Binding In Water Research Articles

On the Accuracy of Determination of Unbound Drug Fraction in Tissue using Diluted Tissue Homogenate

The unbound drug fraction in tissue, f(ut) , is commonly measured in vitro using the diluted tissue homogenate. An appraisal of the calculation procedure that is routinely applied to obtain f(ut) is presented. An accurate detailed calculation that takes into account the drug protein binding in tissue extracellular water and the pH difference between extra- and intracellular water is considered. It turns out that for neutral compounds, the routine calculation provides f(ut) quite accurately. Though for acidic compounds, the routine calculation can considerably underestimate f(ut) up to 1.8-fold for monoprotic and up to 2.4-fold for diprotic ones, whereas for basic compounds, f(ut) can be substantially overestimated up to 1.9-fold for monoprotic and up to 4.3-fold for diprotic ones.

Rational design and synthesis of water-compatible molecularly imprinted polymers for selective solid phase extraction of amiodarone

Novel water-compatible molecularly imprinted polymers (MIPs) selective for amiodarone (AD) were designed via a new methodology which relies on screening library of non-imprinted polymers (NIPs). The NIP library consisted of eighteen cross-linked co-polymers synthesized from monomers commonly used in molecular imprinting. The binding capacity of each polymer in the library was analyzed in two different solvents. Binding in water was used to assess non-specific (hydrophobic) interactions and binding in an appropriate organic solvent was used to assess specific interactions. A good correlation was found between the screening tests and modeling of monomer–template interactions performed using computational approach. Additionally, analysis of template–monomer interactions was performed using UV–vis spectroscopy. As the result, 4-vinylpyridine (4-VP) was selected as the best monomer for developing MIP for AD. The 4-VP-based polymers demonstrated imprinting factor equal 3.9. The polymers performance in SPE was evaluated using AD and its structural analogues. The recovery of AD was as high as 96% when extracted from spiked phosphate buffer (pH 4.5) solution and 82.1% from spiked serum samples. The developed MIP shown as a material with specific binding to AD, comparing to its structural analogues, 1-(2-diethylaminoethoxy)-2,6-diiodo-4-nitrobenzene and lidocaine, which shown 9.9% and 25.4% of recovery from the buffer solution, correspondingly. We believe that the screening of NIP library could be proposed as an alternative to commonly used computational and combinatorial approaches.

Structure, Dynamics, and Reactivity of Hydrated Electrons by Ab Initio Molecular Dynamics

Understanding the properties of hydrated electrons, which were first observed using pulse radiolysis of water in 1962, is crucial because they are key species in many radiation chemistry processes. Although time-resolved spectroscopic studies and molecular simulations have shown that an electron in water (prepared, for example, by water photoionization) relaxes quickly to a localized, cavity-like structure ∼2.5 Å in radius, this picture has recently been questioned. In another experimental approach, negatively charged water clusters of increasing size were studied with photoelectron and IR spectroscopies. Although small water clusters can bind an excess electron, their character is very different from bulk hydrated species. As data on electron binding in liquid water have become directly accessible experimentally, the cluster-to-bulk extrapolations have become a topic of lively debate. Quantum electronic structure calculations addressing experimental measurables have, until recently, been largely limited to small clusters; extended systems were approached mainly with pseudopotential calculations combining a classical description of water with a quantum mechanical treatment of the excess electron. In this Account, we discuss our investigations of electrons solvated in water by means of ab initio molecular dynamics simulations. This approach, applied to a model system of a negatively charged cluster of 32 water molecules, allows us to characterize structural, dynamical, and reactive aspects of the hydrated electron using all of the system's valence electrons. We show that under ambient conditions, the electron localizes into a cavity close to the surface of the liquid cluster. This cavity is, however, more flexible and accessible to water molecules than an analogous area around negatively charged ions. The dynamical process of electron attachment to a neutral water cluster is strongly temperature dependent. Under ambient conditions, the electron relaxes in the liquid cluster and becomes indistinguishable from an equilibrated, solvated electron on a picosecond time scale. In contrast, for solid, cryogenic systems, the electron only partially localizes outside of the cluster, being trapped in a metastable, weakly bound "cushion-like" state. Strongly bound states under cryogenic conditions could only be prepared by cooling equilibrated, liquid, negatively charged clusters. These calculations allow us to rationalize how different isomers of electrons in cryogenic clusters can be observed experimentally. Our results also bring into question the direct extrapolation of properties of cryogenic, negatively charged water clusters to those of electrons in the bulk liquid. Ab initio molecular dynamics represents a unique computational tool for investigating the reactivity of the solvated electron in water. As a prototype, the electron-proton reaction was followed in the 32-water cluster. In accord with experiment, the molecular mechanism is a proton transfer process that is not diffusion limited, but rather controlled by a proton-induced deformation of the excess electron's solvent shell. We demonstrate the necessary ingredients of a successful density functional methodology for the hydrated electron that avoids potential pitfalls, such as self-interaction error, insufficient basis set, or lack of dispersion interactions. We also benchmark the density functional theory methods and outline the path to faithful ab initio simulations of dynamics and reactivity of electrons solvated in extended aqueous systems.

