Schiff Base Interactions Research Articles

Application of Zr-Cluster-Based MOFs for the Adsorptive Removal of Aliphatic Aldehydes (C1 to C5) from an Industrial Solvent.

Metal-organic frameworks (MOFs) are recognized as advanced sorbents for the effective removal and recovery of various hazardous pollutants in liquid and gaseous environments. In this research, the potential applicability of two Zr-based MOFs (UiO-66 (U6) and its amine counterpart UiO-66-NH2 (U6N)) was investigated relative to activated carbon (AC, tested as a reference adsorbent) for the purification of industrial organic solvents (e.g., methanol) from six different carbonyl impurities (CCs (C1 to C5): formaldehyde (FA, CH2O), acetaldehyde (AA, CH3CHO), propionaldehyde (PA, C3H6O), butyraldehyde (BA, C4H8O), isovaleraldehyde (IA, C5H10O), and valeraldehyde (VA, C5H10O)). In the sorptive removal of these CCs (both individually and in binary mixtures with FA), U6N showed higher efficacy in capturing all of the target CCs than U6 and AC. The adsorption selectivity of U6N toward single CC compounds was in the order of PA (165.1 mg g-1) > BA (158.9 mg g-1) > IA (154 mg g-1) > AA (136 mg g-1) > VA (131.5 mg g-1) > FA (120 mg g-1). In all binary mixtures, U6N selectively captured FA over the heavier CCs (C2-C5) by 1.5-3.3 times due to the steric hindrance of the C2-C5 aliphatic tails in the pore diffusion mechanism. The preferential adsorption of FA onto U6N can also be accounted for by the contribution of chemical bonding (Schiff base interaction) between the -NH2 groups in U6N and the C═O functionalities (aldehyde molecules) and physisorption, as confirmed by density functional theory (DFT) calculations. Theoretical DFT simulations also revealed that the competition between aldehyde molecules for Brønsted acidic sites (μ3-OH of Zr-clusters) created minor distortions in the U6/U6N frameworks.

5-Formylcytosine organizes nucleosomes and forms Schiff base interactions with histones in mouse embryonic stem cells.

Nucleosomes are the basic unit of chromatin that help the packaging of genetic material while controlling access to the genetic information. The underlying DNA sequence, together with transcription-associated proteins and chromatin remodelling complexes, are important factors that influence the organization of nucleosomes. Here, we show that the naturally occurring DNA modification, 5-formylcytosine (5fC) is linked to tissue-specific nucleosome organization. Our study reveals that 5fC is associated with increased nucleosome occupancy in vitro and in vivo. We demonstrate that 5fC-associated nucleosomes at enhancers in the mammalian hindbrain and heart are linked to elevated gene expression. Our study also reveals the formation of a reversible-covalent Schiff base linkage between lysines of histone proteins and 5fC within nucleosomes in a cellular environment. We define their specific genomic loci in mouse embryonic stem cells and look into the biological consequences of these DNA-histone Schiff base sites. Collectively, our findings show that 5fC is a determinant of nucleosome organization and plays a role in establishing distinct regulatory regions that control transcription.

Double network self-healing film based on metal chelation and Schiff-base interaction and its biological activities

Here, we report a series of novel anticancer self-healing double-network films. The first network is based on the dynamic interaction between the aldehyde groups on dialdehyde groups-modified poly (ethylene glycol) (DPEG) and amino groups on chitosan (CH), and the second one is the metal coordination-chelation interaction. The double-network films are synthesized and characterized. The spectroscopic data show the formation of double-network films and their properties. The film has the ability to heal the external mechanical cracks by itself. According to the results, the order of the self-healing property is as follows: (CH/DPEG) 15 film > (CH/DPEG) 15-Ca2+ film > (CH/DPEG) 15-Zn2+ film > (CH/DPEG) 15-Cu2+ film. The activity data show that metal chelation interaction causes different influence on antibacterial and anticancer activities of the double-network films. The order is (CH/DPEG) 15-Cu2+ film > (CH/DPEG) 15-Zn2+ film > (CH/DPEG) 15 film > (CH/DPEG) 15-Ca2+ film. This paper provides a novel view on the effects of metal chelation interaction on the film’s self-healing properties and its biological activities. Therefore, the prepared double-network films might be used in cancer treatment in clinical application as anticancer coatings.

