Displacement Of Water Molecules Research Articles

C 60 Binds to and Deforms Nucleotides

Atomistic molecular dynamics simulations are performed for up to 20 ns to monitor the formation and the stability of complexes composed of single- or double-strand DNA molecules and C 60 in aqueous solution. Despite the hydrophobic nature of C 60, our results show that fullerenes strongly bind to nucleotides. The binding energies are in the range −27 to −42 kcal/mol; by contrast, the binding energy of two fullerenes in aqueous solution is only −7.5 kcal/mol. We observe the displacement of water molecules from the region between the nucleotides and the fullerenes and we attribute the large favorable interaction energies to hydrophobic interactions. The features of the DNA-C 60 complexes depend on the nature of the nucleotides: C 60 binds to double-strand DNA, either at the hydrophobic ends or at the minor groove of the nucleotide. C 60 binds to single-strand DNA and deforms the nucleotides significantly. Unexpectedly, when the double-strand DNA is in the A-form, fullerenes penetrate into the double helix from the end, form stable hybrids, and frustrate the hydrogen bonds between end-group basepairs in the nucleotide. When the DNA molecule is damaged (specifically, a gap was created by removing a piece of the nucleotide from one helix), fullerenes can stably occupy the damaged site. We speculate that this strong association may negatively impact the self-repairing process of the double-strand DNA. Our results clearly indicate that the association between C 60 and DNA is stronger and more favorable than that between two C 60 molecules in water. Therefore, our simulation results suggest that C 60 molecules have potentially negative impact on the structure, stability, and biological functions of DNA molecules.

Kinetic and crystallographic studies of glucopyranose spirohydantoin and glucopyranosylamine analogs inhibitors of glycogen phosphorylase

Glycogen phosphorylase (GP) is currently exploited as a target for inhibition of hepatic glycogenolysis under high glucose conditions. Spirohydantoin of glucopyranose and N-acetyl-beta-D-glucopyranosylamine have been identified as the most potent inhibitors of GP that bind at the catalytic site. Four spirohydantoin and three beta-D-glucopyranosylamine analogs have been designed, synthesized and tested for inhibition of GP in kinetic experiments. Depending on the functional group introduced, the K(i) values varied from 16.5 microM to 1200 microM. In order to rationalize the kinetic results, we determined the crystal structures of the analogs in complex with GP. All the inhibitors bound at the catalytic site of the enzyme, by making direct and water-mediated hydrogen bonds with the protein and by inducing minor movements of the side chains of Asp283 and Asn284, of the 280s loop that blocks access of the substrate glycogen to the catalytic site, and changes in the water structure in the vicinity of the site. The differences observed in the Ki values of the analogs can be interpreted in terms of variations in hydrogen bonding and van der Waals interactions, desolvation effects, ligand conformational entropy, and displacement of water molecules on ligand binding to the catalytic site.

Diffusion Histograms in CADASIL

See related article, pages 2559–2565 Diffusion MRI is a unique tool to investigate the microstructure of cerebral tissue. Diffusion-driven displacements of water molecules can probe the tissue architecture at a microscopic scale well beyond the usual image resolution.1 Diffusion is a 3D process. In cerebral white matter, where the movements of water molecules are maximal along the bundles of axons, molecular mobility may be anisotropic. In acute ischemia, cytotoxic edema, which occurs after the failure of ATP-dependent ionic pumps at the cell membrane, is responsible for a reduction of the extracellular space and increased tortuosity. These structural alterations are presumably responsible for the major reduction in the random movements of water molecules (eg, diffusion) detected early after arterial occlusion. Conversely, beyond the acute phase of ischemia, MRI diffusion has been used to measure the loss of structural components responsible for …

Ligand Exchange in Pd(II)-NaCl-H2O and Pd(II)-HCl-H2O Systems: Quantum-Chemical Consideration