1,8-Naphthyridine Based Artificial Receptors for Selective Monosaccharide Binding in Water

1,8-Naphthyridine based bi-bracchial macrocyclic 2 and cage-type macrobicyclic receptor 3 bind monosaccharides in water under physiologically relevant conditions through a combination of hydrophobic, electrostatic and hydrogen bonding interactions. The dissociation constants (Kd) for the complexes between 1,8-naphthyridine receptors 1-3 with a variety of neutral and negatively charged monosaccharides in water were determined by fluorimetric and UV/vis titration. The observed values are in the range from ˜ 0.3 to ≥10 mM, and are similar to the Kd reported for lectin/monosaccharide complexes. Among the monosaccharide substrates tested, receptor 2 showed the strongest binding affinity for sialic acid (Kd = ˜ 0.3 mM), a monosaccharide that plays many important roles in a wide variety of physiological and pathological processes. Interestingly, receptors 2 and 3 display the ability to discriminate between closely related monosaccharide substrates by opposite variation of the fluorescence emission intensity. Keywords: 1,8-Naphthyridine receptors, sialic acid, lectin mimetics, physiologically relevant conditions, selective binding, cell-cell recognition, inflammation, cell differentiation, tumor cell colonization, metastasis, anticancer drugs, supramolecular chemistry, organic solvents, fluorescence, condensation, buffer

オキシエチレン鎖を有するポリ（メタフェニレン）誘導体の水中での二重らせん形成とコール酸塩捕捉を介した一方向巻き一重らせんへの変換

オキシエチレン鎖を有するポリ（メタフェニレン）誘導体の水中での二重らせん形成とコール酸塩捕捉を介した一方向巻き一重らせんへの変換

Copper complexing ligands and organic matter characterization in the northern Adriatic Sea

The study on dissolved organic ligands capable to complex copper ions (L T), surface-active substances (SAS) and dissolved organic carbon (DOC) in the Northern Adriatic Sea station (ST 101) under the influence of Po River was conducted in period from 2006–2008. The acidity of surface-active organic material (Ac r) was followed as well. The results are compared to temperature and salinity distributions. On that way, the contribution of the different pools of ligands capable to complex Cu ions could be determined as well as the influence of aging and transformation of the organic matter. The L T values in the investigated period were in the range of 40–300 nmol l −1. The range of DOC values for surface and bottom samples were 0.84–1.87 mg l −1 and 0.80–1.30 mg l −1, respectively. Total SAS concentrations in the bottom layer were 0.045–0.098 mg l −1 in equiv. of Triton-X-100 while those in the surface layer were 0.050–0.143 mg l −1 in equiv. of Triton-X-100. The majority of organic ligands responsible for Cu binding in surface water originate from new phytoplankton production promoted by river borne nutrients. Older, transformed organic matter, possessing higher relative acidity, is the main contributor to the pool of organic ligands that bind copper in the bottom samples. It was estimated that ∼9% of DOC in surface samples and ∼12% of DOC in the bottom samples are present as ligands capable to complex copper ions.

