Ion Binding Properties Research Articles

The role of the STAS domain in SLC26A9 for chloride ion transporter function

The anion exchanger solute carrier family 26 (SLC26)A9, consisting of the transmembrane (TM) domain and the cytoplasmic STAS domain, plays an essential role in regulating chloride transport across cell membranes. Recent studies have indicated that C-terminal helices block the entrance of the putative ion transport pathway. However, the precise functions of the STAS domain and C-terminal helix, as well as the underlying molecular mechanisms governing the transport process, remain poorly understood. In this study, we performed molecular dynamics simulations of three distinct models of human SLC26A9, full-length, STAS domain removal (ΔSTAS), and C-terminus removal (ΔC), to investigate their conformational dynamics and ion-binding properties. Stable binding of ions to the binding sites was exclusively observed in the ΔC model in these simulations. Comparing the full-length and ΔC simulations, the ΔC model displayed enhanced motion of the STAS domain. Furthermore, comparing the ΔSTAS and ΔC simulations, the ΔSTAS simulation failed to exhibit stable ion bindings to the sites despite the absence of the C-terminus blocking the ion transmission pathway in both systems. These results suggest that the removal of the C-terminus not only unblocks the access of ions to the permeation pathway but also triggers STAS domain motion, gating the TM domain to promote ions’ entry into their binding site. Further analysis revealed that the asymmetric motion of the STAS domain leads to the expansion of the ion permeation pathway within the TM domain, resulting in the stiffening of the flexible TM12 helix near the ion-binding site. This structural change in the TM12 helix stabilizes chloride ion binding, which is essential for SLC26A9’s alternate-access mechanism. Overall, our study provides new insights into the molecular mechanisms of SLC26A9 transport and may pave the way for the development of novel treatments for diseases associated with dysregulated ion transport.

Probing Ion-Receptor Interactions in Halide Complexes of Octamethyl Calix[4]Pyrrole.

Ion receptors are molecular hosts that bind ionic guests, often with great selectivity. The interplay of solvation and ion binding in anion host-guest complexes in solution governs the binding efficiency and selectivity of such ion receptors. To gain molecular-level insight into the intrinsic binding properties of octamethyl calix[4]pyrrole (omC4P) host molecules with halide guest ions, we performed cryogenic ion vibrational spectroscopy (CIVS) of omC4P in complexes with fluoride, chloride, and bromide ions. We interpret the spectra using density functional theory, describing the infrared spectra of these complexes with both harmonic and anharmonic second-order vibrational perturbation theory (VPT2) calculations. The NH stretching modes of the pyrrole moieties serve as sensitive probes of the ion binding properties, as their frequencies encode the ion-receptor interactions. While scaled harmonic spectra reproduce the experimental NH stretching modes of the chloride and bromide complexes in broad strokes, the high proton affinity of fluoride introduces strong anharmonic effects. As a result, the spectrum of F-·omC4P is not even qualitatively captured by harmonic calculations, but it is recovered very well by VPT2 calculations. In addition, the VPT2 calculations recover the intricate coupling of the NH stretching modes with overtones and combination bands of CH stretching and NH bending modes and with low-frequency vibrations of the omC4P macrocycle, which are apparent for all of the halide ion complexes investigated here. A comparison of the CIVS spectra with infrared spectra of solutions of the same ion-receptor complexes in d3-acetonitrile and d6-acetone shows how ion solvation changes the ion-receptor interactions for the different halide ions.

Modulation in Charge Transfer Characteristics of Flexible Bis-Benzimidazole Probes: Independent Sensing Mechanisms for Hg²⁺ and F⁻

Flexible bis-benzimidazole-based V-shaped amphiphilic probes (1, 2) have been designed that form a fluorescent nanoscopic assembly in the aqueous medium. The ion-binding properties of compound 1 are investigated in both...

Differences in Conformational Sampling and Intrinsic Electric Fields Drive Ion Binding in Telomeric and TERRA G-Quadruplexes.

