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Cited by 318

The DOI matches its Crossref record; 50 of the 50 references it cites were found in a registry or an index.

Aromatic–Proline Interactions: Electronically Tunable CH/π Interactions

Open access
Zondlo, Neal J.·2013·Accounts of Chemical Research
DOI 10.1021/ar300087y
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Abstract

Proline residues have unique roles in protein folding, structure, and function. Proline and the aromatic amino acids comprise the encoded cyclic protein residues. Aromatic protein side chains are defined by their negatively charged π faces, while the faces of the proline ring are partially positively charged. This polarity results from their two-point connection of the side chain to the electron-withdrawing protein backbone, and the lower electronegativity of hydrogen compared to carbon, nitrogen, and oxygen. The hydrogens adjacent to the carbonyl and amide nitrogen, Hα and Hδ, respectively, are the most partially positive. Proline's side chain is also conformationally restricted, allowing for interaction with aromatic residues with minimal entropic or steric penalty. Proline and aromatic residues can interact favorably with each other, due to both the hydrophobic effect and the interaction between the π aromatic face and the polarized C-H bonds, called a CH/π interaction. Aromatic-proline interactions can occur locally, for example, to stabilize cis-amide bonds, and over larger distances, in the tertiary structures of proteins, and intermolecularly in protein-protein interactions. In peptides and proteins, aromatic-proline sequences more readily adopt cis-prolyl amide bonds, where the aromatic ring interacts with the proline ring in the cis conformation. In aromatic-proline sequences, Trp and Tyr are more likely to induce cis-amide bonds than Phe, suggesting an aromatic electronic effect. This result would be expected for a CH/π interaction, in which a more electron-rich aromatic would have a stronger (more cis-stabilizing) interaction with partial positive charges on prolyl hydrogens. In this Account, we describe our investigations into the nature of local aromatic-proline interactions, using peptide models. We synthesized a series of 26 peptides, TXPN, varying X from electron-rich to electron poor aromatic amino acids, and found that the population of cis-amide bond (Ktrans/cis) is tunable by aromatic electronics. With 4-substituted phenylalanines, we observed a Hammett correlation between aromatic electronics and Ktrans/cis, with cis-trans isomerism electronically controllable by 1.0 kcal/mol. All aromatic residues exhibit a higher cis population than Ala or cyclohexylalanine, with Trp showing the strongest aromatic-proline interaction. In addition, proline stereoelectronic effects can modulate cis-trans isomerism by an additional 1.0 kcal/mol. The aromatic-proline interaction is enthalpic, consistent with its description as a CH/π interaction. Proline-aromatic sequences can also promote cis-prolyl bonds, either through interactions of the aromatic ring with the preceding cis-proline or with the Hα prior to cis-proline. Within proline-rich peptides, sequences commonly found in natively disordered proteins, aromatic residues promote multiple cis-amide bonds due to multiple favorable aromatic-proline interactions. Collectively, we found aromatic-proline interactions to be significantly CH/π in nature, tunable by aromatic electronics. We discuss these data in the context of aromatic-proline and aromatic-glycine interactions in local structure, in tertiary structure, in protein-protein interactions, and in protein assemblies.

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Metadata

Authors
Zondlo, N. J.
Venue
Accounts of Chemical Research
Publisher
American Chemical Society (ACS)
Published
2012-11-13
Volume
46
Issue
4
Pages
1039-1049
ISSN
  • 0001-4842 (ISSN-L)
  • 1520-4898
DOI
10.1021/ar300087y
OpenAlex
W2029076044
Cited by
318
References
50
FWCI
5.46
Type
journal article
Language
en
Open access
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