Schiff base interaction tuned mesoporous organosilica nanoplatforms with pH-responsive degradability for efficient anti-cancer drug delivery in vivo.

Chemically incorporating Schiff base interactions into silicate frameworks endows the obtained mesoporous organosilica based drug carriers with ultrafast pH-responsive degradability and efficient anti-cancer drug release kinetics, resulting in enhanced cancer therapy.

Structural insights into ion conduction by channelrhodopsin 2.

The light-gated ion channel channelrhodopsin 2 (ChR2) from Chlamydomonas reinhardtii is a major optogenetic tool. Photon absorption starts a well-characterized photocycle, but the structural basis for the regulation of channel opening remains unclear. We present high-resolution structures of ChR2 and the C128T mutant, which has a markedly increased open-state lifetime. The structure reveals two cavities on the intracellular side and two cavities on the extracellular side. They are connected by extended hydrogen-bonding networks involving water molecules and side-chain residues. Central is the retinal Schiff base that controls and synchronizes three gates that separate the cavities. Separate from this network is the DC gate that comprises a water-mediated bond between C128 and D156 and interacts directly with the retinal Schiff base. Comparison with the C128T structure reveals a direct connection of the DC gate to the central gate and suggests how the gating mechanism is affected by subtle tuning of the Schiff base's interactions.

Dynamic Self-Assembly of Gold/Polymer Nanocomposites: pH-Encoded Switching between 1D Nanowires and 3D Nanosponges.

The design of tunable dynamic self-assembly of nanoparticles with switchable assembled dimensions and morphologies is a challenging goal whose realization is vital for the evolution of smart nanomaterials. Herein, we report on chitosan polymer as an effective supramolecular "glue" for aldehyde-modified Au nanoparticles to reversibly modulate the states of self-assembled nanocomposites. By simultaneous integration of dynamic covalent Schiff base interactions and noncovalent hydrogen bonds, the chitosan/Au nanocomposites could reversibly transform their assembled morphologies from one-dimensional nanowires to three-dimensional nanosponges in response to the variation of pH value. Moreover, the obtained nanosponges could be used as an efficient pH-controlled cargo release system.

Fabrication, self-assembly and biomedical applications of luminescent sodium hyaluronate with aggregation-induced emission feature

Organic dyes with aggregation-induced emission (AIE) feature have recently attracted much research attention for biomedical applications due to their inimitable optical superiority. Although many reports have demonstrated for fabricating AIE-active nanoprobes, the synthesis of AIE-active natural polymers is still very limited. In this work, fluorescent organic nanoparticles (FONs) with AIE feature have been prepared through formation of Schiff base interaction between amino-terminated AIE dye (PhE) and oxidation sodium hyaluronate (OSH). The final copolymers (denoted as PhE-OSH) were characterized by means of 1H nuclear magnetic resonance spectroscopy, transmission electron microscopy, fluorescent spectroscopy and X-ray photoelectron spectroscopy. The potential of using PhE-OSH in biomedical applications were examined by cell viability assay as well as confocal imaging capability. Results suggested that PhE can facilely conjugate with OSH through formation of Schiff base. The synthesized PhE-OSH FONs exhibited well dispersibility in aqueous solution, small size, strong fluorescence and good biocompatibility. Taken together, we developed a novel strategy for fabrication of AIE-active FONs, which showed great potential for biomedical applications.

Structure and Oxidation of Pyrrole Adducts Formed between Aflatoxin B2a and Biological Amines.