The formation of G-quadruplexes (GQs) occurs in guanine-rich sequences of DNA and RNA, producing highly stable and structurally diverse noncanonical nucleic acid structures. GQs play crucial roles in regulating transcription, translation, and replication and maintaining the genome, among others; thus, changes to their structures can lead to diseases such as cancer. Previous studies using polarizable molecular dynamics simulations have shown differences in ion binding properties between telomeric and telomeric repeat-containing RNA GQs despite architectural similarities. Here, we used volume-based metadynamics and repulsive potential simulations in conjunction with polarizable force fields to quantify the impact of ion binding on the GQ dynamics and ion binding free energies. Furthermore, we describe how GQs exert electric fields on their surroundings to link dynamics with variations in the electronic structure. Our findings provide new insights into the energetic, physical, and conformational properties of GQs and expose subtle but important differences between DNA and RNA GQs with the same fold.

Unraveling the Impact of Acetylation Patterns in Chitosan Oligomers on Cu2+ Ion Binding: Insights from DFT Calculations.

Chitosans are partially acetylated polymers of glucosamine, structurally characterized by their degree of polymerization as well as their fraction and pattern of acetylation. These parameters strongly influence the physico-chemical properties and biological activities of chitosans, but structure-function relationships are only poorly understood. As an example, we here investigated the influence of acetylation on chitosan-copper complexation using density functional theory. We investigated the electronic structures of completely deacetylated and partially acetylated chitosan oligomers and their copper-bound complexes. Frontier molecular orbital theory revealed bonding orbitals for electrophiles and antibonding orbitals for nucleophiles in fully deacetylated glucosamine oligomers, while partially acetylated oligomers displayed bonding orbitals for both electrophiles and nucleophiles. Our calculations showed that the presence of an acetylated subunit in a chitosan oligomer affects the structural and the electronic properties of the oligomer by generating new intramolecular interactions with the free amino group of neighboring deacetylated subunits, thereby influencing its polarity. Furthermore, the band gap energy calculated from the fully and partially deacetylated oligomers indicates that the mobility of electrons in partially acetylated chitosan oligomers is higher than in fully deacetylated oligomers. In addition, fully deacetylated oligomers form more stable complexes with higher bond dissociation energies with copper than partially acetylated ones. Interestingly, in partially acetylated oligomers, the strength of copper binding was found to be dependent on the pattern of acetylation. Our study provides first insight into the influence of patterns of acetylation on the electronic and ion binding properties of chitosans. Depending on the intended application, the obtained results can serve as a guide for the selection of the optimal chitosan for a specific purpose.

Molecular complexation properties of Cd2+ by algal organic matter from Scenedesmus obliquus

A detailed understanding the metals binding with algal organic matter (AOM) is essential to gain a deeper insight into the toxicity and migration of metals in algae cell. However, the molecular complexation mechanism of the metals binding with AOM remains unclear. In this study, cadmium ion (Cd2+) binding properties of AOMs from Scenedesmus obliquus, which included extracellular organic matter (EOM) and intracellular organic matter (IOM), were screened. When Cd2+ < 0.5 mg/L, the accumulation of Cd2+ could reach 40%, while Cd2+ > 0.5 mg/L, the accumulation of Cd2+ was only about 10%. EOM decreased gradually (from 8.51 to 3.98 mg/L), while IOM increased gradually (from 9.62 to 21.00 mg/L). The spectral characteristics revealed that IOM was richer in peptides/proteins and had more hydrophilic than EOM. Both EOM and IOM contained three protein-like components (containing tryptophan and tyrosine) and one humic-like component, and their contents in IOM were higher than that in EOM. The tryptophan protein-like substances changed greatly during Cd2+ binding, and that the tryptophan protein-like substances complexed to Cd2+ before tyrosine protein-like substances in IOM was identified. Moreover, the functional groups of N-H, O-H, and CO in AOM played an important role, and the N-H group was priority to interacts with Cd2+ in the complexing process. More functional groups (such as C-O and C-N) were involved in the metals complexing in EOM than in IOM. It could be concluded that Cd2+ stress promoted the secretion of AOM in Scenedesmus obliquus, and proteins in AOM could complex Cd2+ and alleviate its toxicity to algal cell. These findings provided deep insights into the interaction mechanism of AOM with Cd2+ in aquatic environments.