Recognition Preference of Rhodamine-Thiospirolactams for Mercury(II) in Aqueous Solution

This work presents the design, syntheses, photophysical properties and Hg(2+)-binding of the red-emitting rhodamine derivatives RS1, RS2, and RS3 with different coordination ability and different spatial effects that derived from rhodamine thiohydrazone chromophores and respective carboxaldehydes (benzaldehyde, pyridine-2-carboxaldehyde, ferrocenecarboxaldehyde). Chemosensors RS2 and RS3 afford turn-on fluorescence enhancement and display high brightness in water with the EC(50) for Hg(2+) of 0.5 ppb. The fluorescence intensities are nearly proportional to the amount of Hg(2+) at ppb level, when employing 100 nM probes in water. The fluorescence responses of these two chemosensors are Hg(II) specific, and the probes are selective for Hg(II) over alkali, alkaline earth metals, divalent first-row transition metal ions, and Group 12 congeners Zn(II) and Cd(II), as well as heavy metals Pb(II) and Ag(I). X-ray crystal structure analyses exhibit the thioether derivative of the spirolactone in these compounds. Hg(II)-specific binding in water would make the opening of the spirolactam ring and consequently causes the appearance of strong absorption at visible range, and the obvious and characteristic color change from colorless to pink. Compared to the thioamides, the improved selectivity for Hg(2+) is attributed to the poorer coordination affinity of the thioether over other interference metal ions.

Entropic Cost of Protein−Ligand Binding and Its Dependence on the Entropy in Solution

Two theoretical formulations are proposed and compared for the loss of translational and rotational entropy upon protein-ligand binding in water. The two theories share the same approach to evaluate the translational and rotational entropy of the ligand when bound. The potential of the bound ligand is modeled by six harmonic oscillators that are parametrized from the force and torque magnitudes measured in a molecular dynamics simulation, yielding vibrational and librational entropies. In the aqueous phase, the theories differ because there is no unique way to assign the total entropy to molecules in solution. In one approach, the ligand is allowed unrestricted access to the full solution volume at the standard concentration and is assigned the same translational and rotational entropy as if it were an ideal gas. We term this a "molecule-frame" (MF) theory because it considers configurational space in the reference frame of the molecule of interest. The entropy of the solvent is penalized because it is excluded from the molecule's volume. In the second theory, all molecules including the solvent are confined by their neighbors in mean-field configurational volumes. This we term a "system-frame" (SF) theory because the configurational space available to all molecules is considered in the reference frame of the whole system. Molecules have vibrational and librational entropy in the same way as they do when bound. In addition, the discrete size of the solvent molecules quantizes the configurational space into an effective number of minima according to the solute molecule's standard concentration and the mean volume of a solvent molecule. This leads to the cratic entropy expressed in terms of the solute molecule's mole fraction. The equivalent number of minima in rotational space depends on both the solute molecule's volume and the solvent molecule's volume. This leads to an equation for the orientational entropy based on the proposed concept of "angle fraction". The MF and SF theories are applied to calculate the translational and rotational entropy losses involved in the formation of six different protein-ligand complexes, in two of which the ligand is water. The MF entropy losses range from -80 to -142 J K(-1) mol(-1) for ligands at the 1 M standard-state concentration and from -52 to -63 J K(-1) mol(-1) for water at the 55.6 M standard-state concentration. They depend logarithmically on both the number and strength of interactions between the ligand and protein through the forces and torques. This is observed to lead to moderate dependencies on the ligands' moments of inertia and masses. The SF entropy losses are smaller and range from -50 to -75 J K(-1) mol(-1) for ligands at the 1 M standard-state concentration and from 0 to -12 J K(-1) mol(-1) for water. They depend logarithmically on the ligand solvent's molecular volume and weakly on the relative strengths of the ligand's interactions with the protein and water. The cratic entropy loss in water at the standard concentration is constant and is also demonstrated to be implicit in MF theories. Entropy losses from the two approaches are also compared with those from other computational approaches and with experiment. The use of the force and torque magnitudes leads to smaller bound volumes than are obtained from ligand-displacement approaches. The general agreement of the SF entropy losses with those from experiment suggests that the SF theory is more consistent with the assumptions made in experimental measurements than the MF solvation theories, which would require a compensating entropy gain in the solvent in order to agree.