Aflatoxin B2a has been shown to bind to proteins through a dialdehyde intermediate under physiological conditions. The proposed structure of this adduct has been published showing a Schiff base interaction, but adequate verification using structural elucidation instrumental techniques has not been performed. In this work, we synthesized the aflatoxin B2a amino acid adduct under alkaline conditions, and the formation of a new product was determined using high performance liquid chromatography-time-of-flight mass spectrometry. The resulting accurate mass was used to generate a novel proposed chemical structure of the adduct in which the dialdehyde forms a pyrrole ring with primary amines rather than the previously proposed Schiff base interaction. The pyrrole structure was confirmed using 1H, 13C, correlation spectroscopy, heteronuclear single quantum correlation, and heteronuclear multiple bond correlation NMR and tandem mass spectrometry. Reaction kinetics show that the reaction is overall second order and that the rate increases as pH increases. Additionally, this study shows for the first time that aflatoxin B2a dialdehyde forms adducts with phosphatidylethanolamines and does so through pyrrole ring formation, which makes it the first aflatoxin-lipid adduct to be structurally identified. Furthermore, oxidation of the pyrrole adduct produced a product that was 16 m/z heavier. When the aflatoxin B2a-lysine (ε) adduct was oxidized, it gave a product with an accurate mass, mass fragmentation pattern, and 1H NMR spectrum that match aflatoxin B1-lysine, which suggest the transformation of the pyrrole ring to a pyrrolin-2-one ring. These data give new insight into the fate and chemical properties of biological adducts formed from aflatoxin B2a as well as possible interferences with known aflatoxin B1 exposure biomarkers.

One novel humidity-resistance formaldehyde molecular probe based hydrophobic diphenyl sulfone urea dry-gel: Synthesis, sensing performance and mechanism

The work designs a novel hydrophobic organic dry-gel named diamino diphenyl sulfone (DDS) urea for selectively detecting formaldehyde in air. It is synthesized by using octadecylisothiocyanate and diamino diphenyl sulfone as reactants in tetrahydrofuran solution at 70°C. The dry-gel is obtained by freezing drying. Sulfanilamide urea dry-gel acts as the contrastive material which is synthesized in a similar condition. The dry-gel coated Quartz Crystal Microbalance (QCM) sensor exhibits a rapid and reversible selective response towards formaldehyde gas. Repeated measurement results show high sensitivity and low detection limit (1ppm) for formaldehyde detection. The gas sensing and contact angle tests indicate its stability under different humidity conditions. Based on the adsorption isotherm experiments, it reveals that adsorption enthalpy change between DDS urea dry-gel and HCHO molecules locates the range of chemical adsorption, endowing the sensor satisfactory selectivity and reversibility. Sensing mechanism of formaldehyde sensor has been proved by a simulation calculation based on a quantum chemistry software Gaussian though comparing the interaction between amine group or carbamido and formaldehyde. The calculation results reveal that Schiff base interaction between the amine group and aldehyde group is more responsible for formaldehyde sensing instead of hydrogen bond interaction between carbamido and aldehyde group.

Substrate-independent, Schiff base interactions to fabricate lysine-functionalized surfaces with fibrinolytic activity.

Mimicking natural fibrinolytic mechanisms that covalently bind lysine-ligands (free ε-amino and carboxylic groups) onto biomaterial surfaces is an attractive strategy to prevent clot formation on blood contact materials. However, the modification process is typically complicated and limited due to the diversity of biomaterials. Herein, we describe a simple, substrate-independent protocol to prepare a lysine-ligand functionalized layer on biomaterial surfaces. This approach is based on the adsorption and cross-linking of aldehyde-functionalized poly(N-(2,2-dimethoxyethyl)methacrylamide) (APDMEA) and amino-functionalized polymethacryloyl-l-lysine (APMLys) on a variety of substrates, such as polyurethane (PU), polydimethylsiloxane (PDMS), polyvinylchloride (PVC), stainless steel (SS) and cellulose acetate (CA). The lysine-ligand functionalized layer on substrates highly enhanced the specific adsorption of plasminogen from plasma and showed good chemical stability and excellent biocompatibility with L929 cells using the MTT assay. Moreover, for example, after the adsorbed plasminogen was activated and converted into plasmin, the fibrinolytic functionalization of CA was demonstrated using a modified plasma recalcification assay. Collectively, considering the advantages of simplicity, environmental friendliness and substrate-independence, the present study might therefore represent a general approach for the construction of a biointerface with fibrinolytic activity.

Molecular assembly of Schiff Base interactions: construction and application.

Molecular assembly of Schiff Base interactions: construction and application.

Retinal chromophore structure and Schiff base interactions in red-shifted channelrhodopsin-1 from Chlamydomonas augustae.