Carbazole diester strapped calix[4]pyrrole: Synthesis, anion binding and self-assembly based on ion pair recognition

A new carbazole strapped calix[4]pyrrole 1 has been synthesized and ion binding properties was investigated using 1H NMR, isothermal titration calorimetry and single crystal X-ray diffraction analyses. Compared to the parent octamethyl calix[4]pyrrole 2, receptor 1 showed enhanced binding towards halide anions. Solid state structural analysis revealed that receptor 1 is capable of binding various halide salts showing different binding modes depending on the bound ion pairs. Interestingly, complexes of tetrabutyammonium (TBA+), tetraethylammonium (TEA+) and tetramethylammonium (TMA+) salts of chloride anion displayed three distinctly different binding geometries in the solid state. As a result, the linear supramolecular polymers seen in the crystal lattices are also dramatically different for these three chloride complexes of 1. Combination of 1H NMR and solid state studies revealed that binding of anion in one condition do not translates to another completely. Receptor 1 also found to form 1/1 complexes with CsCl, CsBr and CsI salts and 1D coordination polymer chains are stabilized in the solid state. Overall, construction of four different 1D linear chains are described for chloride anion based on ion pair recognition. In addition, the solid state structure of ion pair complex with CsI salt is unprecedented in the calix[4]pyrrole chemistry. Moreover, under solid-to-liquid extraction condition, receptor 1 is able to solubilise CsF and CsCl ion pairs in chloroform in which these salts are otherwise insoluble.

Nesfatin-3 possesses divalent metal ion binding properties, which remain hidden in the nucleobindin-2 precursor protein

BackgroundNucleobindin-2 (Nucb2) is a multidomain protein that, due to its structure, participates in many physiological processes. It was originally identified in several regions of the hypothalamus. However, more recent studies have redefined and extended the function of Nucb2 far beyond its initially observed role as a negative modulator of food intake.ResultsPreviously, we described Nucb2 as structurally divided into two parts: the Zn2+-sensitive N-terminal half and the Ca2+-sensitive C-terminal half. Here, we investigated the structural and biochemical properties of its C-terminal half, which, after posttranslational processing, yields the formation of a fully uncharacterized peptide product known as nesfatin-3. Nesfatin-3 likely contains all the key respective structural regions of Nucb2. Hence, we expected that its molecular properties and affinity toward divalent metal ions might resemble those of Nucb2. Surprisingly, the obtained results showed that the molecular properties of nesftain-3 were completely different from those of its precursor protein. Moreover, we designed our work as a comparative analysis of two nesfatin-3 homologs. We noticed that in their apo forms, both proteins had similar shapes and existed in solution as extended molecules. They both interacted with divalent metal ions, and this interaction manifested itself in a compaction of the protein molecules. Despite their similarities, the differences between the homologous nesfatin-3s were even more informative. Each of them favored interaction with a different metal cation and displayed unique binding affinities compared either to each other or to Nucb2.ConclusionsThe observed alterations suggested different from Nucb2 physiological roles of nesfatin-3 and different impacts on the functioning of the tissues and on metabolism and its control. Our results clearly demonstrated that nesfatin-3 possessed divalent metal ion binding properties, which remained hidden in the nucleobindin-2 precursor protein.

Thermodynamics of Li+-Crown Ether Interactions in Aqueous Solvent.

