Cu(I) recognition via cation-pi and methionine interactions in CusF.
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ABSTRACT:
SUBMITTER: Xue Y
PROVIDER: S-EPMC2850561 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The periplasmic Cu(+)/Ag(+) chaperone CusF features a novel cation-π interaction between a Cu(+)/Ag(+) ion and Trp44 at the metal binding site. The nature and strength of the Cu(+)/Ag(+)-Trp44 interactions were investigated using computational methodologies. Quantum-mechanical (QM) calculations showed that the Cu(+) and Ag(+) interactions with Trp44 are of similar strength (~14 kcal/mol) and bond order. Quantum-mechanical/molecular-mechanical (QM/MM) calculations showed that Cu(+) binds in a distorted tetrahedral coordination environment in the Trp44Met mutant, which lacks the cation-π interaction. Molecular dynamics (MD) simulations of CusF in the apo and Cu(+)-bound states emphasized the importance of the Cu(+)-Trp44 interaction in protecting Cu(+) from water oxidation. The protein structure does not change over the time scale of hundreds of nanoseconds in the metal-bound state. The metal recognition site exhibits small motions in the apo state but remains largely preorganized toward metal binding. Trp44 remains oriented to form the cation-π interaction in the apo state and faces an energetic penalty to move away from the metal ion. Cu(+) binding quenches the protein's internal motions in regions linked to binding CusB, suggesting that protein motions play an essential role in Cu(+) transfer to CusB.
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Project description:The periplasmic metallochaperone CusF coordinates Cu(I) and Ag(I) through a unique site consisting of a Met(2)His motif as well as a Cu(I)-pi interaction between a nearby tryptophan, W44, and the metal ion. Through mutational analyses we investigate here the role that W44 in CusF plays in metal coordination. Nuclear magnetic resonance spectra show that the specificity of CusF for Cu(I) and Ag(I) is not altered by mutation of W44. X-ray absorption spectroscopy studies reveal that W44 protects the bound Cu(I) from oxidation as well as from adventitious ligands. Competition assays demonstrate that W44 does not significantly contribute to the affinity of CusF for metal, but that substitution of W44 by methionine, which forms a fourth Cu(I) ligand, substantially increases the affinity. These studies indicate that W44 is important in maintaining a moderate-affinity and solvent-shielded three-coordinate environment for Cu(I), which has implications for the function of CusF as a metallochaperone.
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Project description:Cation-pi interactions in protein structures are identified and evaluated by using an energy-based criterion for selecting significant sidechain pairs. Cation-pi interactions are found to be common among structures in the Protein Data Bank, and it is clearly demonstrated that, when a cationic sidechain (Lys or Arg) is near an aromatic sidechain (Phe, Tyr, or Trp), the geometry is biased toward one that would experience a favorable cation-pi interaction. The sidechain of Arg is more likely than that of Lys to be in a cation-pi interaction. Among the aromatics, a strong bias toward Trp is clear, such that over one-fourth of all tryptophans in the data bank experience an energetically significant cation-pi interaction.
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Project description:Cation-pi bonds and amino-aromatic interactions are known to be important contributors to protein architecture and stability, and their role in ligand-protein interactions has also been reported. Many biologically active amines contain substituted ammonium moieties, and cation-pi bonding and amino-aromatic interactions often enable these molecules to associate with proteins. The role of organic cation-pi bonding and amino-aromatic interactions in the recognition of small-molecule amines and peptides by proteins is an important topic for those involved in structure-based drug design, and although the number of structures determined for proteins displaying these interactions is small, general features are beginning to emerge. This review explores the role of cation-pi bonding and amino-aromatic interactions in the biological molecular recognition of amine ligands. Perspectives on the design of ammonium-ligand-binding sites are also discussed.
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Project description:Ab initio calculations were carried out for a benzyl-substituted iminium cation derived from (E)-crotonaldehyde and a chiral imidazolidinone that was developed as an organocatalyst by MacMillan et al. At the MP2 level of theory it is predicted that the phenyl group is close to the iminium moiety in the most stable conformer, suggesting that the cation-π interaction contributes to the stabilization of this conformer. Energy decomposition analyses on model systems indicate that the electrostatic and polarization terms make significant contribution to the attractive interactions between the benzene ring and the iminium cation.
