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Sample records for hemoglobin docking sites

  1. 8-anilino-1-naphthaline sulfonate binds at the hemoglobin allosteric regulatory sites: inhibitory analyses

    International Nuclear Information System (INIS)

    Bokut', S.B.; Parul', D.A.; Yachnik, N.N.; Milyutin, A.A.

    2001-01-01

    The present study focused on the localization at least one of the ANS binding sites in the major form of human hemoglobin HbA. High-resolution docking predict ANS binding to the hemoglobin central cavity. Steady-state fluorescence titration data obtained in the absence/presence of natural effector inositol hexaphosphate (IHP) allowed to conclude that IHP competitively inhibited ANS binding to HbA. Thus, we must conclude that one of the ANS binding sites is central cavity, which makes it possible to monitor changes at this region upon ligation/deligation, effector binding and changes in hemoglobin structure

  2. Hemoglobin

    Science.gov (United States)

    1993-03-08

    affinity, which is less at low levels of hemoglobin saturation, increases markedly as fractional saturation increases. Thus, high affinity for 02 at... diphosphoglycerate (2,3-DPG), and carbon dioxide (Co 2). Since they are linked to 02 binding, they are called oxygen-linked effectors. The oxygen...hemoglobin molecule because of the negative charge of the ions. 2,3- Diphosphoglycerate is a molecule formed during the breakdown of sugar in normal human

  3. Nonenzymatic glycosylation of human hemoglobin at multiple sites

    International Nuclear Information System (INIS)

    Shapiro, R.; McManus, M.; Garrick, L.; McDonald, M.J.; Bunn, H.F.

    1979-01-01

    The most abundant minor hemoglobin component of human hemolysate is Hb A1c, which has glucose bound to the N-terminus of the beta chain by a ketoamine linkage. Hb A1c is formed slowly and continuously throughout the 120 day lifespan of the red cell. It can be synthesized in vitro by incubating purified hemoglobin with 14C-glucose. Other minor components, Hb A1a1 and Hb A1a2 are adducts of sugar phosphates at the N-terminus of the beta chain. Hb A1b contains an unidentified nonphosphorylated sugar at the beta N-terminus. In addition, a significant portion of the major hemoglobin component (Hb Ao) is also glycosylated by a glucose ketoamine linkage at other sites on the molecule, including the N-terminus of the alpha chain and the epsilon-amino group of several lysine residues on both the alpha and the beta chains. The results indicate that the interaction of glucose and hemoglobin is rather nonspecific and suggests that other proteins are modified in a similar fashion

  4. Molecular recognition of malachite green by hemoglobin and their specific interactions: insights from in silico docking and molecular spectroscopy.

    Science.gov (United States)

    Peng, Wei; Ding, Fei; Peng, Yu-Kui; Sun, Ying

    2014-01-01

    Malachite green is an organic compound that can be widely used as a dyestuff for various materials; it has also emerged as a controversial agent in aquaculture. Since malachite green is proven to be carcinogenic and mutagenic, it may become a hazard to public health. For this reason, it is urgently required to analyze this controversial dye in more detail. In our current research, the interaction between malachite green and hemoglobin under physiological conditions was investigated by the methods of molecular modeling, fluorescence spectroscopy, circular dichroism (CD) as well as hydrophobic ANS displacement experiments. From the molecular docking, the central cavity of hemoglobin was assigned to possess high-affinity for malachite green, this result was corroborated by time-resolved fluorescence and hydrophobic ANS probe results. The recognition mechanism was found to be of static type, or rather the hemoglobin-malachite green complex formation occurred via noncovalent interactions such as π-π interactions, hydrogen bonds and hydrophobic interactions with an association constant of 10(4) M(-1). Moreover, the results also show that the spatial structure of the biopolymer was changed in the presence of malachite green with a decrease of the α-helix and increase of the β-sheet, turn and random coil suggesting protein damage, as derived from far-UV CD and three-dimensional fluorescence. Results of this work will help to further comprehend the molecular recognition of malachite green by the receptor protein and the possible toxicological profiles of other compounds, which are the metabolites and ramifications of malachite green.

  5. Site-specific semisynthetic variant of human hemoglobin

    International Nuclear Information System (INIS)

    Hefta, S.A.; Lyle, S.B.; Busch, M.R.; Harris, D.E.; Matthew, J.B.; Gurd, F.R.N.

    1988-01-01

    A single round of Edman degradation was employed to remove the NH 2 -terminal valine from isolated α chains of human hemoglobin. Reconstitution of normal β chains with truncated or substituted α chains was used to form truncated (des-Val 1 -α1) and substituted ([[1- 13 C]Gly 1 ]α1) tetrameric hemoglobin analogs. Structural homology of the analogs with untreated native hemoglobin was established by using several spectroscopic and physical methods. Functional studies indicate that the reconstituted tetrameric protein containing des-Val 1 -α chains has a higher affinity for oxygen, is less influenced by chloride ions or 2,3-biphosphoglycerate, and shows lower cooperativity than native hemoglobin. These results confirm the key functional role of the α-chain NH 2 terminus in mediating cooperative oxygen binding across the dimer interface. The NH 2 -terminal pK/sub 1/2/ value was determined for the [ 13 C]glycine-substituted analog to be 7.46 +/- 0.09 at 15 0 C in the carbon monoxide-liganded form. This value, measured directly by 13 C NMR, agrees with the determination made by the less-direct 13 CO 2 method and confirms the role of this residue as a contributor to the alkaline Bohr effect; however, it is consistent with the presence of an NH 2 -terminal salt bridge to the carboxylate of Arg-141 of the α chain in the liganded form

  6. Cellulase enzyme: Homology modeling, binding site identification and molecular docking

    Science.gov (United States)

    Selvam, K.; Senbagam, D.; Selvankumar, T.; Sudhakar, C.; Kamala-Kannan, S.; Senthilkumar, B.; Govarthanan, M.

    2017-12-01

    Cellulase is an enzyme that degrades the linear polysaccharide like cellulose into glucose by breaking the β-1,4- glycosidic bonds. These enzymes are the third largest enzymes with a great potential towards the ethanol production and play a vital role in degrading the biomass. The production of ethanol depends upon the ability of the cellulose to utilize the wide range of substrates. In this study, the 3D structure of cellulase from Acinetobacter sp. was modeled by using Modeler 9v9 and validated by Ramachandran plot. The accuracy of the predicted 3D structure was checked using Ramachandran plot analysis showed that 81.1% in the favored region, compatibility of an atomic model (3D) with amino acid sequence (1D) for the model was observed as 78.21% and 49.395% for Verify 3D and ERRAT at SAVES server. As the binding efficacy with the substrate might suggests the choice of the substrate as carbon and nitrogen sources, the cellobiose, cellotetraose, cellotetriose and laminaribiose were employed in the docking studies. The docking of cellobiose, cellotetraose, cellotetriose and laminaribiose with cellulase exhibited the binding energy of -6.1523 kJ/mol, -7.8759 kJ/mol,-6.1590 kJ/mol and -6.7185 kJ/mol, respectively. These docking studies revealed that cellulase has the greater potential towards the cellotetraose as a substrate for the high yield of ethanol.

  7. Hemoglobin cleavage site-specificity of the Plasmodium falciparum cysteine proteases falcipain-2 and falcipain-3.

    Directory of Open Access Journals (Sweden)

    Shoba Subramanian

    Full Text Available The Plasmodium falciparum cysteine proteases falcipain-2 and falcipain-3 degrade host hemoglobin to provide free amino acids for parasite protein synthesis. Hemoglobin hydrolysis has been described as an ordered process initiated by aspartic proteases, but cysteine protease inhibitors completely block the process, suggesting that cysteine proteases can also initiate hemoglobin hydrolysis. To characterize the specific roles of falcipains, we used three approaches. First, using random P(1 - P(4 amino acid substrate libraries, falcipain-2 and falcipain-3 demonstrated strong preference for cleavage sites with Leu at the P(2 position. Second, with overlapping peptides spanning alpha and beta globin and proteolysis-dependent (18O labeling, hydrolysis was seen at many cleavage sites. Third, with intact hemoglobin, numerous cleavage products were identified. Our results suggest that hemoglobin hydrolysis by malaria parasites is not a highly ordered process, but rather proceeds with rapid cleavage by falcipains at multiple sites. However, falcipain-2 and falcipain-3 show strong specificity for P(2 Leu in small peptide substrates, in agreement with the specificity in optimized small molecule inhibitors that was identified previously. These results are consistent with a principal role of falcipain-2 and falcipain-3 in the hydrolysis of hemoglobin by P. falciparum and with the possibility of developing small molecule inhibitors with optimized specificity as antimalarial agents.

  8. Plasticity of the Binding Site of Renin: Optimized Selection of Protein Structures for Ensemble Docking.

    Science.gov (United States)

    Strecker, Claas; Meyer, Bernd

    2018-05-02

    Protein flexibility poses a major challenge to docking of potential ligands in that the binding site can adopt different shapes. Docking algorithms usually keep the protein rigid and only allow the ligand to be treated as flexible. However, a wrong assessment of the shape of the binding pocket can prevent a ligand from adapting a correct pose. Ensemble docking is a simple yet promising method to solve this problem: Ligands are docked into multiple structures, and the results are subsequently merged. Selection of protein structures is a significant factor for this approach. In this work we perform a comprehensive and comparative study evaluating the impact of structure selection on ensemble docking. We perform ensemble docking with several crystal structures and with structures derived from molecular dynamics simulations of renin, an attractive target for antihypertensive drugs. Here, 500 ns of MD simulations revealed binding site shapes not found in any available crystal structure. We evaluate the importance of structure selection for ensemble docking by comparing binding pose prediction, ability to rank actives above nonactives (screening utility), and scoring accuracy. As a result, for ensemble definition k-means clustering appears to be better suited than hierarchical clustering with average linkage. The best performing ensemble consists of four crystal structures and is able to reproduce the native ligand poses better than any individual crystal structure. Moreover this ensemble outperforms 88% of all individual crystal structures in terms of screening utility as well as scoring accuracy. Similarly, ensembles of MD-derived structures perform on average better than 75% of any individual crystal structure in terms of scoring accuracy at all inspected ensembles sizes.

  9. Hemoglobin Rahere, a human hemoglobin variant with amino acid substitution at the 2,3-diphosphoglycerate binding site. Functional consequences of the alteration and effects of bezafibrate on the oxygen bindings.

    OpenAIRE

    Sugihara, J; Imamura, T; Nagafuchi, S; Bonaventura, J; Bonaventura, C; Cashon, R

    1985-01-01

    We encountered an abnormal hemoglobin (Rahere), with a threonine residue replacing the beta 82 (EF6) lysine residue at the binding site of 2,3-diphosphoglycerate, which was responsible for overt erythrocytosis in two individuals of a Japanese family. Hemoglobin Rahere shows a lower oxygen affinity on the binding of 2,3-diphosphoglycerate or chloride ions than hemoglobin A. Although a decrease in the positive charge density at the binding sites of 2,3-diphosphoglycerate in hemoglobin Rahere ap...

  10. DARC 2.0: Improved Docking and Virtual Screening at Protein Interaction Sites.

    Directory of Open Access Journals (Sweden)

    Ragul Gowthaman

    Full Text Available Over the past decade, protein-protein interactions have emerged as attractive but challenging targets for therapeutic intervention using small molecules. Due to the relatively flat surfaces that typify protein interaction sites, modern virtual screening tools developed for optimal performance against "traditional" protein targets perform less well when applied instead at protein interaction sites. Previously, we described a docking method specifically catered to the shallow binding modes characteristic of small-molecule inhibitors of protein interaction sites. This method, called DARC (Docking Approach using Ray Casting, operates by comparing the topography of the protein surface when "viewed" from a vantage point inside the protein against the topography of a bound ligand when "viewed" from the same vantage point. Here, we present five key enhancements to DARC. First, we use multiple vantage points to more accurately determine protein-ligand surface complementarity. Second, we describe a new scheme for rapidly determining optimal weights in the DARC scoring function. Third, we incorporate sampling of ligand conformers "on-the-fly" during docking. Fourth, we move beyond simple shape complementarity and introduce a term in the scoring function to capture electrostatic complementarity. Finally, we adjust the control flow in our GPU implementation of DARC to achieve greater speedup of these calculations. At each step of this study, we evaluate the performance of DARC in a "pose recapitulation" experiment: predicting the binding mode of 25 inhibitors each solved in complex with its distinct target protein (a protein interaction site. Whereas the previous version of DARC docked only one of these inhibitors to within 2 Å RMSD of its position in the crystal structure, the newer version achieves this level of accuracy for 12 of the 25 complexes, corresponding to a statistically significant performance improvement (p < 0.001. Collectively then, we find

  11. Hemoglobin Rahere, a human hemoglobin variant with amino acid substitution at the 2,3-diphosphoglycerate binding site. Functional consequences of the alteration and effects of bezafibrate on the oxygen bindings.

    Science.gov (United States)

    Sugihara, J; Imamura, T; Nagafuchi, S; Bonaventura, J; Bonaventura, C; Cashon, R

    1985-09-01

    We encountered an abnormal hemoglobin (Rahere), with a threonine residue replacing the beta 82 (EF6) lysine residue at the binding site of 2,3-diphosphoglycerate, which was responsible for overt erythrocytosis in two individuals of a Japanese family. Hemoglobin Rahere shows a lower oxygen affinity on the binding of 2,3-diphosphoglycerate or chloride ions than hemoglobin A. Although a decrease in the positive charge density at the binding sites of 2,3-diphosphoglycerate in hemoglobin Rahere apparently shifts the allosteric equilibrium toward the low affinity state, it greatly diminishes the cofactor effects by anions. The oxygen affinity of the patient's erythrocytes is substantially lowered by the presence of bezafibrate, which combines with sites different from those of 2,3-diphosphoglycerate in either hemoglobin Rahere or hemoglobin A.

  12. Docking and molecular dynamics studies of peripheral site ligand–oximes as reactivators of sarin-inhibited human acetylcholinesterase

    NARCIS (Netherlands)

    Almeida, J.S.F.D. de; Cuya Guizado, T.R.; Guimarães, A.P.; Ramalho, T.C.; Gonçalves, A.S.; Koning, M.C. de; França, T.C.C.

    2016-01-01

    In the present work, we performed docking and molecular dynamics simulations studies on two groups of long-tailored oximes designed as peripheral site binders of acetylcholinesterase (AChE) and potential penetrators on the blood brain barrier. Our studies permitted to determine how the tails anchor

  13. Non-site-specific allosteric effect of oxygen on human hemoglobin under high oxygen partial pressure.

    Science.gov (United States)

    Takayanagi, Masayoshi; Kurisaki, Ikuo; Nagaoka, Masataka

    2014-04-08

    Protein allostery is essential for vital activities. Allosteric regulation of human hemoglobin (HbA) with two quaternary states T and R has been a paradigm of allosteric structural regulation of proteins. It is widely accepted that oxygen molecules (O2) act as a "site-specific" homotropic effector, or the successive O2 binding to the heme brings about the quaternary regulation. However, here we show that the site-specific allosteric effect is not necessarily only a unique mechanism of O2 allostery. Our simulation results revealed that the solution environment of high O2 partial pressure enhances the quaternary change from T to R without binding to the heme, suggesting an additional "non-site-specific" allosteric effect of O2. The latter effect should play a complementary role in the quaternary change by affecting the intersubunit contacts. This analysis must become a milestone in comprehensive understanding of the allosteric regulation of HbA from the molecular point of view.

  14. Identification of the quinolinedione inhibitor binding site in Cdc25 phosphatase B through docking and molecular dynamics simulations

    Science.gov (United States)

    Ge, Yushu; van der Kamp, Marc; Malaisree, Maturos; Liu, Dan; Liu, Yi; Mulholland, Adrian J.

    2017-11-01

    Cdc25 phosphatase B, a potential target for cancer therapy, is inhibited by a series of quinones. The binding site and mode of quinone inhibitors to Cdc25B remains unclear, whereas this information is important for structure-based drug design. We investigated the potential binding site of NSC663284 [DA3003-1 or 6-chloro-7-(2-morpholin-4-yl-ethylamino)-quinoline-5, 8-dione] through docking and molecular dynamics simulations. Of the two main binding sites suggested by docking, the molecular dynamics simulations only support one site for stable binding of the inhibitor. Binding sites in and near the Cdc25B catalytic site that have been suggested previously do not lead to stable binding in 50 ns molecular dynamics (MD) simulations. In contrast, a shallow pocket between the C-terminal helix and the catalytic site provides a favourable binding site that shows high stability. Two similar binding modes featuring protein-inhibitor interactions involving Tyr428, Arg482, Thr547 and Ser549 are identified by clustering analysis of all stable MD trajectories. The relatively flexible C-terminal region of Cdc25B contributes to inhibitor binding. The binding mode of NSC663284, identified through MD simulation, likely prevents the binding of protein substrates to Cdc25B. The present results provide useful information for the design of quinone inhibitors and their mechanism of inhibition.

  15. Identification of the quinolinedione inhibitor binding site in Cdc25 phosphatase B through docking and molecular dynamics simulations.

    Science.gov (United States)

    Ge, Yushu; van der Kamp, Marc; Malaisree, Maturos; Liu, Dan; Liu, Yi; Mulholland, Adrian J

    2017-11-01

    Cdc25 phosphatase B, a potential target for cancer therapy, is inhibited by a series of quinones. The binding site and mode of quinone inhibitors to Cdc25B remains unclear, whereas this information is important for structure-based drug design. We investigated the potential binding site of NSC663284 [DA3003-1 or 6-chloro-7-(2-morpholin-4-yl-ethylamino)-quinoline-5, 8-dione] through docking and molecular dynamics simulations. Of the two main binding sites suggested by docking, the molecular dynamics simulations only support one site for stable binding of the inhibitor. Binding sites in and near the Cdc25B catalytic site that have been suggested previously do not lead to stable binding in 50 ns molecular dynamics (MD) simulations. In contrast, a shallow pocket between the C-terminal helix and the catalytic site provides a favourable binding site that shows high stability. Two similar binding modes featuring protein-inhibitor interactions involving Tyr428, Arg482, Thr547 and Ser549 are identified by clustering analysis of all stable MD trajectories. The relatively flexible C-terminal region of Cdc25B contributes to inhibitor binding. The binding mode of NSC663284, identified through MD simulation, likely prevents the binding of protein substrates to Cdc25B. The present results provide useful information for the design of quinone inhibitors and their mechanism of inhibition.

  16. Location of the higher affinity copper site on human hemoglobin by the use of the spin label technique

    International Nuclear Information System (INIS)

    Tabak, M.; Louro, S.R.W.

    1983-11-01

    Addition of copper (II) ions to Cys β-93 maleimide spin-labelled human hemoglobin A produces a dramatic decrease in the amplitude of the spin-label ESR spectra. This effect was analyzed in the framework of Leigh's theory which permits interspin distances to be deduced from the effect of dipolar coupling on the ESR spectra and led to an estimate of 9A as the distance between the label and the higher affinity copper site. Taking into account the previous results which suggest that four nitrogen atoms coordinate with copper, and that the N terminal val β-1 and His β-2 residues are involved, the location of the higher affinity copper site is proposed to be at the β 1 β 2 interface of the hemoglobin molecule, involving the N terminal of one β subunit and the C terminal of the other. (Author) [pt

  17. Binding site analysis of full-length α1a adrenergic receptor using homology modeling and molecular docking

    International Nuclear Information System (INIS)

    Pedretti, Alessandro; Elena Silva, Maria; Villa, Luigi; Vistoli, Giulio

    2004-01-01

    The recent availability of crystal structure of bovine rhodopsin offers new opportunities in order to approach the construction of G protein coupled receptors. This study focuses the attention on the modeling of full-length α 1a adrenergic receptor (α 1a -AR) due to its biological role and significant implications in pharmacological treatment of benign prostate hyperplasia. This work could be considered made up by two main steps: (a) the construction of full structure of α 1a -AR, through homology modeling methods; (b) the automated docking of an endogenous agonist, norepinephrine, and of an antagonist, WB-4101, using BioDock program. The obtained results highlight the key residues involved in binding sites of both agonists and antagonists, confirming the mutagenesis data and giving new suggestions for the rational design of selective ligands

  18. The low molecular weight protein PsaI stabilizes the light-harvesting complex II docking site of photosystem I

    DEFF Research Database (Denmark)

    Plöchinger, Magdalena; Torabi, Salar; Rantala, Marjaana

    2016-01-01

    PsaI represents one of three low molecular weight peptides of PSI. Targeted inactivation of the plastid PsaI gene in Nicotiana tabacum has no measurable effect on photosynthetic electron transport around PSI or on accumulation of proteins involved in photosynthesis. Instead, the lack of Psa......I destabilizes the association of PsaL and PsaH to PSI, both forming the light-harvesting complex (LHC)II docking site of PSI. These alterations at the LHCII binding site surprisingly did not prevent state transition but led to an increased incidence of PSI-LHCII complexes, coinciding with an elevated...

  19. QSAR, docking and ADMET studies of artemisinin derivatives for antimalarial activity targeting plasmepsin II, a hemoglobin-degrading enzyme from P. falciparum.

    Science.gov (United States)

    Qidwai, Tabish; Yadav, Dharmendra K; Khan, Feroz; Dhawan, Sangeeta; Bhakuni, R S

    2012-01-01

    This work presents the development of quantitative structure activity relationship (QSAR) model to predict the antimalarial activity of artemisinin derivatives. The structures of the molecules are represented by chemical descriptors that encode topological, geometric, and electronic structure features. Screening through QSAR model suggested that compounds A24, A24a, A53, A54, A62 and A64 possess significant antimalarial activity. Linear model is developed by the multiple linear regression method to link structures to their reported antimalarial activity. The correlation in terms of regression coefficient (r(2)) was 0.90 and prediction accuracy of model in terms of cross validation regression coefficient (rCV(2)) was 0.82. This study indicates that chemical properties viz., atom count (all atoms), connectivity index (order 1, standard), ring count (all rings), shape index (basic kappa, order 2), and solvent accessibility surface area are well correlated with antimalarial activity. The docking study showed high binding affinity of predicted active compounds against antimalarial target Plasmepsins (Plm-II). Further studies for oral bioavailability, ADMET and toxicity risk assessment suggest that compound A24, A24a, A53, A54, A62 and A64 exhibits marked antimalarial activity comparable to standard antimalarial drugs. Later one of the predicted active compound A64 was chemically synthesized, structure elucidated by NMR and in vivo tested in multidrug resistant strain of Plasmodium yoelii nigeriensis infected mice. The experimental results obtained agreed well with the predicted values.

  20. Molecular docking simulations provide insights in the substrate binding sites and possible substrates of the ABCC6 transporter.

    Directory of Open Access Journals (Sweden)

    Mohammad Jakir Hosen

    Full Text Available The human ATP-binding cassette family C member 6 (ABCC6 gene encodes an ABC transporter protein (ABCC6, primarily expressed in liver and kidney. Mutations in the ABCC6 gene cause pseudoxanthoma elasticum (PXE, an autosomal recessive connective tissue disease characterized by ectopic mineralization of the elastic fibers. The pathophysiology underlying PXE is incompletely understood, which can at least partly be explained by the undetermined nature of the ABCC6 substrates as well as the unknown substrate recognition and binding sites. Several compounds, including anionic glutathione conjugates (N-ethylmaleimide; NEM-GS and leukotriene C4 (LTC4 were shown to be modestly transported in vitro; conversely, vitamin K3 (VK3 was demonstrated not to be transported by ABCC6. To predict the possible substrate binding pockets of the ABCC6 transporter, we generated a 3D homology model of ABCC6 in both open and closed conformation, qualified for molecular docking and virtual screening approaches. By docking 10 reported in vitro substrates in our ABCC6 3D homology models, we were able to predict the substrate binding residues of ABCC6. Further, virtual screening of 4651 metabolites from the Human Serum Metabolome Database against our open conformation model disclosed possible substrates for ABCC6, which are mostly lipid and biliary secretion compounds, some of which are found to be involved in mineralization. Docking of these possible substrates in the closed conformation model also showed high affinity. Virtual screening expands this possibility to explore more compounds that can interact with ABCC6, and may aid in understanding the mechanisms leading to PXE.

  1. Molecular docking.

    Science.gov (United States)

    Morris, Garrett M; Lim-Wilby, Marguerita

    2008-01-01

    Molecular docking is a key tool in structural molecular biology and computer-assisted drug design. The goal of ligand-protein docking is to predict the predominant binding mode(s) of a ligand with a protein of known three-dimensional structure. Successful docking methods search high-dimensional spaces effectively and use a scoring function that correctly ranks candidate dockings. Docking can be used to perform virtual screening on large libraries of compounds, rank the results, and propose structural hypotheses of how the ligands inhibit the target, which is invaluable in lead optimization. The setting up of the input structures for the docking is just as important as the docking itself, and analyzing the results of stochastic search methods can sometimes be unclear. This chapter discusses the background and theory of molecular docking software, and covers the usage of some of the most-cited docking software.

  2. Hemoglobin (image)

    Science.gov (United States)

    Hemoglobin is the most important component of red blood cells. It is composed of a protein called ... exchanged for carbon dioxide. Abnormalities of an individual's hemoglobin value can indicate defects in the normal balance ...

  3. QSAR, docking, dynamic simulation and quantum mechanics studies to explore the recognition properties of cholinesterase binding sites.

    Science.gov (United States)

    Correa-Basurto, J; Bello, M; Rosales-Hernández, M C; Hernández-Rodríguez, M; Nicolás-Vázquez, I; Rojo-Domínguez, A; Trujillo-Ferrara, J G; Miranda, René; Flores-Sandoval, C A

    2014-02-25

    A set of 84 known N-aryl-monosubstituted derivatives (42 amides: series 1 and 2, and 42 imides: series 3 an 4, from maleic and succinic anhydrides, respectively) that display inhibitory activity toward both acetylcholinesterase and butyrylcholinesterase (ChEs) was considered for Quantitative structure-activity relationship (QSAR) studies. These QSAR studies employed docking data from both ChEs that were previously submitted to molecular dynamics (MD) simulations. Donepezil and galanthamine stereoisomers were included to analyze their quantum mechanics properties and for validating the docking procedure. Quantum parameters such as frontier orbital energies, dipole moment, molecular volume, atomic charges, bond length and reactivity parameters were measured, as well as partition coefficients, molar refractivity and polarizability were also analyzed. In order to evaluate the obtained equations, four compounds: 1a (4-oxo-4-(phenylamino)butanoic acid), 2a ((2Z)-4-oxo-4-(phenylamino)but-2-enoic acid), 3a (2-phenylcyclopentane-1,3-dione) and 4a (2-phenylcyclopent-4-ene-1,3-dione) were employed as independent data set, using only equations with r(m(test))²>0.5. It was observed that residual values gave low value in almost all series, excepting in series 1 for compounds 3a and 4a, and in series 4 for compounds 1a, 2a and 3a, giving a low value for 4a. Consequently, equations seems to be specific according to the structure of the evaluated compound, that means, series 1 fits better for compound 1a, series 3 or 4 fits better for compounds 3a or 4a. Same behavior was observed in the butyrylcholinesterase (BChE). Therefore, obtained equations in this QSAR study could be employed to calculate the inhibition constant (Ki) value for compounds having a similar structure as N-aryl derivatives described here. The QSAR study showed that bond lengths, molecular electrostatic potential and frontier orbital energies are important in both ChE targets. Docking studies revealed that

  4. Polar bear hemoglobin and human Hb A0: same 2,3-diphosphoglycerate binding site but asymmetry of the binding?

    Science.gov (United States)

    Pomponi, Massimo; Bertonati, Claudia; Patamia, Maria; Marta, Maurizio; Derocher, Andrew E; Lydersen, Christian; Kovacs, Kit M; Wiig, Oystein; Bårdgard, Astrid J

    2002-11-01

    Polar bear (Ursus maritimus) hemoglobin (Hb) shows a low response to 2,3-diphosphoglycerate (2,3-DPG), compared to human Hb A0, even though these proteins have the same 2,3-DPG-binding site. In addition, polar bear Hb shows a high response to chloride and an alkaline Bohr effect (deltalog P50/deltapH) that is significantly greater than that of human Hb A0. The difference in sequence Pro (Hb A0)-->Gly (polar bear Hb) at position A2 in the A helix seems to be critical for reduced binding of 2,3-DPG. Our results also show that the A2 position may influence not only the flexibility of the A helix, but that differences in flexibility of the first turn of the A helix may affect the unloading of oxygen for the intrinsic ligand affinities of the alpha and beta chains. However, preferential binding to either chain can only take place if there is appreciable asymmetric binding of the phosphoric effector. Regarding this point, 31P NMR data suggest a loss of symmetry of the 2,3-DPG-binding site in the deoxyHb-2,3-DPG complex.

  5. Three tapasin docking sites in TAP cooperate to facilitate transporter stabilization and heterodimerization

    Science.gov (United States)

    Leonhardt, Ralf M.; Abrahimi, Parwiz; Mitchell, Susan M.; Cresswell, Peter

    2014-01-01

    The transporter associated with antigen processing (TAP) translocates peptide antigens into the lumen of the endoplasmic reticulum (ER) for loading onto major histocompatibility complex (MHC) class I molecules. MHC class I acquires its peptide cargo in the peptide loading complex (PLC), an oligomeric complex that the chaperone tapasin organizes by bridging TAP to MHC class I and recruiting accessory molecules such as ERp57 and calreticulin. Three tapasin binding sites on TAP have been described, two of which are located in the N-terminal domains (N domains) of TAP1 and TAP2. The third binding site is present in the core transmembrane domain (coreTMD) of TAP1 and is only used by the unassembled subunits. Tapasin is required to promote TAP stability, but through which binding site(s) it is acting is unknown. In particular the role of tapasin binding to the coreTMD of TAP1 single chains is mysterious as this interaction is lost upon TAP2 association. In this study, we map the respective binding site in TAP1 to the polar face of the amphipathic transmembrane helix TM9 and identify key residues that are essential to establish the interaction. We find that this interaction is dispensable for the peptide transport function but essential to achieve full stability of human TAP1. The interaction is also required for proper heterodimerization of the transporter. Based on similar results obtained using TAP mutants lacking tapasin binding to either N domain, we conclude that all three tapasin-binding sites in TAP cooperate to achieve high transporter stability and efficient heterodimerization. PMID:24501197

  6. Next-generation site-directed transgenesis in the malaria vector mosquito Anopheles gambiae: self-docking strains expressing germline-specific phiC31 integrase.

    Directory of Open Access Journals (Sweden)

    Janet M Meredith

    Full Text Available Diseases transmitted by mosquitoes have a devastating impact on global health and the situation is complicated due to difficulties with both existing control measures and the impact of climate change. Genetically modified mosquitoes that are refractory to disease transmission are seen as having great potential in the delivery of novel control strategies. The Streptomyces phage phiC31 integrase system has been successfully adapted for site-directed transgene integration in a range of insects, thus overcoming many limitations due to size constraints and random integration associated with transposon-mediated transformation. Using this technology, we previously published the first site-directed transformation of Anopheles gambiae, the principal vector of human malaria. Mosquitoes were initially engineered to incorporate the phiC31 docking site at a defined genomic location. A second phase of genetic modification then achieved site-directed integration of an anti-malarial effector gene. In the current publication we report improved efficiency and utility of the phiC31 integrase system following the generation of Anopheles gambiae self-docking strains. Four independent strains, with docking sites at known locations on three different chromosome arms, were engineered to express integrase under control of the regulatory regions of the nanos gene from Anopheles gambiae. The resulting protein accumulates in the posterior oocyte to provide integrase activity at the site of germline development. Two self-docking strains, exhibiting significantly different levels of integrase expression, were assessed for site-directed transgene integration and found to demonstrate greatly improved survival and efficiency of transformation. In the fight against malaria, it is imperative to establish a broad repertoire of both anti-malarial effector genes and tissue-specific promoters to regulate their expression, enabling those offering maximum effect with minimum fitness

  7. A python-based docking program utilizing a receptor bound ligand shape: PythDock.

    Science.gov (United States)

    Chung, Jae Yoon; Cho, Seung Joo; Hah, Jung-Mi

    2011-09-01

    PythDock is a heuristic docking program that uses Python programming language with a simple scoring function and a population based search engine. The scoring function considers electrostatic and dispersion/repulsion terms. The search engine utilizes a particle swarm optimization algorithm. A grid potential map is generated using the shape information of a bound ligand within the active site. Therefore, the searching area is more relevant to the ligand binding. To evaluate the docking performance of PythDock, two well-known docking programs (AutoDock and DOCK) were also used with the same data. The accuracy of docked results were measured by the difference of the ligand structure between x-ray structure, and docked pose, i.e., average root mean squared deviation values of the bound ligand were compared for fourteen protein-ligand complexes. Since the number of ligands' rotational flexibility is an important factor affecting the accuracy of a docking, the data set was chosen to have various degrees of flexibility. Although PythDock has a scoring function simpler than those of other programs (AutoDock and DOCK), our results showed that PythDock predicted more accurate poses than both AutoDock4.2 and DOCK6.2. This indicates that PythDock could be a useful tool to study ligand-receptor interactions and could also be beneficial in structure based drug design.

  8. Fish hemoglobins

    OpenAIRE

    Souza,P.C. de; Bonilla-Rodriguez,G.O.

    2007-01-01

    Vertebrate hemoglobin, contained in erythrocytes, is a globular protein with a quaternary structure composed of 4 globin chains (2 alpha and 2 beta) and a prosthetic group named heme bound to each one. Having myoglobin as an ancestor, hemoglobin acquired the capacity to respond to chemical stimuli that modulate its function according to tissue requirements for oxygen. Fish are generally submitted to spatial and temporal O2 variations and have developed anatomical, physiological and biochemica...

  9. A combined spectroscopic and molecular docking study on site selective binding interaction of Toluidine blue O with Human and Bovine serum albumins

    Energy Technology Data Exchange (ETDEWEB)

    Selva Sharma, Arumugam [Department of Chemistry, Bharathiar University, Coimbatore 641046 (India); Anandakumar, Shanmugam [Department of Bioinformatics, Bharathiar University, Coimbatore 641046 (India); Ilanchelian, Malaichamy, E-mail: chelian73@yahoo.com [Department of Chemistry, Bharathiar University, Coimbatore 641046 (India)

    2014-07-01

    In the present investigation the interaction of a biologically active photodynamic therapeutic agent Toluidine blue O (TBO) with Serum albumins viz Human serum albumin (HSA) and Bovine serum albumin (BSA) was studied using absorption, emission, circular dichroism spectroscopy and molecular docking experiments. The emission titration experiments between HSA/BSA and TBO revealed the existence of strong interactions between TBO and the proteins. The site competitive experiment of HSA and BSA showed that the primary binding site of TBO is located in site I of HSA/BSA involving hydrophobic, hydrogen bonding and electrostatic interaction. To ascertain the results of site competitive experiments, molecular docking was utilized to characterize the binding models of TBO–HSA/BSA complexes. From the molecular docking studies, free energy calculations were undertaken to examine the energy contributions and the role of various amino acid residues of HSA/BSA in TBO binding. The existence of Forster Resonance Energy Transfer (FRET) between the ligand and the protein was utilized to calculate the donor–acceptor distance of TBO and protein. The TBO induced conformational changes of HSA/BSA was established using synchronous emission, three dimensional emission and circular dichroism studies. - Highlights: • Site selective binding interaction of TBO with HSA and BSA were investigated. • TBO quenches the intrinsic fluorescence of HSA/BSA by static quenching process. • Computational studies of TBO with HSA/BSA substantiate the experimental findings. • 3D and CD spectral studies of TBO–HSA/BSA revealed structural changes in protein. • The distance (r) between TBO and HSA/BSA were estimated from FRET theory.

  10. Membrane docking geometry of GRP1 PH domain bound to a target lipid bilayer: an EPR site-directed spin-labeling and relaxation study.

    Directory of Open Access Journals (Sweden)

    Huai-Chun Chen

    Full Text Available The second messenger lipid PIP(3 (phosphatidylinositol-3,4,5-trisphosphate is generated by the lipid kinase PI3K (phosphoinositide-3-kinase in the inner leaflet of the plasma membrane, where it regulates a broad array of cell processes by recruiting multiple signaling proteins containing PIP(3-specific pleckstrin homology (PH domains to the membrane surface. Despite the broad importance of PIP(3-specific PH domains, the membrane docking geometry of a PH domain bound to its target PIP(3 lipid on a bilayer surface has not yet been experimentally determined. The present study employs EPR site-directed spin labeling and relaxation methods to elucidate the membrane docking geometry of GRP1 PH domain bound to bilayer-embedded PIP(3. The model target bilayer contains the neutral background lipid PC and both essential targeting lipids: (i PIP(3 target lipid that provides specificity and affinity, and (ii PS facilitator lipid that enhances the PIP(3 on-rate via an electrostatic search mechanism. The EPR approach measures membrane depth parameters for 18 function-retaining spin labels coupled to the PH domain, and for calibration spin labels coupled to phospholipids. The resulting depth parameters, together with the known high resolution structure of the co-complex between GRP1 PH domain and the PIP(3 headgroup, provide sufficient constraints to define an optimized, self-consistent membrane docking geometry. In this optimized geometry the PH domain engulfs the PIP(3 headgroup with minimal bilayer penetration, yielding the shallowest membrane position yet described for a lipid binding domain. This binding interaction displaces the PIP(3 headgroup from its lowest energy position and orientation in the bilayer, but the headgroup remains within its energetically accessible depth and angular ranges. Finally, the optimized docking geometry explains previous biophysical findings including mutations observed to disrupt membrane binding, and the rapid lateral

  11. New Computational Approaches for NMR-based Drug Design: A Protocol for Ligand Docking to Flexible Target Sites

    International Nuclear Information System (INIS)

    Gracia, Luis; Speidel, Joshua A.; Weinstein, Harel

    2006-01-01

    NMR-based drug design has met with some success in the last decade, as illustrated in numerous instances by Fesik's ''ligand screening by NMR'' approach. Ongoing efforts to generalize this success have led us to the development of a new paradigm in which quantitative computational approaches are being integrated with NMR derived data and biological assays. The key component of this work is the inclusion of the intrinsic dynamic quality of NMR structures in theoretical models and its use in docking. A new computational protocol is introduced here, designed to dock small molecule ligands to flexible proteins derived from NMR structures. The algorithm makes use of a combination of simulated annealing monte carlo simulations (SA/MC) and a mean field potential informed by the NMR data. The new protocol is illustrated in the context of an ongoing project aimed at developing new selective inhibitors for the PCAF bromodomains that interact with HIV Tat

  12. DockingShop: A Tool for Interactive Molecular Docking

    Energy Technology Data Exchange (ETDEWEB)

    Lu, Ting-Cheng; Max, Nelson L.; Ding, Jinhui; Bethel, E. Wes; Crivelli, Silvia N.

    2005-04-24

    Given two independently determined molecular structures, the molecular docking problem predicts the bound association, or best fit between them, while allowing for conformational changes of the individual molecules during construction of a molecular complex. Docking Shop is an integrated environment that permits interactive molecular docking by navigating a ligand or protein to an estimated binding site of a receptor with real-time graphical feedback of scoring factors as visual guides. Our program can be used to create initial configurations for a protein docking prediction process. Its output--the structure of aprotein-ligand or protein-protein complex--may serve as an input for aprotein docking algorithm, or an optimization process. This tool provides molecular graphics interfaces for structure modeling, interactive manipulation, navigation, optimization, and dynamic visualization to aid users steer the prediction process using their biological knowledge.

  13. Fish hemoglobins

    Directory of Open Access Journals (Sweden)

    P.C. de Souza

    2007-06-01

    Full Text Available Vertebrate hemoglobin, contained in erythrocytes, is a globular protein with a quaternary structure composed of 4 globin chains (2 alpha and 2 beta and a prosthetic group named heme bound to each one. Having myoglobin as an ancestor, hemoglobin acquired the capacity to respond to chemical stimuli that modulate its function according to tissue requirements for oxygen. Fish are generally submitted to spatial and temporal O2 variations and have developed anatomical, physiological and biochemical strategies to adapt to the changing environmental gas availability. Structurally, most fish hemoglobins are tetrameric; however, those from some species such as lamprey and hagfish dissociate, being monomeric when oxygenated and oligomeric when deoxygenated. Fish blood frequently possesses several hemoglobins; the primary origin of this finding lies in the polymorphism that occurs in the globin loci, an aspect that may occasionally confer advantages to its carriers or even be a harmless evolutionary remnant. On the other hand, the functional properties exhibit different behaviors, ranging from a total absence of responses to allosteric regulation to drastic ones, such as the Root effect.

