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Abstract:
Polyglutamine (polyQ) expansion beyond a pathological threshold is associated with a number of neurodegenerative diseases. The polyQ tract of several proteins, such as androgen receptor (AR) [1], huntingtin [2] and CBP [3], can adopt α-helix conformations propagated and stabilized by unusual bifurcated hydrogen bonds, in which the side and main chains of glutamine residues simultaneously donate a hydrogen to the backbone carbonyl of residue i-4.[1] Using a combination of solution NMR and molecular dynamics we have studied in detail how the sequence context influences the helical content of the polyQ tract of AR and expanded the analysis to the tract of the TBP protein. We have exploited our observations to present rules to design linear peptides that fold into short single α-helices by concatenating glutamine side chain to main chain hydrogen bonds. The resulting peptides are highly soluble, uncharged and contain only natural amino acids. An important feature of these peptides is their versatility: several hydrophobic residues can act as efficient H-bond acceptors and the design can also incorporate a pH-sensitive switch or can be complemented by electrostatic interactions between charged side chains. Remarkably, our scaffold design defines the identity of only a fraction of the peptide residues and the rest can be chosen or optimized for specific applications. As a proof of concept, we have designed two helical peptides that successfully bind to the globular target RAP74-CTD.