Channelrhodopsins (ChRs), which form a distinct branch of the microbial rhodopsin family, control phototaxis in green algae. Because ChRs can be expressed and function in neuronal membranes as light-gated cation channels, they have rapidly become an important optogenetic tool in neurobiology. While channelrhodopsin-2 from the unicellular alga Chlamydomonas reinhardtii (CrChR2) is the most commonly used and extensively studied optogenetic ChR, little is known about the properties of the diverse group of other ChRs. In this study, near-infrared confocal resonance Raman spectroscopy along with hydrogen–deuterium exchange and site-directed mutagenesis were used to study the structure of red-shifted ChR1 from Chlamydomonas augustae (CaChR1). These measurements reveal that (i) CaChR1 has an all-trans-retinal structure similar to those of the light-driven proton pump bacteriorhodopsin (BR) and sensory rhodopsin II but different from that of the mixed retinal composition of CrChR2, (ii) lowering the pH from 7 to 2 or substituting neutral residues for Glu169 or Asp299 does not significantly shift the ethylenic stretch frequency more than 1–2 cm–1 in contrast to BR in which a downshift of 7–9 cm–1 occurs reflecting neutralization of the Asp85 counterion, and (iii) the CaChR1 protonated Schiff base (SB) has stronger hydrogen bonding than BR. A model is proposed to explain these results whereby at pH 7 the predominant counterion to the SB is Asp299 (the homologue to Asp212 in BR) while Glu169 (the homologue to Asp85 in BR) exists in a neutral state. We observe an unusual constancy of the resonance Raman spectra over the broad range from pH 9 to 2 and discuss its implications. These results are in accord with recent visible absorption and current measurements of CaChR1 [Sineshchekov, O. A., et al. (2013) Intramolecular proton transfer in channelrhodopsins. Biophys. J. 104, 807–817; Li, H., et al. (2014) Role of a helix B lysine residue in the photoactive site in channelrhodopsins. Biophys. J. 106, 1607–1617].

Facile fabrication and cell imaging applications of aggregation-induced emission dye-based fluorescent organic nanoparticles

Aggregation-induced emission (AIE) dye-based fluorescent organic nanoparticles (FONs) were prepared via Schiff base interactions between an AIE dye and a carbohydrate polymer (carboxymethyl chitosan). The obtained FONs with uniform size, high water dispersibility, strong fluorescence and high biocompatibility were explored for cell imaging applications.

Energy decomposition analysis of the metal-imine bond in [(CO) 4M–SB] (M = Cr, Mo, W; SB: RHC [dbnd]N–CH 2CH 2–N [dbnd]CHR)

The electronic and molecular structures of the metal-Schiff base complexes [(CO) 4M–SB] (M: Cr, Mo, W; SB: RHC N–CH 2CH 2–N CHR, R = C 6H 5, C 6F 5, Ortho-, Meta- and Para-XC 6H 4 (X = F, Cl, Br,CH 3)) have been investigated at the DFT level using the exchange correlation functional BP86. The nature of the TM−Schiff base interactions was analyzed with charge and energy decomposition methods. The octahedral equilibrium geometries have C 2v symmetry. The (CO) 4M–SB bond dissociation energies vary little for different substituents R. The calculated values indicate rather strong bonds which exhibit the trend for the different metals M = Mo ( D e = 59.8–65.4 kcal/mol) < Cr ( D e = 62.3–67.8 kcal/mol) < W ( D e = 69.9–75.8 kcal/mol). The energy decomposition analysis suggests that the (CO) 4M–SB attractive interactions come mainly from electrostatic attraction which provide ∼60% to ∆E int while ∼40% come from orbital interactions. The latter term arises mainly (∼70%) through (CO) 4M ← SB σ donation from the nitrogen lone-pair orbitals while a much smaller part (∼20%) comes from (CO) 4M→SB π backdonation. The transition metals carry large negative partial charges between −2.3 e for M = Cr and −1.1e for M = W.