Lithium ion-based batteries are ubiquitous in modern technology due to applications in personal electronics and high-capacity storage for electric vehicles. Concerns about lithium supply and battery waste have prompted interest in lithium recycling methods. The crown ether 12-crown-4 has been studied for its abilities to form stable complexes with lithium ions (Li+). In this paper, molecular dynamics simulations are applied to examine the binding properties of a 12-crown-4-Li+ system in aqueous solution. It was found that 12-crown-4 did not form stable complexes with Li+ in aqueous solution due to the binding geometry which was prone to interference by surrounding water molecules. In addition, the binding properties of sodium ions (Na+) to 12-crown-4 are examined for comparison. Subsequently, calculations were performed with the crown ethers 15-crown-5 and 18-crown-6 to study their complexation with Li+ as well as Na+. It was determined that binding was unfavorable for both types of ions for all three crown ethers tested, though 15-crown-5 and 18-crown-6 showed a marginally greater affinity for Li+ than 12-crown-4. Metastable minima present in the potential of mean force for Na+ render binding marginally more likely there. We discuss these results in the context of membrane-based applications of crown ethers for Li+ separations.

Thermodynamic analysis of metal oxides, metal peroxides and metal hydrides

The standard entropy differences between metal oxides (metal peroxides) and metal elements Δ S were roughly expressed by the following equation, |Δ S | ∝ Rln|Δ V |, R: gas constant, Δ V : volume differences below 10 cm 3 /molO 2 , which is similar to the relation of metal hydrides. It was presumed that the entropy of oxygen in the metal oxides and the metal peroxides, together with the entropy of hydrogen in the metal hydrides can be controlled by the thermodynamics of ideal gas. Those volume differences were increased by increasing of the work function based on the small ion binding properties. However, the absolute values of the standard enthalpy differences |Δ H | had large values at Δ V of -22 to 8 cm 3 /molO 2 . The thermodynamic stabilities which are the absolute values of the standard enthalpy differences decreased in the order, metal oxides > metal peroxides > metal hydrides. • The relation between standard entropy and volume differences Δ S, Δ V was analyzed. • |Δ S | linearly increased with ln|Δ V | below 2⊡3⊡ • The slope was approximately gas constant R. • |Δ H | had large values at Δ V of -22 to 8cm 3 /molO 2 ,Δ H standard enthalpy differences. • |Δ H | decreased in the order, metal oxides > metal peroxides > metal hydrides.

Sequence-Specific Structural Features and Solvation Properties of Transcription Factor Binding DNA Motifs: Insights from Molecular Dynamics Simulation.

Sequence-specific recognition of transcription factor (TF) binding motifs in the target site of DNA over the vast amount of non-target DNA is of primary importance for the transcriptional regulation of gene expression by the TFs. Binding of TFs to the target site of DNA relies not only on the direct contact formation but also on the structural and conformational features of DNA. Recognition of DNA structural features or shape readout by proteins is an important factor in the context of TF-DNA interaction. Based on the atomistic molecular simulation, here we report the sequence-dependent unique structural features, solvation, and ion-binding properties of biologically relevant AT- and GC-rich human TF binding motifs in DNA. Counterion and water distribution around the motif is found to be sensitive to the motif sequence, which is accompanied with the DNA shape features. The motif sequence affects the electrostatic potential along the grooves, and cytosine methylation alters the DNA shape features. Characteristic solvation properties of TF binding motif DNA fragments infer that an ionic environment and hydration influences are essential to describe TF-DNA interactions.

In-vitro evaluation of indigenous probiotic lactobacilli for lead bio-adsorption potential, its tolerance and complex stability

Probiotic lactic acid bacteria exhibit metal ion binding properties, which can be employed as metal bio-adsorbents in the human system. Lead is a prevalent dietary contaminant that causes lead toxicity in humans, especially children. In the present investigation, we evaluated the indigenous lactobacilli for their lead bioadsorption potential that can offer a pre-emptive approach for bioremediating lead toxicity. After standardizing the lead bioadsorption assay, ten probiotic lactobacilli showing lead retention of >80% in the pellet were selected. Statistical correlation analysis on lead bioadsorption assay, factors affecting lead and lead resistance profiling revealed L. plantarum HD 51 as the most potent lead adsorber. Scanning electron microscopy of L. plantarum HD 51 demonstrated that the binding occurred on the bacterial cell wall. Hence L. plantarum HD-51 could be used as a biotherapeutic agent to reduce the body’s burden on lead by sequestering it out of the human body.

