Zwitterionic Amino Acids Research Articles

Interaction and Mechanism between Imidazolium Ionic Liquids and the Zwitterionic Amino Acid Tyr: a DFT Study

Interaction and Mechanism between Imidazolium Ionic Liquids and the Zwitterionic Amino Acid Tyr: a DFT Study

Translating a Low‐Molecular‐Weight MRI Probe Sensitive to Amino Acid Neurotransmitters into a PAMAM Dendrimer Conjugate: The Impact of Conjugation

AbstractA novel nano‐sized MRI probe sensitive to zwitterionic amino acid neurotransmitters (ZNTs) was prepared by the conjugation of bismacrocyclic ZNT‐responsive units to a generation 4 (G4) polyamidoamine (PAMAM) dendrimer. In vitro evaluation through 1H NMR relaxometric titrations provided binding profiles revealing a surface morphology‐dependent interaction with the ZNTs. The positively charged dendrimeric periphery gave higher initial relaxivities and a milder decrease upon interaction with the target molecules. To improve solubility under physiologically relevant conditions, polyethylene glycol (PEG) units were additionally conjugated to the dendrimeric surface. The PEGylated conjugate displayed discrimination towards acetylcholine and a slightly increased binding affinity towards glutamate over the massively abundant competitive metabolite hydrogencarbonate.

Solubility Enhancement of Simvastatin through Surfactant Addition for Development of Hydrophobic Drug-Loaded Gelatin Hydrogel

This study aims to synthesize simvastatin hydrogel as drug delivery system with surfactant addition for improving solubility of simvastatin. Surfactants used in the study were the zwitterionic amino acid of arginine and nonionic surface-active agent of polysorbate 80. The solubility study was conducted by pouring of an excess mass of simvastatin into the solution of a surfactant in a conical flask. The sample was shaken up to 72 h in a mechanical water bath shaker at a varied temperature of 25, 40, and 50 °C. The amount of drug dissolved in solution was analyzed by UV/Visible spectrophotometer at 238 nm. The results showed that the simvastatin solubility is profoundly influenced by the surfactant type, surfactant concentration, and temperature. Polysorbate 80 exhibited as a better surfactant than arginine and an enhancement up to 1400 times, in respect of without any addition of a surfactant, was observed. Based on the solubility study, simvastatin-loaded gelatin hydrogel composite was formulated and the characterization (FTIR and SEM) showed the successful impregnation. The hydrogel microparticles of featured swelling indexes in the range of 2–6 for every patch and presented a sustained release profile.

Hybrid Materials Based on MF-4SC Membranes and Carbon Nanotubes: Transport Properties and Characteristics of DP-sensors in Hydrophobic Amino Acid Solutions

Perfluorinated sulfonated cation-exchange membranes MF-4SC containing 0.5–3.0% of carbon nanotubes (CNTs) have been synthesized. A correlation between the water uptake and transport properties of the membranes in the K+-form and the sensitivity of DP-sensors (with the analytical signal in the form of a Donnan potential) to the analyte and interfering ions in solutions of hydrophobic amino acids (alanine, valine, and phenylalanine) has been found. Hybrid membrane samples that provide the highest sensitivity of DP-sensors to amino acid cations and zwitterions and the lowest sensitivity to hydroxonium ions at pH < 7 in a concentration range of 1.0 × 10–4–1.0 × 10–1 M have been selected. Membrane modification has led to a decrease in the relative error and the relative standard deviation in the determination of amino acid ions by a factor of 3 and 1.5, respectively.