Water Rearrangement around the Schiff Base in the Late K (KL) Intermediate of the Bacteriorhodopsin Photocycle

Previous FTIR studies at room temperature have distinguished KL (late K) from K (early K) as distinct photocycle intermediates of all-trans bacteriorhodopsin differentiated by the prominence of their hydrogen out-of-plane bending vibration (HOOP) bands at 985 and 957 cm-1, respectively. Earlier we showed that in the next photointermediate, L, the C15,N-HOOP appears as a set of several bands at around 1064 cm-1, which were shown to be due to the interaction of the Schiff base with water (Maeda et al. Biochemistry 2002, 41, 3803). The present study examines water rearrangement around the Schiff base in K and KL by analysis of the HOOP bands and the water vibration bands. (1) Studies of the thermal transformation of the primary photoproduct K formed at 80 K upon warming to 135 and 170 K confirm that a K-like photoproduct formed at 135 K is an intermediate between K and L. From its HOOP band at 985 cm-1, this photoproduct can be assigned to KL. (2) In KL, as in L, the C15,N-HOOP band is affected upon replacement of H2O by H218O water indicating the Schiff base's interaction with water. This feature was not observed for K. (3) The water molecule that is affected by the T46V mutation undergoes a perturbation in KL as in L, and to a smaller extent in K. However, in KL, the water does not exhibit the intense band seen in L. (4) A water molecule near Asp85 (most likely Water401), which is perturbed only slightly in K, is more strongly perturbed in KL and in L.

How allosteric effectors can bind to the same protein residue and produce opposite shifts in the allosteric equilibrium.

Monoaldehyde allosteric effectors of hemoglobin were designed, using molecular modeling software (GRID), to form a Schiff base adduct with the Val 1 alpha N-terminal nitrogens and interact via a salt bridge with Arg 141 alpha of the opposite subunit. The designed molecules were synthesized if not available. It was envisioned that the molecules, which are aldehyde acids, would produce a high-affinity hemoglobin with potential interest as antisickling agents similar to other aldehyde acids reported earlier. X-ray crystallographic analysis indicated that the aldehyde acids did bind as modeled de novo in symmetry-related pairs to the alpha subunit N-terminal nitrogens. However, oxygen equilibrium curves run on solutions obtained from T- (tense) state hemoglobin crystals of reacted effector molecules produced low-affinity hemoglobins. The shift in the allosteric equilibrium was opposite to that expected. We conclude that the observed shift in allosteric equilibrium was due to the acid group on the monoaldehyde aromatic ring that forms a salt bridge with the guanidinium ion of Arg 141 alpha on the opposite subunit. This added constraint to the T-state structure that ties two subunits across the molecular symmetry axis shifts the equilibrium further toward the T-state. We tested this idea by comparing aldehydes that form Schiff base interactions with the same Val 1 alpha residues but do not interact across the dimer subunit symmetry axis (a new one in this study with no acid group and others that have had determined crystal structures). The latter aldehydes shift the allosteric equilibrium toward the R-state. A hypothesis to predict the direction in shift of the allosteric equilibrium is made and indicates that it is not exclusively where the molecule binds but how it interacts with the protein to stabilize or destabilize the T- (tense) allosteric state.

Bisaldehyde allosteric effectors as molecular ratchets and probes.

Four new series of monoaldehyde bisacids and bisaldehyde bisacids with varying chain lengths have been synthesized and evaluated as allosteric effectors of hemoglobin. Molecular modeling, oxygen equilibrium, and crystallographic studies were combined for structure/function studies. Crystallographic analyses of the bisaldehydes reveal that Schiff base interaction occurred exclusively between Val 1 alpha and Lys 99 alpha of the opposite alpha chain even though the two terminal Val 1 alpha nitrogens are ideally spaced to also form cross-links. The reason for the observed mode of binding appears to be the influence of chain direction set by key substitutions on the bisaldehyde molecule. Even longer chain derivatives that could overcome the direction set by the key functional groups bind in the same manner. These studies support the general conclusion that long flexible molecules prefer to bind along cavity walls, like double-sided molecular sticky tape, rather than span large open spaces with few chances for interaction. The cross-linked bisaldehydes bind at the same site when incubated under both allosteric states and exhibit reduced cooperativity with a significant decrease in oxygen affinity. The chain length acts as a molecular ratchet and dictates the degree of allosteric effect observed. The tighter the cross-link, the greater the constraint on the tense- (T-) state and the stronger the allosteric effect that is produced. The monoaldehyde bisacids bind in the same fashion with Schiff base formation at Val 1 alpha while the acid that replaces the second aldehyde moiety forms a salt bridge with Lys 99 alpha of the opposite subunit. This class of molecules has weaker allosteric effector activity as would be expected with replacement of one covalent bond by a salt bridge. The importance of Lys 99 alpha on the allosteric equilibrium is confirmed.

