Structural and energetic effects in the molecular recognition of amino acids by 18-crown-6

Absolute 18-crown-6 (18C6) affinities of five amino acids (AAs) are determined using guided ion beam tandem mass spectrometry techniques. The AAs examined in this work include glycine (Gly), alanine (Ala), lysine (Lys), histidine (His), and arginine (Arg). Theoretical electronic structure calculations are performed to determine stable geometries and energetics for neutral and protonated 18C6 and the AAs as well as the proton bound complexes comprised of these species, (AA)H(+)(18C6). The proton affinities (PAs) of Gly and Ala are lower than the PA of 18C6, whereas the PAs of Lys, His, and Arg exceed that of 18C6. Therefore, the collision-induced dissociation (CID) behavior of the (AA)H(+)(18C6) complexes differs markedly across these systems. CID of the complexes to Gly and Ala produces H(+)(18C6) as the dominant and lowest energy pathway. At elevated energies, H(+)(AA) was produced in competition with H(+)(18C6) as a result of the relatively favorable entropy change in the formation of H(+)(AA). In contrast, CID of the complexes to the protonated basic AAs results in the formation of H(+)(AA) as the only direct CID product. H(+)(18C6) was not observed, even at elevated energies, as a result of unfavorable enthalpy and entropy change associated with its formation. Excellent agreement between the measured and calculated (AA)H(+)-18C6 bond dissociation energies (BDEs) is found with M06 theory for all complexes except (His)H(+)(18C6), where theory overestimates the strength of binding. In contrast, B3LYP theory significantly underestimates the (AA)H(+)-18C6 BDEs in all cases. Among the basic AAs, Lys exhibits the highest binding affinity for 18C6, suggesting that the side chains of Lys residues are the preferred binding site for 18C6 complexation in peptides and proteins. Gly and Ala exhibit greater 18C6 binding affinities than Lys, suggesting that the N-terminal amino group provides another favorable binding site for 18C6. Trends in the 18C6 binding affinities among the five AAs examined here exhibit an inverse correlation with the polarizability and proton affinity of the AA. Therefore, the ability of the N-terminal amino group to compete for 18C6 complexation is best for Gly and should become increasing less favorable as the size of the side chain substituent increases.     

The complexation of the ammonium ion by 18-crown-6 in different solvents and by noncyclic ligands,crown ethers and cryptands in methanol

The complexation of the ammonium ion with the macrocyclic ligand 18-crown-6 was studied using calorimetric and potentiometric titrations in different solvents. In water and dimethyl sulphoxide the stability constants had the lowest values compared with all other solvents examined. No specific interactions between the ammonium ion and solvent molecules were observed. Crown ethers formed more stable complexes in methanol with the ammonium ion than diaza crown ethers. The most stable complexes were formed with cryptands. The highest values of the stability constants for the reaction with macrocyclic and macrobicyclic ligands were measured if the dimensions of the ammonium ion and of the cavities were nearly identical.     

Structural and energetic effects in the molecular recognition of protonated peptidomimetic bases by 18-crown-6

Absolute 18-crown-6 (18C6) affinities of nine protonated peptidomimetic bases are determined using guided ion beam tandem mass spectrometry techniques. The bases (B) included in this work are mimics for the n-terminal amino group and the side chains of the basic amino acids, i.e., the favorable sites for binding of 18C6 to peptides and proteins. Isopropylamine is chosen as a mimic for the n-terminal amino group, imidazole and 4-methylimidazole are chosen as mimics for the side chain of histidine (His), 1-methylguanidine is chosen as a mimic for the side chain of arginine (Arg), and several primary amines including methylamine, ethylamine, n-propylamine, n-butylamine, and 1,5-diamino pentane as mimics for the side chain of lysine (Lys). Theoretical electronic structure calculations are performed to determine stable geometries and energetics for neutral and protonated 18C6 and the peptidomimetic bases, as well as the proton bound complexes comprised of these species, (B)H(+)(18C6). The measured 18C6 binding affinities of the Lys side chain mimics are larger than the measured binding affinities of the mimics for Arg and His. These results suggest that the Lys side chains should be the preferred binding sites for 18C6 complexation to peptides and proteins. Present results also suggest that competition between Arg or His and Lys for 18C6 is not significant. The mimic for the n-terminal amino group exhibits a measured binding affinity for 18C6 that is similar to or greater than that of the Lys side chain mimics. However, theory suggests that binding to n-terminal amino group mimic is weaker than that to all of the Lys mimics. These results suggest that the n-terminal amino group may compete with the Lys side chains for 18C6 complexation.     