Enhancing the Permeability and Antifouling Properties of Polyamide Composite Reverse Osmosis Membrane by Surface Modification with Zwitterionic Amino Acid l‐Arginine

AbstractThe increase of the permeability and antifouling properties of reverse osmosis (RO) membranes is always significant in desalination. In this study, zwitterionic amino acid l‐Arginine (Arg) is grafted onto the self‐made RO membrane by one‐step method to construct the zwitterionic surface for enhancing the performances of the membranes. X‐ray photoelectron spectroscopy verifies the successful covalent attachment of Arg onto the membrane surface. Atomic force microscopy, contact angle, and zeta potential measurements manifest that the modified membrane surface becomes smoother, more hydrophilic, and less negatively charged. The contact angles decrease from 72.6° to 43.7° after Arg‐modification. For the optimized modified membrane, its water flux increases from original 45.46 to 63.51 L m−2 h−1 (improved by 39.7%); while the salt rejection ascends from 96.42% to 98.08%. Using bovine serum albumin and dodecyltrimethyl ammonium bromide as model foulants, fouling‐resistant properties of the modified membranes are estimated by three‐time cycle filtration tests. The experimental results show that the modified membranes have superior fouling‐resistant and easy‐cleaning properties. Mechanism concerning the roles of grafting Arg in the enhancement of the performances of the resulting membranes is proposed.

Electrostatic attraction-repulsion model with Cinchona alkaloid-based zwitterionic chiral stationary phases exemplified for zwitterionic analytes

In the present paper, we demonstrated that Cinchona alkaloid cyclohexyl sulfonic acid-based zwitterionic chiral selectors (SOs) and the respective chiral stationary phases (CSPs) can be successfully employed for the enantioseparation of underivatized thus zwitterionic amino acids (the selectands, SAs) even in the absence of ionic additives in the eluent, generally used as displacer counter-ions in ion exchange chromatography. Therefore, we provided evidence that cooperative “intramolecular and intermolecular counter-ion effects” of the zwitterionic SO moiety and the zwitterionic SAs can be sufficient to modulate alone the retention characteristics without a loss of stereoselectivity. Four fully constrained β-amino acids were used as target compounds for this study.The analyses were carried out with either neat methanol, acetonitrile, water or their binary hydro-organic mixtures. A U-shaped retention profile was observed both with methanol- and acetonitrile-based eluents.Except a few cases, enantioselectivity experienced a remarkable amelioration at the “balanced region” of a buffer free hydroorganic mobile phase composition. At “the bottom” of the U-shaped curve, high α- and resolution values could be reached with most of the screened mobile phases. An electrostatically driven “attraction-repulsion model” was postulated to explain the very favourable characteristic of the two studied zwitterion-type CSPs for the retention and enantiomer separation of zwitterionic analytes.

Regeneration of ergothioneine after reaction with singlet oxygen

Ergothioneine (ET), an imidazole-2-thione derivative of histidine betaine, is generally considered an antioxidant. Important antioxidants are typically regenerated from their oxidized products, to prevent the interceptors from being lost after a single chemical reaction with a reactive oxygen species. However, no mechanism for the complete regeneration of ET has yet been uncovered. Here we define a non-enzymatic multi-step cycle for the regeneration of ET after reaction with singlet oxygen (1O2). All reaction steps were verified by density functional theory computations. Four molecules of GSH are used per turn to detoxify 1O2 to water. Pure 1O2 was generated by thermolysis at 37 °C of the endoperoxide DHPNO2. Addition of 1 mM ET to 10 mM DHPNO2 and 10 mM GSH increased the production of oxidized GSH (GSSG), measured by LC-MS/MS, by a factor of 26 (water) and 28 (D2O), respectively. In the same assay, the ring of ET alone was able to drive the cycle at equal speed; thus, the zwitterionic amino acid backbone was not involved. Our data suggest that ET reacts at least 4-fold faster with 1O2 than ascorbic acid. ET must now be viewed as tightly linked with the GSH/GSSG redox couple. The necessary thiol foundation is present in all mammalian and vertebrate cells, and also in all species that generate ET, such as cyanobacteria, mycobacteria, and fungi. Regeneration provides a decisive advantage for ET over other reactive, but non-recoverable, compounds. Our findings substantiate the importance of ET for the eradication of noxious 1O2.