The behavior of potassium tetrachloropalladate(II) in media simulating biological liquids is studied. The rate of aquation in aqueous NaCl solutions is shown to be higher than the rate at which the Cl− ligand enters the inner coordination sphere of the Pd atom. In HCl solutions, the formation of the Pd chloro complexes predominates due to protonation of water molecules in the composition of aqua complexes. The reactions of replacement of the ligands (H2O molecules and H3O+ ion) in the planar Pd(II) complexes by the chloride ion are studied by the ZINDO/1 method. All the complexes containing H2O and H3O+ ligands, except for [Pd(H2O)4]2+, contain intramolecular hydrogen bonds. The ZINDO/1 and RHF/STO-6G(d) calculations revealed “nonclassic” symmetrical O⋯ H⋯O hydrogen bond in the [[Pd(H2O)3(H3O)]3+ and trans-[Pd(H2O)2(H3O)Cl]2+ complexes. The replacement of the H3O+ ion by the Cl− ion at the first three steps is thermodynamically more advantageous than the displacement of water molecules from the metal coordination sphere. The logarithms of stepwise stability constants of Pd(II) chloro complexes are found to correlate linearly with the enthalpies (ZINDO/1, PM3) of reactions of H2O replacement by Cl−.

Electrochemical and XPS studies of decylamides of α-amino acids adsorption on carbon steel in acidic environment

Corrosion inhibition of steel in hydrochloric acid by decylamides of α-amino acids derivatives was studied using gravimetric and electrochemical techniques. Protection efficiencies of 90% were obtained with 100 ppm of tyrosine and glycine derivatives, while alanine and valine derivatives reached only 80%. The order of increasing inhibition efficiency was correlated with the modification of the molecular structure of inhibitors. Potentiodynamic polarization curves indicated that both the decylamide of tyrosine and glycine acted primarily as anodic type inhibitors, whereas the decylamide of alanine and valine were of the cathodic type. Thermodynamic parameters and Flory–Huggins adsorption isotherms described the experimental findings. The number of active sites, equilibrium constant, enthalpy and change of free energy were computed for all inhibitors studied. This information suggested that organic molecules were adsorbed and displaced water molecules from the steel surface. X-ray photoelectron spectroscopy confirmed that species of N, C and O interacted with steel to form a continuous protective film.

Knowledge-Based Elastic Potentials for Docking Drugs or Proteins with Nucleic Acids

Elastic ellipsoidal functions defined by the observed hydration patterns around the DNA bases provide a new basis for measuring the recognition of ligands in the grooves of double-helical structures. Here a set of knowledge-based potentials suitable for quantitative description of such behavior is extracted from the observed positions of water molecules and amino acid atoms that form hydrogen bonds with the nitrogenous bases in high resolution crystal structures. Energies based on the displacement of hydrogen-bonding sites on drugs in DNA-crystal complexes relative to the preferred locations of water binding around the heterocyclic bases are low, pointing to the reliability of the potentials and the apparent displacement of water molecules by drug atoms in these structures. The validity of the energy functions has been further examined in a series of sequence substitution studies based on the structures of DNA bound to polyamides that have been designed to recognize the minor-groove edges of Watson-Crick basepairs. The higher energies of binding to incorrect sequences superimposed (without conformational adjustment or displacement of polyamide ligands) on observed high resolution structures confirm the hypothesis that the drug subunits associate with specific DNA bases. The knowledge-based functions also account satisfactorily for the measured free energies of DNA-polyamide association in solution and the observed sites of polyamide binding on nucleosomal DNA. The computations are generally consistent with mechanisms by which minor-groove binding ligands are thought to recognize DNA basepairs. The calculations suggest that the asymmetric distributions of hydrogen-bond-forming atoms on the minor-groove edge of the basepairs may underlie ligand discrimination of G·C from C·G pairs, in addition to the commonly believed role of steric hindrance. The analysis of polyamide-bound nucleosomal structures reveals other discrepancies in the expected chemical design, including unexpected contacts to DNA and modified basepair targets of some ligands. The ellipsoidal potentials thus appear promising as a mathematical tool for the study of drug- and protein-DNA interactions and for gaining new insights into DNA-binding mechanisms.