Structure/function studies of QS-21 adjuvant: assessment of triterpene aldehyde and glucuronic acid roles in adjuvant function

QS-21, a purified Quillaja saponaria saponin immunologic adjuvant, contains two functional groups that we hypothesized to be involved in the adjuvant mechanism of action through charge or Schiff base interaction with a cellular target. Derivatives, prepared by modification of these sites, were prepared and tested for their ability to augment the immunogenicity of the antigen ovalbumin (OVA) in C57BL 6 mice. QS-21 derivatives that were modified at the carboxyl group on an anionic sugar, glucuronic acid, retained adjuvant activity for antibody stimulation, inducing relative increases in antibody titers similar to those induced by QS-21, although the minimum adjuvant dose required for this stimulation was increased several fold relative to the dose of unmodified QS-21. One of these derivatives also retained significant activity for induction of OVA-specific cytotoxic T-lymphocytes. In contrast, QS-21 derivatives modified at an aldehyde on the triterpene did not show adjuvant activity for antibody stimulation or for induction of cytotoxic T-lymphocytes, suggesting that this functional group may be involved in the adjuvant mechanism.

Resonance Raman evidence for secondary protein—Schiff base interactions in bacteriorhodopsin: correlation of the primary excitation mechanism with a model for proton pumping and visual transduction

Resonance Raman spectra of bacteriorhodopsin (in various isotopically labelled and natural environments) and rhodopsins demonstrate that in all bacteriorhodopsin species with protonated Schiff base linkages, there is a secondary protein-Schiff base interaction. Steady state resonance Raman spectra of 15 N labelled purple membrane fragments and kinetic resonance Raman spectra (k.r.R.s.) as a function of pH, are consistent with the suggestion that the e-amino group of a lysine residue is responsible for this secondary protein-protonated Schiff base interaction. Spectra of bacteriorhodopsin photo-intermediates with unprotonated Schiff base linkages demonstrate that the secondary protein-Schiff base interaction is absent in these species. These results, together with the accessibility of the protonated Schiff base in bacteriorhodopsin (bR 570 ) to solvent from the external medium and the insensitivity to pH of the secondary lysine-Schiff base complex in bR 570 , suggest a structure for the complex in which the Schiff base proton is interacting with an amino acid side chain in an unprotonated configuration. In addition k.r.R.s. as a function of pH has demonstrated that the protein-Schiff base complex has a p K &gt; 12 before light absorption and a p K in the range between 9.9 and 10.3 microseconds after light absorpion. These results suggest a molecular mechanism for proton pumping, which appears to account for the changes that are observed in the visible absorption spectrum and the resonance Raman spectrum as a function of proton pumping and pH. Finally, our results on bacteriorhodopsin and rhodopsin indicate that the primary excitation mechanism in these pigments, which produce remarkably similar absorption red shifts on similar time scales with different chromophore conformations and Schiff base interactions, must involve some region in the active site removed from the Schiff base and unrelated to a simple 11- cis to all- trans isomerization. A proton translocation in the protein together with retinal structural alteration (Lewis 1978) certainly fits all our observations and results in plausible molecular transformations which can account for the spectral similarities of all rhodopsins and bacteriorhodopsin while accounting for their functional diversity.

Stabilization of the avian progesterone receptor by inhibitors

The avian progesterone receptor is known to be very temperature-labile; its hormone binding activity is lost within minutes at 37°C. However, when the receptor is first treated with pyridoxal 5'-phosphate, in the presence of sodium borohydride, the receptor is stabilized dramatically and can be incubated for up to 2 h at 37°C without loss of activity. Pyridoxal 5'-phosphate is known to block the binding of receptor to ATP-Sepharose, apparently by a Schiff base interaction with the receptor. Other such inhibitors were also tested for any stabilizing effect. Two of these, o-phenanthroline and aurintricarboxylic acid, decreased the stability of the receptor, while a very significant stabilization was observed after treatment with sodium molybdate. In addition to this effect, sodium molybdate appears to block activation or transformation of the progesterone receptor to the form which is able to bind to ATP-Sepharose. Once the receptor is in this activated form, sodium molybdate is no longer inhibitory whereas pyridoxal 5'-phosphate is still a potent inhibitor of ATP-Sepharose binding. These results indicate that the two stabilizing agents act through different mechanisms.