  14. A modeling of the structure and favorable H-docking sites and defects for the high-pressure silica polymorph stishovite

    Science.gov (United States)

    Gibbs, G. V.; Cox, D. F.; Ross, N. L.

    Employing first-principles methods, the docking sites for H were determined and H, Al, and vacancy defects were modeled with an infinite periodic array of super unit cells each consisting of 27 contiguous symmetry nonequivalent unit cells of the crystal structure of stishovite. A geometry optimization of the super-cell structure reproduces the observed bulk structure within the experimental error when P1 translational symmetry was assumed and an array of infinite extent was generated. A mapping of the valence electrons for the structure displays mushroom-shaped isosurfaces on the O atom, one on each side of the plane of the OSi3 triangle in the nonbonded region. An H atom, placed in a cell near the center of the super cell, was found to dock upon geometry optimization at a distance of 1.69 Å from the O atom with the OH vector oriented nearly perpendicular to the plane of the triangle such that the OH vector makes a angle of 91° with respect to [001]. However, an optimization of a super cell with an Al atom replacing Si and an H atom placed nearby in a centrally located cell resulted in an OH distance of 1.02 Å with the OH vector oriented perpendicular to [001] as observed in infrared studies. The geometry-optimized position of the H atom was found to be in close agreement with that (0.44, 0.12, 0.0) determined in an earlier study of the theoretical electron density distribution. The docking of the H atom at this site was found to be 330 kJ mol-1 more stable than a docking of the atom just off the shared OO edge of the octahedra as determined for rutile. A geometry optimization of a super cell with a missing Si generated a vacant octahedra that is 20% larger than that of the SiO6 octahedra. The valence electron density distribution displayed by the two-coordinate O atoms that coordinate the vacant octahedral site is very similar to those displayed by the bent SiOSi angles in coesite. The internal distortions induced by the defect were found to diminish rather

  15. Hemoglobin C disease

    Science.gov (United States)

    Clinical hemoglobin C ... Hemoglobin C is an abnormal type of hemoglobin, the protein in red blood cells that carries oxygen. It is ... Americans. You are more likely to have hemoglobin C disease if someone in your family has had ...

  16. Combinatorial multispectral, thermodynamics, docking and site-directed mutagenesis reveal the cognitive characteristics of honey bee chemosensory protein to plant semiochemical.

    Science.gov (United States)

    Tan, Jing; Song, Xinmi; Fu, Xiaobin; Wu, Fan; Hu, Fuliang; Li, Hongliang

    2018-05-09

    In the chemoreceptive system of insects, there are always some soluble binding proteins, such as some antennal-specific chemosensory proteins (CSPs), which are abundantly distributed in the chemosensory sensillar lymph. The antennal-specific CSPs usually have strong capability to bind diverse semiochemicals, while the detailed interaction between CSPs and the semiochemicals remain unclear. Here, by means of the combinatorial multispectral, thermodynamics, docking and site-directed mutagenesis, we detailedly interpreted a binding interaction between a plant semiochemical β-ionone and antennal-specific CSP1 from the worker honey bee. Thermodynamic parameters (ΔH  0) indicate that the interaction is mainly driven by hydrophobic forces and electrostatic interactions. Docking prediction results showed that there are two key amino acids, Phe44 and Gln63, may be involved in the interacting process of CSP1 to β-ionone. In order to confirm the two key amino acids, site-directed mutagenesis were performed and the binding constant (K A ) for two CSP1 mutant proteins was reduced by 60.82% and 46.80% compared to wild-type CSP1. The thermodynamic analysis of mutant proteins furtherly verified that Phe44 maintained an electrostatic interaction and Gln63 contributes hydrophobic and electrostatic forces. Our investigation initially elucidates the physicochemical mechanism of the interaction between antennal-special CSPs in insects including bees to plant semiochemicals, as well as the development of twice thermodynamic analysis (wild type and mutant proteins) combined with multispectral and site-directed mutagenesis methods. Copyright © 2018. Published by Elsevier B.V.

  17. Structure and function of hemoglobin variants at an internal hydrophobic site: Consequences of mutations at the β 27 (B9) position

    International Nuclear Information System (INIS)

    Huang, Yue; Pagnier, J.; Magne, P.; Kister, J.; Poyart, C.; Baklouti, F.; Delaunay, J.; Fermi, G.; Perutz, M.F.

    1990-01-01

    The authors have studied the structure-function relationships in newly discovered hemoglobin (Hb) mutants with substitutions occurring at the tight and highly hydrophobic cluster between the B and G helices in the β chains, namely, Hb Knossos or β A27S and Hb Grange-Blanche or β A27V. The β A27S mutant has a 50% decrease in oxygen affinity relative to native human Hb A, while the β A27V mutant has an increased oxygen affinity. They have also engineered the artificial β A27T mutation through site-directed mutagenesis. This new mutant exhibits functional properties similar to those of Hb A. None of these mutants is unstable. X-ray analyses show that the substitution of Val for Ala may reduce the relative stability of the T structure of the molecule through packing effects in the β chains; for the β A27S mutant a new hydrogen bond between serine and the carbonyl O at β 23 (B5) Val is observed and is likely to increase the relative stability of the T structure in the mutant hemoglobin. However, no significant changes in the crystals were observed for these mutants between the quaternary R and T structures relative to native Hb A. They conclude that small tertiary structural changes in the tight hydrophobic B-G helix interface are sufficient to induce functional abnormalities resulting in either low or high intrinsic oxygen affinities

  18. Dimerization of DOCK2 is essential for DOCK2-mediated Rac activation and lymphocyte migration.

    Directory of Open Access Journals (Sweden)

    Masao Terasawa

    Full Text Available The migratory properties of lymphocytes depend on DOCK2, an atypical Rac activator predominantly expressed in hematopoietic cells. Although DOCK2 does not contain the Dbl homology domain typically found in guanine nucleotide exchange factors (GEFs, DOCK2 mediates the GTP-GDP exchange reaction for Rac via its DOCK homology region (DHR-2 (also known as CZH2 or Docker domain. DOCK2 DHR-2 domain is composed of three lobes, and Rac binding site and catalytic center are generated entirely from lobes B and C. On the other hand, lobe A has been implicated in dimer formation, yet its physiological significance remains unknown. Here, we report that lobe A-mediated DOCK2 dimerization is crucial for Rac activation and lymphocyte migration. We found that unlike wild-type DOCK2, DOCK2 mutant lacking lobe A failed to restore motility and polarity when expressed in thymoma cells and primary T cells lacking endogenous expression of DOCK2. Similar results were obtained with the DOCK2 point mutant having a defect in dimerization. Deletion of lobe A from the DHR-2 domain did not affect Rac GEF activity in vitro. However, fluorescence resonance energy transfer analyses revealed that lobe A is required for DOCK2 to activate Rac effectively during cell migration. Our results thus indicate that DOCK2 dimerization is functionally important under the physiological condition where only limited amounts of DOCK2 and Rac are localized to the plasma membrane.

  19. Homology modeling and docking of AahII-Nanobody complexes reveal the epitope binding site on AahII scorpion toxin.

    Science.gov (United States)

    Ksouri, Ayoub; Ghedira, Kais; Ben Abderrazek, Rahma; Shankar, B A Gowri; Benkahla, Alia; Bishop, Ozlem Tastan; Bouhaouala-Zahar, Balkiss

    2018-02-19

    Scorpion envenoming and its treatment is a public health problem in many parts of the world due to highly toxic venom polypeptides diffusing rapidly within the body of severely envenomed victims. Recently, 38 AahII-specific Nanobody sequences (Nbs) were retrieved from which the performance of NbAahII10 nanobody candidate, to neutralize the most poisonous venom compound namely AahII acting on sodium channels, was established. Herein, structural computational approach is conducted to elucidate the Nb-AahII interactions that support the biological characteristics, using Nb multiple sequence alignment (MSA) followed by modeling and molecular docking investigations (RosettaAntibody, ZDOCK software tools). Sequence and structural analysis showed two dissimilar residues of NbAahII10 CDR1 (Tyr27 and Tyr29) and an inserted polar residue Ser30 that appear to play an important role. Indeed, CDR3 region of NbAahII10 is characterized by a specific Met104 and two negatively charged residues Asp115 and Asp117. Complex dockings reveal that NbAahII17 and NbAahII38 share one common binding site on the surface of the AahII toxin divergent from the NbAahII10 one's. At least, a couple of NbAahII10 - AahII residue interactions (Gln38 - Asn44 and Arg62, His64, respectively) are mainly involved in the toxic AahII binding site. Altogether, this study gives valuable insights in the design and development of next generation of antivenom. Copyright © 2018 Elsevier Inc. All rights reserved.

  20. Ligand uptake in Mycobacterium tuberculosis truncated hemoglobins is controlled by both internal tunnels and active site water molecules [version 2; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Ignacio Boron

    2015-07-01

    Full Text Available Mycobacterium tuberculosis, the causative agent of human tuberculosis, has two proteins belonging to the truncated hemoglobin (trHb family. Mt-trHbN presents well-defined internal hydrophobic tunnels that allow O2 and •ŸNO to migrate easily from the solvent to the active site, whereas Mt-trHbO possesses tunnels interrupted by a few bulky residues, particularly a tryptophan at position G8. Differential ligand migration rates allow Mt-trHbN to detoxify Ÿ•NO, a crucial step for pathogen survival once under attack by the immune system, much more efficiently than Mt-trHbO. In order to investigate the differences between these proteins, we performed experimental kinetic measurements, Ÿ•NO decomposition, as well as molecular dynamics simulations of the wild type Mt-trHbN and two mutants, VG8F and VG8W. These mutations affect both the tunnels accessibility as well as the affinity of distal site water molecules, thus modifying the ligand access to the iron. We found that a single mutation allows Mt-trHbN to acquire ligand migration rates comparable to those observed for Mt-trHbO, confirming that ligand migration is regulated by the internal tunnel architecture as well as by water molecules stabilized in the active site.

  1. Protein docking prediction using predicted protein-protein interface

    Directory of Open Access Journals (Sweden)

    Li Bin

    2012-01-01

    Full Text Available Abstract Background Many important cellular processes are carried out by protein complexes. To provide physical pictures of interacting proteins, many computational protein-protein prediction methods have been developed in the past. However, it is still difficult to identify the correct docking complex structure within top ranks among alternative conformations. Results We present a novel protein docking algorithm that utilizes imperfect protein-protein binding interface prediction for guiding protein docking. Since the accuracy of protein binding site prediction varies depending on cases, the challenge is to develop a method which does not deteriorate but improves docking results by using a binding site prediction which may not be 100% accurate. The algorithm, named PI-LZerD (using Predicted Interface with Local 3D Zernike descriptor-based Docking algorithm, is based on a pair wise protein docking prediction algorithm, LZerD, which we have developed earlier. PI-LZerD starts from performing docking prediction using the provided protein-protein binding interface prediction as constraints, which is followed by the second round of docking with updated docking interface information to further improve docking conformation. Benchmark results on bound and unbound cases show that PI-LZerD consistently improves the docking prediction accuracy as compared with docking without using binding site prediction or using the binding site prediction as post-filtering. Conclusion We have developed PI-LZerD, a pairwise docking algorithm, which uses imperfect protein-protein binding interface prediction to improve docking accuracy. PI-LZerD consistently showed better prediction accuracy over alternative methods in the series of benchmark experiments including docking using actual docking interface site predictions as well as unbound docking cases.

  2. Protein docking prediction using predicted protein-protein interface.

    Science.gov (United States)

    Li, Bin; Kihara, Daisuke

    2012-01-10

    Many important cellular processes are carried out by protein complexes. To provide physical pictures of interacting proteins, many computational protein-protein prediction methods have been developed in the past. However, it is still difficult to identify the correct docking complex structure within top ranks among alternative conformations. We present a novel protein docking algorithm that utilizes imperfect protein-protein binding interface prediction for guiding protein docking. Since the accuracy of protein binding site prediction varies depending on cases, the challenge is to develop a method which does not deteriorate but improves docking results by using a binding site prediction which may not be 100% accurate. The algorithm, named PI-LZerD (using Predicted Interface with Local 3D Zernike descriptor-based Docking algorithm), is based on a pair wise protein docking prediction algorithm, LZerD, which we have developed earlier. PI-LZerD starts from performing docking prediction using the provided protein-protein binding interface prediction as constraints, which is followed by the second round of docking with updated docking interface information to further improve docking conformation. Benchmark results on bound and unbound cases show that PI-LZerD consistently improves the docking prediction accuracy as compared with docking without using binding site prediction or using the binding site prediction as post-filtering. We have developed PI-LZerD, a pairwise docking algorithm, which uses imperfect protein-protein binding interface prediction to improve docking accuracy. PI-LZerD consistently showed better prediction accuracy over alternative methods in the series of benchmark experiments including docking using actual docking interface site predictions as well as unbound docking cases.

  3. Intracellular signaling of the Ufo/Axl receptor tyrosine kinase is mediated mainly by a multi-substrate docking-site.

    Science.gov (United States)

    Braunger, J; Schleithoff, L; Schulz, A S; Kessler, H; Lammers, R; Ullrich, A; Bartram, C R; Janssen, J W

    1997-06-05

    Ufo/Axl belongs to a new family of receptor tyrosine kinases with an extracellular structure similar to that of neural cell adhesion molecules. In order to elucidate intracellular signaling, the cytoplasmic moiety of Ufo/Axl was used to screen an expression library according to the CORT (cloning of receptor targets) method. Three putative Ufo substrates were identified: phospholipase Cgamma1 (PLCgamma), as well as p85alpha and p85beta subunits of phosphatidylinositol 3'-kinase (PI3-kinase). Subsequently, chimeric EGFR/Ufo receptors consisting of the extracellular domains of the epidermal growth factor receptor (EGFR) and the transmembrane and intracellular moiety of Ufo were engineered. Using different far-Western blot analyses and coimmunoprecipitation assays, receptor binding of PLCgamma and p85 proteins as well as GRB2, c-src and lck was examined in vitro and in vivo. Competitive inhibition of substrate binding and mutagenesis experiments with EGFR/Ufo constructs revealed C-terminal tyrosine 821 (EILpYVNMDEG) as a docking site for multiple effectors, namely PLCgamma, p85 proteins, GRB2, c-src and lck. Tyrosine 779 (DGLpYALMSRC) demonstrated an additional, but lower binding affinity for the p85 proteins in vitro. In addition, binding of PLCgamma occurred through tyrosine 866 (AGRpYVLCPST). Moreover, our in vivo data indicate that further direct or indirect binding sites for PLCgamma, GRB2, c-src and lck on the human Ufo receptor may exist.

  4. Site fidelity and home range of the longsnout seahorse Hippocampus reidi (Teleostei: Syngnathidae) at the Varadero dock, northwest Cuba

    OpenAIRE

    de la Nuez Hernández, Daril; Pastor Gutiérrez, Lourdes; Pérez Angulo, Alejandro; Piloto Cubero, Yuliet; Corrada Wong, Raúl Igor

    2016-01-01

    Fish populations of the Syngnathidae family, including the charismatic seahorse, have significantly declined worldwide during the last decades. Up to now, these populations have been poorly researched in their habitat in Cuba. The objective of this study was to determinate site fidelity and home range of the longsnout seahorse (Hippocampus reidi Ginsburg, 1933), which has been poorly studied and has been classified as a Data Deficient (DD) species by the IUCN. Sampling was conducted between A...

  5. Lack of conventional oxygen-linked proton and anion binding sites does not impair allosteric regulation of oxygen binding in dwarf caiman hemoglobin

    Science.gov (United States)

    Fago, Angela; Malte, Hans; Storz, Jay F.; Gorr, Thomas A.

    2013-01-01

    In contrast to other vertebrate hemoglobins (Hbs) whose high intrinsic O2 affinities are reduced by red cell allosteric effectors (mainly protons, CO2, organic phosphates, and chloride ions), crocodilian Hbs exhibit low sensitivity to organic phosphates and high sensitivity to bicarbonate (HCO3−), which is believed to augment Hb-O2 unloading during diving and postprandial alkaline tides when blood HCO3− levels and metabolic rates increase. Examination of α- and β-globin amino acid sequences of dwarf caiman (Paleosuchus palpebrosus) revealed a unique combination of substitutions at key effector binding sites compared with other vertebrate and crocodilian Hbs: β82Lys→Gln, β143His→Val, and β146His→Tyr. These substitutions delete positive charges and, along with other distinctive changes in residue charge and polarity, may be expected to disrupt allosteric regulation of Hb-O2 affinity. Strikingly, however, P. palpebrosus Hb shows a strong Bohr effect, and marked deoxygenation-linked binding of organic phosphates (ATP and DPG) and CO2 as carbamate (contrasting with HCO3− binding in other crocodilians). Unlike other Hbs, it polymerizes to large complexes in the oxygenated state. The highly unusual properties of P. palpebrosus Hb align with a high content of His residues (potential sites for oxygenation-linked proton binding) and distinctive surface Cys residues that may form intermolecular disulfide bridges upon polymerization. On the basis of its singular properties, P. palpebrosus Hb provides a unique opportunity for studies on structure-function coupling and the evolution of compensatory mechanisms for maintaining tissue O2 delivery in Hbs that lack conventional effector-binding residues. PMID:23720132

  6. Radioimmunochemical characterization of hemoglobins Lepore and Kenya: unique antigenic determinants located on hybrid hemoglobins

    International Nuclear Information System (INIS)

    Garver, F.A.; Altay, G.; Baker, M.M.; Gravely, M.; Huisman, T.H.J.

    1978-01-01

    Antisera were produced in rabbits to the three known types of Lepore hemoglobins, which contain hybrid delta-β non-α-chains, and to hemoglobin Kenya, which has a hybrid γ-β non-α-chain. By using a sensitive radioimmunoassay technique, the absorbed antisera were shown to contain an antibody population that was specific for the hybrid hemoglobin and did not cross-react with normal hemoglobins. However, with the absorbed Lepore-specific antisera, the three known types of Lepore hemoglobins were antigenically indistinguishable from each other, suggesting that antibodies are not produced to the primary structural differences which define the three non-α-chains of the Lepore hemoglobins. These studies demonstrate that the non-α-subunits of hemoglobins Lepore and Kenya possess unique antigenic determinant sites, evidently resulting from an altered polypeptide conformation

  7. Effects of wood preservative leachates from docks

    Energy Technology Data Exchange (ETDEWEB)

    Wendt, P.H.; Van Dolah, R.F.; Bobo, M.Y.; Mathews, T.D. [South Carolina Marine Resources Research Inst., Charleston, SC (United States)

    1994-12-31

    Recent evidence indicates that the wood preservative commonly used in dock pilings (chromated copper arsenate or CCA) is highly toxic to several estuarine organisms in laboratory experiments. Increasing demand for residential docks prompted a field study intended to complement these earlier laboratory investigations. Objectives of the study were to: (1) examine concentrations of Cu, Cr, and As in sediments and oysters from intertidal locations in several creeks with and without high densities of docks; (2) examine the bioaccumulation of wood preservative leachates by laboratory-reared oysters transferred to field sites near and distant from newly constructed docks; and (3) investigate the acute toxicity of wood preservative leachates for several species of estuarine fishes and invertebrates exposed to these compounds in the field. Preliminary results indicate that sediment concentrations of all three metals were well below ER-L levels reported by Long and Morgan at all but one dock site. In an ancillary study, 24h LC{sub 50} bioassays were performed using rotifers (Brachionus plicatilis) which were exposed to pore water from sediments in creeks with and without docks. Toxicities of bulk sediments from the same sites were examined using Microtox which measures decreases in bioluminescence of marine bacteria (Photobacterium phosphoreum) as a function of sediment concentration. Neither the rotifer nor the Microtox bioassays showed any significant differences in toxicity between creeks with and without docks.

  8. Text Mining for Protein Docking.

    Directory of Open Access Journals (Sweden)

    Varsha D Badal

    2015-12-01

    Full Text Available The rapidly growing amount of publicly available information from biomedical research is readily accessible on the Internet, providing a powerful resource for predictive biomolecular modeling. The accumulated data on experimentally determined structures transformed structure prediction of proteins and protein complexes. Instead of exploring the enormous search space, predictive tools can simply proceed to the solution based on similarity to the existing, previously determined structures. A similar major paradigm shift is emerging due to the rapidly expanding amount of information, other than experimentally determined structures, which still can be used as constraints in biomolecular structure prediction. Automated text mining has been widely used in recreating protein interaction networks, as well as in detecting small ligand binding sites on protein structures. Combining and expanding these two well-developed areas of research, we applied the text mining to structural modeling of protein-protein complexes (protein docking. Protein docking can be significantly improved when constraints on the docking mode are available. We developed a procedure that retrieves published abstracts on a specific protein-protein interaction and extracts information relevant to docking. The procedure was assessed on protein complexes from Dockground (http://dockground.compbio.ku.edu. The results show that correct information on binding residues can be extracted for about half of the complexes. The amount of irrelevant information was reduced by conceptual analysis of a subset of the retrieved abstracts, based on the bag-of-words (features approach. Support Vector Machine models were trained and validated on the subset. The remaining abstracts were filtered by the best-performing models, which decreased the irrelevant information for ~ 25% complexes in the dataset. The extracted constraints were incorporated in the docking protocol and tested on the Dockground unbound

  9. Site-directed mutagenesis under the direction of in silico protein docking modeling reveals the active site residues of 3-ketosteroid-Δ1-dehydrogenase from Mycobacterium neoaurum.

    Science.gov (United States)

    Qin, Ning; Shen, Yanbing; Yang, Xu; Su, Liqiu; Tang, Rui; Li, Wei; Wang, Min

    2017-07-01

    3-Ketosteroid-Δ 1 -dehydrogenases (KsdD) from Mycobacterium neoaurum could transform androst-4-ene-3,17-dione (AD) to androst-1,4-diene-3,17-dione. This reaction has a significant effect on the product of pharmaceutical steroid. The crystal structure and active site residues information of KsdD from Mycobacterium is not yet available, which result in the engineering of KsdD is tedious. In this study, by the way of protein modeling and site-directed mutagenesis, we find that, Y122, Y125, S138, E140 and Y541 from the FAD-binding domain and Y365 from the catalytic domain play a key role in this transformation. Compared with the wild type, the decline in AD conversion for mutants illustrated that Y125, Y365, and Y541 were essential to the function of KsdD. Y122, S138 and E140 contributed to the catalysis of KsdD. The following analysis revealed the catalysis mechanism of these mutations in KsdD of Mycobacterium. These information presented here facilitate the manipulation of the catalytic properties of the enzyme to improve its application in the pharmaceutical steroid industry.

  10. Extracellular Signal-Regulated Kinase 2 (ERK2) Phosphorylation Sites and Docking Domain on the Nuclear Pore Complex Protein Tpr Cooperatively Regulate ERK2-Tpr Interaction

    Czech Academy of Sciences Publication Activity Database

    Vomastek, Tomáš; Iwanicky, M. P.; Burack, W. R.; Tiwari, D.; Kumar, D.; Parsons, J. T.; Weber, M. J.; Nandicoori, V. K.

    2008-01-01

    Roč. 28, č. 22 (2008), s. 6954-6966 ISSN 0270-7306 R&D Projects: GA AV ČR IAA500200716 Institutional research plan: CEZ:AV0Z50200510 Keywords : erk * docking domain * cell growth Subject RIV: EE - Microbiology, Virology Impact factor: 5.942, year: 2008

  11. The Hemoglobin E Thalassemias

    Science.gov (United States)

    Fucharoen, Suthat; Weatherall, David J.

    2012-01-01

    Hemoglobin E (HbE) is an extremely common structural hemoglobin variant that occurs at high frequencies throughout many Asian countries. It is a β-hemoglobin variant, which is produced at a slightly reduced rate and hence has the phenotype of a mild form of β thalassemia. Its interactions with different forms of α thalassemia result in a wide variety of clinical disorders, whereas its coinheritance with β thalassemia, a condition called hemoglobin E β thalassemia, is by far the most common severe form of β thalassemia in Asia and, globally, comprises approximately 50% of the clinically severe β-thalassemia disorders. PMID:22908199

  12. Towards ligand docking including explicit interface water molecules.

    Directory of Open Access Journals (Sweden)

    Gordon Lemmon

    Full Text Available Small molecule docking predicts the interaction of a small molecule ligand with a protein at atomic-detail accuracy including position and conformation the ligand but also conformational changes of the protein upon ligand binding. While successful in the majority of cases, docking algorithms including RosettaLigand fail in some cases to predict the correct protein/ligand complex structure. In this study we show that simultaneous docking of explicit interface water molecules greatly improves Rosetta's ability to distinguish correct from incorrect ligand poses. This result holds true for both protein-centric water docking wherein waters are located relative to the protein binding site and ligand-centric water docking wherein waters move with the ligand during docking. Protein-centric docking is used to model 99 HIV-1 protease/protease inhibitor structures. We find protease inhibitor placement improving at a ratio of 9:1 when one critical interface water molecule is included in the docking simulation. Ligand-centric docking is applied to 341 structures from the CSAR benchmark of diverse protein/ligand complexes [1]. Across this diverse dataset we see up to 56% recovery of failed docking studies, when waters are included in the docking simulation.

  13. SAMPL4 & DOCK3.7: lessons for automated docking procedures

    Science.gov (United States)

    Coleman, Ryan G.; Sterling, Teague; Weiss, Dahlia R.

    2014-03-01

    The SAMPL4 challenges were used to test current automated methods for solvation energy, virtual screening, pose and affinity prediction of the molecular docking pipeline DOCK 3.7. Additionally, first-order models of binding affinity were proposed as milestones for any method predicting binding affinity. Several important discoveries about the molecular docking software were made during the challenge: (1) Solvation energies of ligands were five-fold worse than any other method used in SAMPL4, including methods that were similarly fast, (2) HIV Integrase is a challenging target, but automated docking on the correct allosteric site performed well in terms of virtual screening and pose prediction (compared to other methods) but affinity prediction, as expected, was very poor, (3) Molecular docking grid sizes can be very important, serious errors were discovered with default settings that have been adjusted for all future work. Overall, lessons from SAMPL4 suggest many changes to molecular docking tools, not just DOCK 3.7, that could improve the state of the art. Future difficulties and projects will be discussed.

  14. Phylogeny of Echinoderm Hemoglobins.

    Directory of Open Access Journals (Sweden)

    Ana B Christensen

    Full Text Available Recent genomic information has revealed that neuroglobin and cytoglobin are the two principal lineages of vertebrate hemoglobins, with the latter encompassing the familiar myoglobin and α-globin/β-globin tetramer hemoglobin, and several minor groups. In contrast, very little is known about hemoglobins in echinoderms, a phylum of exclusively marine organisms closely related to vertebrates, beyond the presence of coelomic hemoglobins in sea cucumbers and brittle stars. We identified about 50 hemoglobins in sea urchin, starfish and sea cucumber genomes and transcriptomes, and used Bayesian inference to carry out a molecular phylogenetic analysis of their relationship to vertebrate sequences, specifically, to assess the hypothesis that the neuroglobin and cytoglobin lineages are also present in echinoderms.The genome of the sea urchin Strongylocentrotus purpuratus encodes several hemoglobins, including a unique chimeric 14-domain globin, 2 androglobin isoforms and a unique single androglobin domain protein. Other strongylocentrotid genomes appear to have similar repertoires of globin genes. We carried out molecular phylogenetic analyses of 52 hemoglobins identified in sea urchin, brittle star and sea cucumber genomes and transcriptomes, using different multiple sequence alignment methods coupled with Bayesian and maximum likelihood approaches. The results demonstrate that there are two major globin lineages in echinoderms, which are related to the vertebrate neuroglobin and cytoglobin lineages. Furthermore, the brittle star and sea cucumber coelomic hemoglobins appear to have evolved independently from the cytoglobin lineage, similar to the evolution of erythroid oxygen binding globins in cyclostomes and vertebrates.The presence of echinoderm globins related to the vertebrate neuroglobin and cytoglobin lineages suggests that the split between neuroglobins and cytoglobins occurred in the deuterostome ancestor shared by echinoderms and vertebrates.

  15. The Performance of Several Docking Programs at Reproducing Protein–Macrolide-Like Crystal Structures

    Directory of Open Access Journals (Sweden)

    Alejandro Castro-Alvarez

    2017-01-01

    Full Text Available The accuracy of five docking programs at reproducing crystallographic structures of complexes of 8 macrolides and 12 related macrocyclic structures, all with their corresponding receptors, was evaluated. Self-docking calculations indicated excellent performance in all cases (mean RMSD values ≤ 1.0 and confirmed the speed of AutoDock Vina. Afterwards, the lowest-energy conformer of each molecule and all the conformers lying 0–10 kcal/mol above it (as given by Macrocycle, from MacroModel 10.0 were subjected to standard docking calculations. While each docking method has its own merits, the observed speed of the programs was as follows: Glide 6.6 > AutoDock Vina 1.1.2 > DOCK 6.5 >> AutoDock 4.2.6 > AutoDock 3.0.5. For most of the complexes, the five methods predicted quite correct poses of ligands at the binding sites, but the lower RMSD values for the poses of highest affinity were in the order: Glide 6.6 ≈ AutoDock Vina ≈ DOCK 6.5 > AutoDock 4.2.6 >> AutoDock 3.0.5. By choosing the poses closest to the crystal structure the order was: AutoDock Vina > Glide 6.6 ≈ DOCK 6.5 ≥ AutoDock 4.2.6 >> AutoDock 3.0.5. Re-scoring (AutoDock 4.2.6//AutoDock Vina, Amber Score and MM-GBSA improved the agreement between the calculated and experimental data. For all intents and purposes, these three methods are equally reliable.

  16. AnchorDock for Blind Flexible Docking of Peptides to Proteins.

    Science.gov (United States)

    Slutzki, Michal; Ben-Shimon, Avraham; Niv, Masha Y

    2017-01-01

    Due to increasing interest in peptides as signaling modulators and drug candidates, several methods for peptide docking to their target proteins are under active development. The "blind" docking problem, where the peptide-binding site on the protein surface is unknown, presents one of the current challenges in the field. AnchorDock protocol was developed by Ben-Shimon and Niv to address this challenge.This protocol narrows the docking search to the most relevant parts of the conformational space. This is achieved by pre-folding the free peptide and by computationally detecting anchoring spots on the surface of the unbound protein. Multiple flexible simulated annealing molecular dynamics (SAMD) simulations are subsequently carried out, starting from pre-folded peptide conformations, constrained to the various precomputed anchoring spots.Here, AnchorDock is demonstrated using two known protein-peptide complexes. A PDZ-peptide complex provides a relatively easy case due to the relatively small size of the protein, and a typical peptide conformation and binding region; a more challenging example is a complex between USP7 N-term and a p53-derived peptide, where the protein is larger, and the peptide conformation and a binding site are generally assumed to be unknown. AnchorDock returned native-like solutions ranked first and third for the PDZ and USP7 complexes, respectively. We describe the procedure step by step and discuss possible modifications where applicable.

  17. Interaction of thyroid hormone and hemoglobin: nature of the interaction and effect of hemoglobin on thyroid hormone radioimmunoassay

    International Nuclear Information System (INIS)

    Davis, P.J.; Yoshida, K.; Schoenl, M.

    1980-01-01

    Gel filtration of human erythrocyte (RBC) lysate incubated with labeled thyroxine (Tu) or triiodothyronine (Tt) revealed co-elution of a major iodothyronine-binding fraction (R-2) and hemoglobin. Solutions of purified human hemoglobin and Tt also showed co-elution of hormone and hemoglobin. Because hematin and protoporphyrin were shown to bind labeled Tt, the oxygen-binding site on hemoglobin was excluded as the site of iodothyronine-hemoglobin interaction. Analysis of hormone binding by heme and globin moieties showed Tt binding to be limited to the heme fraction. Addition of excess unlabeled Tt to hemoglobin or heme incubated with labeled Tt indicated 75% to 90% of hormone binding was poorly dissociable. These observations suggested that the presence of hemoglobin in RBC lysate or in serum could influence the measurement of Tu and Tt by specific radioimmunoassay (RIA). Subsequent studies of the addition to serum of human hemoglobin revealed a significant reduction in Tt and Tu detectable by RIA in the presence of this protein. The effect was influenced by the concentration of hemoglobin and by duration and temperature of incubations of hemoglobin and serum prior to RIA

  18. Spacecraft rendezvous and docking

    DEFF Research Database (Denmark)

    Jørgensen, John Leif

    1999-01-01

    The phenomenons and problems encountered when a rendezvous manoeuvre, and possible docking, of two spacecrafts has to be performed, have been the topic for numerous studies, and, details of a variety of scenarios has been analysed. So far, all solutions that has been brought into realization has...... been based entirely on direct human supervision and control. This paper describes a vision-based system and methodology, that autonomously generates accurate guidance information that may assist a human operator in performing the tasks associated with both the rendezvous and docking navigation...

  19. Virtual screening with AutoDock Vina and the common pharmacophore engine of a low diversity library of fragments and hits against the three allosteric sites of HIV integrase: participation in the SAMPL4 protein-ligand binding challenge.

    Science.gov (United States)

    Perryman, Alexander L; Santiago, Daniel N; Forli, Stefano; Martins, Diogo Santos; Olson, Arthur J

    2014-04-01

    To rigorously assess the tools and protocols that can be used to understand and predict macromolecular recognition, and to gain more structural insight into three newly discovered allosteric binding sites on a critical drug target involved in the treatment of HIV infections, the Olson and Levy labs collaborated on the SAMPL4 challenge. This computational blind challenge involved predicting protein-ligand binding against the three allosteric sites of HIV integrase (IN), a viral enzyme for which two drugs (that target the active site) have been approved by the FDA. Positive control cross-docking experiments were utilized to select 13 receptor models out of an initial ensemble of 41 different crystal structures of HIV IN. These 13 models of the targets were selected using our new "Rank Difference Ratio" metric. The first stage of SAMPL4 involved using virtual screens to identify 62 active, allosteric IN inhibitors out of a set of 321 compounds. The second stage involved predicting the binding site(s) and crystallographic binding mode(s) for 57 of these inhibitors. Our team submitted four entries for the first stage that utilized: (1) AutoDock Vina (AD Vina) plus visual inspection; (2) a new common pharmacophore engine; (3) BEDAM replica exchange free energy simulations, and a Consensus approach that combined the predictions of all three strategies. Even with the SAMPL4's very challenging compound library that displayed a significantly lower amount of structural diversity than most libraries that are conventionally employed in prospective virtual screens, these approaches produced hit rates of 24, 25, 34, and 27 %, respectively, on a set with 19 % declared binders. Our only entry for the second stage challenge was based on the results of AD Vina plus visual inspection, and it ranked third place overall according to several different metrics provided by the SAMPL4 organizers. The successful results displayed by these approaches highlight the utility of the computational

  20. Virtual screening with AutoDock Vina and the common pharmacophore engine of a low diversity library of fragments and hits against the three allosteric sites of HIV integrase: participation in the SAMPL4 protein-ligand binding challenge

    Science.gov (United States)

    Perryman, Alexander L.; Santiago, Daniel N.; Forli, Stefano; Santos-Martins, Diogo; Olson, Arthur J.

    2014-04-01

    To rigorously assess the tools and protocols that can be used to understand and predict macromolecular recognition, and to gain more structural insight into three newly discovered allosteric binding sites on a critical drug target involved in the treatment of HIV infections, the Olson and Levy labs collaborated on the SAMPL4 challenge. This computational blind challenge involved predicting protein-ligand binding against the three allosteric sites of HIV integrase (IN), a viral enzyme for which two drugs (that target the active site) have been approved by the FDA. Positive control cross-docking experiments were utilized to select 13 receptor models out of an initial ensemble of 41 different crystal structures of HIV IN. These 13 models of the targets were selected using our new "Rank Difference Ratio" metric. The first stage of SAMPL4 involved using virtual screens to identify 62 active, allosteric IN inhibitors out of a set of 321 compounds. The second stage involved predicting the binding site(s) and crystallographic binding mode(s) for 57 of these inhibitors. Our team submitted four entries for the first stage that utilized: (1) AutoDock Vina (AD Vina) plus visual inspection; (2) a new common pharmacophore engine; (3) BEDAM replica exchange free energy simulations, and a Consensus approach that combined the predictions of all three strategies. Even with the SAMPL4's very challenging compound library that displayed a significantly lower amount of structural diversity than most libraries that are conventionally employed in prospective virtual screens, these approaches produced hit rates of 24, 25, 34, and 27 %, respectively, on a set with 19 % declared binders. Our only entry for the second stage challenge was based on the results of AD Vina plus visual inspection, and it ranked third place overall according to several different metrics provided by the SAMPL4 organizers. The successful results displayed by these approaches highlight the utility of the computational

  1. Synthesis and molecular docking of pyrimidine incorporated novel ...

    Indian Academy of Sciences (India)

    APOORVA MISRA

    2018-03-09

    Mar 9, 2018 ... aDepartment of Chemistry, Banasthali Vidyapith, Banasthali, Rajasthan 304 022, India ... serotonin 5-HT6 receptor antagonist,22 hepatitis-A virus ..... Molecular docking structure and ligand protein binding sites of MTX- (a) ...

  2. Computational methods for molecular docking

    Energy Technology Data Exchange (ETDEWEB)

    Klebe, G. [BASF AG, Ludwigshafen (Germany); Lengauer, T.

    1995-12-31

    This tutorial was one of eight tutorials selected to be presented at the Third International Conference on Intelligent Systems for Molecular Biology which was held in the United Kingdom from July 16 to 19, 1995. Recently, it has been demonstrated that the knowledge of the three-dimensional structure of the protein can be used to derive new protein ligands with improved binding properties. This tutorial focuses on the following questions: What is its binding affinity toward a particular receptor? What are putative conformations of a ligand at the binding site? What are the similarities of different ligands in terms of their recognition capabilities? Where and in which orientation will a ligand bind to the active site? How is a new putative protein ligand selected? An overview is presented of the algorithms which are presently used to handle and predict protein-ligand interactions and to dock small molecule ligands into proteins.

  3. Study of methyl bromide reactivity with human and mouse hemoglobin

    African Journals Online (AJOL)

    A study has been carried out on in-vitro reactivity of human and mouse hemoglobin spectrophotometrically at physiological pH, using different protein to reagent ratios. Hemoglobin side chains were modified with different concentrations of methyl bromide on agro-soil fumigant. To ascertain if the site of alkylation was the ...

  4. Sequence alignment reveals possible MAPK docking motifs on HIV proteins.

    Directory of Open Access Journals (Sweden)

    Perry Evans

    Full Text Available Over the course of HIV infection, virus replication is facilitated by the phosphorylation of HIV proteins by human ERK1 and ERK2 mitogen-activated protein kinases (MAPKs. MAPKs are known to phosphorylate their substrates by first binding with them at a docking site. Docking site interactions could be viable drug targets because the sequences guiding them are more specific than phosphorylation consensus sites. In this study we use multiple bioinformatics tools to discover candidate MAPK docking site motifs on HIV proteins known to be phosphorylated by MAPKs, and we discuss the possibility of targeting docking sites with drugs. Using sequence alignments of HIV proteins of different subtypes, we show that MAPK docking patterns previously described for human proteins appear on the HIV matrix, Tat, and Vif proteins in a strain dependent manner, but are absent from HIV Rev and appear on all HIV Nef strains. We revise the regular expressions of previously annotated MAPK docking patterns in order to provide a subtype independent motif that annotates all HIV proteins. One revision is based on a documented human variant of one of the substrate docking motifs, and the other reduces the number of required basic amino acids in the standard docking motifs from two to one. The proposed patterns are shown to be consistent with in silico docking between ERK1 and the HIV matrix protein. The motif usage on HIV proteins is sufficiently different from human proteins in amino acid sequence similarity to allow for HIV specific targeting using small-molecule drugs.

  5. Rice (Oryza) hemoglobins

    Science.gov (United States)

    Hemoglobins (Hbs) corresponding to non-symbiotic (nsHb) and truncated (tHb) Hbs have been identified in rice (Oryza). This review discusses the major findings from the current studies on rice Hbs. At the molecular level, a family of the nshb genes, consisting of hb1, hb2, hb3, hb4 and hb5, and a sin...