Correlation between UV-VIS spectra and the structure of Cu(II) complexes with hydrogenated dextran in alkaline solutions

UV-VIS spectrophotometric investigations of Cu(II) complexes with hydroge-nated dextran showed that the complexation of Cu(II)-ions began at pH > 7. The formation of Cu(II) complexes with dextran monomer units was observed at pH 7-12. With further increase in solution pH > 12, the Cu(II)-dextran complex decomposed to Cu(OH)42~-ions and dextran. With increasing solution pH the absorption maximum of complex solutions increased and shifted to shorter wavelength (hypsochromic shift) compared with uncomplexed Cu(II). The UV spectra displayed bathochromic shifts. The changes of UV-VIS spectra with increasing in solution pH confirmed the formation of different kinds of complex species. The correlation between the results of UV-VIS spectrophotometry and the central metal ionligand coordination predicted that the copper binding within the complex depended on the pH and participation H2O molecules. Dextran complexes with Cu(II) were formed by the displacement of water molecules from the coordination sphere of copper by OH groups. The analysis indicated that the Cu(II) center was coordinated to two glucopyranose units of dextran. The spectrophotometric parameters of the investigated complexes were characteristic of a Cu(II)-ion in a square-planar or tetragon ally distorted octahedral coordination.

Effect of kaolinite and Ca-montmorillonite on the alleviation of soil water repellency

The effects of adding 1–3% (weight) kaolinite or Ca-montmorillonite on the wettability of silica sand, made highly water repellent with stearic acid, was studied during wetting and prolonged drying phases at 50°C. The persistence of water repellency was estimated with the water drop penetration time (WDPT) test. After wetting water repellency disappeared in all the samples. During the drying phase, water repellency re-appeared in all samples (untreated and clay-treated) as the water content decreased below 1%. Repellency did, however, not reach pre-wetting levels. The effect of clay additions on water repellency differed strongly between the two clay types. Kaolinite reduced WDPT, while Ca-montmorillonite caused an increase in WDPT in the already highly repellent sand. Potential mechanisms for the alleviation effectiveness of kaolinite are proposed, with key factors being the high adhesion forces between water and clay mineral surfaces, and the ability kaolinite to disperse. In the case of Ca-montmorillonite, its lower affinity for water may lead to a displacement of water molecules at mineral surfaces by amphiphilic organic compounds, which may result in increased repellency. This phenomenon clearly requires further investigation.

Studies on interpolymer self-organisation behaviour of protoporphyrin IX bound poly(carboxylic acid)s with complimentary polymers by means of fluorescence techniques

Covalently bound protoporphyrin IX was used as a fluorophore to investigate the interpolymer complex formation between the poly(carboxylic acid)s, PMAA/PAA and poly( N-vinyl pyrrolidone), PVP, poly(ethylene oxide), PEO or poly(ethylene glycol), PEG. Absorption and emission spectral properties of protoporphyrin IX bound to PAA, PMAA and PVP have been studied. Protoporphyrin IX in poly(MAA-co-PPIX) was found to be present in the dimer or higher aggregated form at low pH due to the environmental restriction imposed by the polymer whereas in the case of poly(AA-co-PPIX) and poly(VP-co-PPIX), PPIX exists in monomeric form. The fluorescence intensity and lifetime of PPIX bound to poly(carboxylic acid)s increase on complexation through hydrogen bonding with PVP, PEO and PEG due to the displacement of water molecules in the vicinity of the PPIX. Poly(MAA-co-PPIX) shows longer fluorescence lifetime due to the more compact interpolymer complexation as compared to poly(AA-co-PPIX) due to the enhanced hydrophobicity of PMAA. Poly(VP-co-PPIX) shows a decrease in the fluorescence lifetime on complexation with PMAA or PAA due to the hydrophilic and microgel like environment of the fluorophore bound to PVP. The contrasting behaviour of the same polymer adduct with respect to the site of the fluorophore is interpreted to be due to the solvent structure which determines the environment of the fluorophore.

Constrained photophysics of 3-acetyl-4-oxo-6,7-dihydro-12H indolo-[2,3-a] quinolizine in micellar environments: a spectrofluorometric study.

Photophysical properties of 3-acetyl-4-oxo-6,7-dihydro-12H indolo-[2,3-a] quinolizine (AODIQ) have been studied in different aqueous micellar environments using steady-state and time-resolved emission spectroscopy. The charge transfer (CT) fluorescence exhibits appreciable hypsochromic shift, along with an enhancement in the fluorescence intensity in all the micellar media. This is associated with an increase in the fluorescence anisotropy (r), which suggests that the fluorophore molecule experiences motionally restricted environments upon binding with the micelles. Fluorescence spectral position and fluorescence quenching studies suggest that the fluorescing moiety does not penetrate into the core of the micellar units; rather it binds at the micelle-water interfacial region. The binding constant and free energy change during probe-micelle binding have been evaluated from relevant fluorescence data. Light has been thrown on the mode of action of urea on micelle bound probes. The results are interpreted in terms of the model that urea displaces water molecules from the micellar interface and the consequent destabilization leads to the expulsion of the probe molecules from the interfacial region. Polarity and viscosity of the microenvironments around the probe have been determined in the micellar systems.