Palladium‐Catalyzed Asymmetric Decarboxylative Allylation of Azlactone Enol Carbonates: Fast Access to Enantioenriched α‐Allyl Quaternary Amino Acids

We report a fast protocol for the synthesis of enantioenriched quaternary 4‐allyl oxazol‐5‐ones. The key step is a Pd‐catalyzed enantioselective Tsuji allylation of azlactone allyl enol carbonates, which can be easily prepared starting from racemic α‐amino acids. The use of (R,R)‐DACH‐phenyl Trost chiral ligand allowed the attainment of the allylated derivatives in very good yields (83–98 %) and with ee up to 85 %. Scaling up the allylation protocol to gram quantities did not affect the yields end ee values. The produced 4‐allyl azlactones can be converted into the corresponding quaternary amino acids or submitted to further synthetic elaborations exploiting the allyl moiety as a handle for the attachment of alkyl and aryl groups. After hydrolysis of the azlactone ring, the zwitterionic amino acids can be attained in enantiopure or nearly optically pure form through only one recrystallization step.

A low-molecular-weight ditopic MRI probe for ratiometric sensing of zwitterionic amino acid neurotransmitters.

We report a novel ditopic Gd(iii)-based probe selective to zwitterionic amino acid neurotransmitters (ZNTs) crafted for ratiometric MRI imaging. The probe displayed increased binding affinity to ZNTs and non-synchronized concentration-dependent changes of the r1- and r2-relaxivity. Through the application of a T2/T1 weighted MRI strategy, we demonstrated signal enhancement for cooperatively bound glutamate and γ-aminobutyric acid ZNTs over competitive hydrogencarbonate, which remained MR silent.

Ultrasensitive SERS Substrate for Label-Free Therapeutic-Drug Monitoring of Paclitaxel and Cyclophosphamide in Blood Serum.

Surface-enhanced Raman spectroscopy (SERS) has recently emerged as an innovative tool for therapeutic-drug monitoring (TDM), making it an ideal candidate for personalized treatment. Herein, we report a layer-by-layer (LbL) approach for the fabrication of a highly reproducible hybrid SERS substrate based on graphene oxide (GO)-supported l-cysteine-functionalized starlike gold nanoparticles (SAuNPs). These designed substrates were utilized for TDM of paclitaxel and cyclophosphamide in blood serum. The SAuNPs' efficient binding at the edges of GO creates a better SERS hotspot with enhanced Raman sensitivity because of the spacing of ∼2.28 nm between the SAuNPs. In addition, the hierarchically modified substrate with a self-assembled monolayer of zwitterionic amino acid l-cysteines acts like a brush layer to prevent SERS-hotspot blockages and fouling by blood-serum proteins. The antifouling nature of the substrate was determined quantitatively by a bichinchonic acid assay using bovine-serum albumin (BSA) as a protein model on the l-cysteine SAuNPs@GO hybrid substrate (the test) and a cysteamine SAuNPs@GO substrate (the control). The l-cysteine SAuNPs@GO hybrid exhibited 80.57% lower BSA fouling compared with that of the cysteamine SAuNPs@GO substrate. The SERS spectra were acquired within 20 s, with detection limits of 1.5 × 10-8 M for paclitaxel and 5 × 10-9 M for cyclophosphamide in blood serum. Such sensitivities are 4 times and 1 order of magnitude higher than the currently available sophisticated analytical techniques, which involve high costs with each analysis.

Reduction of OH vibrational frequencies in amino acids by positron attachment.

Positron affinities have been calculated for five amino acid molecules (asparagine, cysteine, glycine, proline, and serine) with the intramolecular COOH···NH2  hydrogen-bonded motif as a function of the OH distance using two computational methods, namely multicomponent molecular orbital theory and pseudopotential model. Since the elongation of the carboxylic OH bond leads to the formation of highly polarized zwitterionic amino acid with COO- ···NH3+  structure, the calculated positron affinity significantly increases with the elongation of the OH distance. This indicates that the OH bond strength is significantly weakened by positron attachment. We discuss the reduction of OH vibrational frequencies using effective one-dimensional potential energy curves for neutral and positron-attached amino acid molecules. © 2018 Wiley Periodicals, Inc.

Polar Imperfections in Amino Acid Crystals: Design, Structure, and Emerging Functionalities.