  6. Effects of administration of a local anaesthetic and/or an NSAID and of docking length on the behaviour of piglets during 5 h after tail docking

    DEFF Research Database (Denmark)

    Herskin, Mette S.; Di Giminiani, Pierpaolo; Thodberg, Karen

    2016-01-01

    cautery 2–4 days after birth and based on behaviour during docking as well as the following 5 h. The study involved three main factors: local anaesthetic (Lidocain), NSAID (Meloxicam) and docking length. Either 100%, 75%, 50% or 25% of the tails were left on the body of the piglets. Irrespective...... that effects of this management routine are more persistent than earlier suggested, and suggesting that docking length may influence the post-surgical behaviour of piglets. By use of the present sites of injection and dosages, neither local anaesthetic nor NSAID had marked effects on post-surgical behavioural......In many countries, piglets are tail docked to prevent tail biting. The aim of this study was 1) to evaluate the efficacy of a local anaesthetic and/or NSAID to reduce pain caused by tail docking; and 2) to examine interactions with docking length. This was examined in 295 piglets docked by hot iron...

  7. Rendezvous and docking tracker

    Science.gov (United States)

    Ray, Art J.; Ross, Susan E.; Deming, Douglas R.

    1986-01-01

    A conceptual solid-state rendezvous and docking tracker (RDT) has been devised for generating range and attitude data for a docking vehicle relative to a target vehicle. Emphasis is placed on the approach of the Orbiter to a link with the Space Station. Three laser illuminators ring the optical axis of the lens a directed toward retroreflectors on the target vehicle. Each retroreflector is equipped with a bandpass filter for a designated illumination frequency. Data are collected sequentially over a 20 deg field of view as the range closes to 100-1000 m. A fourth ranging retroreflector 0.3 m from center is employed during close-in maneuvers. The system provides tracking data on motions with 6 deg of freedom, and furnishes 500 msec updates (to be enhanced to 100 msec) to the operator at a computer console.

  8. EPR studies of cooperative binding of Cu (II) to hemoglobin

    International Nuclear Information System (INIS)

    Louro, S.R.W.; Tabak, M.

    1983-07-01

    The investigation of the relative affinities of the two pairs of hemoglobin copper sites by monitoring the EPR spectra of the complexes formed by the reaction of copper with deoxyhemoglobin is reported. A model in which two sites are assumed to accept copper ions in a noncooperative way is not able to predict the experimental results. Thus it is conclude that the binding of these ions to hemoglobin is a cooperative phenomenon. (Author) [pt

  9. Molecular Docking Study on Galantamine Derivatives as Cholinesterase Inhibitors.

    Science.gov (United States)

    Atanasova, Mariyana; Yordanov, Nikola; Dimitrov, Ivan; Berkov, Strahil; Doytchinova, Irini

    2015-06-01

    A training set of 22 synthetic galantamine derivatives binding to acetylcholinesterase was docked by GOLD and the protocol was optimized in terms of scoring function, rigidity/flexibility of the binding site, presence/absence of a water molecule inside and radius of the binding site. A moderate correlation was found between the affinities of compounds expressed as pIC50 values and their docking scores. The optimized docking protocol was validated by an external test set of 11 natural galantamine derivatives and the correlation coefficient between the docking scores and the pIC50 values was 0.800. The derived relationship was used to analyze the interactions between galantamine derivatives and AChE. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Remote docking apparatus

    International Nuclear Information System (INIS)

    Dent, T.H.; Sumpman, W.C.; Wilhelm, J.J.

    1981-01-01

    The remote docking apparatus comprises a support plate with locking devices mounted thereon. The locking devices are capable of being inserted into tubular members for suspending the support plate therefrom. A vertical member is attached to the support plate with an attachment mechanism attached to the vertical member. A remote access manipulator is capable of being attached to the attachment mechanism so that the vertical member can position the remote access manipulator so that the remote access manipulator can be initially attached to the tubular members in a well defined manner

  11. Confirming therapeutic target of protopine using immobilized β2 -adrenoceptor coupled with site-directed molecular docking and the target-drug interaction by frontal analysis and injection amount-dependent method.

    Science.gov (United States)

    Liu, Guangxin; Wang, Pei; Li, Chan; Wang, Jing; Sun, Zhenyu; Zhao, Xinfeng; Zheng, Xiaohui

    2017-07-01

    Drug-protein interaction analysis is pregnant in designing new leads during drug discovery. We prepared the stationary phase containing immobilized β 2 -adrenoceptor (β 2 -AR) by linkage of the receptor on macroporous silica gel surface through N,N'-carbonyldiimidazole method. The stationary phase was applied in identifying antiasthmatic target of protopine guided by the prediction of site-directed molecular docking. Subsequent application of immobilized β 2 -AR in exploring the binding of protopine to the receptor was realized by frontal analysis and injection amount-dependent method. The association constants of protopine to β 2 -AR by the 2 methods were (1.00 ± 0.06) × 10 5 M -1 and (1.52 ± 0.14) × 10 4 M -1 . The numbers of binding sites were (1.23 ± 0.07) × 10 -7 M and (9.09 ± 0.06) × 10 -7 M, respectively. These results indicated that β 2 -AR is the specific target for therapeutic action of protopine in vivo. The target-drug binding occurred on Ser 169 in crystal structure of the receptor. Compared with frontal analysis, injection amount-dependent method is advantageous to drug saving, improvement of sampling efficiency, and performing speed. It has grave potential in high-throughput drug-receptor interaction analysis. Copyright © 2017 John Wiley & Sons, Ltd.

  12. Spectrofluorometric and Molecular Modeling Studies on Binding of Nitrite Ion with Bovine Hemoglobin: Effect of Nitrite Ion on Amino Acid Residues

    Science.gov (United States)

    Madrakian, T.; Bagheri, H.; Afkhami, A.

    2015-05-01

    The interaction between nitrite ion and bovine hemoglobin was investigated by a spectrofluorometric technique. The experimental results indicated that the interaction causes a static quenching of the fluorescence of bovine hemoglobin, that the binding reaction is spontaneous, and that H-bonding interactions play a major role in binding of this ion to bovine hemoglobin. The formation constant for this interaction was calculated. Based on Förster's theory of nonradiative energy transfer, the binding distance between this ion and bovine hemoglobin was determined. Furthermore, the interaction of nitrite ion with tyrosine and tryptophan was investigated with synchronous fluorescence. There was no significant shift of the maximum emission wavelength with interactions of the mentioned ion with bovine hemoglobin, which implies that interaction of nitrite ion with bovine hemoglobin does not affect the microenvironment around the tryptophan and tyrosine residues. Furthermore, the effect of nitrite ion on amino acid residues of bovine hemoglobin was studied by a molecular docking technique.

  13. Interaction of the minocycline with extracelluar protein and intracellular protein by multi-spectral techniques and molecular docking

    Science.gov (United States)

    Fang, Qing; Wang, Yirun; Hu, Taoying; Liu, Ying

    2017-02-01

    The interaction of minocyeline (MNC) with extracelluar protein (lysozyme, LYSO) or intracellular protein (bovine hemoglobin, BHb) was investigated using multi-spectral techniques and molecular docking in vitro. Fluorescence studies suggested that MNC quenched LYSO/BHb fluorescence in a static mode with binding constants of 2.01 and 0.26 × 104 L•mol-1 at 298 K, respectively. The LYZO-MNC system was more easily influenced by temperature (298 and 310 K) than the BHb-MNC system. The thermodynamic parameters demonstrated that hydrogen bonds and van der Waals forces played the major role in the binding process. Based on the Förster theory of nonradiative energy transfer, the binding distances between MNC and the inner tryptophan residues of LYSO and BHb were calculated to be 4.34 and 3.49 nm, respectively. Furthermore, circular dichroism spectra (CD), Fourier transforms infrared (FTIR), UV-vis, and three-dimensional fluorescence spectra results indicated the secondary structures of LYSO and BHb were partially destroyed by MNC with the α-helix percentage of LYZO-MNC increased (17.8-28.6%) while that of BHb-MNC was decreased (41.6-39.6%). UV-vis spectral results showed these binding interactions could cause conformational and some micro-environmental changes of LYSO and BHb. In accordance with the results of molecular docking, In LYZO-MNC system, MNC was mainly bound in the active site hinge region where Trp-62 and Trp-63 are located, and in MNC-BHb system, MNC was close to the subunit α 1 of BHb, molecular docking analysis supported the thermodynamic results well. The work contributes to clarify the mechanism of MNC with two proteins at molecular level.

  14. Dichloromethane as an antisickling agent in sickle cell hemoglobin

    Energy Technology Data Exchange (ETDEWEB)

    Schoenborn, B.P.; North, B.E.

    1977-01-01

    Observations are reported that show that dichloromethane (DCM) does have a significant effect on the oxygen binding properties of hemoglobin. At DCM pressures high enough to prevent or reverse sickling, DCM would lower the oxygen affinity of hemoglobin, therefore reducing oxygen transport at low oxygen pressure. This decrease in oxygen affinity might, however, increase the oxygen availability to tissue as long as a sufficiently large lung P/sub O/sub 2// is maintained. Crystallographic studies show that site D4 has a much lower affinity for DCM than site D3 while sites D1 and D2 show a higher affinity.

  15. Transcriptional Dysregulation of MYC Reveals Common Enhancer-Docking Mechanism

    Directory of Open Access Journals (Sweden)

    Jurian Schuijers

    2018-04-01

    Full Text Available Summary: Transcriptional dysregulation of the MYC oncogene is among the most frequent events in aggressive tumor cells, and this is generally accomplished by acquisition of a super-enhancer somewhere within the 2.8 Mb TAD where MYC resides. We find that these diverse cancer-specific super-enhancers, differing in size and location, interact with the MYC gene through a common and conserved CTCF binding site located 2 kb upstream of the MYC promoter. Genetic perturbation of this enhancer-docking site in tumor cells reduces CTCF binding, super-enhancer interaction, MYC gene expression, and cell proliferation. CTCF binding is highly sensitive to DNA methylation, and this enhancer-docking site, which is hypomethylated in diverse cancers, can be inactivated through epigenetic editing with dCas9-DNMT. Similar enhancer-docking sites occur at other genes, including genes with prominent roles in multiple cancers, suggesting a mechanism by which tumor cell oncogenes can generally hijack enhancers. These results provide insights into mechanisms that allow a single target gene to be regulated by diverse enhancer elements in different cell types. : Schuijers et al. show that a conserved CTCF site at the promoter of the MYC oncogene plays an important role in enhancer-promoter looping with tumor-specific super-enhancers. Perturbation of this site provides a potential therapeutic vulnerability. Keywords: gene regulation, super-enhancers, chromosome structure, enhancer docking

  16. Non-invasive hemoglobin monitoring.

    Science.gov (United States)

    Joseph, Bellal; Haider, Ansab; Rhee, Peter

    2016-09-01

    Technology has transformed the practice of medicine and surgery in particular over the last several decades. This change in practice has allowed diagnostic and therapeutic tests to be performed less invasively. Hemoglobin monitoring remains one of the most commonly performed diagnostic tests in the United States. Recently, non-invasive hemoglobin monitoring technology has gained popularity. The aim of this article is to review the principles of how this technology works, pros and cons, and the implications of non-invasive hemoglobin technology particularly in trauma surgery. Copyright © 2015 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.

  17. Autonomous spacecraft rendezvous and docking

    Science.gov (United States)

    Tietz, J. C.; Almand, B. J.

    A storyboard display is presented which summarizes work done recently in design and simulation of autonomous video rendezvous and docking systems for spacecraft. This display includes: photographs of the simulation hardware, plots of chase vehicle trajectories from simulations, pictures of the docking aid including image processing interpretations, and drawings of the control system strategy. Viewgraph-style sheets on the display bulletin board summarize the simulation objectives, benefits, special considerations, approach, and results.

  18. A comparative analysis of clustering algorithms: O{sub 2} migration in truncated hemoglobin I from transition networks

    Energy Technology Data Exchange (ETDEWEB)

    Cazade, Pierre-André; Berezovska, Ganna; Meuwly, Markus, E-mail: m.meuwly@unibas.ch [Department of Chemistry, University of Basel, Klingelbergstrasse 80, CH-4056 Basel (Switzerland); Zheng, Wenwei; Clementi, Cecilia [Department of Chemistry, Rice University, 6100 Main St., Houston, Texas 77005 (United States); Prada-Gracia, Diego; Rao, Francesco [School of Soft Matter Research, Freiburg Institute for Advanced Studies, Albertstrasse 19, 79104 Freiburg im Breisgau (Germany)

    2015-01-14

    The ligand migration network for O{sub 2}–diffusion in truncated Hemoglobin N is analyzed based on three different clustering schemes. For coordinate-based clustering, the conventional k–means and the kinetics-based Markov Clustering (MCL) methods are employed, whereas the locally scaled diffusion map (LSDMap) method is a collective-variable-based approach. It is found that all three methods agree well in their geometrical definition of the most important docking site, and all experimentally known docking sites are recovered by all three methods. Also, for most of the states, their population coincides quite favourably, whereas the kinetics of and between the states differs. One of the major differences between k–means and MCL clustering on the one hand and LSDMap on the other is that the latter finds one large primary cluster containing the Xe1a, IS1, and ENT states. This is related to the fact that the motion within the state occurs on similar time scales, whereas structurally the state is found to be quite diverse. In agreement with previous explicit atomistic simulations, the Xe3 pocket is found to be a highly dynamical site which points to its potential role as a hub in the network. This is also highlighted in the fact that LSDMap cannot identify this state. First passage time distributions from MCL clusterings using a one- (ligand-position) and two-dimensional (ligand-position and protein-structure) descriptor suggest that ligand- and protein-motions are coupled. The benefits and drawbacks of the three methods are discussed in a comparative fashion and highlight that depending on the questions at hand the best-performing method for a particular data set may differ.

  19. Nonlinear photoacoustic spectroscopy of hemoglobin.

    Science.gov (United States)

    Danielli, Amos; Maslov, Konstantin; Favazza, Christopher P; Xia, Jun; Wang, Lihong V

    2015-05-18

    As light intensity increases in photoacoustic imaging, the saturation of optical absorption and the temperature dependence of the thermal expansion coefficient result in a measurable nonlinear dependence of the photoacoustic (PA) signal on the excitation pulse fluence. Here, under controlled conditions, we investigate the intensity-dependent photoacoustic signals from oxygenated and deoxygenated hemoglobin at varied optical wavelengths and molecular concentrations. The wavelength and concentration dependencies of the nonlinear PA spectrum are found to be significantly greater in oxygenated hemoglobin than in deoxygenated hemoglobin. These effects are further influenced by the hemoglobin concentration. These nonlinear phenomena provide insights into applications of photoacoustics, such as measurements of average inter-molecular distances on a nm scale or with a tuned selection of wavelengths, a more accurate quantitative PA tomography.

  20. Nonlinear photoacoustic spectroscopy of hemoglobin

    International Nuclear Information System (INIS)

    Danielli, Amos; Maslov, Konstantin; Favazza, Christopher P.; Xia, Jun; Wang, Lihong V.

    2015-01-01

    As light intensity increases in photoacoustic imaging, the saturation of optical absorption and the temperature dependence of the thermal expansion coefficient result in a measurable nonlinear dependence of the photoacoustic (PA) signal on the excitation pulse fluence. Here, under controlled conditions, we investigate the intensity-dependent photoacoustic signals from oxygenated and deoxygenated hemoglobin at varied optical wavelengths and molecular concentrations. The wavelength and concentration dependencies of the nonlinear PA spectrum are found to be significantly greater in oxygenated hemoglobin than in deoxygenated hemoglobin. These effects are further influenced by the hemoglobin concentration. These nonlinear phenomena provide insights into applications of photoacoustics, such as measurements of average inter-molecular distances on a nm scale or with a tuned selection of wavelengths, a more accurate quantitative PA tomography

  1. Nonlinear photoacoustic spectroscopy of hemoglobin

    Energy Technology Data Exchange (ETDEWEB)

    Danielli, Amos; Maslov, Konstantin; Favazza, Christopher P.; Xia, Jun; Wang, Lihong V., E-mail: LHWANG@WUSTL.EDU [Optical Imaging Laboratory, Department of Biomedical Engineering, Washington University in St. Louis, One Brookings Drive, St. Louis, Missouri 63130 (United States)

    2015-05-18

    As light intensity increases in photoacoustic imaging, the saturation of optical absorption and the temperature dependence of the thermal expansion coefficient result in a measurable nonlinear dependence of the photoacoustic (PA) signal on the excitation pulse fluence. Here, under controlled conditions, we investigate the intensity-dependent photoacoustic signals from oxygenated and deoxygenated hemoglobin at varied optical wavelengths and molecular concentrations. The wavelength and concentration dependencies of the nonlinear PA spectrum are found to be significantly greater in oxygenated hemoglobin than in deoxygenated hemoglobin. These effects are further influenced by the hemoglobin concentration. These nonlinear phenomena provide insights into applications of photoacoustics, such as measurements of average inter-molecular distances on a nm scale or with a tuned selection of wavelengths, a more accurate quantitative PA tomography.

  2. Proposed docking interface between peptidoglycan and the target recognition domain of zoocin A

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Yinghua [Department of Chemistry, University of Alabama, Tuscaloosa, AL 35487 (United States); Simmonds, Robin S. [Department of Microbiology and Immunology, University of Otago, Dunedin (New Zealand); Timkovich, Russell, E-mail: rtimkovi@bama.ua.edu [Department of Chemistry, University of Alabama, Tuscaloosa, AL 35487 (United States)

    2013-11-15

    Highlights: •Peptidoglycan added to zoocin rTRD perturbs NMR resonances around W115. •Simulations predict docking to a shallow surface groove near W115. •The docking interface is similar to mammalian antibody–antigen sites. •EDTA binds to a distinct surface site. -- Abstract: A docking model is proposed for the target recognition domain of the lytic exoenzyme zoocin A with the peptidoglycan on the outer cell surface of sensitive bacterial strains. Solubilized fragments from such peptidoglycans perturb specific backbone and side chain amide resonances in the recombinant form of the domain designated rTRD as detected in two-dimensional {sup 1}H–{sup 15}N correlation NMR spectra. The affected residues comprise a shallow surface cleft on the protein surface near W115, N53, N117, and Q105 among others, which interacts with the peptide portion of the peptidoglycan. Calculations with AutoDock Vina provide models of the docking interface. There is approximate homology between the rTDR-peptidoglycan docking site and the antigen binding site of Fab antibodies with the immunoglobin fold. EDTA was also found to bind to rTRD, but at a site distinct from the proposed peptidoglycan docking site.

  3. Arbitrary protein−protein docking targets biologically relevant interfaces

    Directory of Open Access Journals (Sweden)

    Martin Juliette

    2012-05-01

    Full Text Available Abstract Background Protein-protein recognition is of fundamental importance in the vast majority of biological processes. However, it has already been demonstrated that it is very hard to distinguish true complexes from false complexes in so-called cross-docking experiments, where binary protein complexes are separated and the isolated proteins are all docked against each other and scored. Does this result, at least in part, reflect a physical reality? False complexes could reflect possible nonspecific or weak associations. Results In this paper, we investigate the twilight zone of protein-protein interactions, building on an interesting outcome of cross-docking experiments: false complexes seem to favor residues from the true interaction site, suggesting that randomly chosen partners dock in a non-random fashion on protein surfaces. Here, we carry out arbitrary docking of a non-redundant data set of 198 proteins, with more than 300 randomly chosen "probe" proteins. We investigate the tendency of arbitrary partners to aggregate at localized regions of the protein surfaces, the shape and compositional bias of the generated interfaces, and the potential of this property to predict biologically relevant binding sites. We show that the non-random localization of arbitrary partners after protein-protein docking is a generic feature of protein structures. The interfaces generated in this way are not systematically planar or curved, but tend to be closer than average to the center of the proteins. These results can be used to predict biological interfaces with an AUC value up to 0.69 alone, and 0.72 when used in combination with evolutionary information. An appropriate choice of random partners and number of docking models make this method computationally practical. It is also noted that nonspecific interfaces can point to alternate interaction sites in the case of proteins with multiple interfaces. We illustrate the usefulness of arbitrary docking

  4. Arbitrary protein−protein docking targets biologically relevant interfaces

    International Nuclear Information System (INIS)

    Martin, Juliette; Lavery, Richard

    2012-01-01

    Protein-protein recognition is of fundamental importance in the vast majority of biological processes. However, it has already been demonstrated that it is very hard to distinguish true complexes from false complexes in so-called cross-docking experiments, where binary protein complexes are separated and the isolated proteins are all docked against each other and scored. Does this result, at least in part, reflect a physical reality? False complexes could reflect possible nonspecific or weak associations. In this paper, we investigate the twilight zone of protein-protein interactions, building on an interesting outcome of cross-docking experiments: false complexes seem to favor residues from the true interaction site, suggesting that randomly chosen partners dock in a non-random fashion on protein surfaces. Here, we carry out arbitrary docking of a non-redundant data set of 198 proteins, with more than 300 randomly chosen "probe" proteins. We investigate the tendency of arbitrary partners to aggregate at localized regions of the protein surfaces, the shape and compositional bias of the generated interfaces, and the potential of this property to predict biologically relevant binding sites. We show that the non-random localization of arbitrary partners after protein-protein docking is a generic feature of protein structures. The interfaces generated in this way are not systematically planar or curved, but tend to be closer than average to the center of the proteins. These results can be used to predict biological interfaces with an AUC value up to 0.69 alone, and 0.72 when used in combination with evolutionary information. An appropriate choice of random partners and number of docking models make this method computationally practical. It is also noted that nonspecific interfaces can point to alternate interaction sites in the case of proteins with multiple interfaces. We illustrate the usefulness of arbitrary docking using PEBP (Phosphatidylethanolamine binding

  5. Hemoglobin C, S-C, and E Diseases

    Science.gov (United States)

    ... quickly than others, resulting in chronic anemia. Hemoglobin C disease Hemoglobin C disease occurs mostly in blacks. ... a common complication of hemoglobin C disease. Hemoglobin S-C disease Hemoglobin S-C disease occurs in people who ...

  6. Genetic and developmental variation of hemoglobin in the deermouse, Peromyscus maniculatus.

    Science.gov (United States)

    Maybank, K M; Dawson, W D

    1976-04-01

    A genetic investigation of electrophoretic hemoglobin variants of the deermouse, Peromyscus maniculatus, shows three alleles, Hblf, Hblr, and Hblo, at a duplicated site controlling the six adult phenotypes. The Hblf allele has not been described previously. The hemoglobin locus is not closely linked to the albino locus. Fetal hemoglobin is distinct from any of the adult components and has a slower electrophoretic mobility. The fetal phenotype changes to the adult type between the days 15 and 18 of prenatal life.

  7. The pickup and delivery problem with cross-docking opportunity

    DEFF Research Database (Denmark)

    Petersen, Hanne Løhmann; Røpke, Stefan

    2011-01-01

    delivery by one truck, or by being picked up and transported to the cross-dock by one vehicle, and subsequently delivered at its final destination by another vehicle. Handling times at customers sites and terminal are given. A typical daily instance includes 500-1,000 requests. We solve the problem using...

  8. CT-docking patient stretcher

    International Nuclear Information System (INIS)

    Mirvis, S.E.; Owens, E.; Maslyn, J.; Rizutto, M.

    1990-01-01

    This paper assesses the use of a patient stretcher that directly docks to a CT scanner for acutely injured and/or critically ill patients. The stretcher permits performance of radiography and acts as a platform for critical care monitoring and patient support devices. During a 1-year period, the prototype CT-docking stretcher was used for 35 patients sustaining acute trauma and 25 patients from critical care units. Observations were elicited from physicians, nurses and technologists concerning the advantages or disadvantages of the docking stretcher. Advantages of the CT-docking stretcher included time saved in moving patients to the CT table from the admitting/emergency ward, transfer of critically ill patients onto the stretcher in the controlled environment of the intensive care unit rather than the CT suite, increasing CT throughput by direct docking of the patient stretcher to the CT scanner rather than manual transfer of complex support and monitoring devices with the patient, decreased risk associated with physical movement of patients with potentially unstable spinal injuries or unstable physiologic status, and decrease in potential for injury to medical personnel performing patient transfer

  9. Dry dock gate stability modelling

    Science.gov (United States)

    Oktoberty; Widiyanto; Sasono, E. J.; Pramono, S.; Wandono, A. T.

    2018-03-01

    The development of marine transportation needs in Indonesia increasingly opens national shipyard business opportunities to provide shipbuilding services to the shipbuilding vessels. That emphasizes the stability of prime. The ship's decking door becomes an integral part of the efficient place and the specification of the use of the asset of its operational ease. This study aims to test the stability of Dry Dock gate with the length of 35.4 meters using Maxsurf and Hydromax in analyzing the calculation were in its assessment using interval per 500 mm length so that it can get detail data toward longitudinal and transverse such as studying Ship planning in general. The test result shows dry dock gate meets IMO standard with ballast construction containing 54% and 68% and using fix ballast can produce GMt 1,924 m, tide height 11,357m. The GMt value indicates dry dick gate can be stable and firmly erect at the base of the mouth dry dock. When empty ballast produces GMt 0.996 which means dry dock date is stable, but can easily be torn down. The condition can be used during dry dock gate treatment.

  10. New generation of docking programs: Supercomputer validation of force fields and quantum-chemical methods for docking.

    Science.gov (United States)

    Sulimov, Alexey V; Kutov, Danil C; Katkova, Ekaterina V; Ilin, Ivan S; Sulimov, Vladimir B

    2017-11-01

    Discovery of new inhibitors of the protein associated with a given disease is the initial and most important stage of the whole process of the rational development of new pharmaceutical substances. New inhibitors block the active site of the target protein and the disease is cured. Computer-aided molecular modeling can considerably increase effectiveness of new inhibitors development. Reliable predictions of the target protein inhibition by a small molecule, ligand, is defined by the accuracy of docking programs. Such programs position a ligand in the target protein and estimate the protein-ligand binding energy. Positioning accuracy of modern docking programs is satisfactory. However, the accuracy of binding energy calculations is too low to predict good inhibitors. For effective application of docking programs to new inhibitors development the accuracy of binding energy calculations should be higher than 1kcal/mol. Reasons of limited accuracy of modern docking programs are discussed. One of the most important aspects limiting this accuracy is imperfection of protein-ligand energy calculations. Results of supercomputer validation of several force fields and quantum-chemical methods for docking are presented. The validation was performed by quasi-docking as follows. First, the low energy minima spectra of 16 protein-ligand complexes were found by exhaustive minima search in the MMFF94 force field. Second, energies of the lowest 8192 minima are recalculated with CHARMM force field and PM6-D3H4X and PM7 quantum-chemical methods for each complex. The analysis of minima energies reveals the docking positioning accuracies of the PM7 and PM6-D3H4X quantum-chemical methods and the CHARMM force field are close to one another and they are better than the positioning accuracy of the MMFF94 force field. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Hemoglobin affinity in Andean rodents

    Directory of Open Access Journals (Sweden)

    HRVOJ OSTOJIC

    2002-01-01

    Full Text Available Blood hemoglobin oxygen affinity (P50 was measured in three Andean species and in the laboratory rat (control, all raised near sea level. Chinchilla lanigera (Molina, 1792 has an altitudinal habitat range from low Andean slopes up to 3000 m., while Chinchilla brevicaudata (Waterhouse, 1848 has an altitudinal range from 3000 to 5000 m. The laboratory type guinea pig, wild type guinea pig (Cavia porcellus, (Waterhouse, 1748, and laboratory rat (Rattus norvegicus were also raised at sea level. The Andean species had high hemoglobin oxygen affinities (low P50 compared with the rat. Chinchilla brevicaudata had a higher affinity than Chinchilla lanigera. The wild type guinea pig had a higher affinity than the laboratory type. As has been shown in other species, this is another example of an inverse correlation between the altitude level and the P50 values. This is the first hemoglobin oxygen affinity study in Chinchilla brevicaudata.

  12. Hemoglobin Wayne Trait with Incidental Polycythemia.

    Science.gov (United States)

    Ambelil, Manju; Nguyen, Nghia; Dasgupta, Amitava; Risin, Semyon; Wahed, Amer

    2017-01-01

    Hemoglobinopathies, caused by mutations in the globin genes, are one of the most common inherited disorders. Many of the hemoglobin variants can be identified by hemoglobin analysis using conventional electrophoresis and high performance liquid chromatography; however hemoglobin DNA analysis may be necessary in other cases for confirmation. Here, we report a case of a rare alpha chain hemoglobin variant, hemoglobin Wayne, in a 47-year-old man who presented with secondary polycythemia. Capillary zone electrophoresis and high performance liquid chromatography revealed a significant amount of a hemoglobin variant, which was further confirmed by hemoglobin DNA sequencing as hemoglobin Wayne. Since the patient was not homozygous for hemoglobin Wayne, which is associated with secondary polycythemia, the laboratory diagnosis in this case was critical in ruling out hemoglobinopathy as the etiology of his polycythemia. © 2017 by the Association of Clinical Scientists, Inc.

  13. Hemoglobin and heme scavenger receptors

    DEFF Research Database (Denmark)

    Nielsen, Marianne Jensby; Møller, Holger Jon; Moestrup, Søren Kragh

    2010-01-01

    Heme, the functional group of hemoglobin, myoglobin, and other hemoproteins, is a highly toxic substance when it appears in the extracellular milieu. To circumvent potential harmful effects of heme from hemoproteins released during physiological or pathological cell damage (such as hemolysis...... and rhabdomyolysis), specific high capacity scavenging systems have evolved in the mammalian organism. Two major systems, which essentially function in a similar way by means of a circulating latent plasma carrier protein that upon ligand binding is recognized by a receptor, are represented by a) the hemoglobin...

  14. NASA Docking System (NDS) Technical Integration Meeting

    Science.gov (United States)

    Lewis, James L.

    2010-01-01

    This slide presentation reviews the NASA Docking System (NDS) as NASA's implementation of the International Docking System Standard (IDSS). The goals of the NDS, is to build on proven technologies previously demonstrated in flight and to advance the state of the art of docking systems by incorporating Low Impact Docking System (LIDS) technology into the NDS. A Hardware Demonstration was included in the meeting, and there was discussion about software, NDS major system interfaces, integration information, schedule, and future upgrades.

  15. Spent fuel canister docking station

    International Nuclear Information System (INIS)

    Suikki, M.

    2006-01-01

    The working report for the spent fuel canister docking station presents a design for the operation and structure of the docking equipment located in the fuel handling cell for the spent fuel in the encapsulation plant. The report contains a description of the basic requirements for the docking station equipment and their implementation, the operation of the equipment, maintenance and a cost estimate. In the designing of the equipment all the problems related with the operation have been solved at the level of principle, nevertheless, detailed designing and the selection of final components have not yet been carried out. In case of defects and failures, solutions have been considered for postulated problems, and furthermore, the entire equipment was gone through by the means of systematic risk analysis (PFMEA). During the docking station designing we came across with needs to influence the structure of the actual disposal canister for spent nuclear fuel, too. Proposed changes for the structure of the steel lid fastening screw were included in the report. The report also contains a description of installation with the fuel handling cell structures. The purpose of the docking station for the fuel handling cell is to position and to seal the disposal canister for spent nuclear fuel into a penetration located on the cell floor and to provide suitable means for executing the loading of the disposal canister and the changing of atmosphere. The designed docking station consists of a docking ring, a covering hatch, a protective cone and an atmosphere-changing cap as well as the vacuum technology pertaining to the changing of atmosphere and the inert gas system. As far as the solutions are concerned, we have arrived at rather simple structures and most of the actuators of the system are situated outside of the actual fuel handling cell. When necessary, the equipment can also be used for the dismantling of a faulty disposal canister, cut from its upper end by machining. The

  16. Hemoglobin of mice with radiation-induced mutations at the hemoglobin loci

    International Nuclear Information System (INIS)

    Popp, R.A.; Stratton, L.P.; Hawley, D.K.; Effron, K.

    1979-01-01

    Chemical analyses were done on the abnormal hemoglobins of the five (101 x SEC)F 1 offspring of X- irradiated adult SEC mice to determine which hemoglobin genes were expressed in each hemoglobin variant. Three offspring of irradiated SEC males did not express either of the two kinds of α-chains normally found in all SEC mice. The deficient α-chain synthesis caused these mice to exhibit an α-thalassemia similar to human α-thalassemia. Scanning electron microscopy was used to show that many erythrocytes of mice with α-thalassemia have bizarre shapes; e.g. many erythrocytes appeared flattened or had thorny projections (acanthocytes). One mutant with a tandem duplication of a segment of chromosome 7 (site of locus determining β-chain structure) produced twice as much SEC as 101 β-chain polypeptides. One mutant that probably arose by non-disjunction of chromosome 7's in its unirradiated 101 mother and loss of chromosome 7 from the gamete of its irradiated SEC father did not express the SEC β-chain gene. (author)

  17. Hemoglobin of mice with radiation-induced mutations at the hemoglobin loci

    Energy Technology Data Exchange (ETDEWEB)

    Popp, R A; Stratton, L P; Hawley, D K; Effron, K [Oak Ridge National Lab., TN (USA)

    1979-01-15

    Chemical analyses were done on the abnormal hemoglobins of the five (101 x SEC)F/sub 1/ offspring of X- irradiated adult SEC mice to determine which hemoglobin genes were expressed in each hemoglobin variant. Three offspring of irradiated SEC males did not express either of the two kinds of ..cap alpha..-chains normally found in all SEC mice. The deficient ..cap alpha..-chain synthesis caused these mice to exhibit an ..cap alpha..-thalassemia similar to human ..cap alpha..-thalassemia. Scanning electron microscopy was used to show that many erythrocytes of mice with ..cap alpha..-thalassemia have bizarre shapes; e.g. many erythrocytes appeared flattened or had thorny projections (acanthocytes). One mutant with a tandem duplication of a segment of chromosome 7 (site of locus determining ..beta..-chain structure) produced twice as much SEC as 101 ..beta..-chain polypeptides. One mutant that probably arose by non-disjunction of chromosome 7's in its unirradiated 101 mother and loss of chromosome 7 from the gamete of its irradiated SEC father did not express the SEC ..beta..-chain gene.

  18. Combining self- and cross-docking as benchmark tools: the performance of DockBench in the D3R Grand Challenge 2

    Science.gov (United States)

    Salmaso, Veronica; Sturlese, Mattia; Cuzzolin, Alberto; Moro, Stefano

    2018-01-01

    Molecular docking is a powerful tool in the field of computer-aided molecular design. In particular, it is the technique of choice for the prediction of a ligand pose within its target binding site. A multitude of docking methods is available nowadays, whose performance may vary depending on the data set. Therefore, some non-trivial choices should be made before starting a docking simulation. In the same framework, the selection of the target structure to use could be challenging, since the number of available experimental structures is increasing. Both issues have been explored within this work. The pose prediction of a pool of 36 compounds provided by D3R Grand Challenge 2 organizers was preceded by a pipeline to choose the best protein/docking-method couple for each blind ligand. An integrated benchmark approach including ligand shape comparison and cross-docking evaluations was implemented inside our DockBench software. The results are encouraging and show that bringing attention to the choice of the docking simulation fundamental components improves the results of the binding mode predictions.

  19. An Atomistic View on Human Hemoglobin Carbon Monoxide Migration Processes

    Science.gov (United States)

    Lucas, M. Fátima; Guallar, Víctor

    2012-01-01

    A significant amount of work has been devoted to obtaining a detailed atomistic knowledge of the human hemoglobin mechanism. Despite this impressive research, to date, the ligand diffusion processes remain unclear and controversial. Using recently developed computational techniques, PELE, we are capable of addressing the ligand migration processes. First, the methodology was tested on myoglobin's CO migration, and the results were compared with the wealth of theoretical and experimental studies. Then, we explored both hemoglobin tense and relaxed states and identified the differences between the α-and β-subunits. Our results indicate that the proximal site, equivalent to the Xe1 cavity in myoglobin, is never visited. Furthermore, strategically positioned residues alter the diffusion processes within hemoglobin's subunits and suggest that multiple pathways exist, especially diversified in the α-globins. A significant dependency of the ligand dynamics on the tertiary structure is also observed. PMID:22385860

  20. Blood Test: Hemoglobin A1C

    Science.gov (United States)

    ... Why Are Hemoglobin A1c Tests Done? When a child has diabetes, hemoglobin A1c levels are followed to see how well medicines are working. If a child with diabetes has a high hemoglobin A1c level, it may ...

  1. Characteristic emission in glutaraldehyde polymerized hemoglobin

    International Nuclear Information System (INIS)

    Ma Li; Wang Xiaojun

    2011-01-01

    Hemoglobin with different modifications has been investigated using spectroscopic techniques. A new emission at around 371 nm has been observed under excitation of 305 nm from glutaraldehyde polymerized human hemoglobin. Intensity and peak position of the emission are dependent on both oxidation state and ligand environment and the emission has been identified from the hemoglobin oligomer.

  2. Docking and 3-D QSAR studies on indolyl aryl sulfones. Binding mode exploration at the HIV-1 reverse transcriptase non-nucleoside binding site and design of highly active N-(2-hydroxyethyl)carboxamide and N-(2-hydroxyethyl)carbohydrazide derivatives.

    Science.gov (United States)

    Ragno, Rino; Artico, Marino; De Martino, Gabriella; La Regina, Giuseppe; Coluccia, Antonio; Di Pasquali, Alessandra; Silvestri, Romano

    2005-01-13

    Three-dimensional quantitative structure-activity relationship (3-D QSAR) studies and docking simulations were developed on indolyl aryl sulfones (IASs), a class of novel HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (Silvestri, et al. J. Med. Chem. 2003, 46, 2482-2493) highly active against wild type and some clinically relevant resistant strains (Y181C, the double mutant K103N-Y181C, and the K103R-V179D-P225H strain, highly resistant to efavirenz). Predictive 3-D QSAR models using the combination of GRID and GOLPE programs were obtained using a receptor-based alignment by means of docking IASs into the non-nucleoside binding site (NNBS) of RT. The derived 3-D QSAR models showed conventional correlation (r(2)) and cross-validated (q(2)) coefficients values ranging from 0.79 to 0.93 and from 0.59 to 0.84, respectively. All described models were validated by an external test set compiled from previously reported pyrryl aryl sulfones (Artico, et al. J. Med. Chem. 1996, 39, 522-530). The most predictive 3-D QSAR model was then used to predict the activity of novel untested IASs. The synthesis of six designed derivatives (prediction set) allowed disclosure of new IASs endowed with high anti-HIV-1 activities.

  3. Hemoglobin Test: MedlinePlus Lab Test Information

    Science.gov (United States)

    ... page: https://medlineplus.gov/labtests/hemoglobintest.html Hemoglobin Test To use the sharing features on this page, please enable JavaScript. What is a Hemoglobin Test? A hemoglobin test measures the levels of hemoglobin ...

  4. Autonomous Vision-Based Tethered-Assisted Rover Docking

    Science.gov (United States)

    Tsai, Dorian; Nesnas, Issa A.D.; Zarzhitsky, Dimitri

    2013-01-01

    Many intriguing science discoveries on planetary surfaces, such as the seasonal flows on crater walls and skylight entrances to lava tubes, are at sites that are currently inaccessible to state-of-the-art rovers. The in situ exploration of such sites is likely to require a tethered platform both for mechanical support and for providing power and communication. Mother/daughter architectures have been investigated where a mother deploys a tethered daughter into extreme terrains. Deploying and retracting a tethered daughter requires undocking and re-docking of the daughter to the mother, with the latter being the challenging part. In this paper, we describe a vision-based tether-assisted algorithm for the autonomous re-docking of a daughter to its mother following an extreme terrain excursion. The algorithm uses fiducials mounted on the mother to improve the reliability and accuracy of estimating the pose of the mother relative to the daughter. The tether that is anchored by the mother helps the docking process and increases the system's tolerance to pose uncertainties by mechanically aligning the mating parts in the final docking phase. A preliminary version of the algorithm was developed and field-tested on the Axel rover in the JPL Mars Yard. The algorithm achieved an 80% success rate in 40 experiments in both firm and loose soils and starting from up to 6 m away at up to 40 deg radial angle and 20 deg relative heading. The algorithm does not rely on an initial estimate of the relative pose. The preliminary results are promising and help retire the risk associated with the autonomous docking process enabling consideration in future martian and lunar missions.