Structure of concanavalin A at pH 8: bound solvent and crystal contacts.

Concanavalin A has been crystallized in the presence of the ligand (6-S-beta-D-galactopyranosyl-6-thio)-cyclomaltoheptaose. The crystals are isomorphous to those reported for ConA complexed with peptides at low resolution (3.00-2.75 angstroms). The structure was solved at 1.9 angstroms, with free R and R values of 0.201 and 0.184, respectively. As expected, no molecules of the ligand were bound to the protein. Soaking in the cryobuffer left its fingerprint as 25 molecules of glycerol in the bound solvent, most of them at specific positions. The fact that a glycerol molecule is located in the sugar-binding pocket of each of the four subunits in the asymmetric unit and another is located in two of the peptide-binding sites suggests a recognition phenomenon rather than a displacement of water molecules by glycerol. Crystal contact analysis shows that a relation exists between the residues that form hydrogen bonds to other asymmetric units and the space group: contact Asp58-Ser62 is a universal feature of ConA crystals, while Ser66-His121, Asn69-Asn118 and Tyr100-His205 contacts are general features of the C222(1) crystal form.

Diffusion tensor imaging of adult age differences in cerebral white matter: relation to response time

Diffusion tensor imaging (DTI) measures the displacement of water molecules across tissue components, thus providing information regarding the microstructure of cerebral white matter. Fractional anisotropy (FA), the degree to which diffusion is directionally dependent, is typically higher for compact, homogeneous fiber bundles such as the corpus callosum. Previous DTI studies in adults have demonstrated an age-related decline in white matter FA, but whether the relation between FA and behavioral performance varies as a function of age has not been determined. We investigated adult age differences in FA, and age-related changes in the relation between FA and response time (RT), in a visual target-detection task. The results confirmed that, independently of age, FA is higher in the corpus callosum than in other brain regions. We also observed an age-related decline in FA that did not vary significantly across the brain regions. For both age groups, a lower level of integrity of the cerebral white matter (as indexed by FA), in specific brain regions, was associated with slower responses in the visual task. An age-related change in this relation was evident, however, in that the best predictor of RT for younger adults was FA in the splenium of the corpus callosum, whereas for older adults the best predictor was FA in the anterior limb of the internal capsule. This pattern is consistent with measures of the task-related cortical activation obtained from these same individuals and suggests an age-related increase in the attentional control of responses mediated by corticostriatal or corticothalamic circuits.

Identification of novel binding interactions in the development of potent, selective 2-naphthamidine inhibitors of urokinase. Synthesis, structural analysis, and SAR of N-phenyl amide 6-substitution.

The preparation and assessment of biological activity of 6-substituted 2-naphthamidine inhibitors of the serine protease urokinase plasminogen activator (uPA, or urokinase) is described. 2-Naphthamidine was chosen as a starting point based on synthetic considerations and on modeling of substituent vectors. Phenyl amides at the 6-position were found to improve binding; replacement of the amide with other two-atom linkers proved ineffective. The phenyl group itself is situated near the S1' subsite; substitutions off of the phenyl group accessed S1' and other distant binding regions. Three new points of interaction were defined and explored through ring substitution. A solvent-exposed salt bridge with the Asp60A carboxylate was formed using a 4-alkylamino group, improving affinity to K(i) = 40 nM. Inhibitors also accessed two hydrophobic regions. One interaction is characterized by a tight hydrophobic fit made with a small dimple largely defined by His57 and His99; a weaker, less specific interaction involves alkyl groups reaching into the broad prime-side protein binding region near Val41 and the Cys42-Cys58 disulfide, displacing water molecules and leading to small gains in activity. Many inhibitors accessed two of these three regions. Affinities range as low as K(i) = 6 nM, and many compounds had K(i) < 100 nM, while moderate to excellent selectivity was gained versus four of five members of a panel of relevant serine proteases. Also, some selectivity against trypsin was generated via the interaction with Asp60A. X-ray structures of many of these compounds were used to inform our inhibitor design and to increase our understanding of key interactions. In combination with our exploration of 8-substitution patterns, we have identified a number of novel binding interactions for uPA inhibitors.

Energies of Intermolecular Interaction and Hydration of Benzene Derivatives Molecules Adsorbed on Active Carbon from an Aqueous Solution

Energy heterogeneity of an adsorbent surface does not affect the isotherm of adsorption from aqueous solutions. Therefore, the balance of the changes in the Gibbs energy resulted from the adsorption of sparingly water-soluble substances shows that, in the whole range of filling of the adsorption phase, the pattern of the adsorption isotherm depends on the difference between the energy of the interaction of adsorbed molecules with each other and the energy of their hydration needed to displace water molecules from the adsorption phase. The standard adsorption energy of molecules of benzene and its derivatives from aqueous solutions and the difference between the energy of their interaction in the adsorption phase and the energy of their hydration are determined by the extrapolation of adsorption isotherms of these substances to the standard conditions (θ → 0, C → 0) and to the conditions of maximal approach of the adsorbed molecules to each other (θ → 1). The hydration energy of the molecules of benzene and its derivatives is calculated based on the proportionality of this energy to the sum of the concentration potentials of the components in a saturated solution, where the proportionality coefficient is equal to the number of water molecules interacting with one organic molecule. Calculated energies of phenol and aniline hydration are equal to the energies of H-bonds of phenol (OH···OH2) and amino (NH···OH2) groups. Hydration energies of phenol and aniline derivatives vary according to the effect of a substituent in the benzene ring on the H-bond energy. Negative values of hydration energy of polar hydrophobic molecules result from their hydrophobic effect on water structure. The interaction energy of hydrated and dehydrated adsorbed molecules, whose benzene ring planes are oriented in parallel to the carbon surface, is found from the calculated hydration energies. For H-bond-forming molecules, this energy is equal to the energy of one H-bond formed upon the surface dimerization. The energy of repulsion between polar hydrophobic molecules of benzene derivatives depends on the vertical component of the dipole moment, and is the higher the larger the polar group volume.

Nanogravimetry study of the initial stages of anodic surface oxide film growth at Au in aqueous HClO 4 and H 2SO 4 by means of EQCN

The dependence of the initial stages of anodic oxide film growth at Au on time or log time, τ h, was investigated by means of nanogravimetry using a electrochemical quartz crystal nanobalance (EQCN) which provides a new dimension for such studies, complementary to voltammetry, chronoamperometry and ellipsometry. Films were formed potentiostatically in sulphuric or perchloric acids. The mass to charge ratio determined over the potential range corresponding to Au oxide formation is found to be ca. 6–7 g per mole of electrons, which is close to the value expected for formation of Au/O ads on the electrode surface. The relations between charge and log τ h, or mass and log τ h, were evaluated. The charge for prior formation of O species, determined from reduction voltammetry, increases linearly with the log of the holding time. However, it is of special interest that the mass change in HClO 4 solutions does not increase linearly with the log of the holding time. This is interpreted in terms of co-adsorption of anions and displacement of water molecules. The results enable mechanisms of oxide film formation at Au to be critically appraised.

WaterScore: a novel method for distinguishing between bound and displaceable water molecules in the crystal structure of the binding site of protein-ligand complexes.

We have performed a multivariate logistic regression analysis to establish a statistical correlation between the structural properties of water molecules in the binding site of a free protein crystal structure, with the probability of observing the water molecules in the same location in the crystal structure of the ligand-complexed form. The temperature B-factor, the solvent-contact surface area, the total hydrogen bond energy and the number of protein-water contacts were found to discriminate between bound and displaceable water molecules in the best regression functions obtained. These functions may be used to identify those bound water molecules that should be included in structure-based drug design and ligand docking algorithms. FIGURE The binding site ( thin sticks) of penicillopepsin (3app) with its crystallographically determined water molecules ( spheres) and superimposed ligand (in thick sticks, from complexed structure 1ppk). Water molecules sterically displaced by the ligand upon complexation are shown in cyan. Bound water molecules are shown in blue. Displaced water molecules are shown in yellow. Water molecules removed from the analysis due to a lack of hydrogen bonds to the protein are shown in white. WaterScore correctly predicted waters in blue as Probability=1 to remain bound and waters in yellow as Probability<1x10(-20) to remain bound.