Fluorescent chemosensors containing ruthenium(II) bipyridine as fluorogenic unit and modified calix[4]arene as ionophore: Synthesis, characterization, electrochemistry and ion-binding property

A series of metallo-receptors containing ruthenium(II) bipyridine moiety as signaling unit and calix[4]arene coupled with azacrown as ionophore have been synthesized and characterized. These molecules exhibit metal to ligand charge transfer (MLCT) absorption band at 456 nm and 3MLCT luminescence band at 614 nm. Electrochemical study revealed that the Ru(II) of these complexes oxidize in the potential range + 1.23 to + 1.30 V and the ligands exhibit three redox waves in the potential −1.36 to −1.89 V. Ion-binding property of these molecules has been studied using a large number of metal ions and anions with the aid of luminescence spectral change, which revealed that all of the three receptors bind Hg2+ and Pb2+ strongly, as evident from the enhancement in emission intensity with red shift of λmax. Among anions, H2PO4− and F− exhibited substantial quenching in emission intensity, suggesting their strong interaction with the receptors. To evaluate the binding constants (Ks), luminescence titration of the receptor molecules with the strongly interacting ions have been performed and the Ks values have been calculated from the titration data. The Ks values are in the range 4.77 × 104 to 1.20 × 103 M−1 with descending order of Hg2+ > Pb2+ > H2PO4− > F−. For anions, 1H NMR spectral change were recorded with incremental addition of anions, the results obtained are discussed in light of ion-binding property and mechanism of interaction.

Fluorescent Chemosensors Containing Ruthenium(Ii) Bipyridine as Fluorogenic Unit and Modified Calix[4]Arene as Ionophore: Synthesis, Characterization, Electrochemistry and Ion-Binding Property

Fluorescent Chemosensors Containing Ruthenium(Ii) Bipyridine as Fluorogenic Unit and Modified Calix[4]Arene as Ionophore: Synthesis, Characterization, Electrochemistry and Ion-Binding Property

Mutual effects between single-stranded DNA conformation and Na+-Mg2+ ion competition in mixed salt solutions.

The ion-dependence of single-stranded DNA (ssDNA) conformational changes has attracted growing attention because of its biological and technological importance. Although single-species ion effects have been extensively explored, it is challenging to study the ssDNA conformational properties under mixed monovalent/divalent ion conditions due to the complications of ssDNA flexibility and ion-ion competition. In this study, we apply Langevin dynamics simulations to investigate mixed Na+/Mg2+ ion-dependent ssDNA conformations. The ssDNA structure is described using a coarse-grained model, in which the phosphate, base, and sugar of each nucleotide are represented by three different beads. A novel improvement in our simulation model is that mixed-salt-related electrostatic interactions are computed via combining Manning counterion condensation (MCC) theory with the Monte Carlo tightly bound ion (MCTBI) model. Based on this MCC-MCTBI combination, we report new empirical functions to describe the ion-concentration-dependent and ssDNA conformation/structure-dependent electrostatic effects. The calculation results relating to the ion binding properties and the simulation results relating to the ssDNA conformational properties are validated against experimental results. In addition, our simulation results suggest a quantitative relationship between the ssDNA conformation and Na+-Mg2+ competition; this in turn reveals their mutual impact in the ion atmosphere.

Experimental and theoretical study of novel aminobenzamide-aminonaphthalimide fluorescent dyads with a FRET mechanism.

In this work, both experimental and theoretical methods were used to study the photophysical and metal ion binding properties of a series of new aminobenzamide–aminonaphthalimide (2ABZ–ANAPIM) fluorescent dyads. The 2-aminobenzamide (2ABZ) and 6-aminonaphthalimide (ANAPIM) fluorophores were linked through alkyl chains (C2 to C6) to obtain four fluorescent dyads. These dyads present a highly efficient (0.61 to 0.98) Förster Resonant Energy Transfer (FRET) from the 2ABZ to the ANAPIM due to the 2ABZ emission and ANAPIM excitation band overlap and the configurational stacking of both aromatic systems which allows the energy transfer. These dyads interact with Cu2+ and Hg2+ metal ions in solution inhibiting the FRET mechanism by the cooperative coordination of both 2ABZ and ANAPIM moieties. Both experimental and theoretical results are consistent and describe clearly the photophysical and coordination properties of these new dyads.

