The type II polyproline helix (PPII) is a fundamental secondary structure of proteins. PPII is stabilized in part by n®p* interactions between consecutive carbonyls, via electron delocalization between an electron-donor carbonyl lone pair (n) and an electron-acceptor carbonyl (p*) on the subsequent residue. We previously demonstrated that changes to the electronic properties of the acyl donor can predictably modulate the strength of n®p* interactions, with data from model compounds, in solution in chloroform, in the solid state, and computationally. Herein, we examined whether the electronic properties of acyl capping groups could modulate the stability of PPII in peptides in water. In X-PPGY-NH2 peptides (X = 10 acyl capping groups), the effect of acyl group identity on PPII was quantified by circular dichroism and NMR spectroscopy. Electron-rich acyl groups promoted PPII relative to the standard acetyl (Ac-) group, with the pivaloyl and iso-butyryl groups most significantly increasing PPII. In contrast, acyl derivatives with electron-withdrawing substituents and the formyl group relatively disfavored PPII. Similar results, though lesser in magnitude, were also observed in X-APPGY-NH2 peptides, indicating that the capping group can impact PPII conformation at both proline and non-proline residues. The pivaloyl group was particularly favorable in promoting PPII.
Keywords: intrinsically disordered proteins; noncovalent interactions; peptide design; stereoelectronic effects.
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