  5. Transcriptional Dysregulation of MYC Reveals Common Enhancer-Docking Mechanism.

    Science.gov (United States)

    Schuijers, Jurian; Manteiga, John Colonnese; Weintraub, Abraham Selby; Day, Daniel Sindt; Zamudio, Alicia Viridiana; Hnisz, Denes; Lee, Tong Ihn; Young, Richard Allen

    2018-04-10

    Transcriptional dysregulation of the MYC oncogene is among the most frequent events in aggressive tumor cells, and this is generally accomplished by acquisition of a super-enhancer somewhere within the 2.8 Mb TAD where MYC resides. We find that these diverse cancer-specific super-enhancers, differing in size and location, interact with the MYC gene through a common and conserved CTCF binding site located 2 kb upstream of the MYC promoter. Genetic perturbation of this enhancer-docking site in tumor cells reduces CTCF binding, super-enhancer interaction, MYC gene expression, and cell proliferation. CTCF binding is highly sensitive to DNA methylation, and this enhancer-docking site, which is hypomethylated in diverse cancers, can be inactivated through epigenetic editing with dCas9-DNMT. Similar enhancer-docking sites occur at other genes, including genes with prominent roles in multiple cancers, suggesting a mechanism by which tumor cell oncogenes can generally hijack enhancers. These results provide insights into mechanisms that allow a single target gene to be regulated by diverse enhancer elements in different cell types. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

  6. Hemoglobin Function in Stored Blood.

    Science.gov (United States)

    1974-08-01

    States during 1973. Several advantages over ACA) are important. Blood stored in CPD maintains higher ./ levels of 2,3-DPG (2,3- diphosphoglycerate ) and a...survival and ATP levels in stored blood is explained by the several functions of ATP which are necessary for cell viability. However, ATP levels do...not correlate with oxygen affinity during storage. Levels of 2,3-DPG determine oxygen affinity and thus hemoglobin function. (12,13) When normal levels

  7. Application of the docking program SOL for CSAR benchmark.

    Science.gov (United States)

    Sulimov, Alexey V; Kutov, Danil C; Oferkin, Igor V; Katkova, Ekaterina V; Sulimov, Vladimir B

    2013-08-26

    This paper is devoted to results obtained by the docking program SOL and the post-processing program DISCORE at the CSAR benchmark. SOL and DISCORE programs are described. SOL is the original docking program developed on the basis of the genetic algorithm, MMFF94 force field, rigid protein, precalculated energy grid including desolvation in the frame of simplified GB model, vdW, and electrostatic interactions and taking into account the ligand internal strain energy. An important SOL feature is the single- or multi-processor performance for up to hundreds of CPUs. DISCORE improves the binding energy scoring by the local energy optimization of the ligand docked pose and a simple linear regression on the base of available experimental data. The docking program SOL has demonstrated a good ability for correct ligand positioning in the active sites of the tested proteins in most cases of CSAR exercises. SOL and DISCORE have not demonstrated very exciting results on the protein-ligand binding free energy estimation. Nevertheless, for some target proteins, SOL and DISCORE were among the first in prediction of inhibition activity. Ways to improve SOL and DISCORE are discussed.

  8. Aspartic protease activities of schistosomes cleave mammalian hemoglobins in a host-specific manner

    Directory of Open Access Journals (Sweden)

    Jeffrey W Koehler

    2007-02-01

    Full Text Available We examined the efficiency of digestion of hemoglobin from four mammalian species, human, cow, sheep, and horse by acidic extracts of mixed sex adults of Schistosoma japonicum and S. mansoni. Activity ascribable to aspartic protease(s from S. japonicum and S. mansoni cleaved human hemoglobin. In addition, aspartic protease activities from S. japonicum cleaved hemoglobin from bovine, sheep, and horse blood more efficiently than did the activity from extracts of S. mansoni. These findings support the hypothesis that substrate specificity of hemoglobin-degrading proteases employed by blood feeding helminth parasites influences parasite host species range; differences in amino acid sequences in key sites of the parasite proteases interact less or more efficiently with the hemoglobins of permissive or non-permissive hosts.

  9. Megalin and cubilin are endocytic receptors involved in renal clearance of hemoglobin

    DEFF Research Database (Denmark)

    Gburek, Jakub; Verroust, Pierre J; Willnow, Thomas E

    2002-01-01

    -Sepharose affinity chromatography of solubilized renal brush-border membranes. Apparent dissociation constants of 1.7 microM for megalin and 4.1 microM for cubilin were determined by surface plasmon resonance analysis. The binding was calcium dependent in both cases. Uptake of fluorescence-labeled hemoglobin by BN......The kidney is the main site of hemoglobin clearance and degradation in conditions of severe hemolysis. Herein it is reported that megalin and cubilin, two epithelial endocytic receptors, mediate the uptake of hemoglobin in renal proximal tubules. Both receptors were purified by use of hemoglobin...... not affect the uptake. By use of immunohistochemistry, it was demonstrated that uptake of hemoglobin in proximal tubules of rat, mouse, and dog kidneys occurs under physiologic conditions. Studies on normal and megalin knockout mouse kidney sections showed that megalin is responsible for physiologic...

  10. PLASMA PROTEIN AND HEMOGLOBIN PRODUCTION

    Science.gov (United States)

    Robscheit-Robbins, F. S.; Miller, L. L.; Whipple, G. H.

    1947-01-01

    Given healthy dogs fed abundant iron and protein-free or low protein diets with sustained anemia and hypoproteinemia, we can study the capacity of these animals to produce simultaneously new hemoglobin and plasma protein. Reserve stores of blood protein-building materials are measurably depleted and levels of 6 to 8 gm. per cent for hemoglobin and 4 to 5 gm. per cent for plasma protein can be maintained for weeks or months depending upon the intake of food proteins or amino acid mixtures. These dogs are very susceptible to infection and various poisons. Dogs tire of these diets and loss of appetite terminates many experiments. Under these conditions (double depletion) standard growth mixtures of essential amino acids are tested to show the response in blood protein output and urinary nitrogen balance. As a part of each tabulated experiment one of the essential amino acids is deleted from the complete growth mixture to compare such response with that of the whole mixture. Methionine, threonine, phenylalanine, and tryptophane when singly eliminated from the complete amino acid mixture do effect a sharp rise in urinary nitrogen. This loss of urinary nitrogen is corrected when the individual amino acid is replaced in the mixture. Histidine, lysine, and valine have a moderate influence upon urinary nitrogen balance toward nitrogen conservation. Leucine, isoleucine, and arginine have minimal or no effect upon urinary nitrogen balance when these individual amino acids are deleted from the complete growth mixture of amino acids during 3 to 4 week periods. Tryptophane and to a less extent phenylalanine and threonine when returned to the amino acid mixture are associated with a conspicuous preponderance of plasma protein output over the hemoglobin output (Table 4). Arginine, lysine, and histidine when returned to the amino acid mixture are associated with a large preponderance of hemoglobin output. Various amino acid mixtures under these conditions may give a positive

  11. Hemoglobin Labeled by Radioactive Lysine

    Science.gov (United States)

    Bale, W. F.; Yuile, C. L.; DeLaVergne, L.; Miller, L. L.; Whipple, G. H.

    1949-12-08

    This paper reports on the utilization of tagged epsilon carbon of DL-lysine by a dog both anemic and hypoproteinemic due to repeated bleeding plus a diet low in protein. The experiment extended over period of 234 days, a time sufficient to indicate an erythrocyte life span of at least 115 days based upon the rate of replacement of labeled red cell proteins. The proteins of broken down red cells seem not to be used with any great preference for the synthesis of new hemoglobin.

  12. Homology modeling, docking studies and molecular dynamic simulations using graphical processing unit architecture to probe the type-11 phosphodiesterase catalytic site: a computational approach for the rational design of selective inhibitors.

    Science.gov (United States)

    Cichero, Elena; D'Ursi, Pasqualina; Moscatelli, Marco; Bruno, Olga; Orro, Alessandro; Rotolo, Chiara; Milanesi, Luciano; Fossa, Paola

    2013-12-01

    Phosphodiesterase 11 (PDE11) is the latest isoform of the PDEs family to be identified, acting on both cyclic adenosine monophosphate and cyclic guanosine monophosphate. The initial reports of PDE11 found evidence for PDE11 expression in skeletal muscle, prostate, testis, and salivary glands; however, the tissue distribution of PDE11 still remains a topic of active study and some controversy. Given the sequence similarity between PDE11 and PDE5, several PDE5 inhibitors have been shown to cross-react with PDE11. Accordingly, many non-selective inhibitors, such as IBMX, zaprinast, sildenafil, and dipyridamole, have been documented to inhibit PDE11. Only recently, a series of dihydrothieno[3,2-d]pyrimidin-4(3H)-one derivatives proved to be selective toward the PDE11 isoform. In the absence of experimental data about PDE11 X-ray structures, we found interesting to gain a better understanding of the enzyme-inhibitor interactions using in silico simulations. In this work, we describe a computational approach based on homology modeling, docking, and molecular dynamics simulation to derive a predictive 3D model of PDE11. Using a Graphical Processing Unit architecture, it is possible to perform long simulations, find stable interactions involved in the complex, and finally to suggest guideline for the identification and synthesis of potent and selective inhibitors. © 2013 John Wiley & Sons A/S.

  13. Determination Of Ph Including Hemoglobin Correction

    Science.gov (United States)

    Maynard, John D.; Hendee, Shonn P.; Rohrscheib, Mark R.; Nunez, David; Alam, M. Kathleen; Franke, James E.; Kemeny, Gabor J.

    2005-09-13

    Methods and apparatuses of determining the pH of a sample. A method can comprise determining an infrared spectrum of the sample, and determining the hemoglobin concentration of the sample. The hemoglobin concentration and the infrared spectrum can then be used to determine the pH of the sample. In some embodiments, the hemoglobin concentration can be used to select an model relating infrared spectra to pH that is applicable at the determined hemoglobin concentration. In other embodiments, a model relating hemoglobin concentration and infrared spectra to pH can be used. An apparatus according to the present invention can comprise an illumination system, adapted to supply radiation to a sample; a collection system, adapted to collect radiation expressed from the sample responsive to the incident radiation; and an analysis system, adapted to relate information about the incident radiation, the expressed radiation, and the hemoglobin concentration of the sample to pH.

  14. Hemoglobin Variants: Biochemical Properties and Clinical Correlates

    Science.gov (United States)

    Thom, Christopher S.; Dickson, Claire F.; Gell, David A.; Weiss, Mitchell J.

    2013-01-01

    Diseases affecting hemoglobin synthesis and function are extremely common worldwide. More than 1000 naturally occurring human hemoglobin variants with single amino acid substitutions throughout the molecule have been discovered, mainly through their clinical and/or laboratory manifestations. These variants alter hemoglobin structure and biochemical properties with physiological effects ranging from insignificant to severe. Studies of these mutations in patients and in the laboratory have produced a wealth of information on hemoglobin biochemistry and biology with significant implications for hematology practice. More generally, landmark studies of hemoglobin performed over the past 60 years have established important paradigms for the disciplines of structural biology, genetics, biochemistry, and medicine. Here we review the major classes of hemoglobin variants, emphasizing general concepts and illustrative examples. PMID:23388674

  15. Silencing of dedicator of cytokinesis (DOCK180) obliterates pregnancy by interfering with decidualization due to blockage of nuclear entry of autoimmune regulator (AIRE).

    Science.gov (United States)

    Mohan, Jasna Jagan; Narayan, Prashanth; Padmanabhan, Renjini Ambika; Joseph, Selin; Kumar, Pradeep G; Laloraya, Malini

    2018-03-08

    Dedicator of cytokinesis (DOCK 180) involved in cytoskeletal reorganization is primarily a cytosolic molecule. It is recently shown to be nuclear in HeLa cells but its nuclear function is not known. The spatiotemporal distribution of DOCK180 in uterus was studied in uterine cytoplasmic and nuclear compartments during the "window of implantation." The functional significance of nuclear DOCK180 was explored by homology modeling, co-immunoprecipitation assays, and mass spectrometric analysis. Dock180's role in early pregnancy was ascertained by Dock 180 silencing and subsequent quantitative real-time PCR and Western blotting analysis. Our study shows a nuclear DOCK180 in the uterus during "window of implantation." Estrogen and progesterone mediate expression and nuclear translocation of DOCK180. The nuclear function of DOCK180 is attributed to its ability to import autoimmune regulator (AIRE) into the nucleus. Silencing of Dock180 inhibited AIRE nuclear shuttling which influenced its downstream targets, thereby affecting decidualization with AIRE and HOXA-10 as the major players as well as lack of implantation site formation due to impact on angiogenesis-associated genes. DOCK180 has an indispensable role in pregnancy establishment as knocking down Dock180 abrogates pregnancy by a consolidated impact on decidualization and angiogenesis by regulating AIRE nuclear entry. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Boring crustaceans damage polystyrene floats under docks polluting marine waters with microplastic.

    Science.gov (United States)

    Davidson, Timothy M

    2012-09-01

    Boring isopods damage expanded polystyrene floats under docks and, in the process, expel copious numbers of microplastic particles. This paper describes the impacts of boring isopods in aquaculture facilities and docks, quantifies and discusses the implications of these microplastics, and tests if an alternate foam type prevents boring. Floats from aquaculture facilities and docks were heavily damaged by thousands of isopods and their burrows. Multiple sites in Asia, Australia, Panama, and the USA exhibited evidence of isopod damage. One isopod creates thousands of microplastic particles when excavating a burrow; colonies can expel millions of particles. Microplastics similar in size to these particles may facilitate the spread of non-native species or be ingested by organisms causing physical or toxicological harm. Extruded polystyrene inhibited boring, suggesting this foam may prevent damage in the field. These results reveal boring isopods cause widespread damage to docks and are a novel source of microplastic pollution. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. GalaxyDock BP2 score: a hybrid scoring function for accurate protein-ligand docking

    Science.gov (United States)

    Baek, Minkyung; Shin, Woong-Hee; Chung, Hwan Won; Seok, Chaok

    2017-07-01

    Protein-ligand docking is a useful tool for providing atomic-level understanding of protein functions in nature and design principles for artificial ligands or proteins with desired properties. The ability to identify the true binding pose of a ligand to a target protein among numerous possible candidate poses is an essential requirement for successful protein-ligand docking. Many previously developed docking scoring functions were trained to reproduce experimental binding affinities and were also used for scoring binding poses. However, in this study, we developed a new docking scoring function, called GalaxyDock BP2 Score, by directly training the scoring power of binding poses. This function is a hybrid of physics-based, empirical, and knowledge-based score terms that are balanced to strengthen the advantages of each component. The performance of the new scoring function exhibits significant improvement over existing scoring functions in decoy pose discrimination tests. In addition, when the score is used with the GalaxyDock2 protein-ligand docking program, it outperformed other state-of-the-art docking programs in docking tests on the Astex diverse set, the Cross2009 benchmark set, and the Astex non-native set. GalaxyDock BP2 Score and GalaxyDock2 with this score are freely available at http://galaxy.seoklab.org/softwares/galaxydock.html.

  18. Expression of Cry1Ac toxin-binding region in Plutella xyllostella cadherin-like receptor and studying their interaction mode by molecular docking and site-directed mutagenesis.

    Science.gov (United States)

    Hu, Xiaodan; Zhang, Xiao; Zhong, Jianfeng; Liu, Yuan; Zhang, Cunzheng; Xie, Yajing; Lin, Manman; Xu, Chongxin; Lu, Lina; Zhu, Qing; Liu, Xianjin

    2018-05-01

    Cadherin-like protein has been identified as the primary Bacillus thuringiensis (Bt) Cry toxin receptor in Lepidoptera pests and plays a key role in Cry toxin insecticidal. In this study, we successfully expressed the putative Cry1Ac toxin-binding region (CR7-CR11) of Plutella xylostella cadherin-like in Escherichia coli BL21 (DE3). The expressed CR7-CR11 fragment showed binding ability to Cry1Ac toxin under denaturing (Ligand blot) and non-denaturing (ELISA) conditions. The three-dimensional structure of CR7-CR11 was constructed by homology modeling. Molecular docking results of CR7-CR11 and Cry1Ac showed that domain II and domain III of Cry1Ac were taking part in binding to CR7-CR11, while CR7-CR8 was the region of CR7-CR11 in interacting with Cry1Ac. The interaction of toxin-receptor complex was found to arise from hydrogen bond and hydrophobic interaction. Through the computer-aided alanine mutation scanning, amino acid residues of Cry1Ac (Met341, Asn442 and Ser486) and CR7-CR11 (Asp32, Arg101 and Arg127) were predicted as the hot spot residues involved in the interaction of the toxin-receptor complex. At last, we verified the importance role of these key amino acid residues by binding assay. These results will lay a foundation for further elucidating the insecticidal mechanism of Cry toxin and enhancing Cry toxin insecticidal activity by molecular modification. Copyright © 2018 Elsevier B.V. All rights reserved.

  19. Determination of Human Hemoglobin Derivatives.

    Science.gov (United States)

    Attia, Atef M M; Ibrahim, Fatma A A; Abd El-Latif, Noha A; Aziz, Samir W; Abdelmottaleb Moussa, Sherif A; Elalfy, Mohsen S

    2015-01-01

    The levels of the inactive hemoglobin (Hb) pigments [such as methemoglobin (metHb), carboxyhemoglobin (HbCO) and sulfohemoglobin (SHb)] and the active Hb [in the oxyhemoglobin (oxyHb) form] as well as the blood Hb concentration in healthy non pregnant female volunteers were determined using a newly developed multi-component spectrophotometric method. The results of this method revealed values of SHb% in the range (0.0727-0.370%), metHb% (0.43-1.0%), HbCO% (0.4-1.52%) and oxyHb% (97.06-98.62%). Furthermore, the results of this method revealed values of blood Hb concentration in the range (12.608-15.777 g/dL). The method is highly sensitive, accurate and reproducible.

  20. Biological variability of glycated hemoglobin.

    Science.gov (United States)

    Braga, Federica; Dolci, Alberto; Mosca, Andrea; Panteghini, Mauro

    2010-11-11

    The measurement of glycated hemoglobin (HbA(1c)) has a pivotal role in monitoring glycemic state in diabetic patients. Furthermore, the American Diabetes Association has recently recommended the use of HbA(1c) for diabetes diagnosis, but a clear definition of the clinically allowable measurement error is still lacking. Information on biological variability of the analyte can be used to achieve this goal. We systematically reviewed the published studies on the biological variation of HbA(1c) to check consistency of available data in order to accurately define analytical goals. The nine recruited studies were limited by choice of analytic methodology, population selection, protocol application and statistical analyses. There is an urgent need to determine biological variability of HbA(1c) using a specific and traceable assay, appropriate protocol and appropriate statistical evaluation of data. 2010 Elsevier B.V. All rights reserved.

  1. THE BIOCHEMISTRY OF VITREOSCILLA HEMOGLOBIN

    Directory of Open Access Journals (Sweden)

    Benjamin C. Stark

    2012-10-01

    Full Text Available The hemoglobin (VHb from Vitreoscilla was the first bacterial hemoglobin discovered. Its structure and function have been extensively investigated, and engineering of a wide variety of heterologous organisms to express VHb has been performed to increase their growth and productivity. This strategy has shown promise in applications as far-ranging as the production of antibiotics and petrochemical replacements by microorganisms to increasing stress tolerance in plants. These applications of “VHb technology” have generally been of the “black box” variety, wherein the endpoint studied is an increase in the levels of a certain product or improved growth and survival. Their eventual optimization, however, will require a thorough understanding of the various functions and activities of VHb, and how VHb expression ripples to affect metabolism more generally. Here we review the current knowledge of these topics. VHb's functions all involve oxygen binding (and often delivery in one way or another. Several biochemical and structure-function studies have provided an insight into the molecular details of this binding and delivery. VHb activities are varied. They include supply of oxygen to oxygenases and the respiratory chain, particularly under low oxygen conditions; oxygen sensing and modulation of transcription factor activity; and detoxification of NO, and seem to require interactions of VHb with “partner proteins”. VHb expression affects the levels of ATP and NADH, although not enormously. VHb expression may affect the level of many compounds of intermediary metabolism, and, apparently, alters the levels of expression of many genes. Thus, the metabolic changes in organisms engineered to express VHb are likely to be numerous and complicated.

  2. Led Astray by Hemoglobin A1c

    Directory of Open Access Journals (Sweden)

    Jean Chen MD

    2016-01-01

    Full Text Available Hemoglobin A1c (A1c is used frequently to diagnose and treat diabetes mellitus. Therefore, it is important be aware of factors that may interfere with the accuracy of A1c measurements. This is a case of a rare hemoglobin variant that falsely elevated a nondiabetic patient’s A1c level and led to a misdiagnosis of diabetes. A 67-year-old male presented to endocrine clinic for further management after he was diagnosed with diabetes based on an elevated A1c of 10.7%, which is approximately equivalent to an average blood glucose of 260 mg/dL. Multiple repeat A1c levels remained >10%, but his home fasting and random glucose monitoring ranged from 92 to 130 mg/dL. Hemoglobin electrophoresis and subsequent genetic analysis diagnosed the patient with hemoglobin Wayne, a rare hemoglobin variant. This variant falsely elevates A1c levels when A1c is measured using cation-exchange high-performance liquid chromatography. When the boronate affinity method was applied instead, the patient’s A1c level was actually 4.7%. Though hemoglobin Wayne is clinically silent, this patient was erroneously diagnosed with diabetes and started on an antiglycemic medication. Due to this misdiagnosis, the patient was at risk of escalation in his “diabetes management” and hypoglycemia. Therefore, it is important that providers are aware of factors that may result in hemoglobin A1c inaccuracy including hemoglobin variants.

  3. Hemoglobin Values During Pregnancy | Leffler | Nigerian Medical ...

    African Journals Online (AJOL)

    It is known that the iron turnover in expectant mothers is up to three times that of an average adult. This is reflected in lower hemoglobin levels. The study showed that hemoglobin levels can be maintained by taking Bio-Strath®, provided that the patients' diet contains adequate fresh fruits and vegetables, whole grains, lean ...

  4. Spectroscopic study of gamma irradiated bovine hemoglobin

    International Nuclear Information System (INIS)

    Maghraby, Ahmed Mohamed; Ali, Maha Anwar

    2007-01-01

    In the present study, the effects of ionizing radiation of Cs-137 and Co-60 from 4.95 to 743.14 Gy and from 40 Gy to 300 kGy, respectively, on some bovine hemoglobin characteristics were studied. Such an effect was evaluated using electron paramagnetic resonance (EPR) spectroscopy, and infra-red (IR) spectroscopy. Bovine hemoglobin EPR spectra were recorded and analyzed before and after irradiation and changes were explained in detail. IR spectra of unirradiated and irradiated Bovine hemoglobin were recorded and analyzed also. It was found that ionizing radiation may lead to the increase of free radicals production, the decrease in α-helices contents, which reflects the degradation of hemoglobin molecular structure, or at least its incomplete performance. Results also show that the combined application of EPR and FTIR spectroscopy is a powerful tool for determining structural modification of bovine hemoglobin samples exposed to gamma irradiation

  5. Spin Label Studies of the Hemoglobin-Membrane Interaction During Sickle Hemoglobin Polymerization

    International Nuclear Information System (INIS)

    Falcon Dieguez, Jose E.; Rodi, Pablo; Lores Guevara, Manuel A.; Gennaro, Ana Maria

    2009-12-01

    An enhanced hemoglobin-membrane association has been previously documented in Sickle Cell Anemia. However, it is not known how this interaction is modified during the hemoglobin S polymerization process. In this work, we use a model of reconstituted erythrocytes from ghost membranes whose cytoskeleton proteins had been previously labeled with the 4-maleimido Tempo spin label, and that were subsequently resealed with hemoglobin S or A solutions. Using EPR spectroscopy, we studied the time dependence of the spectral W/S parameter, indicative of the conformational state of cytoskeleton proteins (mainly spectrin) under spontaneous deoxygenation, with the aim of detecting the eventual effects due to hemoglobin S polymerization. The differences observed in the temporal behaviour of W/S in erythrocytes reconstituted with both hemoglobins were considered as experimental evidence of an increment in hemoglobin S-membrane interaction, as a result of the polymerization process of hemoglobin S under spontaneous deoxygenation. (author)

  6. Rosetta Ligand docking with flexible XML protocols.

    Science.gov (United States)

    Lemmon, Gordon; Meiler, Jens

    2012-01-01

    RosettaLigand is premiere software for predicting how a protein and a small molecule interact. Benchmark studies demonstrate that 70% of the top scoring RosettaLigand predicted interfaces are within 2Å RMSD from the crystal structure [1]. The latest release of Rosetta ligand software includes many new features, such as (1) docking of multiple ligands simultaneously, (2) representing ligands as fragments for greater flexibility, (3) redesign of the interface during docking, and (4) an XML script based interface that gives the user full control of the ligand docking protocol.

  7. Vehicle routing with cross-docking

    DEFF Research Database (Denmark)

    Wen, Min; Larsen, Jesper; Clausen, Jens

    2009-01-01

    a set of homogeneous vehicles are used to transport orders from the suppliers to the corresponding customers via a cross-dock. The orders can be consolidated at the cross-dock but cannot be stored for very long because the cross-dock does not have long-term inventory-holding capabilities. The objective...... of the VRPCD is to minimize the total travel time while respecting time window constraints at the nodes and a time horizon for the whole transportation operation. In this paper, a mixed integer programming formulation for the VRPCD is proposed. A tabu search heuristic is embedded within an adaptive memory...... values) within very short computational time....

  8. Evaluation of Docking Target Functions by the Comprehensive Investigation of Protein-Ligand Energy Minima.

    Science.gov (United States)

    Oferkin, Igor V; Katkova, Ekaterina V; Sulimov, Alexey V; Kutov, Danil C; Sobolev, Sergey I; Voevodin, Vladimir V; Sulimov, Vladimir B

    2015-01-01

    The adequate choice of the docking target function impacts the accuracy of the ligand positioning as well as the accuracy of the protein-ligand binding energy calculation. To evaluate a docking target function we compared positions of its minima with the experimentally known pose of the ligand in the protein active site. We evaluated five docking target functions based on either the MMFF94 force field or the PM7 quantum-chemical method with or without implicit solvent models: PCM, COSMO, and SGB. Each function was tested on the same set of 16 protein-ligand complexes. For exhaustive low-energy minima search the novel MPI parallelized docking program FLM and large supercomputer resources were used. Protein-ligand binding energies calculated using low-energy minima were compared with experimental values. It was demonstrated that the docking target function on the base of the MMFF94 force field in vacuo can be used for discovery of native or near native ligand positions by finding the low-energy local minima spectrum of the target function. The importance of solute-solvent interaction for the correct ligand positioning is demonstrated. It is shown that docking accuracy can be improved by replacement of the MMFF94 force field by the new semiempirical quantum-chemical PM7 method.

  9. Evaluation of Docking Target Functions by the Comprehensive Investigation of Protein-Ligand Energy Minima

    Directory of Open Access Journals (Sweden)

    Igor V. Oferkin

    2015-01-01

    Full Text Available The adequate choice of the docking target function impacts the accuracy of the ligand positioning as well as the accuracy of the protein-ligand binding energy calculation. To evaluate a docking target function we compared positions of its minima with the experimentally known pose of the ligand in the protein active site. We evaluated five docking target functions based on either the MMFF94 force field or the PM7 quantum-chemical method with or without implicit solvent models: PCM, COSMO, and SGB. Each function was tested on the same set of 16 protein-ligand complexes. For exhaustive low-energy minima search the novel MPI parallelized docking program FLM and large supercomputer resources were used. Protein-ligand binding energies calculated using low-energy minima were compared with experimental values. It was demonstrated that the docking target function on the base of the MMFF94 force field in vacuo can be used for discovery of native or near native ligand positions by finding the low-energy local minima spectrum of the target function. The importance of solute-solvent interaction for the correct ligand positioning is demonstrated. It is shown that docking accuracy can be improved by replacement of the MMFF94 force field by the new semiempirical quantum-chemical PM7 method.

  10. Candidate Sequence Variants and Fetal Hemoglobin in Children with Sickle Cell Disease Treated with Hydroxyurea

    Science.gov (United States)

    Green, Nancy S.; Ender, Katherine L.; Pashankar, Farzana; Driscoll, Catherine; Giardina, Patricia J.; Mullen, Craig A.; Clark, Lorraine N.; Manwani, Deepa; Crotty, Jennifer; Kisselev, Sergey; Neville, Kathleen A.; Hoppe, Carolyn; Barral, Sandra

    2013-01-01

    Background Fetal hemoglobin level is a heritable complex trait that strongly correlates swith the clinical severity of sickle cell disease. Only few genetic loci have been identified as robustly associated with fetal hemoglobin in patients with sickle cell disease, primarily adults. The sole approved pharmacologic therapy for this disease is hydroxyurea, with effects largely attributable to induction of fetal hemoglobin. Methodology/Principal Findings In a multi-site observational analysis of children with sickle cell disease, candidate single nucleotide polymorphisms associated with baseline fetal hemoglobin levels in adult sickle cell disease were examined in children at baseline and induced by hydroxyurea therapy. For baseline levels, single marker analysis demonstrated significant association with BCL11A and the beta and epsilon globin loci (HBB and HBE, respectively), with an additive attributable variance from these loci of 23%. Among a subset of children on hydroxyurea, baseline fetal hemoglobin levels explained 33% of the variance in induced levels. The variant in HBE accounted for an additional 13% of the variance in induced levels, while variants in the HBB and BCL11A loci did not contribute beyond baseline levels. Conclusions/Significance These findings clarify the overlap between baseline and hydroxyurea-induced fetal hemoglobin levels in pediatric disease. Studies assessing influences of specific sequence variants in these and other genetic loci in larger populations and in unusual hydroxyurea responders are needed to further understand the maintenance and therapeutic induction of fetal hemoglobin in pediatric sickle cell disease. PMID:23409025

  11. Role of Reversible Histidine Coordination in Hydroxylamine Reduction by Plant Hemoglobins (Phytoglobins).

    Science.gov (United States)

    Athwal, Navjot Singh; Alagurajan, Jagannathan; Andreotti, Amy H; Hargrove, Mark S

    2016-10-18

    Reduction of hydroxylamine to ammonium by phytoglobin, a plant hexacoordinate hemoglobin, is much faster than that of other hexacoordinate hemoglobins or pentacoordinate hemoglobins such as myoglobin, leghemoglobin, and red blood cell hemoglobin. The reason for differences in reactivity is not known but could be intermolecular electron transfer between protein molecules in support of the required two-electron reduction, hydroxylamine binding, or active site architecture favoring the reaction. Experiments were conducted with phytoglobins from rice, tomato, and soybean along with human neuroglobin and soybean leghemoglobin that reveal hydroxylamine binding as the rate-limiting step. For hexacoordinate hemoglobins, binding is limited by the dissociation rate constant for the distal histidine, while leghemoglobin is limited by an intrinsically low affinity for hydroxylamine. When the distal histidine is removed from rice phytoglobin, a hydroxylamine-bound intermediate is formed and the reaction rate is diminished, indicating that the distal histidine imidazole side chain is critical for the reaction, albeit not for electron transfer but rather for direct interaction with the substrate. Together, these results demonstrate that phytoglobins are superior at hydroxylamine reduction because they have distal histidine coordination affinity constants near 1, and facile rate constants for binding and dissociation of the histidine side chain. Hexacoordinate hemoglobins such as neuroglobin are limited by tighter histidine coordination that blocks hydroxylamine binding, and pentacoordinate hemoglobins have intrinsically lower hydroxylamine affinities.

  12. Evaluation of the novel algorithm of flexible ligand docking with moveable target-protein atoms.

    Science.gov (United States)

    Sulimov, Alexey V; Zheltkov, Dmitry A; Oferkin, Igor V; Kutov, Danil C; Katkova, Ekaterina V; Tyrtyshnikov, Eugene E; Sulimov, Vladimir B

    2017-01-01

    We present the novel docking algorithm based on the Tensor Train decomposition and the TT-Cross global optimization. The algorithm is applied to the docking problem with flexible ligand and moveable protein atoms. The energy of the protein-ligand complex is calculated in the frame of the MMFF94 force field in vacuum. The grid of precalculated energy potentials of probe ligand atoms in the field of the target protein atoms is not used. The energy of the protein-ligand complex for any given configuration is computed directly with the MMFF94 force field without any fitting parameters. The conformation space of the system coordinates is formed by translations and rotations of the ligand as a whole, by the ligand torsions and also by Cartesian coordinates of the selected target protein atoms. Mobility of protein and ligand atoms is taken into account in the docking process simultaneously and equally. The algorithm is realized in the novel parallel docking SOL-P program and results of its performance for a set of 30 protein-ligand complexes are presented. Dependence of the docking positioning accuracy is investigated as a function of parameters of the docking algorithm and the number of protein moveable atoms. It is shown that mobility of the protein atoms improves docking positioning accuracy. The SOL-P program is able to perform docking of a flexible ligand into the active site of the target protein with several dozens of protein moveable atoms: the native crystallized ligand pose is correctly found as the global energy minimum in the search space with 157 dimensions using 4700 CPU ∗ h at the Lomonosov supercomputer.

  13. Oxygen Measurements in Liposome Encapsulated Hemoglobin

    Science.gov (United States)

    Phiri, Joshua Benjamin

    Liposome encapsulated hemoglobins (LEH's) are of current interest as blood substitutes. An analytical methodology for rapid non-invasive measurements of oxygen in artificial oxygen carriers is examined. High resolution optical absorption spectra are calculated by means of a one dimensional diffusion approximation. The encapsulated hemoglobin is prepared from fresh defibrinated bovine blood. Liposomes are prepared from hydrogenated soy phosphatidylcholine (HSPC), cholesterol and dicetylphosphate using a bath sonication method. An integrating sphere spectrophotometer is employed for diffuse optics measurements. Data is collected using an automated data acquisition system employing lock-in -amplifiers. The concentrations of hemoglobin derivatives are evaluated from the corresponding extinction coefficients using a numerical technique of singular value decomposition, and verification of the results is done using Monte Carlo simulations. In situ measurements are required for the determination of hemoglobin derivatives because most encapsulation methods invariably lead to the formation of methemoglobin, a nonfunctional form of hemoglobin. The methods employed in this work lead to high resolution absorption spectra of oxyhemoglobin and other derivatives in red blood cells and liposome encapsulated hemoglobin (LEH). The analysis using singular value decomposition method offers a quantitative means of calculating the fractions of oxyhemoglobin and other hemoglobin derivatives in LEH samples. The analytical methods developed in this work will become even more useful when production of LEH as a blood substitute is scaled up to large volumes.

  14. Design and Preliminary Testing of the International Docking Adapter's Peripheral Docking Target

    Science.gov (United States)

    Foster, Christopher W.; Blaschak, Johnathan; Eldridge, Erin A.; Brazzel, Jack P.; Spehar, Peter T.

    2015-01-01

    The International Docking Adapter's Peripheral Docking Target (PDT) was designed to allow a docking spacecraft to judge its alignment relative to the docking system. The PDT was designed to be compatible with relative sensors using visible cameras, thermal imagers, or Light Detection and Ranging (LIDAR) technologies. The conceptual design team tested prototype designs and materials to determine the contrast requirements for the features. This paper will discuss the design of the PDT, the methodology and results of the tests, and the conclusions pertaining to PDT design that were drawn from testing.

  15. Why are most EU pigs tail docked?

    DEFF Research Database (Denmark)

    D'eath, R.B.; Niemi, J.K.; Vosough Ahmadi, B.

    2016-01-01

    To limit tail biting incidence, most pig producers in Europe tail dock their piglets. This is despite EU Council Directive 2008/120/EC banning routine tail docking and allowing it only as a last resort. The paper aims to understand what it takes to fulfil the intentions of the Directive...... by examining economic results of four management and housing scenarios, and by discussing their consequences for animal welfare in the light of legal and ethical considerations. The four scenarios compared are: ‘Standard Docked’, a conventional housing scenario with tail docking meeting the recommendations...... for Danish production (0.7 m2/pig); ‘Standard Undocked’, which is the same as ‘Standard Docked’ but with no tail docking, ‘Efficient Undocked’ and ‘Enhanced Undocked’, which have increased solid floor area (0.9 and 1.0 m2/pig, respectively) provision of loose manipulable materials (100 and 200 g/straw per...

  16. Effects of rutin on the redox reactions of hemoglobin.

    Science.gov (United States)

    Lu, Naihao; Ding, Yun; Yang, Zhen; Gao, Pingzhang

    2016-08-01

    Flavonoids are widely used to attenuate oxidative damage in vitro and in vivo. In this study, we investigated the influence of rutin (quercetin-3-rhamnosylglucoside) on hemoglobin (Hb)- dependent redox reactions, i.e. oxidative stability of Hb and its cytotoxic ferryl intermediate. It was found that rutin induced generation of H2O2, which in turn oxidized Hb rapidly. Meanwhile, rutin exhibited anti-oxidant effect by effectively reducing ferryl intermediate back to ferric Hb at physiological pH. In comparison with quercetin, rutin had stronger capability on reducing ferryl species while lesser pro-oxidant effect on H2O2 generation, thus it exhibited more protective effect on H2O2-induced Hb oxidation. Circular dichroism spectrum showed no significant change in the secondary structure of Hb after flavonoid addition, while molecular docking revealed different binding modes of quercetin and rutin with Hb. These results might provide new insights into the potential nutritional and physiological implications of rutin and quercetin with redox active heme proteins regarding their ani- and pro-oxidant effects. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. A role of proton transfer in peroxidase-catalyzed process elucidated by substrates docking calculations

    Directory of Open Access Journals (Sweden)

    Ziemys Arturas

    2001-08-01

    Full Text Available Abstract Background Previous kinetic investigations of fungal-peroxidase catalyzed oxidation of N-aryl hydroxamic acids (AHAs and N-aryl-N-hydroxy urethanes (AHUs revealed that the rate of reaction was independent of the formal redox potential of substrates. Moreover, the oxidation rate was 3–5 orders of magnitude less than for oxidation of physiological phenol substrates, though the redox potential was similar. Results To explain the unexpectedly low reactivity of AHAs and AHUs we made ab initio calculations of the molecular structure of the substrates following in silico docking in the active center of the enzyme. Conclusions AHAs and AHUs were docked at the distal side of heme in the sites formed by hydrophobic amino acid residues that retarded a proton transfer and finally the oxidation rate. The analogous phenol substrates were docked at different sites permitting fast proton transfer in the relay of distal His and water that helped fast substrate oxidation.

  18. Oxygen binding properties of hemoglobin from the white rhinoceros (beta 2-GLU) and the tapir.

    Science.gov (United States)

    Baumann, R; Mazur, G; Braunitzer, G

    1984-04-01

    The beta-chain of rhinoceros hemoglobin contains glutamic acid at position beta 2, and important site for the binding of organic phosphates. We have investigated the oxygen binding properties of this hemoglobin and its interaction with ATP, 2,3-diphosphoglycerate, CO2 and chloride. The results show that the presence of GLU at position beta 2 nearly abolishes the effect of organic phosphates and CO2, whereas the oxygen-linked binding of chloride is not affected. Thus rhinoceros hemoglobin has only protons and chloride anions as major allosteric effectors for the control of its oxygen affinity. From the results obtained with hemoglobin solutions it can be calculated that the blood oxygen affinity of the rhinoceros must be rather high with a P50 of about 20 torr at pH 7.4 and 37 degrees C, which conforms with observations obtained for other large mammals.

  19. Dockomatic - automated ligand creation and docking.

    Science.gov (United States)

    Bullock, Casey W; Jacob, Reed B; McDougal, Owen M; Hampikian, Greg; Andersen, Tim

    2010-11-08

    The application of computational modeling to rationally design drugs and characterize macro biomolecular receptors has proven increasingly useful due to the accessibility of computing clusters and clouds. AutoDock is a well-known and powerful software program used to model ligand to receptor binding interactions. In its current version, AutoDock requires significant amounts of user time to setup and run jobs, and collect results. This paper presents DockoMatic, a user friendly Graphical User Interface (GUI) application that eases and automates the creation and management of AutoDock jobs for high throughput screening of ligand to receptor interactions. DockoMatic allows the user to invoke and manage AutoDock jobs on a single computer or cluster, including jobs for evaluating secondary ligand interactions. It also automates the process of collecting, summarizing, and viewing results. In addition, DockoMatic automates creation of peptide ligand .pdb files from strings of single-letter amino acid abbreviations. DockoMatic significantly reduces the complexity of managing multiple AutoDock jobs by facilitating ligand and AutoDock job creation and management.