Development of calix[4]arenes modified at their narrow- and wide-rims as potential metal ions sensor layers for microcantilever sensors: further studies

The development of a microcantilever (MCL) sensing device capable of simultaneously detecting several metal ionic species in aqueous media with low limits of detection requires a variety of sensing layers that are ion specific. Calix[4]arenes are robust molecules that can be easily modified and have been extensively studied for their ion binding properties. They are also capable of forming self-assembled monolayers (SAMs) on the gold layers of MCLs and are capable of detecting various metal ions with different anionic counterions in aqueous solutions. In this paper, we report on the effect of the alkoxy group in the narrow rim [O-(alkoxycarbonyl)methoxy] substituents of bimodal calix[4]arenes, which have been used as metal ion MCL sensing layers, using classical solution state experimental studies. A DFT computational study to compare the experimental results with several metal ions is also reported herein.

Cation competition and recruitment around the c-kit1 G-quadruplex using polarizable simulations

Nucleic acid-ion interactions are fundamentally important to the physical, energetic, and conformational properties of DNA and RNA. These interactions help fold and stabilize highly ordered secondary and tertiary structures, such as G-quadruplexes (GQs), which are functionally relevant in telomeres, replication initiation sites, and promoter sequences. The c-kit proto-oncogene encodes for a receptor tyrosine kinase and is linked to gastrointestinal stromal tumors, mast cell disease, and leukemia. This gene contains three unique GQ-forming sequences that have proposed antagonistic effects on gene expression. The dominant GQ, denoted c-kit1, has been shown to decrease expression of c-kit transcripts, making the c-kit1 GQ a promising drug target. Toward disease intervention, more information is needed regarding its conformational dynamics and ion binding properties. Therefore, we performed molecular dynamics simulations of the c-kit1 GQ with K+, Na+, Li+, and mixed salt solutions using the Drude-2017 polarizable force field. We evaluated GQ structure, ion sampling, core energetics, ion dehydration and binding, and ion competition and found that each analysis supported the known GQ-ion specificity trend (K+ > Na+ > Li+). We also found that K+ ions coordinate in the tetrad core antiprismatically, whereas Na+ and Li+ align coplanar to guanine tetrads, partially because of their attraction to surrounding water. Further, we showed that K+ occupancy is higher around the c-kit1 GQ and its nucleobases than Na+ and Li+, which tend to interact with backbone and sugar moieties. Finally, we showed that K+ binding to the c-kit1 GQ is faster and more frequent than Na+ and Li+. Such descriptions of GQ-ion dynamics suggest the rate of dehydration as the dominant factor for preference of K+ by DNA GQs and provide insight into noncanonical nucleic acids for which little experimental data exist.

Molecular dynamics simulation of ion binding in aqueous solution of 18-crown-6 ether

Crown ethers are unique compounds with exceptional ion binding properties. We investigate the 18-crown-6 ether molecule binding selectivity for a set of alkali ions (K+, Rb+, Cs+). We employ combination of umbrella sampling technique with the weighted histogram analysis method to derive free energies of ion–ether association. The obtained results are in a good agreement with experimental values available and represent the ion selectivity feature of the 18-crown-6 ether.

Synthesis ofpara-linked azacalix[n]pyridine[n]pyrazines and their uranyl ion binding properties

Based on the fragment coupling strategy, the novel macrocycles,para-linked azacalix[n]pyridine[n]pyrazines (n= 2 and 4) with coexisting different heteroaromatics, were synthesized readily starting from 2,5-dibromopyrazine and 2,6-dibromopyridine.