Crystals are physical arrays delineated by polar surfaces and often contain imperfections of a polar nature. Understanding the structure of such defects on the molecular level is of topical importance since they strongly affect the macroscopic properties of materials. Moreover, polar imperfections in crystals can be created intentionally and specifically designed by doping nonpolar crystals with "tailor-made" additives as dopants, since their incorporation generally takes place in a polar mode. Insertion of dopants also induces a polar deformation of neighboring host molecules, resulting in the creation of polar domains within the crystals. The contribution of the distorted host molecules to the polarity of such domains should be substantial, particularly in crystals composed of molecules with large dipole moments, such as the zwitterionic amino acids, which possess dipole moments as high as ∼14 D. Polar materials are pyroelectric, i.e., they generate surface charge as a result of temperature change. With the application of recent very sensitive instruments for measuring electric currents, coupled with theoretical computations, it has become possible to determine the structure of polar imperfections, including surfaces, at a molecular level. The detection of pyroelectricity requires attachment of electrodes, which might induce various artifacts and modify the surface of the crystal. Therefore, a new method for contactless pyroelectric measurement using X-ray photoelectron spectroscopy was developed and compared to the traditional periodic temperature change technique. Here we describe the molecular-level determination of the structure of imperfections of different natures in molecular crystals and how they affect the macroscopic properties of the crystals, with the following specific examples: (i) Experimental support for the nonclassical crystal growth mechanism as provided by the detection of pyroelectricity from near-surface solvated polar layers present at different faces of nonpolar amino acid crystals. (ii) Enantiomeric disorder in dl-alanine crystals disclosed by detection of anomalously strong pyroelectricity along their nonpolar directions. The presence of such disorder, which is not revealed by accurate diffraction techniques, explains the riddle of their needlelike morphology. (iii) The design of mixed polar crystals of l-asparagine·H2O/l-aspartic acid with controlled degrees of polarity, as determined by pyroelectricity and X-ray diffraction, and their use in mechanistic studies of electrofreezing of supercooled water. (iv) Pyroelectricity coupled with dispersion-corrected density functional theory calculations and molecular dynamics simulations as an analytical method for the molecular-level determination of the structure of polar domains created by doping of α-glycine crystals with different l-amino acids at concentrations below 0.5%. (v) Selective insertion of minute amounts of alcohols within the bulk of α-glycine crystals, elucidating their role as inducers of the metastable β-glycine polymorph. In conclusion, the various examples demonstrate that although these imperfections are present in minute amounts, they can be detected by the sensitive pyroelectric measurement, and by combining them with theoretical computations one can elucidate their diverse emerging functionalities.

Quantum mechanical effects in zwitterionic amino acids: The case of proline, hydroxyproline, and alanine in water.

In this work, we use ab initio molecular dynamics simulations to elucidate the electronic properties of three hydrated zwitterionic amino acids, namely proline, hydroxyproline, and alanine, the former two forming an important constituent of collagen. In all three systems, we find a substantial amount of charge transfer between the amino acids and surrounding solvent, which, rather surprisingly, also involves the reorganization of electron density near the hydrophobic non-polar groups. Water around proline appears to be slightly more polarized, as reflected by the enhanced water dipole moment in its hydration shell. This observation is also complemented by an examination of the IR spectra of the three systems where there is a subtle red and blue shift in the O-H stretch and bend regions, respectively, for proline. We show that polarizability of these amino acids as revealed by a dipole moment analysis involves a significant enhancement from the solvent and that this also involves non-polar groups. Our results suggest that quantum mechanical effects are likely to be important in understanding the coupling between biomolecules and water in general and in hydrophobic interactions.

The effect of amino acid backbone length on molecular packing: crystalline tartrates of glycine, β-alanine, γ-aminobutyric acid (GABA) and DL-α-aminobutyric acid (AABA).