Selective Anion Binding in Water with Use of a Zinc(II) Dipicolylamino Functionalized Diketopiperazine Scaffold

The design and synthesis of a diketopiperazine based anion receptor bearing two dipicolylamino arms complexed to zinc(II) ions is described. This receptor is readily prepared from the dipeptide precursor by a microwave-assisted intramolecular cyclization reaction. Upon addition of zinc(II), the receptor binds di- and triphosphate ions with high affinity and selectivity in aqueous solution, as determined by using a fluorescent indicator displacement assay.

Double helix formation of poly(m-phenylene)s bearing achiral oligo(ethylene oxide) pendants and transformation into an excess of one-handed single helix through cholate binding in water

A water-soluble poly(m-phenylene) bearing an achiral oligo(ethylene oxide) chain at the 5-position was synthesized by the Ni(0)-mediated homo-coupling polycondensation of a 3,5-dibromophenol monomer. The poly(m-phenylene) adopted a single helical conformation in protic media and self-assembled into a double helix in water through aromatic interaction, while it took a random-coil conformation in chloroform. Upon the addition of sodium cholate in water, the double helical poly(m-phenylene) was transformed into single strands, which bound the cholate molecules to form an excess of one-handed single helix.

Water−Benzene Interactions: An Effective Fragment Potential and Correlated Quantum Chemistry Study

Structures and binding in small water-benzene complexes (1-8 water molecules and 1-2 benzene molecules) are studied using the general effective fragment potential (EFP) method. The lowest energy conformers of the clusters were found using a Monte Carlo technique. The binding energies in the smallest clusters (dimers, trimers, and tetramers) were also evaluated with second order perturbation theory (MP2) and coupled cluster theory (CCSD(T)). The EFP method accurately predicts structures and binding energies in the water-benzene complexes. Benzene is polarizable and consequently participates in hydrogen bond networking of water. Since the water-benzene interactions are only slightly weaker than water-water interactions, structures with different numbers of water-water, benzene-water, and benzene-benzene bonds often have very similar binding energies. This is a challenge for computational methods.

Fluoride Binding in Water: A New Environment for a Known Receptor

Binding in a micelle: In the presence of CTABr micelles (see picture), the salophen–UO2 complex 1 binds fluoride in water with the highest affinity ever recorded for a neutral receptor (K≈ ca. 104 M−1). The receptor's location and its orientation within the micellar system are determined by PRE and NOE NMR experiments.

Proton and Trivalent Metal Cation Binding by Dissolved Organic Matter in the Opalinus Clay and the Callovo-Oxfordian Formation

We investigated the proton and trivalent metal binding of dissolved organic matter (DOM) in in situ pore water and anoxic rock extracts of two potential host rocks for the disposal of radioactive waste, i.e., the Opalinus Clay (OPA) and the Callovo-Oxfordian formation (COx). The proton, curium, and europium binding properties of the OPA pore water and the extracted DOM of both rocks were studied with acid-base titrations, time-resolved laser fluorescence spectroscopy (TRLFS), and voltammetry, respectively. Protons were mostly buffered by inorganic compounds. DOM contributed to the total proton buffering capacity of the samples only to a small extent. Significant complexation of curium by DOM was observed for OPA pore water by TRFLS in contrast to little complexation by DOM detected in the OPA and COx extracts. The data on europium binding in OPA pore water were described by the presence of 14.3 microM organic ligands exhibiting a conditional affinity constant of log beta = 6.50. Calculations of europium speciation under in situ conditions indicated that carbonates largely controlled the speciation of europium in OPA and COx. In the OPA formation, the presence of DOM may enhance the solubility of europium by 5 x 10(-8) M, representing about one-third of total dissolvable europium.