  20. Dockomatic - automated ligand creation and docking

    Directory of Open Access Journals (Sweden)

    Hampikian Greg

    2010-11-01

    Full Text Available Abstract Background The application of computational modeling to rationally design drugs and characterize macro biomolecular receptors has proven increasingly useful due to the accessibility of computing clusters and clouds. AutoDock is a well-known and powerful software program used to model ligand to receptor binding interactions. In its current version, AutoDock requires significant amounts of user time to setup and run jobs, and collect results. This paper presents DockoMatic, a user friendly Graphical User Interface (GUI application that eases and automates the creation and management of AutoDock jobs for high throughput screening of ligand to receptor interactions. Results DockoMatic allows the user to invoke and manage AutoDock jobs on a single computer or cluster, including jobs for evaluating secondary ligand interactions. It also automates the process of collecting, summarizing, and viewing results. In addition, DockoMatic automates creation of peptide ligand .pdb files from strings of single-letter amino acid abbreviations. Conclusions DockoMatic significantly reduces the complexity of managing multiple AutoDock jobs by facilitating ligand and AutoDock job creation and management.

  1. Automated docking screens: a feasibility study.

    Science.gov (United States)

    Irwin, John J; Shoichet, Brian K; Mysinger, Michael M; Huang, Niu; Colizzi, Francesco; Wassam, Pascal; Cao, Yiqun

    2009-09-24

    Molecular docking is the most practical approach to leverage protein structure for ligand discovery, but the technique retains important liabilities that make it challenging to deploy on a large scale. We have therefore created an expert system, DOCK Blaster, to investigate the feasibility of full automation. The method requires a PDB code, sometimes with a ligand structure, and from that alone can launch a full screen of large libraries. A critical feature is self-assessment, which estimates the anticipated reliability of the automated screening results using pose fidelity and enrichment. Against common benchmarks, DOCK Blaster recapitulates the crystal ligand pose within 2 A rmsd 50-60% of the time; inferior to an expert, but respectrable. Half the time the ligand also ranked among the top 5% of 100 physically matched decoys chosen on the fly. Further tests were undertaken culminating in a study of 7755 eligible PDB structures. In 1398 cases, the redocked ligand ranked in the top 5% of 100 property-matched decoys while also posing within 2 A rmsd, suggesting that unsupervised prospective docking is viable. DOCK Blaster is available at http://blaster.docking.org .

  2. Detection of Sickle Cell Hemoglobin in Haiti by Genotyping and Hemoglobin Solubility Tests

    Science.gov (United States)

    Carter, Tamar E.; von Fricken, Michael; Romain, Jean R.; Memnon, Gladys; St. Victor, Yves; Schick, Laura; Okech, Bernard A.; Mulligan, Connie J.

    2014-01-01

    Sickle cell disease is a growing global health concern because infants born with the disorder in developing countries are now surviving longer with little access to diagnostic and management options. In Haiti, the current state of sickle cell disease/trait in the population is unclear. To inform future screening efforts in Haiti, we assayed sickle hemoglobin mutations using traditional hemoglobin solubility tests (HST) and add-on techniques, which incorporated spectrophotometry and insoluble hemoglobin separation. We also generated genotype data as a metric for HST performance. We found 19 of 202 individuals screened with HST were positive for sickle hemoglobin, five of whom did not carry the HbS allele. We show that spectrophotometry and insoluble hemoglobin separation add-on techniques could resolve false positives associated with the traditional HST approach, with some limitations. We also discuss the incorporation of insoluble hemoglobin separation observation with HST in suboptimal screening settings like Haiti. PMID:24957539

  3. Moessbauer study of hemoglobin of diabetes

    International Nuclear Information System (INIS)

    Li Aiguo; Ni Xinbo; Cai Yingwen; Zhang Guilin; Zhang Hongde; Ge Yongxin

    2000-01-01

    The hemoglobins from normal adults (Gly-Hb 5%), people infected with diabetes (Gly-Hb 10%) and serious diabetics (Gly-Hb 15%) were investigated by Moessbauer spectroscopy at liquid nitrogen temperature. All the experimental spectra of hemoglobin are composed of three doublets corresponding to oxy-hemoglobin (Oxy-Hb), deoxy-hemoglobin (Deoxy-Hb) and low-spin hemo-chrome (Ls-Hemo) respectively. It is found that Oxy-Hb is decreasing but Deoxy-hb increasing for diabetes. Experimental results also indicate that the line-width of Moessbauer spectra of Oxy-Hb for diabetics is narrower than that for normal adults, showing that while Fe on Oxy-Hb exists in pile-up of some similar states for normal adults, but it becomes in single state for serious diabetes

  4. Methylation of hemoglobin to enhance flocculant performance

    Science.gov (United States)

    An inexpensive bioflocculant, bovine hemoglobin (Hb), has been covalently modified through methylation of the side chain carboxyl groups of aspartic and glutamic acid residues to improve its flocculation activity. Potentiometric titration of the recovered products showed approximately 28% degree of ...

  5. Moessbauer spectroscopic studies of hemoglobin and its isolated subunits

    International Nuclear Information System (INIS)

    Hoy, G.R.; Cook, D.C.; Berger, R.L.; Friedman, F.K.

    1986-01-01

    Samples of 90% enriched 57Fe hemoglobin and its isolated subunits have been prepared. Moessbauer spectroscopic measurements have been made on three such samples. Sample one contained contributions of oxyhemoglobin, deoxyhemoglobin, and carbonmonoxyhemoglobin. This sample was studied from a temperature of 90 K down to 230 mK. Measurements were also made at 4.2 K using a small applied magnetic field of 1.0 T. In general, the measured quadrupole splittings and isomer shifts for each component agreed with previous measurements on single component samples in the literature, and thus demonstrated that chemically enriched hemoglobin has not been altered. The second and third samples were isolated alpha and beta subunits, respectively. We have found measurable Moessbauer spectral differences between the HbO 2 sites in the alpha subunit sample and the beta subunit sample. The measured Moessbauer spectral areas indicate that the iron ion has the largest mean-square displacement at the deoxy Hb sites as compared to that at the oxy- and carbonmonoxy Hb sites. The mean-square displacement at the HbO 2 sites is the smallest

  6. Interactions of cephalexin with bovine serum albumin: displacement reaction and molecular docking

    Directory of Open Access Journals (Sweden)

    Hamed Hamishehkar

    2016-09-01

    Conclusion: The outcomes of spectroscopic methods revealed that the conformation of BSA changed during drug-BSA interaction. The results of FRET propose that CPL quenches the fluorescence of BSA by static quenching and FRET. The displacement study showed that phenylbutazon and ketoprofen displaced CPL, indicating that its binding site on albumin is site I and Gentamicin cannot be displaced from the binding site of CPL. All results of molecular docking method agreed with the results of experimental data.

  7. Cloned Hemoglobin Genes Enhance Growth Of Cells

    Science.gov (United States)

    Khosla, Chaitan; Bailey, James E.

    1991-01-01

    Experiments show that portable deoxyribonucleic acid (DNA) sequences incorporated into host cells make them produce hemoglobins - oxygen-binding proteins essential to function of red blood cells. Method useful in several biotechnological applications. One, enhancement of growth of cells at higher densities. Another, production of hemoglobin to enhance supplies of oxygen in cells, for use in chemical reactions requiring oxygen, as additive to serum to increase transport of oxygen, and for binding and separating oxygen from mixtures of gases.

  8. Hemoglobin levels in normal Filipino pregnant women.

    Science.gov (United States)

    Kuizon, M D; Natera, M G; Ancheta, L P; Platon, T P; Reyes, G D; Macapinlac, M P

    1981-09-01

    The hemoglobin concentrations during pregnancy in Filipinos belonging to the upper income group, who were prescribed 105 mg elemental iron daily, and who had acceptable levels of transferrin saturation, were examined in an attempt to define normal levels. The hemoglobin concentrations for each trimester followed a Gaussian distribution. The hemoglobin values equal to the mean minus one standard deviation were 11.4 gm/dl for the first trimester and 10.4 gm/dl for the second and third trimesters. Using these values as the lower limits of normal, in one group of pregnant women the prevalence of anemia during the last two trimesters was found lower than that obtained when WHO levels for normal were used. Groups of women with hemoglobin of 10.4 to 10.9 gm/dl (classified anemic by WHO criteria but normal in the present study) and those with 11.0 gm/dl and above could not be distinguished on the basis of their serum ferritin levels nor on the degree of decrease in their hemoglobin concentration during pregnancy. Many subjects in both groups, however, had serum ferritin levels less than 12 ng/ml which indicate poor iron stores. It might be desirable in future studies to determine the hemoglobin cut-off point that will delineate subjects who are both non-anemic and adequate in iron stores using serum ferritin levels as criterion for the latter.

  9. High affinity hemoglobin and Parkinson's disease.

    Science.gov (United States)

    Graham, Jeffrey; Hobson, Douglas; Ponnampalam, Arjuna

    2014-12-01

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SN) region of the midbrain. Oxidative damage in this region has been shown to play an important role in the pathogenesis of this disease. Human neurons have been discovered to contain hemoglobin, with an increased concentration seen in the neurons of the SN. High affinity hemoglobin is a clinical entity resulting from mutations that create a functional increase in the binding of hemoglobin to oxygen and an inability to efficiently unload it to tissues. This can result in a number of metabolic compensatory changes, including an elevation in circulating hemoglobin and an increase in the molecule 2,3-diphosphoglycerate (2,3-DPG). Population based studies have revealed that patients with PD have elevated hemoglobin as well as 2,3-DPG levels. Based on these observations, we hypothesize that the oxidative damage seen in PD is related to an underlying high affinity hemoglobin subtype. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Scheduling Trucks in a Cross-Dock with Mixed Service Mode Dock Doors

    DEFF Research Database (Denmark)

    Bodnar, Peter; Azadeh, Kaveh; Koster, René de

    2017-01-01

    The problem considered in this paper is how to schedule inbound and outbound trucks subject to time windows at a multidoor cross-dock. Dock doors can either be dedicated to inbound or outbound trucks or be capable of handling both truck types. In addition, loads are allowed to be temporarily...

  11. Docking screens: right for the right reasons?

    Science.gov (United States)

    Kolb, Peter; Irwin, John J

    2009-01-01

    Whereas docking screens have emerged as the most practical way to use protein structure for ligand discovery, an inconsistent track record raises questions about how well docking actually works. In its favor, a growing number of publications report the successful discovery of new ligands, often supported by experimental affinity data and controls for artifacts. Few reports, however, actually test the underlying structural hypotheses that docking makes. To be successful and not just lucky, prospective docking must not only rank a true ligand among the top scoring compounds, it must also correctly orient the ligand so the score it receives is biophysically sound. If the correct binding pose is not predicted, a skeptic might well infer that the discovery was serendipitous. Surveying over 15 years of the docking literature, we were surprised to discover how rarely sufficient evidence is presented to establish whether docking actually worked for the right reasons. The paucity of experimental tests of theoretically predicted poses undermines confidence in a technique that has otherwise become widely accepted. Of course, solving a crystal structure is not always possible, and even when it is, it can be a lot of work, and is not readily accessible to all groups. Even when a structure can be determined, investigators may prefer to gloss over an erroneous structural prediction to better focus on their discovery. Still, the absence of a direct test of theory by experiment is a loss for method developers seeking to understand and improve docking methods. We hope this review will motivate investigators to solve structures and compare them with their predictions whenever possible, to advance the field.

  12. Protein-protein docking with F(2Dock 2.0 and GB-rerank.

    Directory of Open Access Journals (Sweden)

    Rezaul Chowdhury

    Full Text Available Computational simulation of protein-protein docking can expedite the process of molecular modeling and drug discovery. This paper reports on our new F(2 Dock protocol which improves the state of the art in initial stage rigid body exhaustive docking search, scoring and ranking by introducing improvements in the shape-complementarity and electrostatics affinity functions, a new knowledge-based interface propensity term with FFT formulation, a set of novel knowledge-based filters and finally a solvation energy (GBSA based reranking technique. Our algorithms are based on highly efficient data structures including the dynamic packing grids and octrees which significantly speed up the computations and also provide guaranteed bounds on approximation error.The improved affinity functions show superior performance compared to their traditional counterparts in finding correct docking poses at higher ranks. We found that the new filters and the GBSA based reranking individually and in combination significantly improve the accuracy of docking predictions with only minor increase in computation time. We compared F(2 Dock 2.0 with ZDock 3.0.2 and found improvements over it, specifically among 176 complexes in ZLab Benchmark 4.0, F(2 Dock 2.0 finds a near-native solution as the top prediction for 22 complexes; where ZDock 3.0.2 does so for 13 complexes. F(2 Dock 2.0 finds a near-native solution within the top 1000 predictions for 106 complexes as opposed to 104 complexes for ZDock 3.0.2. However, there are 17 and 15 complexes where F(2 Dock 2.0 finds a solution but ZDock 3.0.2 does not and vice versa; which indicates that the two docking protocols can also complement each other.The docking protocol has been implemented as a server with a graphical client (TexMol which allows the user to manage multiple docking jobs, and visualize the docked poses and interfaces. Both the server and client are available for download. Server: http

  13. Protein-Protein Docking with F2Dock 2.0 and GB-Rerank

    Science.gov (United States)

    Chowdhury, Rezaul; Rasheed, Muhibur; Keidel, Donald; Moussalem, Maysam; Olson, Arthur; Sanner, Michel; Bajaj, Chandrajit

    2013-01-01

    Motivation Computational simulation of protein-protein docking can expedite the process of molecular modeling and drug discovery. This paper reports on our new F2 Dock protocol which improves the state of the art in initial stage rigid body exhaustive docking search, scoring and ranking by introducing improvements in the shape-complementarity and electrostatics affinity functions, a new knowledge-based interface propensity term with FFT formulation, a set of novel knowledge-based filters and finally a solvation energy (GBSA) based reranking technique. Our algorithms are based on highly efficient data structures including the dynamic packing grids and octrees which significantly speed up the computations and also provide guaranteed bounds on approximation error. Results The improved affinity functions show superior performance compared to their traditional counterparts in finding correct docking poses at higher ranks. We found that the new filters and the GBSA based reranking individually and in combination significantly improve the accuracy of docking predictions with only minor increase in computation time. We compared F2 Dock 2.0 with ZDock 3.0.2 and found improvements over it, specifically among 176 complexes in ZLab Benchmark 4.0, F2 Dock 2.0 finds a near-native solution as the top prediction for 22 complexes; where ZDock 3.0.2 does so for 13 complexes. F2 Dock 2.0 finds a near-native solution within the top 1000 predictions for 106 complexes as opposed to 104 complexes for ZDock 3.0.2. However, there are 17 and 15 complexes where F2 Dock 2.0 finds a solution but ZDock 3.0.2 does not and vice versa; which indicates that the two docking protocols can also complement each other. Availability The docking protocol has been implemented as a server with a graphical client (TexMol) which allows the user to manage multiple docking jobs, and visualize the docked poses and interfaces. Both the server and client are available for download. Server: http

  14. DockQ: A Quality Measure for Protein-Protein Docking Models.

    Directory of Open Access Journals (Sweden)

    Sankar Basu

    Full Text Available The state-of-the-art to assess the structural quality of docking models is currently based on three related yet independent quality measures: Fnat, LRMS, and iRMS as proposed and standardized by CAPRI. These quality measures quantify different aspects of the quality of a particular docking model and need to be viewed together to reveal the true quality, e.g. a model with relatively poor LRMS (>10Å might still qualify as 'acceptable' with a descent Fnat (>0.50 and iRMS (<3.0Å. This is also the reason why the so called CAPRI criteria for assessing the quality of docking models is defined by applying various ad-hoc cutoffs on these measures to classify a docking model into the four classes: Incorrect, Acceptable, Medium, or High quality. This classification has been useful in CAPRI, but since models are grouped in only four bins it is also rather limiting, making it difficult to rank models, correlate with scoring functions or use it as target function in machine learning algorithms. Here, we present DockQ, a continuous protein-protein docking model quality measure derived by combining Fnat, LRMS, and iRMS to a single score in the range [0, 1] that can be used to assess the quality of protein docking models. By using DockQ on CAPRI models it is possible to almost completely reproduce the original CAPRI classification into Incorrect, Acceptable, Medium and High quality. An average PPV of 94% at 90% Recall demonstrating that there is no need to apply predefined ad-hoc cutoffs to classify docking models. Since DockQ recapitulates the CAPRI classification almost perfectly, it can be viewed as a higher resolution version of the CAPRI classification, making it possible to estimate model quality in a more quantitative way using Z-scores or sum of top ranked models, which has been so valuable for the CASP community. The possibility to directly correlate a quality measure to a scoring function has been crucial for the development of scoring functions for

  15. DockQ: A Quality Measure for Protein-Protein Docking Models

    Science.gov (United States)

    Basu, Sankar

    2016-01-01

    The state-of-the-art to assess the structural quality of docking models is currently based on three related yet independent quality measures: Fnat, LRMS, and iRMS as proposed and standardized by CAPRI. These quality measures quantify different aspects of the quality of a particular docking model and need to be viewed together to reveal the true quality, e.g. a model with relatively poor LRMS (>10Å) might still qualify as 'acceptable' with a descent Fnat (>0.50) and iRMS (iRMS to a single score in the range [0, 1] that can be used to assess the quality of protein docking models. By using DockQ on CAPRI models it is possible to almost completely reproduce the original CAPRI classification into Incorrect, Acceptable, Medium and High quality. An average PPV of 94% at 90% Recall demonstrating that there is no need to apply predefined ad-hoc cutoffs to classify docking models. Since DockQ recapitulates the CAPRI classification almost perfectly, it can be viewed as a higher resolution version of the CAPRI classification, making it possible to estimate model quality in a more quantitative way using Z-scores or sum of top ranked models, which has been so valuable for the CASP community. The possibility to directly correlate a quality measure to a scoring function has been crucial for the development of scoring functions for protein structure prediction, and DockQ should be useful in a similar development in the protein docking field. DockQ is available at http://github.com/bjornwallner/DockQ/ PMID:27560519

  16. Solvated protein-DNA docking using HADDOCK

    Energy Technology Data Exchange (ETDEWEB)

    Dijk, Marc van; Visscher, Koen M.; Kastritis, Panagiotis L.; Bonvin, Alexandre M. J. J., E-mail: a.m.j.j.bonvin@uu.nl [Utrecht University, Bijvoet Center for Biomolecular Research, Faculty of Science-Chemistry (Netherlands)

    2013-05-15

    Interfacial water molecules play an important role in many aspects of protein-DNA specificity and recognition. Yet they have been mostly neglected in the computational modeling of these complexes. We present here a solvated docking protocol that allows explicit inclusion of water molecules in the docking of protein-DNA complexes and demonstrate its feasibility on a benchmark of 30 high-resolution protein-DNA complexes containing crystallographically-determined water molecules at their interfaces. Our protocol is capable of reproducing the solvation pattern at the interface and recovers hydrogen-bonded water-mediated contacts in many of the benchmark cases. Solvated docking leads to an overall improvement in the quality of the generated protein-DNA models for cases with limited conformational change of the partners upon complex formation. The applicability of this approach is demonstrated on real cases by docking a representative set of 6 complexes using unbound protein coordinates, model-built DNA and knowledge-based restraints. As HADDOCK supports the inclusion of a variety of NMR restraints, solvated docking is also applicable for NMR-based structure calculations of protein-DNA complexes.

  17. Solvated protein–DNA docking using HADDOCK

    International Nuclear Information System (INIS)

    Dijk, Marc van; Visscher, Koen M.; Kastritis, Panagiotis L.; Bonvin, Alexandre M. J. J.

    2013-01-01

    Interfacial water molecules play an important role in many aspects of protein–DNA specificity and recognition. Yet they have been mostly neglected in the computational modeling of these complexes. We present here a solvated docking protocol that allows explicit inclusion of water molecules in the docking of protein–DNA complexes and demonstrate its feasibility on a benchmark of 30 high-resolution protein–DNA complexes containing crystallographically-determined water molecules at their interfaces. Our protocol is capable of reproducing the solvation pattern at the interface and recovers hydrogen-bonded water-mediated contacts in many of the benchmark cases. Solvated docking leads to an overall improvement in the quality of the generated protein–DNA models for cases with limited conformational change of the partners upon complex formation. The applicability of this approach is demonstrated on real cases by docking a representative set of 6 complexes using unbound protein coordinates, model-built DNA and knowledge-based restraints. As HADDOCK supports the inclusion of a variety of NMR restraints, solvated docking is also applicable for NMR-based structure calculations of protein–DNA complexes.

  18. Rendezvous and Docking for Space Exploration

    Science.gov (United States)

    Machula, M. F.; Crain, T.; Sandhoo, G. S.

    2005-01-01

    To achieve the exploration goals, new approaches to exploration are being envisioned that include robotic networks, modular systems, pre-positioned propellants and in-space assembly in Earth orbit, Lunar orbit and other locations around the cosmos. A fundamental requirement for rendezvous and docking to accomplish in-space assembly exists in each of these locations. While existing systems and technologies can accomplish rendezvous and docking in low earth orbit, and rendezvous and docking with crewed systems has been successfully accomplished in low lunar orbit, our capability must extend toward autonomous rendezvous and docking. To meet the needs of the exploration vision in-space assembly requiring both crewed and uncrewed vehicles will be an integral part of the exploration architecture. This paper focuses on the intelligent application of autonomous rendezvous and docking technologies to meet the needs of that architecture. It also describes key technology investments that will increase the exploration program's ability to ensure mission success, regardless of whether the rendezvous are fully automated or have humans in the loop.

  19. Rosetta FlexPepDock ab-initio: simultaneous folding, docking and refinement of peptides onto their receptors.

    Science.gov (United States)

    Raveh, Barak; London, Nir; Zimmerman, Lior; Schueler-Furman, Ora

    2011-04-29

    Flexible peptides that fold upon binding to another protein molecule mediate a large number of regulatory interactions in the living cell and may provide highly specific recognition modules. We present Rosetta FlexPepDock ab-initio, a protocol for simultaneous docking and de-novo folding of peptides, starting from an approximate specification of the peptide binding site. Using the Rosetta fragments library and a coarse-grained structural representation of the peptide and the receptor, FlexPepDock ab-initio samples efficiently and simultaneously the space of possible peptide backbone conformations and rigid-body orientations over the receptor surface of a given binding site. The subsequent all-atom refinement of the coarse-grained models includes full side-chain modeling of both the receptor and the peptide, resulting in high-resolution models in which key side-chain interactions are recapitulated. The protocol was applied to a benchmark in which peptides were modeled over receptors in either their bound backbone conformations or in their free, unbound form. Near-native peptide conformations were identified in 18/26 of the bound cases and 7/14 of the unbound cases. The protocol performs well on peptides from various classes of secondary structures, including coiled peptides with unusual turns and kinks. The results presented here significantly extend the scope of state-of-the-art methods for high-resolution peptide modeling, which can now be applied to a wide variety of peptide-protein interactions where no prior information about the peptide backbone conformation is available, enabling detailed structure-based studies and manipulation of those interactions. © 2011 Raveh et al.

  20. A spectroscopic study on the interaction between gold nanoparticles and hemoglobin

    International Nuclear Information System (INIS)

    Garabagiu, Sorina

    2011-01-01

    Highlights: ► The interaction was studied using UV–vis and fluorescence spectroscopy. ► Gold nanoparticles quench the fluorescence emission of hemoglobin solution. ► The binding and thermodynamic constants were calculated. ► Major impact: electrochemical applications of the complex onto a substrate. -- Abstract: The interaction between horse hemoglobin and gold nanoparticles was studied using optical spectroscopy. UV–vis and fluorescence spectra show that a spontaneous binding process occurred between hemoglobin and gold nanoparticles. The Soret band of hemoglobin in the presence of gold nanoparticles does not show significant changes, which proves that the protein retained its biological function. A shift to longer wavelengths appears in the plasmonic band of gold nanoparticles upon the attachment of hemoglobin molecules. Gold nanoparticles quench the fluorescence emission of tryptophan residues in the structure of hemoglobin. The Stern–Volmer quenching constant, the binding constant and the number of binding sites were also calculated. Thermodynamic parameters indicate that the binding was mainly due to hydrophobic interactions.

  1. Oxygen binding to partially nitrosylated hemoglobin.

    Science.gov (United States)

    Fago, Angela; Crumbliss, Alvin L; Hendrich, Michael P; Pearce, Linda L; Peterson, Jim; Henkens, Robert; Bonaventura, Celia

    2013-09-01

    Reactions of nitric oxide (NO) with hemoglobin (Hb) are important elements in protection against nitrosative damage. NO in the vasculature is depleted by the oxidative reaction with oxy Hb or by binding to deoxy Hb to generate partially nitrosylated Hb (Hb-NO). Many aspects of the formation and persistence of Hb-NO are yet to be clarified. In this study, we used a combination of EPR and visible absorption spectroscopy to investigate the interactions of partially nitrosylated Hb with O2. Partially nitrosylated Hb samples had predominantly hexacoordinate NO-heme geometry and resisted oxidation when exposed to O2 in the absence of anionic allosteric effectors. Faster oxidation occurred in the presence of 2,3-diphosphoglycerate (DPG) or inositol hexaphosphate (IHP), where the NO-heme derivatives had higher levels of pentacoordinate heme geometry. The anion-dependence of the NO-heme geometry also affected O2 binding equilibria. O2-binding curves of partially nitrosylated Hb in the absence of anions were left-shifted at low saturations, indicating destabilization of the low O2 affinity T-state of the Hb by increasing percentages of NO-heme, much as occurs with increasing levels of CO-heme. Samples containing IHP showed small decreases in O2 affinity, indicating shifts toward the low-affinity T-state and formation of inert α-NO/β-met tetramers. Most remarkably, O2-equilibria in the presence of the physiological effector DPG were essentially unchanged by up to 30% NO-heme in the samples. As will be discussed, under physiological conditions the interactions of Hb with NO provide protection against nitrosative damage without impairing O2 transport by Hb's unoccupied heme sites. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins. Copyright © 2013 Elsevier B.V. All rights reserved.

  2. Convergent evolution of hemoglobin switching in jawed and jawless vertebrates.

    Science.gov (United States)

    Rohlfing, Kim; Stuhlmann, Friederike; Docker, Margaret F; Burmester, Thorsten

    2016-02-01

    During development, humans and other jawed vertebrates (Gnathostomata) express distinct hemoglobin genes, resulting in different hemoglobin tetramers. Embryonic and fetal hemoglobin have higher oxygen affinities than the adult hemoglobin, sustaining the oxygen demand of the developing organism. Little is known about the expression of hemoglobins during development of jawless vertebrates (Agnatha). We identified three hemoglobin switches in the life cycle of the sea lamprey. Three hemoglobin genes are specifically expressed in the embryo, four genes in the filter feeding larva (ammocoete), and nine genes correspond to the adult hemoglobin chains. During the development from the parasitic to the reproductive adult, the composition of hemoglobin changes again, with a massive increase of chain aHb1. A single hemoglobin chain is expressed constitutively in all stages. We further showed the differential expression of other globin genes: Myoglobin 1 is most highly expressed in the reproductive adult, myoglobin 2 expression peaks in the larva. Globin X1 is restricted to the embryo; globin X2 was only found in the reproductive adult. Cytoglobin is expressed at low levels throughout the life cycle. Because the hemoglobins of jawed and jawless vertebrates evolved independently from a common globin ancestor, hemoglobin switching must also have evolved convergently in these taxa. Notably, the ontogeny of sea lamprey hemoglobins essentially recapitulates their phylogeny, with the embryonic hemoglobins emerging first, followed by the evolution of larval and adult hemoglobins.

  3. Electro-optical rendezvous and docking sensors

    Science.gov (United States)

    Tubbs, David J.; Kesler, Lynn O.; Sirko, Robert J.

    1991-01-01

    Electro-optical sensors provide unique and critical functionality for space missions requiring rendezvous, docking, and berthing. McDonnell Douglas is developing a complete rendezvous and docking system for both manned and unmanned missions. This paper examines our sensor development and the systems and missions which benefit from rendezvous and docking sensors. Simulation results quantifying system performance improvements in key areas are given, with associated sensor performance requirements. A brief review of NASA-funded development activities and the current performance of electro-optical sensors for space applications is given. We will also describe current activities at McDonnell Douglas for a fully functional demonstration to address specific NASA mission needs.

  4. AnchorDock: Blind and Flexible Anchor-Driven Peptide Docking.

    Science.gov (United States)

    Ben-Shimon, Avraham; Niv, Masha Y

    2015-05-05

    The huge conformational space stemming from the inherent flexibility of peptides is among the main obstacles to successful and efficient computational modeling of protein-peptide interactions. Current peptide docking methods typically overcome this challenge using prior knowledge from the structure of the complex. Here we introduce AnchorDock, a peptide docking approach, which automatically targets the docking search to the most relevant parts of the conformational space. This is done by precomputing the free peptide's structure and by computationally identifying anchoring spots on the protein surface. Next, a free peptide conformation undergoes anchor-driven simulated annealing molecular dynamics simulations around the predicted anchoring spots. In the challenging task of a completely blind docking test, AnchorDock produced exceptionally good results (backbone root-mean-square deviation ≤ 2.2Å, rank ≤15) for 10 of 13 unbound cases tested. The impressive performance of AnchorDock supports a molecular recognition pathway that is driven via pre-existing local structural elements. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Proximity Operations and Docking Sensor Development

    Science.gov (United States)

    Howard, Richard T.; Bryan, Thomas C.; Brewster, Linda L.; Lee, James E.

    2009-01-01

    The Next Generation Advanced Video Guidance Sensor (NGAVGS) has been under development for the last three years as a long-range proximity operations and docking sensor for use in an Automated Rendezvous and Docking (AR&D) system. The first autonomous rendezvous and docking in the history of the U.S. Space Program was successfully accomplished by Orbital Express, using the Advanced Video Guidance Sensor (AVGS) as the primary docking sensor. That flight proved that the United States now has a mature and flight proven sensor technology for supporting Crew Exploration Vehicles (CEV) and Commercial Orbital Transport Systems (COTS) Automated Rendezvous and Docking (AR&D). NASA video sensors have worked well in the past: the AVGS used on the Demonstration of Autonomous Rendezvous Technology (DART) mission operated successfully in spot mode out to 2 km, and the first generation rendezvous and docking sensor, the Video Guidance Sensor (VGS), was developed and successfully flown on Space Shuttle flights in 1997 and 1998. 12 Parts obsolescence issues prevent the construction of more AVGS units, and the next generation sensor was updated to allow it to support the CEV and COTS programs. The flight proven AR&D sensor has been redesigned to update parts and add additional capabilities for CEV and COTS with the development of the Next Generation AVGS at the Marshall Space Flight Center. The obsolete imager and processor are being replaced with new radiation tolerant parts. In addition, new capabilities include greater sensor range, auto ranging capability, and real-time video output. This paper presents some sensor hardware trades, use of highly integrated laser components, and addresses the needs of future vehicles that may rendezvous and dock with the International Space Station (ISS) and other Constellation vehicles. It also discusses approaches for upgrading AVGS to address parts obsolescence, and concepts for minimizing the sensor footprint, weight, and power requirements

  6. Molecular dynamics modeling the synthetic and biological polymers interactions pre-studied via docking

    Science.gov (United States)

    Tsvetkov, Vladimir B.; Serbin, Alexander V.

    2014-06-01

    In previous works we reported the design, synthesis and in vitro evaluations of synthetic anionic polymers modified by alicyclic pendant groups (hydrophobic anchors), as a novel class of inhibitors of the human immunodeficiency virus type 1 ( HIV-1) entry into human cells. Recently, these synthetic polymers interactions with key mediator of HIV-1 entry-fusion, the tri-helix core of the first heptad repeat regions [ HR1]3 of viral envelope protein gp41, were pre-studied via docking in terms of newly formulated algorithm for stepwise approximation from fragments of polymeric backbone and side-group models toward real polymeric chains. In the present article the docking results were verified under molecular dynamics ( MD) modeling. In contrast with limited capabilities of the docking, the MD allowed of using much more large models of the polymeric ligands, considering flexibility of both ligand and target simultaneously. Among the synthesized polymers the dinorbornen anchors containing alternating copolymers of maleic acid were selected as the most representative ligands (possessing the top anti-HIV activity in vitro in correlation with the highest binding energy in the docking). To verify the probability of binding of the polymers with the [HR1]3 in the sites defined via docking, various starting positions of polymer chains were tried. The MD simulations confirmed the main docking-predicted priority for binding sites, and possibilities for axial and belting modes of the ligands-target interactions. Some newly MD-discovered aspects of the ligand's backbone and anchor units dynamic cooperation in binding the viral target clarify mechanisms of the synthetic polymers anti-HIV activity and drug resistance prevention.

  7. SwarmDock and the Use of Normal Modes in Protein-Protein Docking

    Directory of Open Access Journals (Sweden)

    Paul A. Bates

    2010-09-01

    Full Text Available Here is presented an investigation of the use of normal modes in protein-protein docking, both in theory and in practice. Upper limits of the ability of normal modes to capture the unbound to bound conformational change are calculated on a large test set, with particular focus on the binding interface, the subset of residues from which the binding energy is calculated. Further, the SwarmDock algorithm is presented, to demonstrate that the modelling of conformational change as a linear combination of normal modes is an effective method of modelling flexibility in protein-protein docking.

  8. Ligand pose and orientational sampling in molecular docking.

    Directory of Open Access Journals (Sweden)

    Ryan G Coleman

    Full Text Available Molecular docking remains an important tool for structure-based screening to find new ligands and chemical probes. As docking ambitions grow to include new scoring function terms, and to address ever more targets, the reliability and extendability of the orientation sampling, and the throughput of the method, become pressing. Here we explore sampling techniques that eliminate stochastic behavior in DOCK3.6, allowing us to optimize the method for regularly variable sampling of orientations. This also enabled a focused effort to optimize the code for efficiency, with a three-fold increase in the speed of the program. This, in turn, facilitated extensive testing of the method on the 102 targets, 22,805 ligands and 1,411,214 decoys of the Directory of Useful Decoys-Enhanced (DUD-E benchmarking set, at multiple levels of sampling. Encouragingly, we observe that as sampling increases from 50 to 500 to 2000 to 5000 to 20,000 molecular orientations in the binding site (and so from about 1×10(10 to 4×10(10 to 1×10(11 to 2×10(11 to 5×10(11 mean atoms scored per target, since multiple conformations are sampled per orientation, the enrichment of ligands over decoys monotonically increases for most DUD-E targets. Meanwhile, including internal electrostatics in the evaluation ligand conformational energies, and restricting aromatic hydroxyls to low energy rotamers, further improved enrichment values. Several of the strategies used here to improve the efficiency of the code are broadly applicable in the field.

  9. A Novel Docking System for Modular Self-Reconfigurable Robots

    Directory of Open Access Journals (Sweden)

    Tan Zhang

    2017-10-01

    Full Text Available Existing self-reconfigurable robots achieve connections and disconnections by a separate drive of the docking system. In this paper, we present a new docking system with which the connections and disconnections are driven by locomotion actuators, without the need for a separate drive, which reduces the weight and the complexity of the modules. This self-reconfigurable robot consists of two types of fundamental modules, i.e., active and passive modules. By the docking system, two types of connections are formed with the fundamental modules, and the docking and undocking actions are achieved through simple control with less sensory feedback. This paper describes the design of the robotic modules, the docking system, the docking process, and the docking force analysis. An experiment is performed to demonstrate the self-reconfigurable robot with the docking system.

  10. Engineering Evaluation of International Low Impact Docking System Latch Hooks

    Science.gov (United States)

    Martinez, J.; Patin, R.; Figert, J.

    2013-01-01

    The international Low Impact Docking System (iLIDS) provides a structural arrangement that allows for visiting vehicles to dock with the International Space Station (ISS) (Fig 1). The iLIDS docking units are mechanically joined together by a series of active and passive latch hooks. In order to preserve docking capability at the existing Russian docking interfaces, the iLIDS latch hooks are required to conform to the existing Russian design. The latch hooks are classified as being fail-safe. Since the latch hooks are fail-safe, the hooks are not fracture critical and a fatigue based service life assessment will satisfy the structural integrity requirements. Constant amplitude fatigue testing to failure on four sets of active/passive iLIDS latch hooks was performed at load magnitudes of 10, 11, and 12 kips. Failure analysis of the hook fatigue failures identified multi-site fatigue initiation that was effectively centered about the hook mid-plane (consistent with the 3D model results). The fatigue crack initiation distribution implies that the fatigue damage accumulation effectively results in a very low aspect ratio surface crack (which can be simulated as thru-thickness crack). Fatigue damage progression resulted in numerous close proximity fatigue crack initiation sites. It was not possible to determine if fatigue crack coalescence occurs during cyclic loading or as result of the fast fracture response. The presence of multiple fatigue crack initiation sites on different planes will result in the formation of ratchet marks as the cracks coalesce. Once the stable fatigue crack becomes unstable and the fast fracture advances across the remaining ligament and the plane stress condition at a free-surface will result in failure along a 45 deg. shear plane (slant fracture) and the resulting inclined edge is called a shear lip. The hook thickness on the plane of fatigue crack initiation is 0.787". The distance between the shear lips on this plane was on the order of 0

  11. EPR study of manganese(II) binding to 55'-ATP, hemoglobin, and hemocyanin

    Energy Technology Data Exchange (ETDEWEB)

    Chang, S.S. (Duquesne Univ., Pittsburgh); Li, N.C.; Pratt, D.W.

    1975-01-01

    Several divalent metal ions affect the oxygen affinity of hemoglobin and hemocyanin. It is important, therefore, to understand the nature of metal-ion binding to these proteins. By comparing the EPR spectra of Mn(II), 0.001 M, in the absence and presence of carboxyhemoglobin or Limulus oxyhemocyanin (pH 7.3, Trizma buffer), the number of Mn binding sites, n, and the binding constant, K, can be determined. For carboxyhemoglobin, HbCO, we find 0.5 Mn binding sites per heme, K = 450 M/sup -1/. Each hemoglobin tetramer therefore binds two manganous ions suggesting that Mn(II), like Cu(II), may bind preferentially to one of the two types of subunits in hemoglobin. For hemocyanin, HcO/sub 2/, we find n = 5.8, K = 1.55 x 10/sup 3/ M/sup -1/. Each oxyhemocyanine therefore binds approximately six manganous ions, and the binding constant is three times larger than that for HbCO. We have also carried out similar experiments on 5'-ATP, and on solutions of HbCO and ATP containing McCl/sub 2/ or ZnCl/sub 2/. Zn(II) effectively competes with Mn(II) in binding hemoglobin and ATP, whereas Mg(II) does not, in accord with expectations from data on oxygen affinity of hemoglobin. (auth)

  12. Nitrosyl hemoglobins: EPR above 80 K

    Energy Technology Data Exchange (ETDEWEB)

    Wajnberg, E.; Bemski, G.; El-Jaick, L.J.; Alves, O.C.

    1995-03-01

    The EPR spectra of nitrosyl hemoglobin and myoglobin in different conditions (native, denatured and lyophilized), as well as of hematin-NO were obtained in the temperature range of 80 K-280 K. There is a substantial and reversible.decrease of the areas of the EPR spectra of all the hemoglobin samples above 150 K. The interpretation of the results implies the existence of two conformational states in thermal equilibrium only one of which is EPR detectable. Thermodynamical parameters are determined for the hexa and penta-coordinated cases. (author). 25 refs, 3 figs.

  13. Nitrosyl hemoglobins: EPR above 80 K

    International Nuclear Information System (INIS)

    Wajnberg, E.; Bemski, G.; El-Jaick, L.J.; Alves, O.C.

    1995-03-01

    The EPR spectra of nitrosyl hemoglobin and myoglobin in different conditions (native, denatured and lyophilized), as well as of hematin-NO were obtained in the temperature range of 80 K-280 K. There is a substantial and reversible.decrease of the areas of the EPR spectra of all the hemoglobin samples above 150 K. The interpretation of the results implies the existence of two conformational states in thermal equilibrium only one of which is EPR detectable. Thermodynamical parameters are determined for the hexa and penta-coordinated cases. (author). 25 refs, 3 figs

  14. The HADDOCK web server for data-driven biomolecular docking

    NARCIS (Netherlands)

    de Vries, S.J.|info:eu-repo/dai/nl/304837717; van Dijk, M.|info:eu-repo/dai/nl/325811113; Bonvin, A.M.J.J.|info:eu-repo/dai/nl/113691238

    2010-01-01

    Computational docking is the prediction or modeling of the three-dimensional structure of a biomolecular complex, starting from the structures of the individual molecules in their free, unbound form. HADDOC K is a popular docking program that takes a datadriven approach to docking, with support for

  15. CovalentDock Cloud: a web server for automated covalent docking.

    Science.gov (United States)

    Ouyang, Xuchang; Zhou, Shuo; Ge, Zemei; Li, Runtao; Kwoh, Chee Keong

    2013-07-01

    Covalent binding is an important mechanism for many drugs to gain its function. We developed a computational algorithm to model this chemical event and extended it to a web server, the CovalentDock Cloud, to make it accessible directly online without any local installation and configuration. It provides a simple yet user-friendly web interface to perform covalent docking experiments and analysis online. The web server accepts the structures of both the ligand and the receptor uploaded by the user or retrieved from online databases with valid access id. It identifies the potential covalent binding patterns, carries out the covalent docking experiments and provides visualization of the result for user analysis. This web server is free and open to all users at http://docking.sce.ntu.edu.sg/.

  16. Docking to flexible nicotinic acetylcholine receptors

    DEFF Research Database (Denmark)

    Sander, Tommy; Bruun, Anne T; Balle, Thomas

    2010-01-01

    Computational docking to nicotinic acetylcholine receptors (nAChRs) and other members of the Cys-loop receptor family is complicated by the flexibility of the so-called C-loop. As observed in the large number of published crystal structures of the acetylcholine binding protein (AChBP), a structural...

  17. Compodock, a new device for sterile docking

    NARCIS (Netherlands)

    van der Meer, P. F.; Biekart, F. T.; Pietersz, R. N.; Rebers, S. P.; Reesink, H. W.

    2000-01-01

    BACKGROUND: A new device for sterile docking, the Compodock (Fresenius NPBI Transfusion Technology), was developed for connecting PVC tubing for medical use while maintaining sterility. STUDY DESIGN AND METHODS: Sterility of the connections was assessed by welding tubing with a heavy exterior

  18. Solvated protein-DNA docking using HADDOCK

    NARCIS (Netherlands)

    van Dijk, Marc; Visscher, Koen M; Bonvin, Alexandre M.J.J; Kastritis, Panagiotis L.

    2013-01-01

    Interfacial water molecules play an important role in many aspects of protein-DNA specificity and recognition. Yet they have been mostly neglected in the computational modeling of these complexes. We present here a solvated docking protocol that allows explicit inclusion of water molecules in the

  19. Operator learning effects in teleoperated rendezvous & docking

    Science.gov (United States)

    Wilde, M.; Harder, J.; Purschke, R.

    Teleoperation of spacecraft proximity operations and docking requires delicate timing and coordination of spacecraft maneuvers. Experience has shown that human operators show large performance fluctuations in these areas, which are a major factor to be addressed in operator training. In order to allow the quantification of the impact of these human fluctuations on control system performance and the human perception of this performance, a learning curve study was conducted with teleoperated final approach and docking scenarios. Over a period of ten experiment days, three test participants were tasked with repeatedly completing a set of three training scenarios. The scenarios were designed to contain different combinations of the major elements of any final approach and docking situation, and to feature an increasing difficulty level. The individual difficulty levels for the three operators furthermore differed in the level of operator support functions available in their human-machine interfaces. Operator performance in the test scenarios were evaluated in the fields approach success and precision, docking safety, and approach efficiency by a combination of recorded maneuver data and questionnaires. The results show that operator experience and the associated learning curves increase operator performance substantially, regardless of the support system used. The paper also shows that the fluctuations in operator performance and self-perception are substantial between as well as within experiment days, and must be reckoned with in teleoperation system design and mission planning.

  20. Gab Docking Proteins in Cardiovascular Disease, Cancer, and Inflammation

    Directory of Open Access Journals (Sweden)

    Yoshikazu Nakaoka

    2013-01-01

    Full Text Available The docking proteins of the Grb2-associated binder (Gab family have emerged as crucial signaling compartments in metazoans. In mammals, the Gab proteins, consisting of Gab1, Gab2, and Gab3, are involved in the amplification and integration of signal transduction evoked by a variety of extracellular stimuli, including growth factors, cytokines, antigens, and other molecules. Gab proteins lack the enzymatic activity themselves; however, when phosphorylated on tyrosine residues, they provide binding sites for multiple Src homology-2 (SH2 domain-containing proteins, such as SH2-containing protein tyrosine phosphatase 2 (SHP2, phosphatidylinositol 3-kinase regulatory subunit p85, phospholipase Cγ, Crk, and GC-GAP. Through these interactions, the Gab proteins transduce signals from activated receptors into pathways with distinct biological functions, thereby contributing to signal diversification. They are known to play crucial roles in numerous physiological processes through their associations with SHP2 and p85. In addition, abnormal Gab protein signaling has been linked to human diseases including cancer, cardiovascular disease, and inflammatory disorders. In this paper, we provide an overview of the structure, effector functions, and regulation of the Gab docking proteins, with a special focus on their associations with cardiovascular disease, cancer, and inflammation.

  1. Identification of new 2,5-diketopiperazine derivatives as simultaneous effective inhibitors of αβ-tubulin and BCRP proteins: Molecular docking, Structure-Activity Relationships and virtual consensus docking studies

    Science.gov (United States)

    Fani, Najmeh; Sattarinezhad, Elham; Bordbar, Abdol-Khalegh

    2017-06-01

    In the first part of this paper, docking method was employed in order to study the binding mechanism of breast cancer resistance protein (BCRP) with a group of previously synthesized TPS-A derivatives which known as potent inhibitors of this protein to get insight into drug binding site of BCRP and to explore structure-activity relationship of these compounds. Molecular docking results showed that most of these compounds bind in the binding site of BCRP at the interface between the membrane and outer environment. In the second part, a group of designed TPS-A derivatives which showed good binding energies in the binding site of αβ-tubulin in the previous study were chosen to study their binding energies in the binding site of BCRP to investigate their simultaneous inhibitory effect on both αβ-tubulin and BCRP. The results showed that all of these compounds bind to the binding site of BCRP with relatively suitable binding energies and therefore could be potential inhibitors of both αβ-tubulin and BCRP proteins. Finally, virtual consensus docking method was utilized with the aim of design of new 2,5-diketopiperazine derivatives with significant inhibitory effect on both αβ-tubulin and BCRP proteins. For this purpose binding energies of a library of 2,5-diketopiperazine derivatives in the binding sites of αβ-tubulin and BCRP was investigated by using AutoDock and AutoDock vina tools. Molecular docking results revealed that a group of 36 compounds among them exhibit strong anti-tubulin and anti-BCRP activity.

  2. Predictors of hemoglobin in Danish blood donors

    DEFF Research Database (Denmark)

    Kotzé, Sebastian R; Pedersen, Ole B; Petersen, Mikkel S

    2015-01-01

    BACKGROUND: It is well known that blood donors are at increased risk of iron deficiency and subsequent development of iron deficiency anemia. We aimed to investigate the effect of factors influencing hemoglobin (Hb) levels. STUDY DESIGN AND METHODS: Initiated in 2010, the Danish Blood Donor Study...

  3. Rheological Variations among Nigerians with Different Hemoglobin ...

    African Journals Online (AJOL)

    Some Hemorheological determinants such as whole blood viscosity (WBV) and plasma viscosity (PV) and Plasma Fibrinogen Concentration (PFC) were measured with standard methods. We recorded a relatively unchanged whole blood viscosities in subjects with various hemoglobin genotypes (AA, AS and SS; P>0.05, ...

  4. High-altitude adaptations in vertebrate hemoglobins

    DEFF Research Database (Denmark)

    Weber, Roy E.

    2007-01-01

    Vertebrates at high altitude are subjected to hypoxic conditions that challenge aerobic metabolism. O2 transport from the respiratory surfaces to tissues requires matching between the O2 loading and unloading tensions and theO2-affinity of blood, which is an integrated function of hemoglobin......, birds and ectothermic vertebrates at high altitude....

  5. Constraints on mutational pathways of hemoglobin evolution

    DEFF Research Database (Denmark)

    Kumar, Amit; Natarajan, Chandrasekhar; Moriyama, Hideaki

    2016-01-01

    amino acid substitutions that occurred during an evolutionary reduction in hemoglobin (Hb)-O2 affinity in nightjars (nocturnal birds in the family Caprimulgidae).We selected nightjar Hbs for experimental study because ancestral sequence reconstructions indicated that the evolved reduction in Hb-O2...

  6. The pepATTRACT web server for blind, large-scale peptide-protein docking.

    Science.gov (United States)

    de Vries, Sjoerd J; Rey, Julien; Schindler, Christina E M; Zacharias, Martin; Tuffery, Pierre

    2017-07-03

    Peptide-protein interactions are ubiquitous in the cell and form an important part of the interactome. Computational docking methods can complement experimental characterization of these complexes, but current protocols are not applicable on the proteome scale. pepATTRACT is a novel docking protocol that is fully blind, i.e. it does not require any information about the binding site. In various stages of its development, pepATTRACT has participated in CAPRI, making successful predictions for five out of seven protein-peptide targets. Its performance is similar or better than state-of-the-art local docking protocols that do require binding site information. Here we present a novel web server that carries out the rigid-body stage of pepATTRACT. On the peptiDB benchmark, the web server generates a correct model in the top 50 in 34% of the cases. Compared to the full pepATTRACT protocol, this leads to some loss of performance, but the computation time is reduced from ∼18 h to ∼10 min. Combined with the fact that it is fully blind, this makes the web server well-suited for large-scale in silico protein-peptide docking experiments. The rigid-body pepATTRACT server is freely available at http://bioserv.rpbs.univ-paris-diderot.fr/services/pepATTRACT. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  7. Functional and catalytic active sites prediction and docking analysis ...

    African Journals Online (AJOL)

    The initial critical step of reduction of azo bond during the metabolism of azo dyes is catalysed by a group of NADH and FAD dependant enzyme called azoreductases. Although several azoreductases have been identified from microorganisms and partially characterized, very little is known about the structural basis of the ...

  8. Functional and catalytic active sites prediction and docking analysis ...

    African Journals Online (AJOL)

    Bioinformatics

    2015-07-01

    Jul 1, 2015 ... Full Length Research Paper ... been identified from microorganisms and partially characterized, ... understanding of the biodegradation of some of the commercially ... are highly toxic and contain carcinogenic compounds.

  9. Kadar Hemoglobin dan Kecerdasan Intelektual Anak

    Directory of Open Access Journals (Sweden)

    Yuni Kusmiyati

    2013-10-01

    Full Text Available Kualitas sumber daya manusia dipengaruhi oleh inteligensi anak. Skor kecerdasan intelektual yang tidak menetap pada usia tertentu dapat berubah karena faktor genetik, gizi, dan lingkungan. Tujuan penelitian ini adalah mengetahui hubungan kadar hemoglobin dengan kecerdasan intelektual anak. Penelitian observasional dengan desain potong lintang ini dilakukan pada populasi siswa kelas VI Sekolah Dasar Negeri Giwangan Yogyakarta, tahun 2013. Penarikan sampel dilakukan dengan metode simple random sampling terhadap 37 sampel siswa. Instrumen untuk mengukur kecerdasan intelektual dengan Cultural Fair Intelligence Quotient Test yang dirancang untuk meminimalkan pengaruh kultural dengan memperhatikan prosedur evaluasi, instruksi, konten isi, dan respons peserta. Tes dilakukan oleh Biro Psikologi Universitas Ahmad Dahlan Yogyakarta, kadar hemoglobin diukur menggunakan Portable Hemoglobin Digital Analyzer Easy Touch secara digital.Variabel luar indeks massa tubuh diukur langsung menggunakan parameter tinggi badan dan berat badan. Analisis menggunakan uji regresi linier. Hasil penelitian menunjukkan indeks massa tubuh tidak berhubungan dengan kecerdasan intelektual (nilai p = 0,052. Anemia berhubungan cukup dengan kecerdasan anak (r = 0,491 dan berpola positif, semakin tinggi kadar hemoglobin semakin tinggi kecerdasan intelektual anak. Nilai koefisien determinasi 0,241 menerangkan bahwa 24,1% variasi anemia cukup baik untuk menjelaskan variabel kecerdasan intelektual. Ada hubungan antara kadar hemoglobin dengan kecerdasan intelektual (nilai p = 0,002. Quality of human resources is influenced by the child’s intelligent. Intelligence Quotient (IQ score will not settle at a certain age and can change due to genetic factors, nutrition, and the environment. The objective is known relationship of anemia with IQ to child. Method of observational study with cross sectional design. Population are students of class VI elementary school of Giwangan Yogyakarta in

  10. Capillary versus Venous Hemoglobin Determination in the Assessment of Healthy Blood Donors

    Science.gov (United States)

    Patel, Abhilasha J.; Wesley, Robert; Leitman, Susan F.; Bryant, Barbara J.

    2013-01-01

    Background and Objectives To determine the accuracy of fingerstick hemoglobin assessment in blood donors, the performance of a portable hemoglobinometer (HemoCue Hb 201+) was prospectively compared with that of an automated hematology analyzer (Cell-Dyn 4000). Hemoglobin values obtained by the latter were used as the “true” result. Material and Methods Capillary fingerstick samples were assayed by HemoCue in 150 donors. Fingerstick samples from two sites, one on each hand, were obtained from a subset of 50 subjects. Concurrent venous samples were tested using both HemoCue and Cell-Dyn devices. Results Capillary hemoglobin values (HemoCue) were significantly greater than venous hemoglobin values (HemoCue), which in turn were significantly greater than venous hemoglobin values by Cell-Dyn (mean ± SD: 14.05 ± 1.51, 13.89 ± 1.31, 13.62 ± 1.23, respectively; phemoglobin screening criteria (≥12.5 g/dL) by capillary HemoCue, but were deferred by Cell-Dyn values (false-pass). Five donors (3%) were deferred by capillary sampling, but passed by Cell-Dyn (false-fail). Substantial variability in repeated fingerstick HemoCue results was seen (mean hemoglobin 13.72 vs. 13.70 g/dL, absolute mean difference between paired samples 0.76 g/dL). Hand dominance was not a factor. Conclusions Capillary samples assessed via a portable device yielded higher hemoglobin values than venous samples assessed on an automated analyzer. False-pass and false-fail rates were low and acceptable in the donor screening setting, with “true” values not differing by a clinically significant degree from threshold values used to assess acceptability for blood donation. PMID:23294266

  11. A new hemoglobin gene from soybean: a role for hemoglobin in all plants

    DEFF Research Database (Denmark)

    Anderson, C R; Jensen, E O; LLewellyn, D J

    1996-01-01

    We have isolated a new hemoglobin gene from soybean. It is expressed in cotyledons, stems of seedlings, roots, young leaves, and in some cells in the nodules that are associated with the nitrogen-fixing Bradyrhizobium symbiont. This contrasts with the expression of the leghemoglobins, which...... are active only in the infected cells of the nodules. The deduced protein sequence of the new gene shows only 58% similarity to one of the soybean leghemoglobins, but 85-87% similarity to hemoglobins from the nonlegumes Parasponia, Casuarina, and barley. The pattern of expression and the gene sequence...... indicate that this new gene is a nonsymbiotic legume hemoglobin. The finding of this gene in legumes and similar genes in other species strengthens our previous suggestion that genomes of all plants contain hemoglobin genes. The specialized leghemoglobin gene family may have arisen from a preexisting...

  12. Alpha chain hemoglobins with electrophoretic mobility similar to that of hemoglobin S in a newborn screening program

    Directory of Open Access Journals (Sweden)

    Marcilene Rezende Silva

    2013-01-01

    Full Text Available OBJECTIVE: To characterize alpha-chain variant hemoglobins with electric mobility similar to that of hemoglobin S in a newborn screening program. METHODS: βS allele and alpha-thalassemia deletions were investigated in 14 children who had undefined hemoglobin at birth and an electrophoretic profile similar to that of hemoglobin S when they were six months old. Gene sequencing and restriction enzymes (DdeI, BsaJI, NlaIV, Bsu36I and TaqI were used to identify hemoglobins. Clinical and hematological data were obtained from children who attended scheduled medical visits. RESULTS: The following alpha chain variants were found: seven children with hemoglobin Hasharon [alpha2 47(CE5 Asp>His, HbA2:c.142G>C], all associated with alpha-thalassemia, five with hemoglobin Ottawa [alpha1 15(A13 Gly>Arg, HBA1:c.46G>C], one with hemoglobin St Luke's [alpha1 95(G2 Pro>Arg, HBA1:c.287C>G] and another one with hemoglobin Etobicoke [alpha212 84(F5 Ser>Arg, HBA212:c.255C>G]. Two associations with hemoglobin S were found: one with hemoglobin Ottawa and one with hemoglobin St Luke's. The mutation underlying hemoglobin Etobicoke was located in a hybrid α212 allele in one child. There was no evidence of clinically relevant hemoglobins detected in this study. CONCLUSION: Apparently these are the first cases of hemoglobin Ottawa, St Luke's, Etobicoke and the α212 gene described in Brazil. The hemoglobins detected in this study may lead to false diagnosis of sickle cell trait or sickle cell disease when only isoelectric focusing is used in neonatal screening. Additional tests are necessary for the correct identification of hemoglobin variants.

  13. Alpha chain hemoglobins with electrophoretic mobility similar to that of hemoglobin S in a newborn screening program.

    Science.gov (United States)

    Silva, Marcilene Rezende; Sendin, Shimene Mascarenhas; Araujo, Isabela Couto de Oliveira; Pimentel, Fernanda Silva; Viana, Marcos Borato

    2013-01-01

    To characterize alpha-chain variant hemoglobins with electric mobility similar to that of hemoglobin S in a newborn screening program. β(S) allele and alpha-thalassemia deletions were investigated in 14 children who had undefined hemoglobin at birth and an electrophoretic profile similar to that of hemoglobin S when they were six months old. Gene sequencing and restriction enzymes (DdeI, BsaJI, NlaIV, Bsu36I and TaqI) were used to identify hemoglobins. Clinical and hematological data were obtained from children who attended scheduled medical visits. THE FOLLOWING ALPHA CHAIN VARIANTS WERE FOUND: seven children with hemoglobin Hasharon [alpha2 47(CE5) Asp>His, HbA2:c.142G>C], all associated with alpha-thalassemia, five with hemoglobin Ottawa [alpha1 15(A13) Gly>Arg, HBA1:c.46G>C], one with hemoglobin St Luke's [alpha1 95(G2) Pro>Arg, HBA1:c.287C>G] and another one with hemoglobin Etobicoke [alpha212 84(F5) Ser>Arg, HBA212:c.255C>G]. Two associations with hemoglobin S were found: one with hemoglobin Ottawa and one with hemoglobin St Luke's. The mutation underlying hemoglobin Etobicoke was located in a hybrid α212 allele in one child. There was no evidence of clinically relevant hemoglobins detected in this study. Apparently these are the first cases of hemoglobin Ottawa, St Luke's, Etobicoke and the α212 gene described in Brazil. The hemoglobins detected in this study may lead to false diagnosis of sickle cell trait or sickle cell disease when only isoelectric focusing is used in neonatal screening. Additional tests are necessary for the correct identification of hemoglobin variants.

  14. Fetal hemoglobin is much less prone to DNA cleavage compared to the adult protein

    Directory of Open Access Journals (Sweden)

    Sandeep Chakane

    2017-08-01

    Full Text Available Hemoglobin (Hb is well protected inside the red blood cells (RBCs. Upon hemolysis and when free in circulation, Hb can be involved in a range of radical generating reactions and may thereby attack several different biomolecules. In this study, we have examined the potential damaging effects of cell-free Hb on plasmid DNA (pDNA. Hb induced cleavage of supercoiled pDNA (sc pDNA which was proportional to the concentration of Hb applied. Almost 70% of sc pDNA was converted to open circular or linear DNA using 10 µM of Hb in 12 h. Hb can be present in several different forms. The oxy (HbO2 and met forms are most reactive, while the carboxy-protein shows only low hydrolytic activity. Hemoglobin A (HbA could easily induce complete pDNA cleavage while fetal hemoglobin (HbF was three-fold less reactive. By inserting, a redox active cysteine residue on the surface of the alpha chain of HbF by site-directed mutagenesis, the DNA cleavage reaction was enhanced by 82%. Reactive oxygen species were not directly involved in the reaction since addition of superoxide dismutase and catalase did not prevent pDNA cleavage. The reactivity of Hb with pDNA can rather be associated with the formation of protein based radicals. Keywords: Adult hemoglobin, Fetal hemoglobin, Supercoiled plasmid DNA, DNA cleavage, Cysteine, Protein radicals

  15. Lyophilized bovine hemoglobin as a possible reference material for the determination of hemoglobin derivatives in human blood

    NARCIS (Netherlands)

    Maas, BHA; Buursma, A; Ernst, RAJ; Maas, AHJ; Zijlstra, WG

    1998-01-01

    We investigated the suitability of a lyophilized bovine hemoglobin (LBH) preparation containing various fractions of oxyhemoglobin (O(2)Hb), carboxyhemoglobin (COHb), and methemoglobin (MetHb) for quality assessment in multicomponent analysis (MCA) of hemoglobin derivatives. It was demonstrated that

  16. Lyophilized bovine hemoglobin as a possible reference material for the determination of hemoglobin derivatives in human blood

    NARCIS (Netherlands)

    Maas, BHA; Buursma, A; Ernst, RAJ; Maas, AHJ; Zijlstra, WG

    We investigated the suitability of a lyophilized bovine hemoglobin (LBH) preparation containing various fractions of oxyhemoglobin (O(2)Hb), carboxyhemoglobin (COHb), and methemoglobin (MetHb) for quality assessment in multicomponent analysis (MCA) of hemoglobin derivatives. It was demonstrated that

  17. Hemoglobin estimation by the HemoCue® portable hemoglobin photometer in a resource poor setting.

    Science.gov (United States)

    Nkrumah, Bernard; Nguah, Samuel Blay; Sarpong, Nimako; Dekker, Denise; Idriss, Ali; May, Juergen; Adu-Sarkodie, Yaw

    2011-04-21

    In resource poor settings where automated hematology analyzers are not available, the Cyanmethemoglobin method is often used. This method though cheaper, takes more time. In blood donations, the semi-quantitative gravimetric copper sulfate method which is very easy and inexpensive may be used but does not provide an acceptable degree of accuracy. The HemoCue® hemoglobin photometer has been used for these purposes. This study was conducted to generate data to support or refute its use as a point-of-care device for hemoglobin estimation in mobile blood donations and critical care areas in health facilities. EDTA blood was collected from study participants drawn from five groups: pre-school children, school children, pregnant women, non-pregnant women and men. Blood collected was immediately processed to estimate the hemoglobin concentration using three different methods (HemoCue®, Sysmex KX21N and Cyanmethemoglobin). Agreement between the test methods was assessed by the method of Bland and Altman. The Intraclass correlation coefficient (ICC) was used to determine the within subject variability of measured hemoglobin. Of 398 subjects, 42% were males with the overall mean age being 19.4 years. The overall mean hemoglobin as estimated by each method was 10.4 g/dl for HemoCue, 10.3 g/dl for Sysmex KX21N and 10.3 g/dl for Cyanmethemoglobin. Pairwise analysis revealed that the hemoglobin determined by the HemoCue method was higher than that measured by the KX21N and Cyanmethemoglobin. Comparing the hemoglobin determined by the HemoCue to Cyanmethemoglobin, the concordance correlation coefficient was 0.995 (95% CI: 0.994-0.996, p < 0.001). The Bland and Altman's limit of agreement was -0.389 - 0.644 g/dl with the mean difference being 0.127 (95% CI: 0.102-0.153) and a non-significant difference in variability between the two measurements (p = 0.843). After adjusting to assess the effect of other possible confounders such as sex, age and category of person, there was no

  18. A probe to study the toxic interaction of tartrazine with bovine hemoglobin at the molecular level.

    Science.gov (United States)

    Li, Yating; Wei, Haoran; Liu, Rutao

    2014-03-01

    Tartrazine is an artificial azo dye commonly used in food products, but tartrazine in the environment is potentially harmful. The toxic interaction between tartrazine and bovine hemoglobin (BHb) was investigated using fluorescence, synchronous fluorescence, UV-vis absorption, circular dichroism (CD) and molecular modeling techniques under simulated physiological conditions. The fluorescence data showed that tartrazine can bind with BHb to form a complex. The binding process was a spontaneous molecular interaction, in which van der Waals' forces and hydrogen bonds played major roles. Molecular docking results showed that the hydrogen bonds exist between the oxygen atoms at position 31 of tartrazine and the nitrogen atom NZ7 on Lys99, and also between the oxygen atoms at position 15 of tartrazine and the nitrogen atom NZ7 on Lys104, Lys105. The results of UV-vis and CD spectra revealed that tartrazine led to conformational changes in BHb, including loosening of the skeleton structure and decreasing α helix in the secondary structure. The synchronous fluorescence experiment revealed that tartrazine binds into the hemoglobin central cavity, and this was verified using a molecular modeling study. Copyright © 2013 John Wiley & Sons, Ltd.

  19. Insights into catalytic activity of industrial enzyme Co-nitrile hydratase. Docking studies of nitriles and amides.

    Science.gov (United States)

    Peplowski, Lukasz; Kubiak, Karina; Nowak, Wieslaw

    2007-07-01

    Nitrile hydratase (NHase) is an enzyme containing non-corrin Co3+ in the non-standard active site. NHases from Pseudonocardia thermophila JCM 3095 catalyse hydration of nitriles to corresponding amides. The efficiency of the enzyme is 100 times higher for aliphatic nitriles then aromatic ones. In order to understand better this selectivity dockings of a series of aliphatic and aromatic nitriles and related amides into a model protein based on an X-ray structure were performed. Substantial differences in binding modes were observed, showing better conformational freedom of aliphatic compounds. Distinct interactions with postranslationally modified cysteines present in the active site of the enzyme were observed. Modeling shows that water molecule activated by a metal ion may easily directly attack the docked acrylonitrile to transform this molecule into acryloamide. Thus docking studies provide support for one of the reaction mechanisms discussed in the literature.

  20. The Reaction of Oxy Hemoglobin with Nitrite

    DEFF Research Database (Denmark)

    Hathazi, Denisa; Scurtu, Florina; Bischin, Cristina

    2018-01-01

    The autocatalytic reaction between nitrite and the oxy form of globins involves free radicals. For myoglobin (Mb), an initial binding of nitrite to the iron-coordinated oxygen molecule was proposed; the resulting ferrous-peroxynitrate species was not detected, but its decay product, the high...... to a simple kinetic model involving a transient met-aqua form, in contrast to the ferryl detected in the case of Mb in a similar reaction sequence. These data are in line with a previous observation of a transient accumulation of ferryl Hb under auto-catalytic conditions at much lower concentrations......-peroxynitrate. Density functional theory (DFT) calculations support this latter assignment. The reaction allows for differentiating between the reactivities of various chemically modified hemoglobins, including candidates for blood substitutes. Polymerization of hemoglobin slows the nitrite-induced oxidation, in sharp...

  1. Hemoglobin promotes somatic embryogenesis in peanut cultures.

    Science.gov (United States)

    Jayabalan, N; Anthony, P; Davey, M R; Power, J B; Lowe, K C

    2004-02-01

    Critical parameters influencing somatic embryogenesis include growth regulators and oxygen supply. Consequently, the present investigation has focused on optimization of a somatic embryogenic system for peanut (Arachis hypogaea L.) through media supplementation with the auxin, picloram. The latter at 30 mg L(-1) was optimal for inducing regeneration of somatic embryos from cultured explants of zygotic embryos. In contrast, somatic embryogenesis did not occur in the absence of this growth regulator. An assessment has also been made of the beneficial effect on somatic embryogenesis and plant regeneration of the commercial hemoglobin (Hb) solution, Erythrogen. Hemoglobin at 1:50 and 1:100 (v:v) stimulated increases in mean fresh weight (up to a maximum of 57% over control), mean number of explants producing somatic embryos (15%) and mean number of somatic embryos per explant (29%).

  2. Facile Interfacial Electron Transfer of Hemoglobin

    Directory of Open Access Journals (Sweden)

    Chunhai Fan

    2005-12-01

    Full Text Available Abstract: We herein describe a method of depositing hemoglobin (Hb and sulfonated polyaniline (SPAN on GC electrodes that facilitate interfacial protein electron transfer. Well-defined, reproducible, chemically reversible peaks of Hb and SPAN can be obtained in our experiments. We also observed enhanced peroxidase activity of Hb in SPAN films. These results clearly showed that SPAN worked as molecular wires and effectively exchanged electrons between Hb and electrodes.Mediated by Conjugated Polymers

  3. Radio-ligand immunoassay for human hemoglobin variants

    International Nuclear Information System (INIS)

    Javid, J.; Pettis, P.K.; Miller, J.E.

    1981-01-01

    A quantitative method is described for the individual assay of human hemoglobin variants occurring singly or in mixture. The hemoglobin to be assayed is bound to specific antibody; the immune complex is attached to protein A-containing S. aureus and removed from the mixture. The hemoglobin thus isolated is quantified by its ability to bind radiolabeled haptoglobin. The technique is accurate and distinguishes among the 4 hemoglobins tested, namely Hb A, S, C and F. It has the advantage over conventional radioimmunoassay that a single probe, radiolabeled haptoglobin, is needed for the specific assay of any hemoglobin. (Auth.)

  4. Induction of nano pore in Agrobacterial hemoglobin

    Directory of Open Access Journals (Sweden)

    Mojtaba Tousheh

    2014-01-01

    Full Text Available Introduction: A variety of oxygen-transport and -binding proteins exist in organisms including bacteria, protozoans, and fungi all have hemoglobin-like proteins. In addition to dealing with transport and sensing of oxygen, they may also deal with NO2, CO2, sulfide compounds, and even O2 scavenging in environments. Also they detoxified chlorinated materials like P450 enzymes and peroxidases and use as a detector of nitrate and hydrogen peroxide. Pore-forming bacterial globins are interested for filtration. Materials and methods: Although there are data for bacterial toxin as a filter, here we used Agrobacterial hem to induce nano pore in the heme structure using point mutation. Results: Investigations showed that three amino acids leucine 76, alanine 83 and histidine 80 are important for pore formation in Agrobacterium hemoglobin. A point mutation on leucine 76 to glycine, histidine 80 to asparagine and alanine 83 to lysine step by step led to create the nano pore 0.7- 0.8 nm in the globin. Discussion and conclusion: These mutations in bacterial hemoglobin increase the stability when mutation is with it’s at pH7. This mutation decreases the aliphatic index however increase the stability index.

  5. Imidazolidinone adducts of peptides and hemoglobin

    International Nuclear Information System (INIS)

    San George, R.C.; Hoberman, H.D.

    1986-01-01

    Acetaldehyde reacts selectively with the terminal amino groups of the α and β chains of hemoglobin to form stable adducts, the structures of which, based on 13 C NMR studies, are proposed to be diastereomeric 2-methyl imidazolidin-4-ones. In this scheme, acetaldelhyde forms a reversible Schiff base with the α-amino groups of the polypeptide chains which cyclize with the amide nitrogen of the first peptide bond to form the stable imidazolidinone adducts. In support of this mechanism, the authors found that in following the reaction of the peptide val-gly-gly with [1,2- 13 C] acetaldehyde, 13 C NMR resonances attributed to a Schiff base (δ = 170 ppm) were observed which slowly disappeared prior to appearance of resonances from a pair of stable adducts (δ = 70 and 71 ppm) believed to be the diastereomeric imidazolidinones. Schiff base formation appeared to limit the overall rate. Tetraglycine reacted in a similar manner but with a resonance from a single stable adduct observed representing the enantiomeric imidazolidinone adducts of this peptide. Peptides with proline in position 2 should be incapable of forming imidazolidinones, and the authors found that ala-pro-gly did in fact fail to form a stable adduct with acetaldehyde. The 2-methyl imidazolidin-4-one adducts of hemoglobin may be useful in determining the contribution of the amino terminal groups to the structure and functional properties of hemoglobins

  6. Activated Cdc42 kinase regulates Dock localization in male germ cells during Drosophila spermatogenesis.

    Science.gov (United States)

    Abdallah, Abbas M; Zhou, Xin; Kim, Christine; Shah, Kushani K; Hogden, Christopher; Schoenherr, Jessica A; Clemens, James C; Chang, Henry C

    2013-06-15

    Deregulation of the non-receptor tyrosine kinase ACK1 (Activated Cdc42-associated kinase) correlates with poor prognosis in cancers and has been implicated in promoting metastasis. To further understand its in vivo function, we have characterized the developmental defects of a null mutation in Drosophila Ack, which bears a high degree of sequence similarity to mammalian ACK1 but lacks a CRIB domain. We show that Ack, while not essential for viability, is critical for sperm formation. This function depends on Ack tyrosine kinase activity and is required cell autonomously in differentiating male germ cells at or after the spermatocyte stage. Ack associates predominantly with endocytic clathrin sites in spermatocytes, but disruption of Ack function has no apparent effect on clathrin localization and receptor-mediated internalization of Boss (Bride of sevenless) protein in eye discs. Instead, Ack is required for the subcellular distribution of Dock (dreadlocks), the Drosophila homolog of the SH2- and SH3-containing adaptor protein Nck. Moreover, Dock forms a complex with Ack, and the localization of Dock in male germ cells depends on its SH2 domain. Together, our results suggest that Ack-dependent tyrosine phosphorylation recruits Dock to promote sperm differentiation. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Modeling and Proposed Molecular Mechanism of Hydroxyurea Through Docking and Molecular Dynamic Simulation to Curtail the Action of Ribonucleotide Reductase.

    Science.gov (United States)

    Iman, Maryam; Khansefid, Zeynab; Davood, Asghar

    2016-01-01

    Ribonucleotide Reductase (RNR) is an important anticancer chemotherapy target. It has main key role in DNA synthesis and cell growth. Therefore several RNR inhibitors, such as hydroxyurea, have entered the clinical trials. Based on our proposed mechanism, radical site of RNR protein reacts with hydroxyurea in which hydroxyurea is converted into its oxidized form compound III, and whereby the tyrosyl radical is converted into a normal tyrosine residue. In this study, docking and molecular dynamics simulations were used for proposed molecular mechanism of hydroxyurea in RNR inhibition as anticancer agent. The binding affinity of hydroxyurea and compound III to RNR was studied by docking method. The docking study was performed for the crystal structure of human RNR with the radical scavenger Hydroxyurea and its oxidized form to inhibit the human RNR. hydroxyurea and compound III bind at the active site with Tyr-176, which are essential for free radical formation. This helps to understand the functional aspects and also aids in the development of novel inhibitors for the human RNR2. To confirm the binding mode of inhibitors, the molecular dynamics (MD) simulations were performed using GROMACS 4.5.5, based upon the docked conformation of inhibitors. Both of the studied compounds stayed in the active site. The results of MD simulations confirmed the binding mode of ligands, accuracy of docking and the reliability of active conformations which were obtained by AutoDock. MD studies confirm our proposed mechanism in which compound III reacts with the active site residues specially Tyr-176, and inhibits the radical generation and subsequently inhibits the RNR enzyme.

  8. Small angle X-ray scattering on concentrated hemoglobin solutions

    International Nuclear Information System (INIS)

    Zinke, M.; Damaschun, G.; Mueller, J.J.; Ruckpaul, K.

    1978-01-01

    The small-angle X-ray scattering technique was used to determine the intermolecular structure and interaction potentials in oxi-and deoxi-hemoglobin solutions. The pair correlation function obtained by the ZERNICKE-PRINS equation characterizes the intermolecular structure of the hemoglobin molecules. The intermolecular structure is concentration dependent. The hemoglobin molecules have a 'short range order structure' with a range of about 4 molecule diameters at 324 g/l. The potential functions of the hemoglobin-hemoglobin interaction have been determined on the basis of fluid theories. Except for the deoxi-hemoglobin solution having the concentration 370 g/l, the pair interaction consists in a short repulsion and a weak short-range attraction against kT. The potential minimum is between 1.2 - 1.5 nm above the greatest hemoglobin diameter. (author)

  9. Hemoglobin estimation by the HemoCue® portable hemoglobin photometer in a resource poor setting

    Directory of Open Access Journals (Sweden)

    Idriss Ali

    2011-04-01

    Full Text Available Abstract Background In resource poor settings where automated hematology analyzers are not available, the Cyanmethemoglobin method is often used. This method though cheaper, takes more time. In blood donations, the semi-quantitative gravimetric copper sulfate method which is very easy and inexpensive may be used but does not provide an acceptable degree of accuracy. The HemoCue® hemoglobin photometer has been used for these purposes. This study was conducted to generate data to support or refute its use as a point-of-care device for hemoglobin estimation in mobile blood donations and critical care areas in health facilities. Method EDTA blood was collected from study participants drawn from five groups: pre-school children, school children, pregnant women, non-pregnant women and men. Blood collected was immediately processed to estimate the hemoglobin concentration using three different methods (HemoCue®, Sysmex KX21N and Cyanmethemoglobin. Agreement between the test methods was assessed by the method of Bland and Altman. The Intraclass correlation coefficient (ICC was used to determine the within subject variability of measured hemoglobin. Results Of 398 subjects, 42% were males with the overall mean age being 19.4 years. The overall mean hemoglobin as estimated by each method was 10.4 g/dl for HemoCue, 10.3 g/dl for Sysmex KX21N and 10.3 g/dl for Cyanmethemoglobin. Pairwise analysis revealed that the hemoglobin determined by the HemoCue method was higher than that measured by the KX21N and Cyanmethemoglobin. Comparing the hemoglobin determined by the HemoCue to Cyanmethemoglobin, the concordance correlation coefficient was 0.995 (95% CI: 0.994-0.996, p Conclusion Hemoglobin determined by the HemoCue method is comparable to that determined by the other methods. The HemoCue photometer is therefore recommended for use as on-the-spot device for determining hemoglobin in resource poor setting.

  10. DOCLASP - Docking ligands to target proteins using spatial and electrostatic congruence extracted from a known holoenzyme and applying simple geometrical transformations.

    Science.gov (United States)

    Chakraborty, Sandeep

    2014-01-01

    The ability to accurately and effectively predict the interaction between proteins and small drug-like compounds has long intrigued researchers for pedagogic, humanitarian and economic reasons. Protein docking methods (AutoDock, GOLD, DOCK, FlexX and Glide to name a few) rank a large number of possible conformations of protein-ligand complexes using fast algorithms. Previously, it has been shown that structural congruence leading to the same enzymatic function necessitates the congruence of electrostatic properties (CLASP). The current work presents a methodology for docking a ligand into a target protein, provided that there is at least one known holoenzyme with ligand bound - DOCLASP (Docking using CLASP). The contact points of the ligand in the holoenzyme defines a motif, which is used to query the target enzyme using CLASP. If there are significant matches, the holoenzyme and the target protein are superimposed based on congruent atoms. The same linear and rotational transformations are also applied to the ligand, thus creating a unified coordinate framework having the holoenzyme, the ligand and the target enzyme. In the current work, the dipeptidyl peptidase-IV inhibitor vildagliptin was docked to the PI-PLC structure complexed with myo-inositol using DOCLASP. Also, corroboration of the docking of phenylthiourea to the modelled structure of polyphenol oxidase (JrPPO1) from walnut is provided based on the subsequently solved structure of JrPPO1 (PDBid:5CE9). Analysis of the binding of the antitrypanosomial drug suramin to nine non-homologous proteins in the PDB database shows a diverse set of binding motifs, and multiple binding sites in the phospholipase A2-likeproteins from the Bothrops genus of pitvipers. The conformational changes in the suramin molecule on binding highlights the challenges in docking flexible ligands into an already 'plastic' binding site. Thus, DOCLASP presents a method for 'soft docking' ligands to proteins with low computational

  11. Molecular docking of viscosine as a new lipoxygenase inhibitor isolated from Dodonaea viscosa

    Directory of Open Access Journals (Sweden)

    Amir Zada Khan

    2013-03-01

    Full Text Available Viscosine was isolated from Dodonaea viscosa, which showed significant lipoxygenase inhibitory activity (IC50: value 39 ± 0.17. Molecular docking simulations were conducted to explore molecular binding mode, and to help elucidate molecular mechanism behind its significant inhibitory activity. Molecular interactions of viscosine with catalytic triad (His523, His518, Ile875 inside active site of lipoxygenase via hydrogen bonding, seems to be the major factor involved in its significant lipoxygenase inhibitory activity.

  12. Seismic vulnerability assessment of an Italian historical masonry dry dock

    OpenAIRE

    Marco Zucca; Pietro Giuseppe Crespi; Nicola Longarini

    2017-01-01

    The paper presents the seismic vulnerability analysis of the military dry dock built in 1861 inside the Messina’s harbor. The study appears very important not only for the relevance of the dry dock itself, but also for its social, military and symbolic role. As a first step, the historical documentation about the dry dock delivered by the Military Technical Office, in charge of its maintenance, was thoroughly examined. This activity was fundamental to understand the construction methods, the ...

  13. Linear Actuator System for the NASA Docking System

    Science.gov (United States)

    Dick, Brandon N.; Oesch, Christopher; Rupp, Timothy W.

    2017-01-01

    The Linear Actuator System (LAS) is a major sub-system within the NASA Docking System (NDS). The NDS Block 1 will be used on the Boeing Crew Space Transportation (CST-100) system to achieve docking with the International Space Station. Critical functions in the Soft Capture aspect of docking are performed by the LAS. This paper describes the general function of the LAS, the system's key requirements and technical challenges, and the development and qualification approach for the system.

  14. GREEN: A program package for docking studies in rational drug design

    Science.gov (United States)

    Tomioka, Nobuo; Itai, Akiko

    1994-08-01

    A program package, GREEN, has been developed that enables docking studies between ligand molecules and a protein molecule. Based on the structure of the protein molecule, the physical and chemical environment of the ligand-binding site is expressed as three-dimensional grid-point data. The grid-point data are used for the real-time evaluation of the protein-ligand interaction energy, as well as for the graphical representation of the binding-site environment. The interactive docking operation is facilitated by various built-in functions, such as energy minimization, energy contribution analysis and logging of the manipulation trajectory. Interactive modeling functions are incorporated for designing new ligand molecules while considering the binding-site environment and the protein-ligand interaction. As an example of the application of GREEN, a docking study is presented on the complex between trypsin and a synthetic trypsin inhibitor. The program package will be useful for rational drug design, based on the 3D structure of the target protein.

  15. Assessment of Spatial Navigation and Docking Performance During Simulated Rover Tasks

    Science.gov (United States)

    Wood, S. J.; Dean, S. L.; De Dios, Y. E.; Moore, S. T.

    2010-01-01

    INTRODUCTION: Following long-duration exploration transits, pressurized rovers will enhance surface mobility to explore multiple sites across Mars and other planetary bodies. Multiple rovers with docking capabilities are envisioned to expand the range of exploration. However, adaptive changes in sensorimotor and cognitive function may impair the crew s ability to safely navigate and perform docking tasks shortly after transition to the new gravitoinertial environment. The primary goal of this investigation is to quantify post-flight decrements in spatial navigation and docking performance during a rover simulation. METHODS: Eight crewmembers returning from the International Space Station will be tested on a motion simulator during four pre-flight and three post-flight sessions over the first 8 days following landing. The rover simulation consists of a serial presentation of discrete tasks to be completed within a scheduled 10 min block. The tasks are based on navigating around a Martian outpost spread over a 970 sq m terrain. Each task is subdivided into three components to be performed as quickly and accurately as possible: (1) Perspective taking: Subjects use a joystick to indicate direction of target after presentation of a map detailing current orientation and location of the rover with the task to be performed. (2) Navigation: Subjects drive the rover to the desired location while avoiding obstacles. (3) Docking: Fine positioning of the rover is required to dock with another object or align a camera view. Overall operator proficiency will be based on how many tasks the crewmember can complete during the 10 min time block. EXPECTED RESULTS: Functionally relevant testing early post-flight will develop evidence regarding the limitations to early surface operations and what countermeasures are needed. This approach can be easily adapted to a wide variety of simulated vehicle designs to provide sensorimotor assessments for other operational and civilian populations.

  16. Effects of tail docking and docking length on neuroanatomical changes in healed tail tips of pigs

    DEFF Research Database (Denmark)

    Herskin, M S; Thodberg, K; Jensen, Henrik Elvang

    2015-01-01

    % (n=19); or leaving 25% (n=11) of the tail length on the pigs. The piglets were docked between day 2 and 4 after birth using a gas-heated apparatus, and were kept under conventional conditions until slaughter at 22 weeks of age, where tails were removed and examined macroscopically and histologically...

  17. Hemichrome formation during hemoglobin Zurich denaturation

    International Nuclear Information System (INIS)

    Zago, M.A.; Costa, F.F.; Botura, C.; Baffa, O.

    1988-01-01

    Electron paramagnetic resonance (EPR)spectrum of hemoglobin Zurich, after oxidation, storage and heating, showed several absorption derives in the high field region (g ≅ 2) which are indicative of hemichrome formation. Characteristic visible spectra of hemichromes were observed for oxidized Hb Zurich and for its spontaneous precipitate. The proportional increase of EPR signals at g ≅ 2 and decrease at g = 6.37, the constant ratio of absorbance at 540 nm to 280 nm during heating, and the similarity of this ratio for spontaneously precipitated HbA and for Hb Zurich indicate that heme is not lost during the first steps of Hb Zurich denaturation. (author) [pt

  18. Multilevel Parallelization of AutoDock 4.2

    Directory of Open Access Journals (Sweden)

    Norgan Andrew P

    2011-04-01

    Full Text Available Abstract Background Virtual (computational screening is an increasingly important tool for drug discovery. AutoDock is a popular open-source application for performing molecular docking, the prediction of ligand-receptor interactions. AutoDock is a serial application, though several previous efforts have parallelized various aspects of the program. In this paper, we report on a multi-level parallelization of AutoDock 4.2 (mpAD4. Results Using MPI and OpenMP, AutoDock 4.2 was parallelized for use on MPI-enabled systems and to multithread the execution of individual docking jobs. In addition, code was implemented to reduce input/output (I/O traffic by reusing grid maps at each node from docking to docking. Performance of mpAD4 was examined on two multiprocessor computers. Conclusions Using MPI with OpenMP multithreading, mpAD4 scales with near linearity on the multiprocessor systems tested. In situations where I/O is limiting, reuse of grid maps reduces both system I/O and overall screening time. Multithreading of AutoDock's Lamarkian Genetic Algorithm with OpenMP increases the speed of execution of individual docking jobs, and when combined with MPI parallelization can significantly reduce the execution time of virtual screens. This work is significant in that mpAD4 speeds the execution of certain molecular docking workloads and allows the user to optimize the degree of system-level (MPI and node-level (OpenMP parallelization to best fit both workloads and computational resources.

  19. Multilevel Parallelization of AutoDock 4.2.

    Science.gov (United States)

    Norgan, Andrew P; Coffman, Paul K; Kocher, Jean-Pierre A; Katzmann, David J; Sosa, Carlos P

    2011-04-28

    Virtual (computational) screening is an increasingly important tool for drug discovery. AutoDock is a popular open-source application for performing molecular docking, the prediction of ligand-receptor interactions. AutoDock is a serial application, though several previous efforts have parallelized various aspects of the program. In this paper, we report on a multi-level parallelization of AutoDock 4.2 (mpAD4). Using MPI and OpenMP, AutoDock 4.2 was parallelized for use on MPI-enabled systems and to multithread the execution of individual docking jobs. In addition, code was implemented to reduce input/output (I/O) traffic by reusing grid maps at each node from docking to docking. Performance of mpAD4 was examined on two multiprocessor computers. Using MPI with OpenMP multithreading, mpAD4 scales with near linearity on the multiprocessor systems tested. In situations where I/O is limiting, reuse of grid maps reduces both system I/O and overall screening time. Multithreading of AutoDock's Lamarkian Genetic Algorithm with OpenMP increases the speed of execution of individual docking jobs, and when combined with MPI parallelization can significantly reduce the execution time of virtual screens. This work is significant in that mpAD4 speeds the execution of certain molecular docking workloads and allows the user to optimize the degree of system-level (MPI) and node-level (OpenMP) parallelization to best fit both workloads and computational resources.

  20. Relationship of Baseline Hemoglobin Level with Serum Ferritin, Postphlebotomy Hemoglobin Changes, and Phlebotomy Requirements among HFE C282Y Homozygotes

    Directory of Open Access Journals (Sweden)

    Seyed Ali Mousavi

    2015-01-01

    Full Text Available Objectives. We aimed to examine whether baseline hemoglobin levels in C282Y-homozygous patients are related to the degree of serum ferritin (SF elevation and whether patients with different baseline hemoglobin have different phlebotomy requirements. Methods. A total of 196 patients (124 males and 72 females who had undergone therapeutic phlebotomy and had SF and both pre- and posttreatment hemoglobin values were included in the study. Results. Bivariate correlation analysis suggested that baseline SF explains approximately 6 to 7% of the variation in baseline hemoglobin. The results also showed that males who had higher (≥150 g/L baseline hemoglobin levels had a significantly greater reduction in their posttreatment hemoglobin despite requiring fewer phlebotomies to achieve iron depletion than those who had lower (<150 g/L baseline hemoglobin, regardless of whether baseline SF was below or above 1000 µg/L. There were no significant differences between hemoglobin subgroups regarding baseline and treatment characteristics, except for transferrin saturation between male subgroups with SF above 1000 µg/L. Similar differences were observed when females with higher (≥138 g/L baseline hemoglobin were compared with those with lower (<138 g/L baseline hemoglobin. Conclusion. Dividing C282Y-homozygous patients into just two subgroups according to the degree of baseline SF elevation may obscure important subgroup variations.

  1. Relationship of Baseline Hemoglobin Level with Serum Ferritin, Postphlebotomy Hemoglobin Changes, and Phlebotomy Requirements among HFE C282Y Homozygotes

    Science.gov (United States)

    Mousavi, Seyed Ali; Mahmood, Faiza; Aandahl, Astrid; Knutsen, Teresa Risopatron; Llohn, Abid Hussain

    2015-01-01

    Objectives. We aimed to examine whether baseline hemoglobin levels in C282Y-homozygous patients are related to the degree of serum ferritin (SF) elevation and whether patients with different baseline hemoglobin have different phlebotomy requirements. Methods. A total of 196 patients (124 males and 72 females) who had undergone therapeutic phlebotomy and had SF and both pre- and posttreatment hemoglobin values were included in the study. Results. Bivariate correlation analysis suggested that baseline SF explains approximately 6 to 7% of the variation in baseline hemoglobin. The results also showed that males who had higher (≥150 g/L) baseline hemoglobin levels had a significantly greater reduction in their posttreatment hemoglobin despite requiring fewer phlebotomies to achieve iron depletion than those who had lower (baseline hemoglobin, regardless of whether baseline SF was below or above 1000 µg/L. There were no significant differences between hemoglobin subgroups regarding baseline and treatment characteristics, except for transferrin saturation between male subgroups with SF above 1000 µg/L. Similar differences were observed when females with higher (≥138 g/L) baseline hemoglobin were compared with those with lower (baseline hemoglobin. Conclusion. Dividing C282Y-homozygous patients into just two subgroups according to the degree of baseline SF elevation may obscure important subgroup variations. PMID:26380265

  2. Assessment of Microcirculatory Hemoglobin Levels in Normal and Diabetic Subjects using Diffuse Reflectance Spectroscopy in the Visible Region — a Pilot Study

    Science.gov (United States)

    Sujatha, N.; Anand, B. S. Suresh; Nivetha, K. Bala; Narayanamurthy, V. B.; Seshadri, V.; Poddar, R.

    2015-07-01

    Light-based diagnostic techniques provide a minimally invasive way for selective biomarker estimation when tissues transform from a normal to a malignant state. Spectroscopic techniques based on diffuse reflectance characterize the changes in tissue hemoglobin/oxygenation levels during the tissue transformation process. Recent clinical investigations have shown that changes in tissue oxygenation and microcirculation are observed in diabetic subjects in the initial and progressive stages. In this pilot study, we discuss the potential of diffuse reflectance spectroscopy (DRS) in the visible (Vis) range to differentiate the skin microcirculatory hemoglobin levels between normal and advanced diabetic subjects with and without neuropathy. Average concentration of hemoglobin as well as hemoglobin oxygen saturation within the probed tissue volume is estimated for a total of four different sites in the foot sole. The results indicate a statistically significant decrease in average total hemoglobin and increase in hemoglobin oxygen saturation levels for diabetic foot compared with a normal foot. The present study demonstrates the ability of reflectance spectroscopy in the Vis range to determine and differentiate the changes in tissue hemoglobin and hemoglobin oxygen saturation levels in normal and diabetic subjects.

  3. How well do the substrates KISS the enzyme? Molecular docking program selection for feruloyl esterases

    DEFF Research Database (Denmark)

    Udatha, D. B. R. K. Gupta; Sugaya, Nobuyoshi; Olsson, Lisbeth

    2012-01-01

    Molecular docking is the most commonly used technique in the modern drug discovery process where computational approaches involving docking algorithms are used to dock small molecules into macromolecular target structures. Over the recent years several evaluation studies have been reported...

  4. Porphyromonas endodontalis binds, reduces and grows on human hemoglobin.

    Science.gov (United States)

    Zerr, M; Drake, D; Johnson, W; Cox, C D

    2001-08-01

    Porphyromonas endodontalis is a black-pigmented, obligate anaerobic rod-shaped bacterium implicated as playing a major role in endodontic infections. We have previously shown that P. endodontalis requires the porphyrin nucleus, preferably supplied as hemoglobin, as a growth supplement. The bacteria also actively transport free iron, although this activity does not support growth in the absence of a porphyrin source. The purpose of this study was to further investigate the binding and subsequent utilization of human hemoglobin by P. endodontalis. P. endodontalis binds hemoglobin and reduces the Fe(III) porphyrin, resulting in a steady accumulation of ferrous hemoglobin. Reduction of methemoglobin was similar to the extracellular reduction of nitrobluetetrazolium in the presence of oxidizable substrate. Turbidimetric and viable cell determinations showed that P. endodontalis grew when supplied only hemoglobin. Therefore, we conclude that hemoglobin appears to serve as a sole carbon and nitrogen source, and that these bacteria reduce extracellular compounds at the expense of oxidized substrates.

  5. Characterization of hemoglobin-benzo[a]pyrene adducts

    International Nuclear Information System (INIS)

    Haugen, D.A.; Myers, S.R.

    1987-01-01

    Cultures of Syrian hamster embryo (SHE) cells were supplemented with human Hb (0.2 mM heme) and [ 3 H]BP (1 μM). After a 24-h incubation, the medium was removed and subjected to cation-exchange liquid chromatography (CM-Sepharose) to resolve hemoglobins from serum proteins in the medium. The BP-treated Hb was subjected to analysis in each of three column chromatographic systems established for isolation and characterization of human hemoglobin and its genetic and post-translationally modified variants. Results demonstrate that hemoglobin-carcinogen adducts can be resolved from native hemoglobin by established conventional and high-performance liquid chromatographic procedures, suggesting the basis for development of general approaches for isolating and characterizing hemoglobin-carcinogen adducts. The results also suggest the basis for a model system in which adducts between carcinogens and human hemoglobin are formed in cultures of mammalian cells or tissues

  6. Studies on radiation induced changes in bovine hemoglobin type A

    International Nuclear Information System (INIS)

    Wdzieczak, J.; Duda, W.; Leyko, W.

    1978-01-01

    In this paper the structural and functional changes of gamma irradiated bovine hemoglobin are presented. Aqueous solutions/1%/of HbO 2 were irradiated in air with doses ranging from 1 to 4 Mrad. Isoelectric focusing indicated change of the charge of irradiated hemoglobin. The isoelectric point of hemoglobin was displaced towards more acid values with increasing doses, up from 1 Mrad. Fingerprint analysis and peptide column chromatography of irradiated hemoglobin demonstrated disturbances increasing with the dose. These changes were confirmed by amino acid analysis which showed that Cys, Met, Trp, His, Pro and Tyr residues were destroyed or modified following irradiation. At doses exceeding 1 Mrad the irradiated solutions of hemoglobin showed a decrease of heme-heme interaction and an increase of affinity for oxygen. Differences observed in oxygen-dissociation curves seem to be correlated with the radiation induced destruction of amino acid residues which are responsible for the functional properties of hemoglobin. (auth.)

  7. Docking studies of antidepressants against single crystal structure of tryptophan 2, 3-dioxygenase using Molegro Virtual Docker software.

    Science.gov (United States)

    Dawood, Shazia; Zarina, Shamshad; Bano, Samina

    2014-09-01

    Tryptophan 2, 3-dioxygenase (TDO) a heme containing enzyme found in mammalian liver is responsible for tryptophan (Trp) catabolism. Trp is an essential amino acid that is degraded in to N-formylkynurenine by the action of TDO. The protein ligand interaction plays a significant role in structural based drug designing. The current study illustrates the binding of established antidepressants (ADs) against TDO enzyme using in-silico docking studies. For this purpose, Fluoxetine, Paroxetine, Sertraline, Fluvoxamine, Seproxetine, Citalopram, Moclobamide, Hyperforin and Amoxepine were selected. In-silico docking studies were carried out using Molegro Virtual Docker (MVD) software. Docking results show that all ADs fit well in the active site of TDO moreover Hyperforin and Paroxetine exhibited high docking scores of -152.484k cal/mol and -139.706k cal/mol, respectively. It is concluded that Hyperforin and Paroxetine are possible lead molecules because of their high docking scores as compared to other ADs examined. Therefore, these two ADs stand as potent inhibitors of TDO enzyme.

  8. The tyrosine B10 hydroxyl is crucial for oxygen avidity of Ascaris hemoglobin.

    Science.gov (United States)

    Kloek, A P; Yang, J; Mathews, F S; Frieden, C; Goldberg, D E

    1994-01-28

    The parasitic nematode Ascaris suum has a gene encoding a two-domain hemoglobin with remarkable oxygen avidity. The strong interaction with oxygen is a consequence of a particularly slow oxygen off-rate. The single polypeptide chain consists of two domains, each of which can be expressed separately in Escherichia coli as a globin-like protein exhibiting oxygen binding characteristics comparable with the native molecule. Site-directed mutagenesis was performed on the gene segment encoding domain one. The E7 position, involved in forming a hydrogen bond with the liganded oxygen in vertebrate globins, is a glutamine in both Ascaris domains. Conversion of this residue to leucine or alanine produced a hemoglobin variant with an oxygen off-rate 5- or 60-fold faster than that of unaltered domain one. Replacement of the tyrosine B10 with either phenylalanine or leucine (as found in vertebrate globins) yielded hemoglobin mutants with oxygen off-rates 280- or 570-fold faster, approaching rates found with vertebrate myoglobins. The data suggest that the distal glutamine hydrogen bonds with the liganded oxygen and that the tyrosine B10 hydroxyl contributes an additional hydrogen bond that appears substantially responsible for the extreme oxygen avidity of Ascaris hemoglobin.

  9. Covalent docking of selected boron-based serine beta-lactamase inhibitors

    Science.gov (United States)

    Sgrignani, Jacopo; Novati, Beatrice; Colombo, Giorgio; Grazioso, Giovanni

    2015-05-01

    AmpC β-lactamase is a hydrolytic enzyme conferring resistance to β-lactam antibiotics in multiple Gram-negative bacteria. Therefore, identification of non-β-lactam compounds able to inhibit the enzyme is crucial for the development of novel antibacterial therapies. In general, AmpC inhibitors have to engage the highly solvent-exposed catalytic site of the enzyme. Therefore, understanding the implications of ligand-protein induced-fit and water-mediated interactions behind the inhibitor-enzyme recognition process is fundamental for undertaking structure-based drug design process. Here, we focus on boronic acids, a promising class of beta-lactamase covalent inhibitors. First, we optimized a docking protocol able to reproduce the experimentally determined binding mode of AmpC inhibitors bearing a boronic group. This goal was pursued (1) performing rigid and flexible docking calculations aiming to establish the role of the side chain conformations; and (2) investigating the role of specific water molecules in shaping the enzyme active site and mediating ligand protein interactions. Our calculations showed that some water molecules, conserved in the majority of the considered X-ray structures, are needed to correctly predict the binding pose of known covalent AmpC inhibitors. On this basis, we formalized our findings in a docking and scoring protocol that could be useful for the structure-based design of new boronic acid AmpC inhibitors.

  10. Binding of ethyl pyruvate to bovine serum albumin: Calorimetric, spectroscopic and molecular docking studies

    Energy Technology Data Exchange (ETDEWEB)

    Pathak, Mallika [Department of Chemistry, Miranda House, University of Delhi, Delhi 11007 (India); Mishra, Rashmi; Agarwala, Paban K. [Department of Radiation Genetics and Epigenetics, Division of Radioprotective Drug Development Research, Institute of Nuclear Medicine and Allied Sciences, Delhi 110054 (India); Ojha, Himanshu, E-mail: himanshu.drdo@gmail.com [Department of Radiation Genetics and Epigenetics, Division of Radioprotective Drug Development Research, Institute of Nuclear Medicine and Allied Sciences, Delhi 110054 (India); Singh, Bhawna [Department of Radiation Genetics and Epigenetics, Division of Radioprotective Drug Development Research, Institute of Nuclear Medicine and Allied Sciences, Delhi 110054 (India); Singh, Anju; Kukreti, Shrikant [Nucleic Acid Research Laboratory, Department of Chemistry, University of Delhi, Delhi 11007 (India)

    2016-06-10

    Highlights: • ITC study showed binding of ethyl pyruvate with BSA with high binding affinity. • Ethyl pyruvate binding caused conformation alteration of BSA. • Fluorescence quenching mechanism is static in nature. • Electrostatic, hydrogen bonding and hydrophobic forces involved in binding. • Docking confirmed role of electrostatic, hydrogen bonding and hydrophobic forces. - Abstract: Various in vitro and in vivo studies have shown the anti-inflammatory and anticancer potential role of ethyl pyruvate. Bio-distribution of drugs is significantly influenced by the drug-serum protein binding. Therefore, the binding mechanism of the ethyl pyruvate with bovine serum albumin was investigated using UV–vis absorption, fluorescence, circular dichroism, isothermal titration calorimetry and molecular docking techniques. Absorption and fluorescence quenching studies indicated the binding of ethyl pyruvate with protein. Circular dichroism spectra of bovine serum albumin confirmed significant change in the conformation of protein upon binding. Thermodynamic data confirmed that ethyl pyruvate binds to bovine serum albumin at the two different sites with high affinity. Binding of ethyl pyruvate to bovine serum albumin involves hydrogen bonding, van der Waal and hydrophobic interactions. Further, docking studies indicated that ethyl pyruvate could bind significantly at the three binding sites. The results will definitely contribute to the development of ethyl pyruvate as drug.

  11. A review of variant hemoglobins interfering with hemoglobin A1c measurement.

    Science.gov (United States)

    Little, Randie R; Roberts, William L

    2009-05-01

    Hemoglobin A1c (HbA1c) is used routinely to monitor long-term glycemic control in people with diabetes mellitus, as HbA1c is related directly to risks for diabetic complications. The accuracy of HbA1c methods can be affected adversely by the presence of hemoglobin (Hb) variants or elevated levels of fetal hemoglobin (HbF). The effect of each variant or elevated HbF must be examined with each specific method. The most common Hb variants worldwide are HbS, HbE, HbC, and HbD. All of these Hb variants have single amino acid substitutions in the Hb beta chain. HbF is the major hemoglobin during intrauterine life; by the end of the first year, HbF falls to values close to adult levels of approximately 1%. However, elevated HbF levels can occur in certain pathologic conditions or with hereditary persistence of fetal hemoglobin. In a series of publications over the past several years, the effects of these four most common Hb variants and elevated HbF have been described. There are clinically significant interferences with some methods for each of these variants. A summary is given showing which methods are affected by the presence of the heterozygous variants S, E, C, and D and elevated HbF. Methods are divided by type (immunoassay, ion-exchange high-performance liquid chromatography, boronate affinity, other) with an indication of whether the result is artificially increased or decreased by the presence of a Hb variant. Laboratorians should be aware of the limitations of their method with respect to these interferences. 2009 Diabetes Technology Society.

  12. Molecular Dynamics and Docking of Biphenyl: A Potential ...

    African Journals Online (AJOL)

    Results: Molecular docking by FireDock web server showed that biPhe-43 and Trp-43-mutated CD4 inhibited the binding of ... In a 5ns MD simulation, biPhe-43 and Trp-43 mutated CD4 .... 'unbound' MD on UMHPC Linux Cluster SGIAltix.

  13. Interaction of Chelerythrine with Keyhole Limpet Hemocyanin: a Fluorescence Spectroscopy and Molecular Docking Study

    Science.gov (United States)

    Zhong, M.; Long, R. Q.; Wang, Y. H.; Chen, C. L.

    2018-05-01

    The quenching mechanism between chelerythrine (CHE) and keyhole limpet hemocyanin (KLH) was investigated using fluorescence spectroscopy and molecular docking. The experiments were conducted at three different temperatures (293, 298, and 303 K). The results revealed that the intrinsic fluorescence of KLH was strongly quenched by CHE through a static quenching mechanism. The thermodynamic parameters (ΔG, ΔH, and ΔS) of the interaction were calculated, indicating that the interaction between CHE and KLH was spontaneous and that van der Waals forces and hydrogen bond formation played major roles in the binding process. The intrinsic fluorescence of the tyrosine and tryptophan residues in KLH was studied by synchronous fluorescence, which suggested that CHE changed the conformation of KLH. Finally, molecular docking was used to obtain detailed information on the binding sites and binding affinities between CHE and KLH.

  14. Novel α, β-Unsaturated Sophoridinic Derivatives: Design, Synthesis, Molecular Docking and Anti-Cancer Activities

    Directory of Open Access Journals (Sweden)

    Yiming Xu

    2017-11-01

    Full Text Available Using sophoridine 1 and chalcone 3 as the lead compounds, a series of novel α, β-unsaturated sophoridinic derivatives were designed, synthesized, and evaluated for their in vitro cytotoxicity. Structure-activity relationship (SAR analysis indicated that introduction of α, β-unsaturated ketone moiety and heterocyclic group might significantly enhance anticancer activity. Among the compounds, 2f and 2m exhibited potential effects against HepG-2 and CNE-2 human cancer cell lines. Furthermore, molecular docking studies were performed to understand possible docking sites of the molecules on the target proteins and the mode of binding. This work provides a theoretical basis for structural optimizations and exploring anticancer pathways of this kind of compound.

  15. Interaction of anthraquinone dyes with lysozyme: Evidences from spectroscopic and docking studies

    Energy Technology Data Exchange (ETDEWEB)

    Paramaguru, G.; Kathiravan, A.; Selvaraj, S.; Venuvanalingam, P. [School of Chemistry, Bharathidasan University, Tiruchirappalli 620024, Tamil Nadu (India); Renganathan, R., E-mail: rrengas@gmail.com [School of Chemistry, Bharathidasan University, Tiruchirappalli 620024, Tamil Nadu (India)

    2010-03-15

    The interaction between lysozyme and anthraquinone dyes such as Alizarin Red S, Acid blue 129 and Uniblue was studied using steady state, time resolved fluorescence measurements and docking studies. Addition of anthraquinone dyes effectively quenched the intrinsic fluorescence of lysozyme. Fluorescence quenching of lysozyme by dyes has revealed the formation of complex. The number of binding sites (n) and binding constant (K) for all the three dyes was calculated by relevant fluorescence quenching data. Based on Foerster's non-radiative energy transfer theory, distance (r{sub 0}) between the donor (lysozyme) and acceptor (dyes) as well as the critical energy transfer distance (R{sub 0}) has also been calculated. The interaction between dyes and lysozyme occurs through static quenching mechanism as confirmed by time resolved spectroscopy. The conformational change of lysozyme has been analyzed using synchronous fluorescence measurement. Finally, docking studies revealed that specific interactions were observed with the residue of Trp 62.

  16. Interaction of anthraquinone dyes with lysozyme: Evidences from spectroscopic and docking studies

    International Nuclear Information System (INIS)

    Paramaguru, G.; Kathiravan, A.; Selvaraj, S.; Venuvanalingam, P.; Renganathan, R.

    2010-01-01

    The interaction between lysozyme and anthraquinone dyes such as Alizarin Red S, Acid blue 129 and Uniblue was studied using steady state, time resolved fluorescence measurements and docking studies. Addition of anthraquinone dyes effectively quenched the intrinsic fluorescence of lysozyme. Fluorescence quenching of lysozyme by dyes has revealed the formation of complex. The number of binding sites (n) and binding constant (K) for all the three dyes was calculated by relevant fluorescence quenching data. Based on Foerster's non-radiative energy transfer theory, distance (r 0 ) between the donor (lysozyme) and acceptor (dyes) as well as the critical energy transfer distance (R 0 ) has also been calculated. The interaction between dyes and lysozyme occurs through static quenching mechanism as confirmed by time resolved spectroscopy. The conformational change of lysozyme has been analyzed using synchronous fluorescence measurement. Finally, docking studies revealed that specific interactions were observed with the residue of Trp 62.

  17. Synaptotagmin interaction with SNAP-25 governs vesicle docking, priming, and fusion triggering

    DEFF Research Database (Denmark)

    Mohrmann, Ralf; de Wit, Heidi; Connell, Emma

    2013-01-01

    ramifications of proposed SNAP-25 × synaptotagmin-1 interaction in mouse chromaffin cells. We demonstrate that the postulated central binding domain surrounding layer zero covers both SNARE motifs of SNAP-25 and is essential for vesicle docking, priming, and fast fusion-triggering. Mutation of this site caused...... but is required for the full size of the readily releasable pool. Intriguingly, we also found that mutation of synaptotagmin-1 interaction sites led to more pronounced phenotypes in the context of the adult neuronal isoform SNAP-25B than in the embryonic isoform SNAP-25A. Further experiments demonstrated...

  18. Hot atom labeling of myoglobin and hemoglobin and biophysical studies of oxygen and CO binding to carp hemoglobin

    International Nuclear Information System (INIS)

    Astatke, M.

    1992-01-01

    Human Hb, the monomeric Hb of Glycera dibranchiata and horse Mb were modified by replacement of the protoheme with 2,4-dibromodeuteroheme. Following neutron capture by 79 Br and 81 Br, the locations of radioactive Br were determined. Although human Hb had approximately four times the mass and volume of the other proteins, about 9% of the activated Br was inserted into each of the three globins. These results suggest that the insertion is short-range (within 15 angstrom) and that this method could be used to label target sites in various proteins and other biological structures. Carp Hb's containing proto-, meso-, deutero- and dibromoheme were prepared. Kinetic and thermodynamic parameters for oxygen and CO binding were determined at Ph 6 (+IHP) (T-state, low-affinity protein) and Ph 9 (R-state, high-affinity protein). Parameters for the binding of oxygen and CO were related to the properties of the four hemes to estimate the inductive and steric factors in the ligation process. The results suggest that the steric factors are more important for the T-state than for the R-state. The T-state carp Hbs were very readily oxidized. Two new procedures were developed for the rapid determination of oxygen equilibrium isotherms for the T-state carp Hbs. The kinetic and thermodynamic parameters for ligation of oxygen and CO with the isolated carp α-chains were determined. Carp α-chains are the only hemoglobin chains isolated to date that can be classified as T-state. The secondary thermodynamic parameter (δH degrees) was found to be essential for classifying hemoglobins as T- or R-state

  19. Characterization of sulfur mustard induced structural modifications in human hemoglobin by liquid chromatography-tandem mass spectrometry

    NARCIS (Netherlands)

    Noort, D.; Verheij, E.R.; Hulst, A.G.; Jong, L.P.A. de; Benschop, H.P.

    1996-01-01

    In this paper we describe the use of tandem mass spectrometry to identify modified sites in human hemoglobin after in vitro exposure to bis(2- chloroethyl) sulfide (sulfur mustard). Globin isolated from human whole blood which had been exposed to sulfur mustard was degraded with trypsin, and the

  20. Oxygen binding to nitric oxide marked hemoglobin

    International Nuclear Information System (INIS)

    Louro, S.R.W.; Ribeiro, P.C.; Bemski, G.

    1979-04-01

    Electron spin resonance spectra of organic phosphate free human hemoglobin marked with nitric oxide at the sixth coordination position of one of the four hemes allow to observe the transition from the tense (T) to the relaxed (R) conformation, as a function of parcial oxygen pressure. The spectra are composites of contributions from α sub(T), α sub(R) and β chains spectra, showing the presence of only two conformations: T and R. In the absence of organic phosphates NO binds to α and β chains with the same probability, but in the presence of phosphates NO combines preferentially with α chains. The dissociation of NO proceeds at least an order of magnitude faster in T than in R configuration. (author) [pt

  1. Coupling of tertiary and quaternary changes in human hemoglobin: A 1D and 2D NMR study of hemoglobin Saint Mande (βN102Y)

    International Nuclear Information System (INIS)

    Craescu, C.T.; Blouquit, Y.; Mispelter, J.

    1990-01-01

    Hemoglobin Saint Mande (βN102Y) is a low-affinity mutant with the substitution site situated in the quaternary-sensitive α 1 β 2 interface. In adult hemoglobin the Asn102β contributes to the stability of the liganded (R) state, forming a hydrogen bond with Asp94α. The quaternary and tertiary perturbations subsequent to the Tyr for Asn substitution in monocarboxylated hemoglobin Saint Mande have been investigated by one-and two-dimensional nuclear magnetic resonance (NMR) spectroscopy. Analysis of the one-dinensional NMR spectra of the liganded and unliganded samples in 1 H 2 O provides evidence that both R and T quaternary structures of Hb Saint Mande are different from the corresponding ones in HbA. In the monocarboxylated form of the mutant hemoglobin, at acid pH, the authors have observed the disappearance of an R-type hydrogen bond and the appearance of a new one whose proton resonates like a deoxy T marker. Using two-dimensional NMR methods and on the basis of previous results on the monocarboxylated HbA, they have obtained a significant number of resonance assignments in the spectra of monocarboxylated Hb Saint Mande at pH 5.6 in the presence or absence of a strong allosteric effector, inositol hexaphosphate. This enabled us to characterize the tertiary conformational changes triggered by the quaternary-state modification. The observed structural variations are confined within the heme pocket regions but concern both the α and β subunits

  2. Hemoglobin mRNA Changes in the Frontal Cortex of Patients with Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Silvia Vanni

    2018-01-01

    Full Text Available Background: Hemoglobin is the major protein found in erythrocytes, where it acts as an oxygen carrier molecule. In recent years, its expression has been reported also in neurons and glial cells, although its role in brain tissue remains still unknown. Altered hemoglobin expression has been associated with various neurodegenerative disorders. Here, we investigated hemoglobin mRNA levels in brains of patients affected by variant, iatrogenic, and sporadic forms of Creutzfeldt-Jakob disease (vCJD, iCJD, sCJD, respectively and in different genetic forms of prion diseases (gPrD in comparison to Alzheimer's disease (AD subjects and age-matched controls.Methods: Total RNA was obtained from the frontal cortex of vCJD (n = 20, iCJD (n = 11, sCJD (n = 23, gPrD (n = 30, and AD (n = 14 patients and age-matched controls (n = 30. RT-qPCR was performed for hemoglobin transcripts HBB and HBA1/2 using four reference genes for normalization. In addition, expression analysis of the specific erythrocyte marker ALAS2 was performed in order to account for blood contamination of the tissue samples. Hba1/2 and Hbb protein expression was then investigated with immunofluorescence and confocal microscope analysis.Results: We observed a significant up-regulation of HBA1/2 in vCJD brains together with a significant down-regulation of HBB in iCJD. In addition, while in sporadic and genetic forms of prion disease hemoglobin transcripts did not shown any alterations, both chains display a strong down-regulation in AD brains. These results were confirmed also at a protein level.Conclusions: These data indicate distinct hemoglobin transcriptional responses depending on the specific alterations occurring in different neurodegenerative diseases. In particular, the initial site of misfolding event (central nervous system vs. peripheral tissue—together with specific molecular and conformational features of the pathological agent of the disease—seem to dictate the peculiar

  3. Hemoglobin mRNA Changes in the Frontal Cortex of Patients with Neurodegenerative Diseases.

    Science.gov (United States)

    Vanni, Silvia; Zattoni, Marco; Moda, Fabio; Giaccone, Giorgio; Tagliavini, Fabrizio; Haïk, Stéphane; Deslys, Jean-Philippe; Zanusso, Gianluigi; Ironside, James W; Carmona, Margarita; Ferrer, Isidre; Kovacs, Gabor G; Legname, Giuseppe

    2018-01-01

    Background: Hemoglobin is the major protein found in erythrocytes, where it acts as an oxygen carrier molecule. In recent years, its expression has been reported also in neurons and glial cells, although its role in brain tissue remains still unknown. Altered hemoglobin expression has been associated with various neurodegenerative disorders. Here, we investigated hemoglobin mRNA levels in brains of patients affected by variant, iatrogenic, and sporadic forms of Creutzfeldt-Jakob disease (vCJD, iCJD, sCJD, respectively) and in different genetic forms of prion diseases (gPrD) in comparison to Alzheimer's disease (AD) subjects and age-matched controls. Methods: Total RNA was obtained from the frontal cortex of vCJD ( n = 20), iCJD ( n = 11), sCJD ( n = 23), gPrD ( n = 30), and AD ( n = 14) patients and age-matched controls ( n = 30). RT-qPCR was performed for hemoglobin transcripts HBB and HBA1/2 using four reference genes for normalization. In addition, expression analysis of the specific erythrocyte marker ALAS2 was performed in order to account for blood contamination of the tissue samples. Hba1/2 and Hbb protein expression was then investigated with immunofluorescence and confocal microscope analysis. Results: We observed a significant up-regulation of HBA1/2 in vCJD brains together with a significant down-regulation of HBB in iCJD. In addition, while in sporadic and genetic forms of prion disease hemoglobin transcripts did not shown any alterations, both chains display a strong down-regulation in AD brains. These results were confirmed also at a protein level. Conclusions: These data indicate distinct hemoglobin transcriptional responses depending on the specific alterations occurring in different neurodegenerative diseases. In particular, the initial site of misfolding event (central nervous system vs. peripheral tissue)-together with specific molecular and conformational features of the pathological agent of the disease-seem to dictate the peculiar hemoglobin

  4. A thermodynamical measure of cooperativity: application to hemoglobin

    International Nuclear Information System (INIS)

    Jacchieri, S.G.; Ferreira, R.C.

    1984-01-01

    A comparative analysis of the heat requirements for dioxygen exchange is made for hemoglobin and myoglobin, the latter taken as the prototype of the vertebrate hemoglobin's ancestor. it is shown that cooperativity manifests itself also in terms of energy utilization. (Author) [pt

  5. Biphasic oxidation of oxy-hemoglobin in bloodstains

    NARCIS (Netherlands)

    Bremmer, Rolf H.; de Bruin, Daniel M.; de Joode, Maarten; Buma, Wybren Jan; van Leeuwen, Ton G.; Aalders, Maurice C. G.

    2011-01-01

    In forensic science, age determination of bloodstains can be crucial in reconstructing crimes. Upon exiting the body, bloodstains transit from bright red to dark brown, which is attributed to oxidation of oxy-hemoglobin (HbO(2)) to met-hemoglobin (met-Hb) and hemichrome (HC). The fractions of

  6. Haptoglobin radioassay based on binding to solid-phase hemoglobin

    International Nuclear Information System (INIS)

    Hooper, D.C.; Reed, R.A.; Peacock, A.C.

