomers at high concentrations (as shown by size exclusion chromatography and diffusion coefficient measurements) with PPII structure (as shown by circular dichroism spectroscopy and (3)J(HN-C alpha) constants of Gln residues from constant time correlation spectroscopy NMR). Nuclear Overhauser effect spectroscopy and molecular modeling suggest that self-association of these peptides occurs as a result of both hydrophobic and steric effects. Pro side chains present three methylenes to solvent, favoring self-association of polyP through the hydrophobic effect. Gln side chains, with two methylene groups, can adopt a conformation similar to that of Pro side chains, also permitting self-association through the hydrophobic effect. Furthermore, steric clashes between Gln and Pro side chains to the C-terminal side of the polyQ segment favor adoption of the PPII-like structure in the polyQ segment. The conformational adaptability of the polyQ segment permits the cis-inhibitory effect of polyP segments on fibrillation by the polyQ segments in proteins such as huntingtin.
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