Substrates with Discretely Immobilized Silver Nanoparticles for Ultrasensitive Detection of Anions in Water Using Surface-Enhanced Raman Scattering

Positively charged silver nanoparticles, Ag [+], obtained by UV-assisted reduction of silver nitrate using branched poly(ethyleneimine) (BPEI) and 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) solutions as reducing agents, were immobilized on glass surfaces to produce substrates active in surface-enhanced Raman scattering (SERS). Negatively charged silver nanoparticles, Ag [-], synthesized via a modified citrate reduction method, were also investigated for comparison. At a sparse surface coverage of 30 nanoparticles/microm(2), substrates with immobilized Ag [+] showed increasing SERS sensitivity to a variety of anions in water in the order SO(4)(2-) < CN(-) < SCN(-) approximately ClO(4)(-), with corresponding binding constants of 10(5), 3.3 x 10(5), and 10(7) (for both SCN- and ClO(4)(-)) M(-1), respectively. This order followed the Hofmeister series of anion binding in water. Significantly, substrates with Ag [+] allowed limit of detection values of 8.0 x 10(-8) M (8 ppb) and 2.7 x 10(-7) M (7 ppb) for environmentally relevant perchlorate (ClO(4)(-)) and cyanide (CN(-)) anions, respectively. In contrast, substrates with immobilized Ag [-], even upon subsequent modification by a monolayer of BPEI for positive surface charge of the nanoparticles, showed a drastically lower sensitivity to these anions. The high sensitivity of substrates with Ag [+] for anion detection can be attributed to the presence of two types of functional groups, amino and amide, on the nanoparticle surface resulting from UV-assisted fragmentation of BPEI chains. Both amino and amide provide strong binding of anions with Ag [+] nanoparticles due to the synergistic effect through a combination of electrostatic, hydrogen bonding, and dispersive interactions.

Thermodynamics of Xenon Binding to Cryptophane in Water and Human Plasma

Xenon-129 biosensors offer an attractive alternative to conventional MRI contrast agents due to the chemical shift sensitivity and large nuclear magnetic resonance signal of hyperpolarized 129Xe. Here we report the use of fluorescence spectroscopy and isothermal titration calorimetry (ITC) to determine xenon binding affinity and thermodynamics with a water-soluble triacid-cryptophane-A (1). 1 was synthesized in 10 steps with a 4% overall yield. Fluorescence spectroscopy measured an association constant of (1.7 ± 0.2) × 104 M-1 in phosphate buffer at 293 K. ITC measurements at 293 and 310 K yielded association constants of (1.73 ± 0.17) × 104 and (3.01 ± 0.26) × 104 M-1 and indicated a large entropic contribution to xenon binding in water. On the basis of these data, cryptophane 1 showed roughly 2-fold higher affinity for xenon than any previously measured compound. Remarkably, ITC measurements in human plasma at 310 K gave a similar binding constant, KA = (2.19 ± 0.22) × 104 M-1, which supports the development of 129Xe NMR biosensors for biological applications.

A Designed Receptor for pH-Switchable Ion Binding in Water

Molecules with conditional (switchable) properties are of considerable fundamental interest and are potentially useful for a broad range of applications, including chemical sensing. We have prepared a novel receptor, derived from the peracylation of cyclohexane 1,3,5-trimethanol with tyrosine, that suggests that the phenol-amine hydrogen bond may be an effective structural tool in the preparation of molecules with pH-switchable conformations. This conclusion is based on several key observations. First, the proton longitudinal relaxation rates for this molecule change in a pH-dependent fashion, while those for closely related structures do not. Second, NOESY spectra for the receptor change markedly depending on pH, with the spectrum acquired at pH 9.5 displaying NOEs consistent with the calculated "closed" conformation. Third, this molecule serves as a receptor for anions and cations in aqueous solution at high pH, but not at low pH, as demonstrated by UV-vis titrations and isothermal titration calorimetry (ITC).

