Dataset Information

The Role of Aromatic-Aromatic Interactions in Strand-Strand Stabilization of ?-Sheets.

ABSTRACT: Aromatic-aromatic interactions have long been believed to play key roles in protein structure, folding, and binding functions. However, we still lack full understanding of the contributions of aromatic-aromatic interactions to protein stability and the timing of their formation during folding. Here, using an aromatic ladder in the ?-barrel protein, cellular retinoic acid-binding protein 1 (CRABP1), as a case study, we find that aromatic ? stacking plays a greater role in the Phe65-Phe71 cross-strand pair, while in another pair, Phe50-Phe65, hydrophobic interactions are dominant. The Phe65-Phe71 pair spans ?-strands 4 and 5 in the ?-barrel, which lack interstrand hydrogen bonding, and we speculate that it compensates energetically for the absence of strand-strand backbone interactions. Using perturbation analysis, we find that both aromatic-aromatic pairs form after the transition state for folding of CRABP1, thus playing a role in the final stabilization of the ?-sheet rather than in its nucleation as had been earlier proposed. The aromatic interaction between strands 4 and 5 in CRABP1 is highly conserved in the intracellular lipid-binding protein (iLBP) family, and several lines of evidence combine to support a model wherein it acts to maintain barrel structure while allowing the dynamic opening that is necessary for ligand entry. Lastly, we carried out a bioinformatics analysis and found 51 examples of aromatic-aromatic interactions across non-hydrogen-bonded ?-strands outside the iLBPs, arguing for the generality of the role played by this structural motif.

SUBMITTER: Budyak IL

PROVIDER: S-EPMC3778025 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The Role of Aromatic-Aromatic Interactions in Strand-Strand Stabilization of β-Sheets.

Budyak Ivan L IL Zhuravleva Anastasia A Gierasch Lila M LM

Journal of molecular biology 20130628 18

Aromatic-aromatic interactions have long been believed to play key roles in protein structure, folding, and binding functions. However, we still lack full understanding of the contributions of aromatic-aromatic interactions to protein stability and the timing of their formation during folding. Here, using an aromatic ladder in the β-barrel protein, cellular retinoic acid-binding protein 1 (CRABP1), as a case study, we find that aromatic π stacking plays a greater role in the Phe65-Phe71 cross-st ...[more]

PMID: 23810905

Similar Datasets

Project description: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 ? 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, H? and H?, 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 ? aromatic face and the polarized C-H bonds, called a CH/? 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/? 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/? 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 H? 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/? 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.

Dataset Information

The Role of Aromatic-Aromatic Interactions in Strand-Strand Stabilization of ?-Sheets.

Publications

The Role of Aromatic-Aromatic Interactions in Strand-Strand Stabilization of β-Sheets.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure