Aromatic amino acid–metal ion interactions: comparative effects of alkali and Zn2+ on acidity and coordination behavior via QM studies

Gas‐phase complexes of Cu(II) with aliphatic and aromatic α‐amino acids (AA) and diimine ligands, 2,2′‐bipyridyl (bpy) and phenanthroline (phen) are obtained by electrospray ionization of their aqueous‐methanol solutions. The amino acids are found to bind to Cu(II) by their COO− and amino groups in the gas‐phase complexes. The [Cu(II)(AA – H)(bpy)]+· complexes (M+·) show distinct dissociations upon collisional activation. Decarboxylation produces stable (M – CO2)+· ions containing α‐amino alkyl residues coordinated to copper. Further dissociations of radicals derived from aliphatic amino acids involve fission of the CβCγ bond in the alkyl chain that reveals its branching. Leucine and isoleucine are readily distinguished by their different dissociation products. Complexes of aromatic amino acids undergo facile amine group transfer on to copper. Electron distributions in several copper complexes were obtained by ab initio calculations and used to discuss the dissociation products formed from gas‐phase [Cu(II)(AA – H)(bpy)]+· ions.

Carbohydrate amphiphiles for supramolecular biomaterials: Design, self-assembly, and applications

The present work describes the complexe formation of the Cd (II) with amino acids (L-glutamine, L-asparagine, L-valine, L-leucine, α-alanine and glycine) as primary ligands and vitamin-B7 (β-biotin) as secondary ligand by polarographic technique. The Cd (II) formed 1: 1: 1, 1: 1: 2 and 1: 2: 1 complexes at pH = 7.30 ± 0.01, µ = 1.0 M KNO 3 . The Cd (II) showed the two electrons reversible reduction wave with diffusion controlled nature. The trend of the stability constants of the complexes with respect to primary ligand was L-glutamine < L-asparagine < L-valine < L-leucine < α-alanine < L-glycine. The thermodynamic parameters like enthalpy, free energy, and entropy change is also determined. The results showed that the complexes were lesser stable at high temperature and formed with the evolution of heat. 1-3 . The minerals mis-regulation leads to many serious diseases such as oxidative stress diabetes, amyotrophic lateral sclerosis, cancer, inflammatory, neurodegenerative, and potential to various toxic effects etc. 4-10 . In addition to these, toxic effects are reduced with the ligands therapy. The bioactive amino acids and vitamin-B7 complexes with the Cd (II) are also used to prevent excess metal accumulation and toxicity 11 . Amino acid side chain groups are involved in various biological functions such as the molecular recognition and catalytic activity of the enzyme active center and formation of an environment with the metal ions used to in medicinal fields 12 . Weak interactions involving functional groups of coordinated amino acids in metal complexes may mimic the modes and effects of the interactions in metalloproteins. Complexes of amino acids and vitamins with metal ions have great importance because of their physiological and pharmacological activities. Some of the research work reported antitumor activities 13-14 . Biotin is act as cofactor and coenzyme involved in vital biological process such as fatty acid synthesis, gluconeogenesis, amino acids metabolism, and carbon dioxide fixation reaction 15 . Therefore the combination of the amino acids and vitamin-B7 with Cd (II) are used to reduce the metal toxicity. The coordination chemistry of the Cd (II) metal ion has shown too significant for the organisms on complexation with the bioactive ligands by chelating nitrogen and oxygen donor ligands 16 . In the present work, we report the complex formation between Cd 2+ and some L-amino acids and β-biotin with the aim to ascertain the effects of size and basicity of ligand on the stability of complexes.

The human body contains many different types of transition metal ions, such as Zn2+, Cu2+, which are involved in many physiological processes. An excess or deficiency of these ions can cause diseases, such as Alzheimer's disease, which is closely related to the levels of these ions in the body. In-depth understanding of various physiological and pathological mechanisms related to metal ions requires understanding the interaction between metal ions and nearby amino acids at the atomic level. This article selected four transition metal ions: Zn2+, Cu2+, Fe2+, and Mn2+ and the aromatic amino acid Phe, known for its strong coordination capability, as study subjects, comprehensively examining their binding situations. The results show that there are multiple binding modes between them and Phe, and most of the binding modes involve benzene ring coordination. The coordination strength order of the four metal ions with benzene ring, carbonyl O, hydroxyl O and amino N is different. For the lowest energy structure formed by each ion with Phe, all four ions are bound to N, carbonyl O, and benzene ring. Zn2+ is combined with two C's of the benzene ring, Cu2+ with four C's of the benzene ring, and Fe2+ and Mn2+ with the benzene ring as a whole. Part of the reason for this phenomenon may be derived from the tendency of transition metal ions to reach 18e stable structures when bound to ligands. There is a strong binding force between the four ions and Phe, and the binding trend is Cu2+(-294.9kcal/mol) > Zn2+(-261.3kcal/mol) > Fe2+(-247.5kcal/mol) > Mn2+(-220.2kcal/mol). Mayer bond order analysis and molecular orbital localization analysis found that there are very strong chemical interactions between transition metal ions and surrounding atoms, especially with N and carbonyl O. Several initial structures with different coordination modes to Phe were created according to chemical intuition for each divalent cation. Then semiempirical MD simulations at GFN2 level were run on these structures. The numerous generated structures were classified according to some criteria, then representative geometries were preliminarily optimized by TPSSh/6-31G*/LanL2DZ. To get more accurate electronic energies, high-precision quantum chemistry calculations at the level of TPSSh/def2TZVPP//TPSSh/def2QZVPP were carried out on the selected low-lying structures. All the optimized structures were confirmed to be minima without imaginary frequency by performing frequency analyses. Further electronic structure analyses such as IRI, Mayer bond order, IBSI etc. were performed to get more insights into the binding between the transition metal ions and Phe.

EPR study of Cu(II) complexes of tridentate amino acids

In this research, investigation of the adsorption isotherms and the effect of solution conditions such as pH and concentration of complexation of some amino acids with cobalt(II) nitrate six-hydrate upon multi-wall type carbon nanotube (CNT) were done. The adsorption capacity of complexation of amino acids onto the surface of carbon nanotube increased with the pH from acidic to alkaline. At pH = 9 the affinity order of the complexation of amino acids towards carbon nanotube is L-arginine > L-phenylalanine > L-asparagine > L-methionine > L-cysteine > glycine > L-alanine > L-valine > L-histidine. The curves have an important role in the design and optimization of the unit operations such as preservation, drying storing packaging and mixing. The adsorption equilibrium isotherms were fitted by Freundlich, Langmuir and Temkin models, but the Freundlich model is better than other models because is does not assume the surface as homogeneous with respect to adsorption energies and also the r2 value indicates the goodness of fit between the data and the isotherm.

In 30 adults, increasing intake of aromatic amino acids increased calcium excretion and serum IGF-1, but not indices of bone turnover, when compared with similar increases in intake of branched-chain amino acids. The mechanisms involved are not certain but these findings suggest a role for the calcium sensor receptor. In contrast to branched-chain amino acids (BCAAs), aromatic amino acids (AAAs) bind to the calcium sensing receptor (CaR) and thus have an increased potential to affect calcium homeostasis. In this study we compare the effects of increased intake of AAAs versus BCAAs on calcium excretion, serum IGF-1, markers of bone turnover, and 4-hr calcium excretion after an oral calcium load. After two weeks on low-protein metabolic diets, 30 healthy subjects were randomized to a fivefold increase in intake of AAAs or BCAAs for two weeks. Changes in calcium excretion and other measures were compared in the two groups. With the increase in amino acid intake, 24-hr calcium excretion (P = 0.027), IGF-1 (P = 0.022), and 4-hr calcium excretion after an oral load (P = 0.023) increased significantly in the AAA relative to the BCAA group. Group changes in turnover markers did not differ significantly. In comparison with BCAAs, AAAs promoted calcium excretion. The calciuria does not appear to result from increases in bone resorption and may occur by increasing calcium absorption. The AAAs also increased circulating levels of IGF-1. Collectively these findings raise the possibility that AAAs may selectively influence calcium homeostasis through their interactions with the CaR.

In 1987, Pedersen, Cram, and Lehn were awarded the Nobel Prize in Chemistry to honor their achievements in, among other things, the selective recognition of alkali metal ions by synthetic hosts. Almost three decades later, the 2016 Nobel Prize went to Stoddart, Sauvage, and Feringa for the development of artificial molecular machines, in which interlocked molecules play a significant role. Surprisingly, although many rotaxane- and catenane-based molecular machines have been constructed using various templating approaches, alkali metal ions, which are good templates for crown ether synthesis, have only rarely been applied as templates for the assembly of these interlocked molecules. This paucity of examples is probably due to the less well defined coordination numbers and geometries in the complexation of alkali metal ions to common oxygen-containing ligands, resulting in much weaker metal-ligand interactions and less predictable structures for their complexes compared with those formed between transition metal ions and common pyridine-containing ligands. Nevertheless, the ease of removing alkali metal ions from interlocked compounds and their much lower toxicity compared with that of transition metal ions are attractive features that have inspired their use as templates in the synthesis of interlocked molecules. About a decade ago, we began investigating the feasibility of using alkali metal ions to template the formation of catenanes and rotaxanes, with the hope of developing facile, broadly applicable, green, and efficient methods for their construction. We noticed that the interactions between oxygen-containing ligands and alkali metal ions can be strengthened by minimizing the effects of competing interactions from solvent molecules and counteranions. Thus, to increase the solubility of the metal ion salts in less polar solvents (e.g., CH2Cl2, CHCl3) and minimize ion pairing, we chose tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (TFPB), a weakly coordinating anion, as the counteranion for the alkali metal ions applied as templates. Our strategy has been based on the association of simple and general recognition units: (i) the orthogonal arrangement of two oligo(ethylene glycol) chains around an alkali metal ion and (ii) the encircling of a single urea/amide unit by an oligo(ethylene glycol)-containing macrocycle in the presence of a templating alkali metal ion. The former recognition system has allowed the facile construction of many interesting interlocked structures, including cyclic [2]catenane trimers and tetramers; the latter has provided several rotaxanes, including some incorporating monomers of practically important (macro)molecules (e.g., peptides, polymers) and some that behave as switches with unique functions (e.g., catalysis, gelation). The components in these recognition systems possess high flexibility in terms of their structures and the choice of suitable alkali metal ion templates. This Account tells the story of the concept behind this alkali metal ion-templating approach as well as its elaboration, scope, and recent advances. We hope to convince the reader that alkali metal ions are powerful templates for assembling interlocked structures and compounds and also to demonstrate the range of possibilities that they provide for future endeavors.

News from the dark side!

The effects of some alkali metal ions (Na+ and K+) and alkaline earth metal ions (Mg 2+ and Ba2+) on the initial reaction rates of Congregibacter litoralis KT71 β-lactamase hydrolysis of 4-nitrophenyl myristate was investigated by varying the concentrations of the metal ions in the assay mixture which comprised of 100 µl of standard enzyme solution, 200 µl of varying concentration of metal ions, 500 µl of 50 mM sodium phosphate buffer pH 7.5 and 200 µl of 4-nitrophenyl myristate (substrate) which was added last to the assay mixture after an incubation time of 10 minutes at 44 oC. The enzyme activity was measured spectrophotometrically using a UV-780 recording spectrophotometer at a wavelength of 405 nm. The hydrolysis of 4-nitrophenyl myristate to yield 4-nitrophenol was monitored by reading the absorbance at 25 minutes. Results showed that the alkaline earth metal ions (Ba2+ and Mg2+) had higher enzyme activation effect than the alkali metal ions (K+ and Na+) Also, all metal ions except Mg2+ showed enzyme stimulatory effect at low concentrations (&lt;2 mM) but inhibitory at higher ion concentrations (2 mM - 3 mM). Mg 2+ caused a proportionate decrease in enzyme activity from its peak (when metal ion concentration was lowest). Results from this research is of great significance to the industrialist especially where the search for novel lipases with unique characteristics suitable for the industries are inevitable.

苯丙酮尿症等代谢病患者因基因缺陷无法正常代谢食物中的芳香族氨基酸(aromatic amino acids, AAA),常规饮食可能会造成永久性生理损伤,低AAA肽是其重要的蛋白质等同物来源。AAA分离分析技术对低AAA肽的制备和检测至关重要。该领域研究者探索了多种高效的吸附、分离材料,从复杂的蛋白质水解液中选择性吸附脱除AAA以制备符合特定氨基酸限量的低AAA肽类食品,或者建立对AAA特异性提取富集的分离分析策略。该文分析了AAA的结构特点与理化性质,总结了近年来基于活性炭、树脂等吸附材料脱除AAA的技术进展,并从样品前处理、手性分离和吸附-传感3个维度综述了二维纳米材料、分子印迹、环糊精、金属有机骨架等材料在AAA分离分析中的应用。通过探讨各类技术的优缺点,为AAA吸附脱除和分离分析技术的进步提供支撑。

We report the solid-phase synthesis and some pharmacological properties of 23 new analogs of arginine vasopressin (AVP) which have the Phe3 residue replaced by a broad variety of amino acids. Peptides 1-9 have at position 3: (1) the mixed aromatic/aliphatic amino acid thienylalanine (Thi) and the aliphatic amino acids; (2) cyclohexylalanine (Cha); (3) norleucine (Nle); (4) Leu; (5) norvaline (Nva); (6) Val; (7) alpha-aminobutyric acid (Abu); (8) Ala; (9) Gly. Peptides 10-23 have at position 3: the aromatic amino acids, (10) homophenylalanine (Hphe): (11) Tyr; (12) Trp; (13) 2-naphthylalanine (2-Nal); the conformationally-restricted amino acids (14) Pro; (15) 2-aminotetraline-2-carboxylic acid (Atc); the polar amino acids (16) Ser; (17) Thr; (18) Gln; and the charged amino acids (19) Asp; (20) Glu; (21) Arg; (22) Lys; (23) Orn. All 23 new peptides were evaluated for agonistic and, where appropriate, antagonistic activities in in vivo antidiuretic (V2-receptor) and vasopressor (V1a-receptor) assays and in in vitro (no Mg2+) oxytocic assays. The corresponding potencies (units/mg) in these assays for AVP are: 323+/-16; 369+/-6 and 13.9+/-0.5. Peptides 1-9 exhibit the following potencies (units/mg) in these three assays: (1) 379+/-14; 360+/-9; 36.2+/-1.9; (2) 294+/-21: 73.4+/-2.7; 0.33+/-0.02; (3) 249+/-28; 84.6+/-4.3; 4.72+/-0.16; (4) 229+19; 21.4+/-0.6; 2.1+/-0.2; (5) 134+/-5; 31.2+/-0.9; 28.4+/-0.2; (6) 114+/-9; 45.3+2.3; 11.3+/-1.6; (7) 86.7+/-2.5; 4.29+/-0.13; 0.45+/-0.03; (8) 15.5+/-1.5; 0.16+/-0.01; approximately 0.02: (9) 3.76+/-0.03; < 0.02; in vitro oxytocic agonism was not detected. These data show that the aliphatic amino acids Cha, Nle, Leu, Nva and Val are well-tolerated at position 3 in AVP with retention of surprisingly high levels of antidiuretic activity. Peptides 2-9 exhibit significant gains in both antidiuretic/vasopressor (A/P) and antidiuretic/oxytocic (A/O) selectivities relative to AVP. [Thi3]AVP appears to be a more potent antidiuretic and oxytocic agonist than AVP and is equipotent with AVP as a vasopressor agonist. The antidiuretic potencies of peptides 10-23 exhibit drastic losses relative to AVP. They range from a low of 0.018+/-0.001 units/mg for the Lys3 analog (peptide 22) to a high of 24.6+/-4.6 units,mg for the Hphe3 analog (peptide 10). Their vasopressor potencies are also drastically reduced. These range from a low of < 0.002 units/mg for peptide 22 to a high of 8.99+0.44 units/mg for the Atc3 analog (peptide 15). Peptides 10-23 exhibit negligible or undetectable in vitro oxytocic agonism. The findings on peptides 10-23 show that position 3 in AVP is highly intolerant of changes with aromatic, conformationally-restricted, polar and charged amino acids. Furthermore, these findings are in striking contrast to our recent discovery that position 3 in the potent V2/V1a/OT antagonist d(CH2)5D-Tyr(Et)2VAVP tolerates a broad latitude of structural change at position 3 with many of the same amino acids, to give excellent retention of antagonistic potencies. The data on peptides 1-4 offer promising clues to the design of more potent and selective AVP V2 agonists.

This paper presents the vacuum structures of aquacopper(II) bis(amino acid) complexes with glycine, sarcosine, N,N-dimethylglycine, and N-tert-butyl-N-methylglycine estimated using the B3LYP method. The differences between the B3LYP vacuum structures and experimental crystal structures suggested considerable influence of crystal lattice packing effects on the changes in the complexes' geometries. A previously developed molecular mechanics force field for modeling anhydrous copper(II) amino acidates was reoptimized to simulate these changes and predict the properties of both trans and cis anhydrous and aqua copper(II) amino acid complexes. The modeling included experimental molecular and crystal structures of 13 anhydrous and 10 aqua copper(II) amino acidates with the same atom types (Cu(II), C, H, N, and O) but various copper(II) coordination polyhedron geometries, crystal symmetries, and intermolecular interactions. The empirical parameters of the selected potential energy functions were optimized on the B3LYP vacuum copper(II) coordination geometries of three anhydrous copper(II) amino acidates and on experimental crystalline internal coordinates and unit cell dimensions of six anhydrous and six aqua copper(II) amino acid complexes. The respective equilibrium structures were calculated in vacuo and in simulated crystalline environment. The efficacy of the final force field, FFW, was examined. The total root-mean-square deviations between the experimental and theoretical crystal values were 0.018 A in the bond lengths, 2.2 degrees in the valence angles, 5.5 degrees in the torsion angles, and 0.395 A in the unit cell lengths. FFW reproduced the unit cell volumes in the range from -8.1 to 9.6%. The means of Cu to axial water oxygen distances were 2.4 +/- 0.1 A (experiment) and 2.6 +/- 0.1 A (FFW). This paper describes the ability of the molecular mechanics model and FFW force field to simulate the flexibility of the metal coordination polyhedron. The new force field proved effective in predicting the most stable molecular conformation of copper(II) amino acidato systems in vacuo.

A representative set of high resolution x-ray crystal structures of nonhomologous proteins have been examined to determine the preferred positions and orientations of noncovalent interactions between the aromatic side chains of the amino acids phenylalanine, tyrosine, histidine, and tryptophan. To study the primary interactions between aromatic amino acids, care has been taken to examine only isolated pairs (dimers) of amino acids because trimers and higher order clusters of aromatic amino acids behave differently than their dimer counterparts. We find that pairs (dimers) of aromatic side chain amino acids preferentially align their respective aromatic rings in an off-centered parallel orientation. Further, we find that this parallel-displaced structure is 0.5-0.75 kcal/mol more stable than a T-shaped structure for phenylalanine interactions and 1 kcal/mol more stable than a T-shaped structure for the full set of aromatic side chain amino acids. This experimentally determined structure and energy difference is consistent with ab initio and molecular mechanics calculations of benzene dimer, however, the results are not in agreement with previously published analyses of aromatic amino acids in proteins. The preferred orientation is referred to as parallel displaced pi-stacking.

Chemical modification to improve biopharmaceutical properties, especially oral absorption and bioavailability, is a common strategy employed by pharmaceutical chemists. The approach often employs a simple structural modification and utilizes ubiquitous endogenous esterases as activation enzymes, although such enzymes are often unidentified. This report describes the crystal structure and specificity of a novel activating enzyme for valacyclovir and valganciclovir. Our structural insights show that human valacyclovirase has a unique binding mode and specificity for amino acid esters. Biochemical data demonstrate that the enzyme hydrolyzes esters of alpha-amino acids exclusively and displays a broad specificity spectrum for the aminoacyl moiety similar to tricorn-interacting aminopeptidase F1. Crystal structures of the enzyme, two mechanistic mutants, and a complex with a product analogue, when combined with biochemical analysis, reveal the key determinants for substrate recognition; that is, a flexible and mostly hydrophobic acyl pocket, a localized negative electrostatic potential, a large open leaving group-accommodating groove, and a pivotal acidic residue, Asp-123, after the nucleophile Ser-122. This is the first time that a residue immediately after the nucleophile has been found to have its side chain directed into the substrate binding pocket and play an essential role in substrate discrimination in serine hydrolases. These results as well as a phylogenetic analysis establish that the enzyme functions as a specific alpha-amino acid ester hydrolase. Valacyclovirase is a valuable target for amino acid ester prodrug-based oral drug delivery enhancement strategies.