We report a novel 1:1 cocrystal of β-alanine with DL-tartaric acid, C3H7NO2·C4H6O6, (II), and three new molecular salts of DL-tartaric acid with β-alanine {3-azaniumylpropanoic acid-3-azaniumylpropanoate DL-tartaric acid-DL-tartrate, [H(C3H7NO2)2]+·[H(C4H5O6)2]-, (III)}, γ-aminobutyric acid [3-carboxypropanaminium DL-tartrate, C4H10NO2+·C4H5O6-, (IV)] and DL-α-aminobutyric acid {DL-2-azaniumylbutanoic acid-DL-2-azaniumylbutanoate DL-tartaric acid-DL-tartrate, [H(C4H9NO2)2]+·[H(C4H5O6)2]-, (V)}. The crystal structures of binary crystals of DL-tartaric acid with glycine, (I), β-alanine, (II) and (III), GABA, (IV), and DL-AABA, (V), have similar molecular packing and crystallographic motifs. The shortest amino acid (i.e. glycine) forms a cocrystal, (I), with DL-tartaric acid, whereas the larger amino acids form molecular salts, viz. (IV) and (V). β-Alanine is the only amino acid capable of forming both a cocrystal [i.e. (II)] and a molecular salt [i.e. (III)] with DL-tartaric acid. The cocrystals of glycine and β-alanine with DL-tartaric acid, i.e. (I) and (II), respectively, contain chains of amino acid zwitterions, similar to the structure of pure glycine. In the structures of the molecular salts of amino acids, the amino acid cations form isolated dimers [of β-alanine in (III), GABA in (IV) and DL-AABA in (V)], which are linked by strong O-H...O hydrogen bonds. Moreover, the three crystal structures comprise different types of dimeric cations, i.e. (A...A)+ in (III) and (V), and A+...A+ in (IV). Molecular salts (IV) and (V) are the first examples of molecular salts of GABA and DL-AABA that contain dimers of amino acid cations. The geometry of each investigated amino acid (except DL-AABA) correlates with the melting point of its mixed crystal.

Recyclable colorimetric sensor of Cr3 + and Pb2 + ions simultaneously using a zwitterionic amino acid modified gold nanoparticles

In this work, a rapid, simple and sensitive colorimetric sensor for simultaneous (or respective) detection of Cr3+ and Pb2+ using tyrosine functionalized gold nanoparticles (AuNPsTyr) has been developed. Tyrosine, a natural and zwitterionic amino acid, could be as a reducing and capping agent to synthesise AuNPs and allow for the simultaneous and selective detection of Cr3+ and Pb2+. Upon the addition of Cr3+ or Pb2+ (a combination of them), the color of AuNPsTyr solution changes from red to blue grey and the characteristic surface plasmon resonance (SPR) band is red-shifted to 580nm due to the aggregation of AuNPs. Interestingly, the aggregated AuNPsTyr can be regnerated and recycled by removing Pb2+ and Cr3+. Even after 3 rounds, AuNPsTyr show almost the same A580nm/A520nm value for the assays of Pb2+ and Cr3+, indicating the good recyclability of the colorimetric sensor. The responding time (within 1min) and sensitivity of the colorimetric sensor are largely improved after the addition of 0.1M NaCl. Moreover, the AuNPsTyr aggregated by Cr3+ or Pb2+ (a combination of them) show excellent selectivity compared to other metal ions (Cr3+, Pb2+, Fe2+,Cu2+,Zn2+,Cr6+,Ni2+,Co2+,Hg2+,Mn2+,Mg2+,Ca2+,Cd2+). More importantly, the developed sensor manifests good stability at room temperature for 3months, which has been successfully used to determine Cr3+ and Pb2+ in the real water samples with a high sensitivity.

Potentiometric Cross-Sensitive Sensors Based on Perfluorinated Membranes Treated at Different Relative Humidity for Codetermination of Cations and Anions in Alkaline Solutions of Amino Acids

The results of studying characteristics of potentiometric DP-sensors (sensors with the Donnan potential as their analytical signal) are presented for alkaline solutions of a sulfur-containing amino acid with perfluorosulfonic cation exchange membranes subjected to thermal treatment and mechanical deformation at different relative humidity. Correlation between the distribution of sensitivity of DP-sensors towards cations and anions and diffusion permeability of membranes was found. A multisensor system including two DP-sensors based on membranes with optimized properties and a glass electrode for codetermination of potassium cations and amino acid anions and zwitterions in solutions at pH >7 are developed.