Optical Binding in Air

Optical binding between micron-sized oil droplets in air has recently been observed. The experimental setup, consisting in two vertical, counter propagating and diverging laser beams, builds up a three dimensional trap. The cloud of oil droplets, enclosed in a glass cell, progressively fills in the trap where droplets interact one with another. Scattered intensity is observed on a video camera. Interactions involve optical, electrostatic, radiometric and capillary forces. Orders of magnitude are discussed. Chains up to four droplets have been observed, the most stable structure being the doublet and not the single drop. In air, viscosity being one thousand times smaller than in water, mean free path of a micro-sphere is much bigger. That is why mean residence times in metastable states are of the magnitude of a few seconds and that brownian motion quickly drives the trapped droplets in the very minimum of potential energy: the doublet structure. Two stable states have also been obtained for the doublet. Observation of interference indicates that oil droplets are phase-locked onto each other every λ/2. The spraying technique we use, gives droplets smaller than the micron in radius. This is the intermediate case of the Mie range between the small and large wavelength cases. Those new experimental results exhibit the role of the short and long range interactions in optical binding. They are then theoretically discussed both in the ray model and in the Rayleigh approximation, and compared with previous works on optical binding in water. Moreover, in our case, the index contrast is much bigger. It implies stronger scattered intensities, bigger interaction forces with light and therefore, bigger binding forces.

Aflatoxin B1 Binding to Sorbents in Bovine Ruminal Fluid

A recent approach to the problem of contamination of agricultural products by aflatoxin B(1) (AFB(1)) is to add non-nutritional adsorbents to animal diets in order to sequester ingested aflatoxins. We conducted in vitro experiments to develop a rapid and cheap model using ruminal fluid to assess the ability of sorbent materials to bind AFB(1). Seven sorbents (hydrated sodium calcium aluminosilicate; clinoptilolite; zeolite; two types of bentonite; sepiolite; and PHIL 75), commonly added to bovine diets were incubated in water and ruminal fluid in the presence of AFB(1). Hydrated sodium calcium aluminosilicate, sepiolite and one of the bentonites bound 100% of the AFB(1) in the presence of both ruminal fluid and water; clinoptilolite bound about 80% of AFB(1) in both liquids; whereas the affinities for the mycotoxin of zeolite (50%) and the other sample of bentonite (60%) in water seem to be increased by about 40% in ruminal fluid incubations. PHIL 75 had the poorest binding ability: about 30% in water and 45% in ruminal fluid. In view of the differences in toxin binding in water and ruminal fluid, it is preferable to use the ruminal fluid model for the in vitro pre-screening of sorbent materials potentially useful as adjuvants to ruminant feeds.

Amino Acid Binding by 2‐(Guanidiniocarbonyl)pyridines in Aqueous Solvents: A Comparative Binding Study Correlating Complex Stability with Stereoelectronic Factors

A series of guanidiniocarbonylpyridine receptors has been synthesized, and these compounds bind amino acids (carboxylate forms) in aqueous DMSO with association constants ranging from K = 30 to 460 M(-1) as determined by NMR titration experiments. The differences in the complex stabilities can be correlated with steric and electrostatic effects with the aid of calculated complex structures. For example, the electrostatic repulsion between the pyridine nitrogen lone pair and the bound carboxylate makes anion binding less efficient than with the analogous pyrrole receptors previously introduced by us for carboxylate binding in water. Furthermore, steric interactions between the receptor side chain as in 2 b and the bound substrate also disfavor complexation.

Amino acid binding in water by a new guanidiniocarbonyl pyrrole dication: the effect of the experimental conditions on complex stability and stoichiometry

The synthesis and binding properties of a new guanidiniocarbonyl pyrrole dication 2 are reported, which efficiently binds alanine carboxylate with log K ass = 3.9 in buffered water. Due to the increased charge density in this dication, the binding constant is five times larger than for the parent guanidiniocarbonyl pyrrole monocation 1 (log K = 3.2). However, the experimental conditions for determining the binding constant significantly influence both complex stability and stoichiometry. With increasing amount of substrate added during the titration, the overall complex stability decreases due to the increasing ionic strength of the solution. Furthermore, the formation of 1:2 complexes between 2 and 7 becomes increasingly important. Therefore, for the comparison of binding data it has to be assured that exactly the same experimental conditions are used for their determination.