Complexation of crown ethers and heteroanalogs of 18-crown-6 with alkali and alkaline earth metal cations in dichloroethane

Data on the complexing ability of a series of crown ethers and heteroanalogs of 18-crown-6, containing S-, SO-, SO₂- and SONH fragments at the 1- and 10-positions of the macrocyclic ring, with Li, Na, K, Mg and Ba picrates in dichloroethane were obtained from the solubility of the salts in the presence of the crown compounds. It was found that 18-crown-6 is the best but the least selective ligand of all the picrates, while polyethers with SO- and SONH fragments show an appreciable selectivity toward Li⁺, and to a lesser extent, toward Mg⁺. The complexing ability of the disulfone ligand is inappreciable under the conditions studied. A 11 stoichiometry of the complexes has been found for the individual crown-picrate pairs.Translated from Teoreticheskaya i Éksperimental'naya Khimiya, Vol. 24, No. 2, pp. 191–196, March–April, 1988.     

On the rate-limiting steps in the membrane transport of cations across liquid membranes by dibenzo-18-crown-6 and lipophilic crown ether carboxylic acids

The influence of stirring rate on the transport of cations across unsupported liquid membranes was examined in several systems. Systems known to be rate limited by diffusion, dibenzo-18-crown-6/KNO₃ and anti-(8NH)₂18-6A₂/Sr²⁺, showed continuous variation of transport rate over the range 100-600 rpm in stirring speed. In contrast, systems utilizing the carrier 14NH18-6A/K⁺showed plateau regions above approximately 300 rpm. Such a plateau is consistent with a rate limiting interracial process which, with previous evidence, is presumed to be the rate limiting adsorption/desorption of the carrier surfactant from the interface     

Complexes of the Lighter Lanthanoid Nitrates with 15-crown-5 and 18-crown-6 ethers: Synthesis and characterization

Complexes of lanthanoid trinitrates Ln(NO₃)₃ with 15-crown-5 ether 1 (Ln = La, Ce, Pr, Nd, Sm, Eu, Gd) and with 18-crown-6 ether 2 (Ln = La, Ce, Pr, Nd) having a 1:1 stoichiometry as well as 4:3 complexes with 2 (Ln = La, Ce, Pr, Nd, Sm, Eu, Gd) have been synthesized and characterized. All the isolated complexes are solvent free. At 170–220° the 1:1 complexes of 2 are quantitatively transformed into 4:3 complexes. X-Ray powder diagrams of the neodymium complexes with 2 indicate that both the 1:1 and 4:3 complexes are genuine compounds. All the 1:1 complexes show a characteristic IR. absorption band at 875–880 cm^?1 absent from both the spectra of the free ligands and of the 4:3 complexes. The spectroscopic properties (IR. and electronic spectra, fluorescence lifetimes) of the complexes and the low magnetic moments of the Ln(III) ions in the complexes with Ln = Ce-Eu are indicative of a strong interaction between the lanthanoid ions and the crown ethers 1 and 2 .     

Neutral molecule/crown ether interactions 5. Comparison of the C−H acidic interactions of nitromethane and acetonitrile with 18-crown-6 and dibenzo-18-crown-6. Crystal structures of dibenzo-18-crown-6·2 CH3NO2 and dibenzo-18-crown-6·2 CH3CN

Complete structural characterization of dibenzo-18-crown-6·2 CH₃NO₂ and dibenzo-18-crown-6·2 CH₃CN have been carried out, including location and refinement of the methyl hydrogen atoms. Dibenzo-18-crown-6·2 CH₃NO₂ is monoclinic,P2₁/c, with (at –150°C)a=9.573(2),b=14.636(2),c=33.471(7) Å, =93.77(2)°, andD _calc=1.37 g cm^–3 forZ=8. Interactions between the solvent methyl groups and the crown ethers and other solvent nitro groups associate the 1 : 2 complexes into polymeric chains alongb. The acetonitrile adduct exists as discreet 1 : 2 complexes in the solid state with C–H...O interactions exlusively to the ether. This complex is triclinic,P 1, with (at –150°C)a=9.458(6),b=9.570(5),c=14.404(5) Å, =73.18(4), =79.85(5), =66.82(6)°, andD _calc=1.28 g cm^–3 forZ=2. Supplementary Data relating to this article are deposited with the British Library as Supplementary Publication No. SUP 82070 (22 pages).For part 4, see reference [1].     