Amino-Acid-Conjugated Gold Clusters: Interaction of Alanine and Tryptophan with Au8 and Au20

The stability and electronic properties of gold (Au) clusters interacting with the amino acids alanine (Ala) and tryptophan (Trp) in their canonical and zwitterionic configurations were investigated using first-principles density functional theory (DFT). We found that the geometrical structures of the Au clusters and the polarities of the amino acids determine the nature of the interactions in the gas and solvent phases. In the gas phase, the Au8 (D4h) and Au20 (Td) clusters prefer single-site interactions through the amine group for the canonical amino acids, whereas in the solvent phase, the carboxylic site is preferred for the zwitterionic amino acids. The limited screening of the intermolecular interactions introduced by the solvent medium for the canonical forms of Ala and Trp conjugated with the Aun complexes suggests that the bonding is primarily covalent in nature. The screening is significantly more pronounced for the zwitterionic complexes for which the electrostatic interactions dominate. The c...

Evaluating electronic structure methods for accurate calculation of 19 F chemical shifts in fluorinated amino acids.

The ability of electronic structure methods (11 density functionals, HF, and MP2 calculations; two basis sets and two solvation models) to accurately calculate the 19 F chemical shifts of 31 structures of fluorinated amino acids and analogues with known experimental 19 F NMR spectra has been evaluated. For this task, BHandHLYP, ωB97X, and Hartree-Fock with scaling factors (provided within) are most accurate. Additionally, the accuracy of methods to calculate relative changes in fluorine shielding across 23 sets of structural variants, such as zwitterionic amino acids versus side chains only, was also determined. This latter criterion may be a better indicator of reliable methods for the ultimate goal of assigning and interpreting chemical shifts of fluorinated amino acids in proteins. It was found that MP2 and M062X calculations most accurately assess changes in shielding among analogues. These results serve as a guide for computational developments to calculate 19 F chemical shifts in biomolecular environments. © 2017 Wiley Periodicals, Inc.

Recent advance of pH-sensitive nanocarriers targeting solid tumors

pH sensitive nanocarriers have showed the tumor targeted drug delivery and release by enhanced permeability and retention effect and responsiveness of acidic pH conditions of the solid tumors. The protonation and deprotonation of the nanocarriers including pH sensitive polyelectrolytes has been considered as a major mechanism, resulting in substantial conformational change in response to marginal change in the tumor pH conditions. Considering the biocompatible properties for pharmaceutical applications, poly(amino acid) showed low polymer toxicity and the formation of versatile systems for advanced antitumor therapeutic effects. In here, recent researches using cationic (histidine, lysine, and arginine), anionic (aspartic acid and glutamic acid), and zwitterionic amino acid were summarized. Furthermore, pH sensitive nanogels with unique functionality and other pH sensitive polymers were briefly described. pH sensitive nanogels showed reversible drug release by pH cyclization minimizing drug loss and enhancing drug release. In the future, non-spherical pH sensitive nanocarriers would be anticipated to improve the therapeutic effect by long circulation and stealth effect by low phagocytosis.

Hybrid materials based on MF-4SK membranes and hydrated silica and zirconia with sulfonic acid-functionalized surface: transport properties and characteristics of DP-sensors in amino acid solutions with varying pH

Hybrid ion-exchange membranes of MF-4SK brand containing hydrated silica and zirconia nanoparticles with sulfonic acid-functionalized surface have been synthesized. The effect of modification on the properties of materials in the proton and potassium forms and the characteristics of potentiometric sensors based on these materials have been studied. It has been found that membrane modification leads to an increase in the ionic conductivity compared with that of the unmodified MF-4SK sample and, in some cases, to a decrease in diffusion permeability. Variations in the cation transport selectivity provided by the modification of MF-4SK membrane have made it possible to decrease the sensitivity of sensors to interfering hydronium cations in an acid medium and increase the sensitivity to amino acid anions and zwitterions in an alkaline medium. Optimum membrane compositions for the determination of histidine cations at pH 7 have been selected.