Crystal Structures of Allosamidin Derivatives in Complex with Human Macrophage Chitinase

The pseudotrisaccharide allosamidin is a potent family 18 chitinase inhibitor with demonstrated biological activity against insects, fungi, and the Plasmodium falciparum life cycle. The synthesis and biological properties of several derivatives have been reported. The structural interactions of allosamidin with several family 18 chitinases have been determined by x-ray crystallography previously. Here, a high resolution structure of chitotriosidase, the human macrophage chitinase, in complex with allosamidin is presented. In addition, complexes of the allosamidin derivatives demethylallosamidin, methylallosamidin, and glucoallosamidin B are described, together with their inhibitory properties. Similar to other chitinases, inhibition of the human chitinase by allosamidin derivatives lacking a methyl group is 10-fold stronger, and smaller effects are observed for the methyl and C3 epimer derivatives. The structures explain the effects on inhibition in terms of altered hydrogen bonding and hydrophobic interactions, together with displaced water molecules. The data reported here represent a first step toward structure-based design of specific allosamidin derivatives.

Enhanced emission from Eu(III) β-diketone complex combined with ether-type oxygen atoms of di-ureasil organic–inorganic hybrids

Organic–inorganic hybrids, named di-ureasils and described by polyether-based chains grafted to both ends to a siliceous backbone through urea cross linkages, were used as hosts for incorporation of the well-known coordination complex of trivalent europium (Eu 3+) ions described by the formula [Eu(TTA) 3(H 2O) 2] (where TTA stands for thenoyltrifluoroacetone). By comparing with Eu 3+-doped di-ureasil without complex form the new materials prepared here enhanced the quantum efficiency for photoemission of Eu 3+ ions. The enhancement can be explained by the coordination ability of the organic counterpart of the host structure which is strong enough to displace water molecules in [Eu(TTA) 3(H 2O) 2] from the rare earth neighbourhood after the incorporation process. High intensity of Eu 3+ emission was observed with a low non-radiative decay rate under ultraviolet excitation. The quantum efficiency calculated from the decay of 5D 0 emission was 74%, which in the same range of values previously obtained for the most efficient Eu 3+ coordination compounds reported in literature. Luminescence, X-ray absorption and infrared absorption results considered together leads to a picture where the first coordination shell of Eu 3+ is composed of the 6 oxygen atoms of the 3 β-diketonate ligands and 2 ether-like oxygen atoms of the host.

Crystallization in the presence of glycerol displaces water molecules in the structure of thaumatin.

The intensely sweet protein thaumatin has been crystallized at 293 K in the presence of sodium tartrate and 25%(v/v) glycerol for X-ray diffraction data collection at 100 K. A comparison of the three-dimensional structure model derived from a crystal grown in the presence of glycerol with that of a control deprived of this additive reveals only minor changes in the overall structure but a approximately 20% reduction in the number of water molecules. X-ray topography analyses show that the overall quality of the crystals prepared in the presence of this cryoprotectant is enhanced.

An overview on 2-methyl-2,4-pentanediol in crystallization and in crystals of biological macromolecules.

2‐Methyl‐2,4‐pentanediol (MPD) is the most popular chemical additive used for crystallization of biological macromolecules. However, the mechanism of its action on proteins in aqueous solution is not well understood. We have carried out a systematic analysis of the conformation and environment of MPD molecules bound to proteins. We find that the majority of MPD molecules adopt their most stable conformer. They prefer to bind to hydrophobic sites with a distinct preference for leucine side chains. Most MPD binding sites involve amino‐acid residues in helical or β‐sheet structures. MPD binding to proteins is penetrative, leading to displacement of water molecules in grooves and cavities (sometimes ligand‐binding and active sites) on the protein surface. This results in a large reduction of solvent‐accessible area, which can have significant implications for protein stability. The packing of the MPD molecules by the protein is not optimal and usually some other solvent molecules are also bound along with it. Our analysis suggests that MPD is not as strong a denaturant as often suggested. It promotes stabilization of the protein by preferential hydration, which is facilitated by attachment of MPD molecules to the hydrophobic surface.