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Cation-? interactions in lipocalins: structural and functional implications.

ABSTRACT: The cation-? interaction impacts protein folding, structural stability, specificity, and molecular recognition. Cation-? interactions have been overlooked in the lipocalin family. To fill this gap, these interactions were analyzed in the 113 crystal and solution structures from the lipocalin family. The cation-? interactions link previously identified structurally conserved regions and reveal new motifs, which are beyond the reach of a sequence alignment algorithm. Functional and structural significance of the interactions were tested experimentally in human tear lipocalin (TL). TL, a prominent and promiscuous lipocalin, has a key role in lipid binding at the ocular surface. Ligand binding modulation through the loop AB at the "open" end of the barrel has been erroneously attributed solely to electrostatic interactions. Data revealed that the interloop cation-? interaction in the pair Phe28-Lys108 contributes significantly to stabilize the holo-conformation of the loop AB. Numerous energetically significant and conserved cation-? interactions were uncovered in TL and throughout the lipocalin family. Cation-? interactions, such as the highly conserved Trp17-Arg118 pair in TL, were educed in low temperature experiments of mutants with Trp to Tyr substitutions.

SUBMITTER: Gasymov OK

PROVIDER: S-EPMC3734948 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Cation-π interactions in lipocalins: structural and functional implications.

Gasymov Oktay K OK Abduragimov Adil R AR Glasgow Ben J BJ

Biochemistry 20120328 14

The cation-π interaction impacts protein folding, structural stability, specificity, and molecular recognition. Cation-π interactions have been overlooked in the lipocalin family. To fill this gap, these interactions were analyzed in the 113 crystal and solution structures from the lipocalin family. The cation-π interactions link previously identified structurally conserved regions and reveal new motifs, which are beyond the reach of a sequence alignment algorithm. Functional and structural sign ...[more]

PMID: 22439821

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Project description:The chemistry community now recognizes the cation-π interaction as a major force for molecular recognition, joining the hydrophobic effect, the hydrogen bond, and the ion pair in determining macromolecular structure and drug-receptor interactions. This Account provides the author's perspective on the intellectual origins and fundamental nature of the cation-π interaction. Early studies on cyclophanes established that water-soluble, cationic molecules would forego aqueous solvation to enter a hydrophobic cavity if that cavity was lined with π systems. Important gas phase studies established the fundamental nature of the cation-π interaction. The strength of the cation-π interaction (Li(+) binds to benzene with 38 kcal/mol of binding energy; NH4(+) with 19 kcal/mol) distinguishes it from the weaker polar-π interactions observed in the benzene dimer or water-benzene complexes. In addition to the substantial intrinsic strength of the cation-π interaction in gas phase studies, the cation-π interaction remains energetically significant in aqueous media and under biological conditions. Many studies have shown that cation-π interactions can enhance binding energies by 2-5 kcal/mol, making them competitive with hydrogen bonds and ion pairs in drug-receptor and protein-protein interactions. As with other noncovalent interactions involving aromatic systems, the cation-π interaction includes a substantial electrostatic component. The six (four) C(δ-)-H(δ+) bond dipoles of a molecule like benzene (ethylene) combine to produce a region of negative electrostatic potential on the face of the π system. Simple electrostatics facilitate a natural attraction of cations to the surface. The trend for (gas phase) binding energies is Li(+) > Na(+) > K(+) > Rb(+): as the ion gets larger the charge is dispersed over a larger sphere and binding interactions weaken, a classical electrostatic effect. On other hand, polarizability does not define these interactions. Cyclohexane is more polarizable than benzene but a decidedly poorer cation binder. Many studies have documented cation-π interactions in protein structures, where lysine or arginine side chains interact with phenylalanine, tyrosine, or tryptophan. In addition, countless studies have established the importance of the cation-π interaction in a range of biological processes. Our work has focused on molecular neurobiology, and we have shown that neurotransmitters generally use a cation-π interaction to bind to their receptors. We have also shown that many drug-receptor interactions involve cation-π interactions. A cation-π interaction plays a critical role in the binding of nicotine to ACh receptors in the brain, an especially significant case. Other researchers have established important cation-π interactions in the recognition of the "histone code," in terpene biosynthesis, in chemical catalysis, and in many other systems.

Dataset Information

Cation-? interactions in lipocalins: structural and functional implications.

Publications

Cation-π interactions in lipocalins: structural and functional implications.

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