冠醚配合物的研究 XI: 若干苯并-18-冠-6甲基衍生物液膜传输碱金属离子

本文研究了2,3-苯并-11-甲基-18-冠-6,2,3-苯并-8,15-二甲基-18-冠-6和2,3-苯并-8, 11, 15-三甲基-18-冠-6的氯仿液膜对Na^+, K^+, Rb^+的传输速率。结果指出,传输速率随膜相冠醚浓度增是加而增加, 两者成线性关系; 当冠醚的醚环上甲基数增加则传输速率减小; 对同一冠醚, 不同金属离子的传输速率与相应配合物稳定常数的大小顺序有一致关系; 冠醚传输金属离子时, 阴离子一起迁移, 阴离子水合能力越强则传输能力越小; 传输速率与搅拌速度成线性关系。     

Selective molecular recognition of arginine by anionic salt bridge formation with bis-phosphate crown ethers: implications for gas phase peptide acidity from adduct dissociation

Arginine forms a stable noncovalent anionic salt bridge complex with DP (a crown ether which contains two endocyclic dialkylhydrogenphosphate esters). Abundant adduct formation with DP is observed for complexes with arginine, YAKR, HPPGFSPFR, AAKRKAA, RR, RPPGFSPFR, RYLGYL, RGDS, and YGGFMRGL in electrospray ionization mass spectrometry (ESI-MS) experiments. DFT calculations predict a hydrogen bonded salt bridge structure with a protonated guanidinium flanked by two deprotonated phosphates to be the lowest energy structure. Dissociation of DP/peptide adducts reveals that, in general, the relative gas phase acidity of a peptide is dependent on peptide length, with longer peptides being more acidic. In particular, peptides that are six residues or more in length can stabilize the deprotonated C-terminus by extensive hydrogen bonding with the peptide backbone. Dissociation of DP/peptide complexes often yields the deprotonated peptide, allowing for the facile formation of anionic peptides that otherwise would be difficult to generate in high abundance. Although DP has a preference for binding to arginine residues in peptides, DP is also observed to form less abundant complexes with peptides containing multiple lysines. Lys-Xxx-Lys and Lys-Lys sequences form low abundance anionic adducts with DP. For example, KKKK exclusively forms a double adduct with one net negative charge on the complex.     

Reaction of trimethylaluminum with crown ethers. II. The synthesis and crystal structure of (Dibenzo-18-crown-6)tris(trimethylaluminum) and of (18-crown-6)tetrakis(trimethylaluminum)

Both title compounds were prepared by adding AlMe₃ to a suspension of the appropriate crown ether in toluene, followed by reaction in a sealed tube. Both products were obtained in the form of extremely air-sensitive, colorless crystals. [AlMe₃]₃[dibenzo-18-crown-6] crystallizes in space group Pī, witha=8.898(4),b=11.848(5),c=19.060(6) Å, α=74.86(3), β=80.73(4), and γ=67.02(4)°. Refinement led to a final conventional weightedR value of 0.052 for 1800 reflections. [AlMe₃]₄[18-crown-6] belongs to space group Pbcn, witha=18.753(3),b=12.570(6), andc=15.095(6) Å. Refinement was taken toR _w =0.064 for 1320 reflections.     

Thermodynamics of formation for the 18-crown-6-triglycine molecular complex in water-dimethylsulfoxide solvents

The effect of a water-dimethylsulfoxide (DMSO) solvent on the formation of a molecular complex of 18-crown-6 (18C6) with triglycine (diglycylglycine, 3Gly) is studied via calorimetric titration. It is found that switching from water to an H₂O-DMSO mixture with DMSO mole fraction of 0.30 is accompanied by a monotonic increase in the stability of [3Gly18C6] complex, from logK ^° = 1.10 to logK ^° = 2.44, and an increase in the exothermicity of the reaction of its formation, from ?5.9 to ?16.9 kJ/mol. It is shown that the [3Gly18C6] complex exhibits enthalpy stabilization with negative values of enthalpy and entropy over the investigated range of H₂O-DMSO solvents. Analysis of the reagents’ solvation characteristics reveals that the increase in the reaction’s exothermicity of transfer is due to differences in the solvation of [3Gly18C6] and 18C6 with a small solvation contribution from 3Gly. It is concluded that the change in the Gibbs energy of the reaction 3Gly_solv + 18C6_solv ? [3Gly18C6]_solv is due to differences in the change in the solvation state of the complex and the peptide (Δ_tr G ^°([3Gly18C6])-Δ_tr G ^°(3Gly)).     

Kinetics of facilitated proton transfer by polyether 18-crown-6 across the water-1,2-dichloroethane interface

The kinetics of facilitated proton transfer by polyether 18-crown-6 across the water-1,2-dichloroethane interface has been investigated by cyclic voltammetry and ac impedance. It was found that rate apparent constant is quite similar for the several concentrations of 18-crown-6 used in the experiments, the rate constant values (k _s ) were in the range: 0.028, 0.031, 0.027, and 0. 03 cm/s for 0.1, 0.15, 0.2, and 0.25 mM of 18-crown-6.A formal transfer potential of ₀ ^w_i ⁰= 0.01 V was found for the facilitated proton transfer by 18-crown-6 at the water-1,2-dichloroethane interface; this value remained constant in the range of concentration considered in this work. According to the kinetic results, an interfacial reaction between the proton and the polyether 18-crown-6 is discussed in which the polyether does not transfer into the aqueous phase, in the time scale of the experiments. As a consequence, it can be concluded that the solvation and desolvation of ligand and proton play an important role in the rate-determining step.From Elektrokhimiya, Vol. 41, No. 2, 2005, pp. 206–212.Original English Text Copyright © 2005 by Velázquez-Manzanares, Amador-Hernández.This article was submitted by the authors in English.Part of this work was presented at XXV Congreso Latinoamericano de Qu#X00ED;mica in Cancun, Quintana Roo, Mexico, 2002.This revised version was published online in April 2005 with corrections to the article note and article title and cover date.     

