| Abstract
| - The cis−trans isomerization of prolyl amide bonds results in large structural and functional changes in proteins and is a rate-determining step in protein folding. We describe a novel electronic strategy to control cis−trans isomerization, based on the demonstration that interactions between aromatic residues and proline are tunable by aromatic electronics. A series of peptides of sequence TXPN, X = Trp, pyridylalanine, pentafluorophenylalanine, or 4-Z-phenylalanine derivatives (Z = electron-donating, electron-withdrawing, or electron-neutral substituents), was synthesized and Ktrans/cis analyzed by NMR. Electron-rich aromatic residues stabilized cis amide bond formation, while electron-poor aromatics relatively favored trans amide bond formation. A Hammett correlation between aromatic electronics and cis−trans isomerization was observed. These results indicate that the interaction between aromatic residues and proline, which is observed to stabilize cis amide bonds and is also a general stabilizing interaction ubiquitous in proteins and protein−protein complexes, is not stabilized exclusively by a classical hydrophobic effect. To a large extent, the aromatic−prolyl interaction is driven and controllable by an electronic effect between the aromatic ring π-electrons and the proline ring, consistent with a C−H−π interaction as the key stabilizing force. The aromatic−prolyl interaction is electronically tunable by 0.9 kcal/mol and is enthalpic in nature. In addition, by combining aromatic ring electronics and stereoelectronic effects using 4-fluoroprolines, we demonstrate broad tuning (2.0 kcal/mol) of cis−trans isomerism in tetrapeptides. We demonstrate a simple tetrapeptide, TWflpN, that exhibits 60% cis amide bond and adopts a type VIa1 β-turn conformation.
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