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Project description:Carbohydrate recognition is crucial for biological processes ranging from development to immune system function to host-pathogen interactions. The proteins that bind glycans are faced with a daunting task: to coax these hydrophilic species out of water and into a binding site. Here, we examine the forces underlying glycan recognition by proteins. Our previous bioinformatic study of glycan-binding sites indicated that the most overrepresented side chains are electron-rich aromatic residues, including tyrosine and tryptophan. These findings point to the importance of CH-π interactions for glycan binding. Studies of CH-π interactions show a strong dependence on the presence of an electron-rich π system, and the data indicate binding is enhanced by complementary electronic interactions between the electron-rich aromatic ring and the partial positive charge of the carbohydrate C-H protons. This electronic dependence means that carbohydrate residues with multiple aligned highly polarized C-H bonds, such as β-galactose, form strong CH-π interactions, whereas less polarized residues such as α-mannose do not. This information can guide the design of proteins to recognize sugars and the generation of ligands for proteins, small molecules, or catalysts that bind sugars.
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Project description: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 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-π interaction in the pair Phe28-Lys108 contributes significantly to stabilize the holo-conformation of the loop AB. Numerous energetically significant and conserved cation-π interactions were uncovered in TL and throughout the lipocalin family. Cation-π interactions, such as the highly conserved Trp17-Arg118 pair in TL, were educed in low temperature experiments of mutants with Trp to Tyr substitutions.
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Project description:Raw data of the project "Oxidative Cyclization Reagents Reveal Tryptophan Cation-pi interactions"
2024-01-18 | MSV000093891 | MassIVE
Project description:Cation-π interactions play an important role in biomolecular recognition, including interactions between membrane phosphatidylcholine lipids and aromatic amino acids of peripheral proteins. While molecular mechanics coarse grain (CG) force fields are particularly well suited to simulate membrane proteins in general, they are not parameterized to explicitly reproduce cation-π interactions. We here propose a modification of the polarizable MARTINI coarse grain (CG) model enabling it to model membrane binding events of peripheral proteins whose aromatic amino acid interactions with choline headgroups are crucial for their membrane binding. For this purpose, we first collected and curated a dataset of eight peripheral proteins from different families. We find that the MARTINI CG model expectedly underestimates aromatics-choline interactions and is unable to reproduce membrane binding of the peripheral proteins in our dataset. Adjustments of the relevant interactions in the polarizable MARTINI force field yield significant improvements in the observed binding events. The orientation of each membrane-bound protein is comparable to reference data from all-atom simulations and experimental binding data. We also use negative controls to ensure that choline-aromatics interactions are not overestimated. We finally check that membrane properties, transmembrane proteins, and membrane translocation potential of mean force (PMF) of aromatic amino acid side-chain analogues are not affected by the new parameter set. This new version "MARTINI 2.3P" is a significant improvement over its predecessors and is suitable for modeling membrane proteins including peripheral membrane binding of peptides and proteins.
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Project description:In order to probe the energetics associated with a putative cation-π interaction, thermodynamic parameters are determined for complex formation between the Grb2 SH2 domain and tripeptide derivatives of RCO-pTyr-Ac6c-Asn wherein the R group is varied to include different alkyl, cycloalkyl, and aryl groups. Although an indole ring is reputed to have the strongest interaction with a guanidinium ion, binding free energies, ΔG°, for derivatives of RCO-pTyr-Ac6c-Asn bearing cyclohexyl and phenyl groups were slightly more favorable than their indolyl analog. Crystallographic analysis of two complexes reveals that test ligands bind in similar poses with the notable exception of the relative orientation and proximity of the phenyl and indolyl rings relative to an arginine residue of the domain. These spatial orientations are consistent with those observed in other cation-π interactions, but there is no net energetic benefit to such an interaction in this biological system. Accordingly, although cation-π interactions are well documented as important noncovalent forces in molecular recognition, the energetics of such interactions may be mitigated by other nonbonded interactions and solvation effects in protein-ligand associations.
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