Stereochemical dynamics of crown ethers: Ring inversion in isomeric dicyclohexano-18-crown-6 systems as studied by 13C magnetic resonance at low temperature

From ¹³C NMR coalescence temperature measurements, free energies of activation for degenerate ring reversal in two configurationally isomeric dicyclohexano-18-crown-6 ethers have been determined to be $\text{ca}$. 10.2 kcal/mole, with higher barriers for the 1:1 complexes with potassium phenoxide.     

Effect of solvation on the thermodynamics of the formation of molecular complexes of 18-crown-6 ether with glycine in water-dimethylsulfoxide solutions

Complexation of the 18-crown-6 ether (18C6) with glycine (Gly) in mixed H₂O-DMSO solvents with the composition of 0.1, 0.2, and 0.25 mole fraction of DMSO (T = 298.15 K) was studied calorimetrically. Thermodynamic characteristics of the reaction of the formation of the molecular Gly18C6 complex (Δ_r G°, Δ_r H°, TΔ_r S°) were calculated from the calorimetric data. It was established that the change in the stability of the Gly18C6 complex is mainly determined by the predominance of the enthalpy component of the Gibbs energy over the entropy component. It was shown during the analysis of the enthalpy contributions of the reagents to the enthalpy of the reaction of the formation of Gly18C6 that the change in the enthalpy of the reaction upon a change the solvent composition was due to changes in the solvation state of 18C6.     

Ditopic crown ether-guanidinium ion receptors for the molecular recognition of amino acids and small peptides

A series of ditopic synthetic receptors based on a crown ether-guanidinium ion recognition motif is reported. The compounds show binding affinity to selected amino acids, including important neurotransmitters. The effect of the distance of the ammonium and the carboxylate ion, the rigidity of the spacer, and the use of pre-organized pyrrole- and pyrene-guanidinium groups on binding affinity and selectivity are discussed.     

Multi-functionalized chiral crown ethers as enzyme models for the synthesis of peptides. Multiple chiral recognition in the enzyme model

A novel approach to the enzyme model for the synthesis of peptides has been established by using multi-functionalized chiral crown ethers as hosts. The new strategy consists of three key steps as follows. (1) Guest assembly: the host having one free thiol and one thioester withN-protected-amino acid or peptide proceeds via rapid intra-complex thiolysis of-amino acid ester salts to form the dithioester, and assembles two guests. (2) Amide formation: the intramolecular aminolysis occurs between the bound guests to form the amide bond. (3) Peptide chain elongation: as the thiol reactive group is regenerated, the above two reactions are repeated to elongate the peptide chain. In the present paper, we describe the multiple chiral recognition that could be achieved by the chiral crown ether in both the intra-complex thiolysis and the intramolecular aminolysis. For explanation of the chiral recognition, we propose a likely structure for the intermediate of the aminolysis.     

Stability constants of complexes formed by new Schiff-base lariat ethers derived from 4,13-diaza-18-crown-6 with Ag+, Pb2+, Cu2+ cations determined by competitive potentiometry

The stability of complexes formed by a series of Schiff-base lariat ethers, derived from 4,13-diaza-18-crown-6, 1 with Ag⁺, Pb²⁺, Cu²⁺ cations, has been comparatively determined, in methanol: dichloromethane solution. We present here the synthesis and an interesting competitive potentiometry method useful for the stability constant determination for a new family of Schiff-base bibracchial lariat ethers. The stability constants and the selectivity in competitive complexation of Ag⁺, Pb²⁺ and Cu²⁺ cations by macrocyclic receptors 1–7 (L), can be accurately evaluated and species distribution diagrams can be calculated for individual system. In all cases further functionalization of bibracchial lariat ethers 2–7 is accompanied by an increasing of the selectivity, relative to the complexes of the initial 4,13-diaza-18-crown-6 macrocycle 1.     

Engineering O-glycosylation points in non-extended peptides: implications for the molecular recognition of short tumor-associated glycopeptides

The ties that bind: The incorporation of non-natural residues in the peptide backbone allows the design of O-glycosylation points in helical segments. This strategy could help to modulate the binding properties between glycopeptides and their protein receptors, such as lectins and antibodies.