    1979-01-01

    A specific and sensitive assay for haptoglobin based on binding to an easily prepred Sepharose-bound hemoglobin reagent is described. The assay is suitable for directly determining radiolabeled amino acid incorporation into haptoglobin in several liver cell systems in vitro and can be adapted to measure unlabeled free haptoglobin in plasma samples regardlss of the presence of the haptoglobin--hemoglobin complex

  7. Biphasic Oxidation of Oxy-Hemoglobin in Bloodstains

    NARCIS (Netherlands)

    Bremmer, R.H.; de Bruin, D.M.; de Joode, M.; Buma, W.J.; van Leeuwen, T.G.; Aalders, M.C.G.

    2011-01-01

    Background In forensic science, age determination of bloodstains can be crucial in reconstructing crimes. Upon exiting the body, bloodstains transit from bright red to dark brown, which is attributed to oxidation of oxy-hemoglobin (HbO2) to met-hemoglobin (met-Hb) and hemichrome (HC). The fractions

  8. 21 CFR 864.7400 - Hemoglobin A2 assay.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Hemoglobin A2 assay. 864.7400 Section 864.7400 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Hematology Kits and Packages § 864.7400 Hemoglobin A2...

  9. 21 CFR 864.7455 - Fetal hemoglobin assay.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Fetal hemoglobin assay. 864.7455 Section 864.7455 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Hematology Kits and Packages § 864.7455 Fetal hemoglobin...

  10. 21 CFR 522.1125 - Hemoglobin glutamer-200 (bovine).

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Hemoglobin glutamer-200 (bovine). 522.1125 Section... (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM NEW ANIMAL DRUGS § 522.1125 Hemoglobin glutamer-200 (bovine). (a) Specifications. Each 125 milliliter bag contains 13...

  11. Conformational changes in hemoglobin triggered by changing the iron charge

    International Nuclear Information System (INIS)

    Croci, S.; Achterhold, K.; Ortalli, I.; Parak, F. G.

    2008-01-01

    In this work the hemoglobin conformational changes induced by changing the iron charge have been studied and compared with Myoglobin. Moessbauer spectroscopy was used to follow the change of the iron conformation. In order to compare the conformational relaxation of hemoglobin and myoglobin, and to study a possible influence of the quaternary structure, an intermediate metastable state of hemoglobin has been created by low temperature X-ray irradiation of methemoglobin. The irradiation reduces the Fe(III) of the heme groups to Fe(II) Low Spin, where the water is still bound on the sixth coordination. Heating cycles performed at temperatures from 140 K to 200 K allow the molecules to overcome an activation energy barrier and to relax into a stable conformation such as deoxy-hemoglobin or carboxy-hemoglobin, if CO is present. Slightly different structures (conformational substates) reveal themselves as a distribution of energy barriers (ΔG). The distribution of the activation energy, for the decay of the Fe(II) Low Spin intermediate, has been fitted with a Gaussian. For comparison, published myoglobin data were re-analysed in the same way. The average energy value at characteristic temperature is very similar in case of myoglobin and hemoglobin. The larger Gaussian energy distribution for myoglobin with respect to hemoglobin shows that more conformational substates are available. This may be caused by a larger area exposed to water. In hemoglobin, part of the surface of the chains is not water accessible due to the quaternary structure.

  12. Dynamic Docking: A Paradigm Shift in Computational Drug Discovery

    Directory of Open Access Journals (Sweden)

    Dario Gioia

    2017-11-01

    Full Text Available Molecular docking is the methodology of choice for studying in silico protein-ligand binding and for prioritizing compounds to discover new lead candidates. Traditional docking simulations suffer from major limitations, mostly related to the static or semi-flexible treatment of ligands and targets. They also neglect solvation and entropic effects, which strongly limits their predictive power. During the last decade, methods based on full atomistic molecular dynamics (MD have emerged as a valid alternative for simulating macromolecular complexes. In principle, compared to traditional docking, MD allows the full exploration of drug-target recognition and binding from both the mechanistic and energetic points of view (dynamic docking. Binding and unbinding kinetic constants can also be determined. While dynamic docking is still too computationally expensive to be routinely used in fast-paced drug discovery programs, the advent of faster computing architectures and advanced simulation methodologies are changing this scenario. It is feasible that dynamic docking will replace static docking approaches in the near future, leading to a major paradigm shift in in silico drug discovery. Against this background, we review the key achievements that have paved the way for this progress.

  13. Radiation - induced changes in the optical properties of hemoglobin molecule

    International Nuclear Information System (INIS)

    Selim, N.S; El-Marakby, S.M.

    2009-01-01

    Adult male albino rats were exposed to different doses of gamma radiation from Cs-137 source. Hemoglobin samples were analyzed 24 hrs after irradiation. The UV-visible spectrum of hemoglobin molecule was measured in the range 200 to 700 nm. The overall spectrum of the hemoglobin molecule showed hypochromicity that increased with dose increase. To investigate the effect of radiation on the hemoglobin molecule, different parameters of the spectrum were calculated: molar absorption coefficient, absorption cross section, transition dipole moment , dipole length, the optical energy gap and activation energy for each characteristic peak. The obtained results revealed that the radiation effect can induce rearrangement of the transition dipole moments and change molecular energy levels of the hemoglobin molecule

  14. INTRINSIC REGULATION OF HEMOGLOBIN EXPRESSION BY VARIABLE SUBUNIT INTERFACE STRENGTHS

    Science.gov (United States)

    Manning, James M.; Popowicz, Anthony M.; Padovan, Julio C.; Chait, Brian T.; Manning, Lois R.

    2012-01-01

    SUMMARY The expression of the six types of human hemoglobin subunits over time is currently considered to be regulated mainly by transcription factors that bind to upstream control regions of the gene (the “extrinsic” component of regulation). Here we describe how subunit pairing and further assembly to tetramers in the liganded state is influenced by the affinity of subunits for one another (the “intrinsic” component of regulation). The adult hemoglobin dimers have the strongest subunit interfaces and the embryonic hemoglobins are the weakest with fetal hemoglobins of intermediate strength, corresponding to the temporal order of their expression. These variable subunit binding strengths and the attenuating effects of acetylation contribute to the differences with which these hemoglobin types form functional O2-binding tetramers consistent with gene switching. PMID:22129306

  15. Molecular docking study of Papaver alkaloids to some alkaloid receptors

    Directory of Open Access Journals (Sweden)

    A. Nofallah

    2017-11-01

    Full Text Available Background and objectives: More than 40 different alkaloids have been obtained from opium the most important of which are morphine, codeine, papaverine, noscapine and tabaine. Opioid alkaloids produce analgesia by affecting areas of the brain that have peptides with pharmacological pseudo-opioid properties. These alkaloids show important effects on some intracellular peptides like mu, delta, and kappa receptors. Therefore, studying the effects of these alkaloids on different receptors is essential. Methods: Molecular docking is a well-known method in exploring the protein-ligand interactions. In this research, five important alkaloids were docked to crystal structure of human mu opioid receptor (4DKL, human delta opioid receptor (4EJ4 and human kappa opioid receptor (4DJH which were retrieved from protein databank. The 3D-structures of alkaloids were drawn by chembiooffice2010 and minimized with hyperchem package and submitted to molecular docking utilizing autodock-vina. Flexibility of the proteins was considered. The docking studies were performed to compare the affinity of these five alkaloids to the mentioned receptors. Results: We computationally docked each alkaloid compound onto each receptor structure and estimated their binding affinity based on dock scores. Dock score is a criteria including binding energy which utilized here for prediction and comparison of the binding affinities. Binding interactions of the docked alkaloids in receptor pockets were also visually inspected and compared. Conclusion: In this approach, using docking study as a computational method provided a valuable insight of opioid receptor pocket structures which would be essential to design more efficient drugs in pain managements and addiction treatments.

  16. Imaging Flash Lidar for Safe Landing on Solar System Bodies and Spacecraft Rendezvous and Docking

    Science.gov (United States)

    Amzajerdian, Farzin; Roback, Vincent E.; Bulyshev, Alexander E.; Brewster, Paul F.; Carrion, William A; Pierrottet, Diego F.; Hines, Glenn D.; Petway, Larry B.; Barnes, Bruce W.; Noe, Anna M.

    2015-01-01

    NASA has been pursuing flash lidar technology for autonomous, safe landing on solar system bodies and for automated rendezvous and docking. During the final stages of the landing from about 1 kilometer to 500 meters above the ground, the flash lidar can generate 3-Dimensional images of the terrain to identify hazardous features such as craters, rocks, and steep slopes. The onboard flight computer can then use the 3-D map of terrain to guide the vehicle to a safe location. As an automated rendezvous and docking sensor, the flash lidar can provide relative range, velocity, and bearing from an approaching spacecraft to another spacecraft or a space station. NASA Langley Research Center has developed and demonstrated a flash lidar sensor system capable of generating 16,000 pixels range images with 7 centimeters precision, at 20 Hertz frame rate, from a maximum slant range of 1800 m from the target area. This paper describes the lidar instrument and presents the results of recent flight tests onboard a rocket-propelled free-flyer vehicle (Morpheus) built by NASA Johnson Space Center. The flights were conducted at a simulated lunar terrain site, consisting of realistic hazard features and designated landing areas, built at NASA Kennedy Space Center specifically for this demonstration test. This paper also provides an overview of the plan for continued advancement of the flash lidar technology aimed at enhancing its performance to meet both landing and automated rendezvous and docking applications.

  17. Customizable de novo design strategies for DOCK: Application to HIVgp41 and other therapeutic targets.

    Science.gov (United States)

    Allen, William J; Fochtman, Brian C; Balius, Trent E; Rizzo, Robert C

    2017-11-15

    De novo design can be used to explore vast areas of chemical space in computational lead discovery. As a complement to virtual screening, from-scratch construction of molecules is not limited to compounds in pre-existing vendor catalogs. Here, we present an iterative fragment growth method, integrated into the program DOCK, in which new molecules are built using rules for allowable connections based on known molecules. The method leverages DOCK's advanced scoring and pruning approaches and users can define very specific criteria in terms of properties or features to customize growth toward a particular region of chemical space. The code was validated using three increasingly difficult classes of calculations: (1) Rebuilding known X-ray ligands taken from 663 complexes using only their component parts (focused libraries), (2) construction of new ligands in 57 drug target sites using a library derived from ∼13M drug-like compounds (generic libraries), and (3) application to a challenging protein-protein interface on the viral drug target HIVgp41. The computational testing confirms that the de novo DOCK routines are robust and working as envisioned, and the compelling results highlight the potential utility for designing new molecules against a wide variety of important protein targets. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  18. Effect of Multiple Mutations in the Hemoglobin- and Hemoglobin-Haptoglobin-Binding Proteins, HgpA, HgpB, and HgpC, of Haemophilus influenzae Type b

    OpenAIRE

    Morton, Daniel J.; Whitby, Paul W.; Jin, Hongfan; Ren, Zhen; Stull, Terrence L.

    1999-01-01

    Haemophilus influenzae requires heme for growth and can utilize hemoglobin and hemoglobin-haptoglobin as heme sources. We previously identified two hemoglobin- and hemoglobin-haptoglobin-binding proteins, HgpA and HgpB, in H. influenzae HI689. Insertional mutation of hgpA and hgpB, either singly or together, did not abrogate the ability to utilize or bind either hemoglobin or the hemoglobin-haptoglobin complex. A hemoglobin affinity purification method was used to isolate a protein of approxi...

  19. Diffusion coefficients of oxygen and hemoglobin as obtained simultaneously from photometric determination of the oxygenation of layers of hemoglobin solutions

    NARCIS (Netherlands)

    Spaan, J. A.; Kreuzer, F.; van Wely, F. K.

    1980-01-01

    The oxygenation of layers of deoxygenated hemoglobin solutions after a sudden exposure to a gas containing oxygen at a partial pressure P1 has been studied by a photometric method. Layer thicknesses varied between 50 and 250 micron, hemoglobin concentrations between 0.1 and 0.34kg/l, and oxygen

  20. Peptides Trapping Dioxins: A Docking-Based Inverse Screening Approach

    Directory of Open Access Journals (Sweden)

    German Perez

    2013-01-01

    Full Text Available A rapid and cost-effective computational methodology for designing and rationalizing the selection of small peptides as receptors for dioxin-like compounds was proposed. The backbone of the dioxin Ah receptor binding site was used to design a series of penta- and hexapeptide libraries, with 1400 elements in total. Peptide flexibility was considered and 10 conformers were found to be a good option to represent peptide conformational space with fair speed-accuracy ratio. Each peptide conformer was treated as a possible receptor, generating a dedicated box and then running a docking process using as ligands a family of 76 dibenzo-p-dioxins and 113 dibenzofurans mono- and polychlorinated. Significant predictions were confirmed by comparing primary structure of top and bottom ranked peptides binding dioxins confirming that scrambled positions of the same amino acids gave completely different predicted binding. The hexapeptide EWFQPW, with the best binding score, was chosen as selective sorbent material in solid-phase extraction. The retention performances were tested using the 2,3,7,8-tetrachlorodibenzo-p-dioxin and two polychlorinated biphenyls in order to verify the hexapeptide specificity. The solid-phase extraction experimental procedure was optimized, and analytical parameters of hexapeptide sorbent material were compared with the resin without hexapeptide and a commercial reversed phase cartridge.

  1. Molecular docking, spectroscopic studies and quantum calculations on nootropic drug.

    Science.gov (United States)

    Uma Maheswari, J; Muthu, S; Sundius, Tom

    2014-04-05

    A systematic vibrational spectroscopic assignment and analysis of piracetam [(2-oxo-1-pyrrolidineacetamide)] have been carried out using FT-IR and FT-Raman spectral data. The vibrational analysis was aided by an electronic structure calculation based on the hybrid density functional method B3LYP using a 6-311G++(d,p) basis set. Molecular equilibrium geometries, electronic energies, IR and Raman intensities, and harmonic vibrational frequencies have been computed. The assignments are based on the experimental IR and Raman spectra, and a complete assignment of the observed spectra has been proposed. The UV-visible spectrum of the compound was recorded and the electronic properties, such as HOMO and LUMO energies and the maximum absorption wavelengths λmax were determined by the time-dependent DFT (TD-DFT) method. The geometrical parameters, vibrational frequencies and absorption wavelengths were compared with the experimental data. The complete vibrational assignments are performed on the basis of the potential energy distributions (PED) of the vibrational modes in terms of natural internal coordinates. The simulated FT-IR, FT-Raman, and UV spectra of the title compound have been constructed. Molecular docking studies have been carried out in the active site of piracetam by using Argus Lab. In addition, the potential energy surface, HOMO and LUMO energies, first-order hyperpolarizability and the molecular electrostatic potential have been computed. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Histopathologic Study Following Administration of Liposome-Encapsulated Hemoglobin in the Normovolemic Rat

    National Research Council Canada - National Science Library

    Rudolph, Alan

    1995-01-01

    ... bovine hemoglobin in the normovolemic rat. We have also examined the administration of the liposome vehicle, tetrameric bovine hemoglobin, and liposome encapsulated bovine hemoglobin that had been lyophilized with 300 mM trehalose...

  3. Fructosamine and Hemoglobin A1c Correlations in HIV-Infected Adults in Routine Clinical Care: Impact of Anemia and Albumin Levels

    Directory of Open Access Journals (Sweden)

    Luisa Duran

    2015-01-01

    Full Text Available Fructosamine is an alternative method to hemoglobin A1c (HbA1c for determining average glycemia. However, its use has not been extensively evaluated in persons living with HIV (PLWH. We examined the relationship between HbA1c and fructosamine values, specifically focusing on anemia (which can affect HbA1c and albumin as a marker of liver disease. We included 345 PLWH from two sites. We examined Spearman rank correlations between fructosamine and HbA1c and performed linear test for trends to compare fructosamine and HbA1c correlations by hemoglobin and albumin quartiles. We examined discrepant individuals with values elevated only on one test. We found a correlation of 0.70 between fructosamine and HbA1c levels. Trend tests for correlations between fructosamine and HbA1c were significant for both albumin (p=0.05 and hemoglobin (p=0.01 with the lowest correlations in the lowest hemoglobin quartile. We identified participants with unremarkable HbA1c values but elevated fructosamine values. These discrepant individuals had lower mean hemoglobin levels than those elevated by both tests. We demonstrated a large correlation between HbA1c and fructosamine across a range of hemoglobin and albumin levels. There were discrepant cases particularly among those with lower hemoglobin levels. Future studies are needed to clarify the use of fructosamine for diabetes management in PWLH.

  4. Genomic organization and evolution of the Atlantic salmon hemoglobin repertoire

    Directory of Open Access Journals (Sweden)

    Phillips Ruth B

    2010-10-01

    Full Text Available Abstract Background The genomes of salmonids are considered pseudo-tetraploid undergoing reversion to a stable diploid state. Given the genome duplication and extensive biological data available for salmonids, they are excellent model organisms for studying comparative genomics, evolutionary processes, fates of duplicated genes and the genetic and physiological processes associated with complex behavioral phenotypes. The evolution of the tetrapod hemoglobin genes is well studied; however, little is known about the genomic organization and evolution of teleost hemoglobin genes, particularly those of salmonids. The Atlantic salmon serves as a representative salmonid species for genomics studies. Given the well documented role of hemoglobin in adaptation to varied environmental conditions as well as its use as a model protein for evolutionary analyses, an understanding of the genomic structure and organization of the Atlantic salmon α and β hemoglobin genes is of great interest. Results We identified four bacterial artificial chromosomes (BACs comprising two hemoglobin gene clusters spanning the entire α and β hemoglobin gene repertoire of the Atlantic salmon genome. Their chromosomal locations were established using fluorescence in situ hybridization (FISH analysis and linkage mapping, demonstrating that the two clusters are located on separate chromosomes. The BACs were sequenced and assembled into scaffolds, which were annotated for putatively functional and pseudogenized hemoglobin-like genes. This revealed that the tail-to-tail organization and alternating pattern of the α and β hemoglobin genes are well conserved in both clusters, as well as that the Atlantic salmon genome houses substantially more hemoglobin genes, including non-Bohr β globin genes, than the genomes of other teleosts that have been sequenced. Conclusions We suggest that the most parsimonious evolutionary path leading to the present organization of the Atlantic salmon

  5. Genomic organization and evolution of the Atlantic salmon hemoglobin repertoire

    Science.gov (United States)

    2010-01-01

    Background The genomes of salmonids are considered pseudo-tetraploid undergoing reversion to a stable diploid state. Given the genome duplication and extensive biological data available for salmonids, they are excellent model organisms for studying comparative genomics, evolutionary processes, fates of duplicated genes and the genetic and physiological processes associated with complex behavioral phenotypes. The evolution of the tetrapod hemoglobin genes is well studied; however, little is known about the genomic organization and evolution of teleost hemoglobin genes, particularly those of salmonids. The Atlantic salmon serves as a representative salmonid species for genomics studies. Given the well documented role of hemoglobin in adaptation to varied environmental conditions as well as its use as a model protein for evolutionary analyses, an understanding of the genomic structure and organization of the Atlantic salmon α and β hemoglobin genes is of great interest. Results We identified four bacterial artificial chromosomes (BACs) comprising two hemoglobin gene clusters spanning the entire α and β hemoglobin gene repertoire of the Atlantic salmon genome. Their chromosomal locations were established using fluorescence in situ hybridization (FISH) analysis and linkage mapping, demonstrating that the two clusters are located on separate chromosomes. The BACs were sequenced and assembled into scaffolds, which were annotated for putatively functional and pseudogenized hemoglobin-like genes. This revealed that the tail-to-tail organization and alternating pattern of the α and β hemoglobin genes are well conserved in both clusters, as well as that the Atlantic salmon genome houses substantially more hemoglobin genes, including non-Bohr β globin genes, than the genomes of other teleosts that have been sequenced. Conclusions We suggest that the most parsimonious evolutionary path leading to the present organization of the Atlantic salmon hemoglobin genes involves

  6. Fluorometric and molecular docking investigation on the binding characteristics of SB202190 to human serum albumin

    International Nuclear Information System (INIS)

    Nasruddin, Ahmad N.; Feroz, Shevin R.; Mukarram, Abdul K.; Mohamad, Saharuddin B.; Tayyab, Saad

    2016-01-01

    The interaction of SB202190, a p38 mitogen-activated protein kinase inhibitor with the main drug transporter in human circulation, human serum albumin (HSA) was studied using fluorescence spectroscopy and in silico docking methods. The association constant, K a of the binding reaction was determined to be 3.24±0.07×10 4 M −1 at 25 °C based on fluorescence quenching titration results. The values of enthalpy change and entropy change for the interaction were found as −8.54 kJ mol −1 and 58.01 J mol −1 K −1 , respectively. Both thermodynamic data and docking results suggested the involvement of hydrophobic and van der Waals forces in the complex formation. Three-dimensional fluorescence data of SB202190–HSA complex demonstrated significant changes in the microenvironment around the protein fluorophores upon drug binding. Comparison of HSA thermograms obtained in the absence and the presence of SB202190 suggested improved protein thermal stability upon complexation with the drug. Competitive drug displacement results as well as modeling data concluded the preferred binding site of SB202190 on HSA as Sudlow's site I. - Highlights: • SB202190 interacts with HSA with moderate affinity. • Involvement of hydrophobic and van der Waals forces in SB202190 binding. • SB202190 binding results in microenvironmental changes around fluorophores. • Sudlow's site I is the preferred binding site of SB202190.

  7. Structural and Mechanistic Insights into Hemoglobin-catalyzed Hydrogen Sulfide Oxidation and the Fate of Polysulfide Products

    Energy Technology Data Exchange (ETDEWEB)

    Vitvitsky, Victor; Yadav, Pramod K.; An, Sojin; Seravalli, Javier; Cho, Uhn-Soo; Banerjee, Ruma (Michigan-Med); (UNL)

    2017-02-17

    Hydrogen sulfide is a cardioprotective signaling molecule but is toxic at elevated concentrations. Red blood cells can synthesize H2S but, lacking organelles, cannot dispose of H2S via the mitochondrial sulfide oxidation pathway. We have recently shown that at high sulfide concentrations, ferric hemoglobin oxidizes H2S to a mixture of thiosulfate and iron-bound polysulfides in which the latter species predominates. Here, we report the crystal structure of human hemoglobin containing low spin ferric sulfide, the first intermediate in heme-catalyzed sulfide oxidation. The structure provides molecular insights into why sulfide is susceptible to oxidation in human hemoglobin but is stabilized against it in HbI, a specialized sulfide-carrying hemoglobin from a mollusk adapted to life in a sulfide-rich environment. We have also captured a second sulfide bound at a postulated ligand entry/exit site in the α-subunit of hemoglobin, which, to the best of our knowledge, represents the first direct evidence for this site being used to access the heme iron. Hydrodisulfide, a postulated intermediate at the junction between thiosulfate and polysulfide formation, coordinates ferric hemoglobin and, in the presence of air, generated thiosulfate. At low sulfide/heme iron ratios, the product distribution between thiosulfate and iron-bound polysulfides was approximately equal. The iron-bound polysulfides were unstable at physiological glutathione concentrations and were reduced with concomitant formation of glutathione persulfide, glutathione disulfide, and H2S. Hence, although polysulfides are unlikely to be stable in the reducing intracellular milieu, glutathione persulfide could serve as a persulfide donor for protein persulfidation, a posttranslational modification by which H2S is postulated to signal.

  8. Synthesis, docking and anticancer activity studies of D-proline ...

    Indian Academy of Sciences (India)

    D-proline-incorporated wainunuamide — a cyclic octapeptide was synthesized and characterized ... Cyclic octapeptide; molecular docking; solution phase synthesis; anticancer activity ..... dynamics and their binding affinities, using free energy.

  9. Passive, Failure-Tolerant Docking and Undocking with Articulated Magnets

    Data.gov (United States)

    National Aeronautics and Space Administration — Current spacecraft docking relies on active movement (e.g. thrusters) to close the gap between participants, and to separate them when undocking. I intend to develop...

  10. Synthesis, in vitro anti-inflammatory activity and molecular docking ...

    Indian Academy of Sciences (India)

    alkyl and heterocyclic alkyl moieties were synthesized, characterized and subsequently evaluated for ... Docking studies with these compounds against cyclooxygenase-2 receptor ...... thiadiazole derivatives as possible anti-tubercular agents.

  11. Optimal Rendezvous and Docking Simulator for Elliptical Orbits, Phase I

    Data.gov (United States)

    National Aeronautics and Space Administration — It is proposed to develop and implement a simulation of spacecraft rendezvous and docking guidance, navigation, and control in elliptical orbit. The foundation of...

  12. Molecular docking studies on rocaglamide, a traditional Chinese ...

    African Journals Online (AJOL)

    Keywords: Periodontitis, Inflammation, Rocaglamide, Molecular docking, Lamarckian ... Index Medicus, JournalSeek, Journal Citation Reports/Science Edition, ... chronic, bacterial infection-associated auto- .... The binding pocket in this case.

  13. Two-photon excited fluorescence emission from hemoglobin

    Science.gov (United States)

    Sun, Qiqi; Zeng, Yan; Zhang, Wei; Zheng, Wei; Luo, Yi; Qu, Jianan Y.

    2015-03-01

    Hemoglobin, one of the most important proteins in blood, is responsible for oxygen transportation in almost all vertebrates. Recently, we discovered two-photon excited hemoglobin fluorescence and achieved label-free microvascular imaging based on the hemoglobin fluorescence. However, the mechanism of its fluorescence emission still remains unknown. In this work, we studied the two-photon excited fluorescence properties of the hemoglobin subunits, heme/hemin (iron (II)/(III) protoporphyrin IX) and globin. We first studied the properties of heme and the similar spectral and temporal characteristics of heme and hemoglobin fluorescence provide strong evidence that heme is the fluorophore in hemoglobin. Then we studied the fluorescence properties of hemin, globin and methemoglobin, and found that the hemin may have the main effect on the methemoglobin fluorescence and that globin has tryptophan fluorescence like other proteins. Finally, since heme is a centrosymmetric molecule, that the Soret band fluorescence of heme and hemoglobin was not observed in the single photon process in the previous study may be due to the parity selection rule. The discovery of heme two-photon excited fluorescence may open a new window for heme biology research, since heme as a cofactor of hemoprotein has many functions, including chemical catalysis, electron transfer and diatomic gases transportation.

  14. Quantifying risk of penile prosthesis infection with elevated glycosylated hemoglobin.

    Science.gov (United States)

    Wilson, S K; Carson, C C; Cleves, M A; Delk, J R

    1998-05-01

    Elevation of glycosylated hemoglobin above levels of 11.5 mg.% has been considered a contraindication to penile prosthesis implantation in diabetic patients. We determine the predictive value of glycosylated hemoglobin A1C in penile prosthesis infections in diabetic and nondiabetic patients to confirm or deny this prevalent opinion. We conducted a 2-year prospective study of 389 patients, including 114 diabetics, who underwent 3-piece penile prosthesis implantation. All patients had similar preoperative preparation without regard to diabetic status, control or glycosylated hemoglobin A1C level. Risk of infection was statistically analyzed for diabetics versus nondiabetics, glycosylated hemoglobin A1C values above and below 11.5 mg.%, insulin dependent versus oral medication diabetics, and fasting blood sugars above and below 180 mg.%. Prosthesis infections developed in 10 diabetics (8.7%) and 11 nondiabetics (4.0%). No increased infection rate was observed in diabetics with high fasting sugars or diabetics on insulin. There was no statistically significant increased infection risk with increased levels of glycosylated hemoglobin A1C among all patients or among only the diabetics. In fact, there was no meaningful difference in the median or mean level of glycosylated hemoglobin A1C in the infected and noninfected patients regardless of diabetes. Use of glycosylated hemoglobin A1C values to identify and exclude surgical candidates with increased risk of infections is not proved by this study. Elevation of fasting sugar or insulin dependence also does not increase risk of infection in diabetics undergoing prosthesis implantation.

  15. Postoperative hemoglobin level in patients with femoral neck fracture.

    Science.gov (United States)

    Nagra, Navraj S; Van Popta, Dmitri; Whiteside, Sigrid; Holt, Edward M

    2016-01-01

    The aim of this study was to analyze the changes of hemoglobin levels in patients undergoing fixation for femoral neck fracture. Peroperative hemoglobin levels of patients who underwent either dynamic hip screw (DHS) fixation (n=74; mean age: 80 years) or hip hemiarthroplasty (n=104; mean age: 84 years) for femoral neck fracture was monitored. There was a statistically and clinically significant mean drop of 31.1 g/L between the preoperative (D0) and postoperative Day 5 Hb levels (pmeasurement, DHS patients had lower hemoglobin values over hemiarthroplasty patients (p=0.046). The decrease in hemoglobin in the first 24-hour postoperative period (D0 to Day 1) is an underestimation of the ultimate lowest value in hemoglobin found at Day 2. Relying on the Day 1 hemoglobin level could be detrimental to patient care. We propose a method of predicting patients likely to be transfused and recommend a protocol for patients undergoing femoral neck fracture surgery to standardize postoperative hemoglobin monitoring.

  16. Expression of fully functional tetrameric human hemoglobin in Escherichia coli

    International Nuclear Information System (INIS)

    Hoffman, S.J.; Looker, D.L.; Roehrich, J.M.; Cozart, P.E.; Durfee, S.L.; Tedesco, J.L.; Stetler, G.L.

    1990-01-01

    Synthesis genes encoding the human α- and β-globin polypeptides have been expressed from a single operon in Escherichia coli. The α- and β-globin polypeptides associate into soluble tetramers, incorporate heme, and accumulate to >5% of the total cellular protein. Purified recombinant hemoglobin has the correct stoichiometry of α- and β-globin chains and contains a full complement of heme. Each globin chain also contains an additional methionine as an extension to the amino terminus. The recombinant hemoglobin has a C 4 reversed-phase HPLC profile essentially identical to that of human hemoglobin A 0 and comigrates with hemoglobin A 0 on SDS/PAGE. The visible spectrum and oxygen affinity are similar to that of native human hemoglobin A 0 . The authors have also expressed the α- and β-globin genes separately and found that the expression of the α-globin gene alone results in a marked decrease in the accumulation of α-globin in the cell. Separate expression of the β-globin gene results in high levels of insoluble β-globin. These observations suggest that the presence of α- and β-globin in the same cell stabilizes α-globin and aids the correct folding of β-globin. This system provides a simple method for expressing large quantities of recombinant hemoglobin and allows facile manipulation of the genes encoding hemoglobin to produce functionally altered forms of this protein

  17. Using the MWC model to describe heterotropic interactions in hemoglobin

    Science.gov (United States)

    Rapp, Olga

    2017-01-01

    Hemoglobin is a classical model allosteric protein. Research on hemoglobin parallels the development of key cooperativity and allostery concepts, such as the ‘all-or-none’ Hill formalism, the stepwise Adair binding formulation and the concerted Monod-Wymann-Changuex (MWC) allosteric model. While it is clear that the MWC model adequately describes the cooperative binding of oxygen to hemoglobin, rationalizing the effects of H+, CO2 or organophosphate ligands on hemoglobin-oxygen saturation using the same model remains controversial. According to the MWC model, allosteric ligands exert their effect on protein function by modulating the quaternary conformational transition of the protein. However, data fitting analysis of hemoglobin oxygen saturation curves in the presence or absence of inhibitory ligands persistently revealed effects on both relative oxygen affinity (c) and conformational changes (L), elementary MWC parameters. The recent realization that data fitting analysis using the traditional MWC model equation may not provide reliable estimates for L and c thus calls for a re-examination of previous data using alternative fitting strategies. In the current manuscript, we present two simple strategies for obtaining reliable estimates for MWC mechanistic parameters of hemoglobin steady-state saturation curves in cases of both evolutionary and physiological variations. Our results suggest that the simple MWC model provides a reasonable description that can also account for heterotropic interactions in hemoglobin. The results, moreover, offer a general roadmap for successful data fitting analysis using the MWC model. PMID:28793329

  18. 78 FR 59914 - Foreign-Trade Zone 160-Anchorage, Alaska; Application for Reorganization Under Alternative Site...

    Science.gov (United States)

    2013-09-30

    ...: Site 1 (56.89 acres)--the Port of Anchorage and Port of Anchorage Industrial Park, 1075 Dock Rd., 1076... acres)--619 East Ship Creek Ave., Anchorage; Site 6 (12.2 acres)-- Douglas Management Company, 660...

  19. Modifications of hemoglobin and myoglobin by Maillard reaction products (MRPs.

    Directory of Open Access Journals (Sweden)

    Aristos Ioannou

    Full Text Available High performance liquid chromatography (HPLC coupled with a Fraction Collector was employed to isolate Maillard reaction products (MRPs formed in model systems comprising of asparagine and monosaccharides in the 60-180°C range. The primary MRP which is detected at 60°C is important for Acrylamide content and color/aroma development in foods and also in the field of food biotechnology for controlling the extent of the Maillard reaction with temperature. The discrete fractions of the reaction products were reacted with Hemoglobin (Hb and Myoglobin (Mb at physiological conditions and the reaction adducts were monitored by UV-vis and Attenuated Total Reflection-Fourier transform infrared (FTIR spectrophotometry. The UV-vis kinetic profiles revealed the formation of a Soret transition characteristic of a low-spin six-coordinated species and the ATR-FTIR spectrum of the Hb-MRP and Mb-MRP fractions showed modifications in the protein Amide I and II vibrations. The UV-vis and the FTIR spectra of the Hb-MRPs indicate that the six-coordinated species is a hemichrome in which the distal E7 Histidine is coordinated to the heme Fe and blocks irreversibly the ligand binding site. Although the Mb-MRPs complex is a six-coordinated species, the 1608 cm-1 FTIR band characteristic of a hemichrome was not observed.

  20. Hemoglobin redox reactions and red blood cell aging.

    Science.gov (United States)

    Rifkind, Joseph M; Nagababu, Enika

    2013-06-10

    The physiological mechanism(s) for recognition and removal of red blood cells (RBCs) from circulation after 120 days of its lifespan is not fully understood. Many of the processes thought to be associated with the removal of RBCs involve oxidative stress. We have focused on hemoglobin (Hb) redox reactions, which is the major source of RBC oxidative stress. The importance of Hb redox reactions have been shown to originate in large parts from the continuous slow autoxidation of Hb producing superoxide and its dramatic increase under hypoxic conditions. In addition, oxidative stress has been shown to be associated with redox reactions that originate from Hb reactions with nitrite and nitric oxide (NO) and the resultant formation of highly toxic peroxynitrite when NO reacts with superoxide released during Hb autoxidation. The interaction of Hb, particularly under hypoxic conditions with band 3 of the RBC membrane is critical for the generating the RBC membrane changes that trigger the removal of cells from circulation. These changes include exposure of antigenic sites, increased calcium leakage into the RBC, and the resultant leakage of potassium out of the RBC causing cell shrinkage and impaired deformability. The need to understand the oxidative damage to specific membrane proteins that result from redox reactions occurring when Hb is bound to the membrane. Proteomic studies that can pinpoint the specific proteins damaged under different conditions will help elucidate the cellular aging processes that result in cells being removed from circulation.

  1. Modifications of hemoglobin and myoglobin by Maillard reaction products (MRPs).

    Science.gov (United States)

    Ioannou, Aristos; Varotsis, Constantinos

    2017-01-01

    High performance liquid chromatography (HPLC) coupled with a Fraction Collector was employed to isolate Maillard reaction products (MRPs) formed in model systems comprising of asparagine and monosaccharides in the 60-180°C range. The primary MRP which is detected at 60°C is important for Acrylamide content and color/aroma development in foods and also in the field of food biotechnology for controlling the extent of the Maillard reaction with temperature. The discrete fractions of the reaction products were reacted with Hemoglobin (Hb) and Myoglobin (Mb) at physiological conditions and the reaction adducts were monitored by UV-vis and Attenuated Total Reflection-Fourier transform infrared (FTIR) spectrophotometry. The UV-vis kinetic profiles revealed the formation of a Soret transition characteristic of a low-spin six-coordinated species and the ATR-FTIR spectrum of the Hb-MRP and Mb-MRP fractions showed modifications in the protein Amide I and II vibrations. The UV-vis and the FTIR spectra of the Hb-MRPs indicate that the six-coordinated species is a hemichrome in which the distal E7 Histidine is coordinated to the heme Fe and blocks irreversibly the ligand binding site. Although the Mb-MRPs complex is a six-coordinated species, the 1608 cm-1 FTIR band characteristic of a hemichrome was not observed.

  2. Individualized anemia management reduces hemoglobin variability in hemodialysis patients.

    Science.gov (United States)

    Gaweda, Adam E; Aronoff, George R; Jacobs, Alfred A; Rai, Shesh N; Brier, Michael E

    2014-01-01

    One-size-fits-all protocol-based approaches to anemia management with erythropoiesis-stimulating agents (ESAs) may result in undesired patterns of hemoglobin variability. In this single-center, double-blind, randomized controlled trial, we tested the hypothesis that individualized dosing of ESA improves hemoglobin variability over a standard population-based approach. We enrolled 62 hemodialysis patients and followed them over a 12-month period. Patients were randomly assigned to receive ESA doses guided by the Smart Anemia Manager algorithm (treatment) or by a standard protocol (control). Dose recommendations, performed on a monthly basis, were validated by an expert physician anemia manager. The primary outcome was the percentage of hemoglobin concentrations between 10 and 12 g/dl over the follow-up period. A total of 258 of 356 (72.5%) hemoglobin concentrations were between 10 and 12 g/dl in the treatment group, compared with 208 of 336 (61.9%) in the control group; 42 (11.8%) hemoglobin concentrations were hemoglobin concentrations were >12 g/dl in the treatment group compared with 46 (13.4%) in the control group. The median ESA dosage per patient was 2000 IU/wk in both groups. Five participants received 6 transfusions (21 U) in the treatment group, compared with 8 participants and 13 transfusions (31 U) in the control group. These results suggest that individualized ESA dosing decreases total hemoglobin variability compared with a population protocol-based approach. As hemoglobin levels are declining in hemodialysis patients, decreasing hemoglobin variability may help reduce the risk of transfusions in this population.

  3. Exponential Repulsion Improves Structural Predictability of Molecular Docking

    Czech Academy of Sciences Publication Activity Database

    Bazgier, Václav; Berka, K.; Otyepka, M.; Banáš, P.

    2016-01-01

    Roč. 37, č. 28 (2016), s. 2485-2494 ISSN 0192-8651 Institutional support: RVO:61389030 Keywords : cyclin-dependent kinases * structure-based design * scoring functions * cdk2 inhibitors * force-field * ligand interactions * drug discovery * purine * potent * protein-kinase-2 * molecular docking * dock 6.6 * drug design * cyclin-dependent kinase 2 * directory of decoys Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 3.229, year: 2016

  4. Companies hone in on radar-docking technology

    Science.gov (United States)

    Howell, Elizabeth

    2009-11-01

    As NASA prepares to retire the Space Shuttle next year, two private space firms have tested docking technology that could be used on the next generation of US spacecraft. In September, Canadian firm Neptec tested a new radar system on the Space Shuttle Discovery that allows spacecraft to dock more easily. Meanwhile, Space Exploration Technologies (SpaceX) based in California has revealed that it tested out a new proximity sensor, dubbed "Dragoneye", on an earlier shuttle mission in July.

  5. A primer on wood as dock construction material

    Science.gov (United States)

    Stan Lebow

    2007-01-01

    To be a successful marina owner and operator, it’s important to understand all the facets of one’s facility, including the intricacies of one part of the marina that most boaters take for granted: the docks. When it comes to dock construction, marinas have a wide-range of materials to choose from, with one of the most commonly used materials being preservative-treated...

  6. Relationship between maternal hemoglobin and perinatal outcome

    International Nuclear Information System (INIS)

    Bakhtiar, U.J.; Khan, Y.; Nisar, R.

    2007-01-01

    To Study the Relationship between Maternal Hemoglobin and Perinatal outcome in a cohort of 860 pregnant women and to highlight the importance of antenatal care regarding maternal health and fetal outcome. All Singleton pregnancies delivering at Pakistan Railway Hospital Rawalpindi from January 2004 to December 2005 that fulfilled the required criteria were included. Out of the 860 patients, 402 were anemic (<11gm/dl) and 458 were non anemic. Perinatal outcome included preterm delivery, low birth weight, intrauterine growth retardation, perinatal death, low apgr scores and intrauterine fetal deaths. Risk of preterm and Low birth weight among anemic women was 3.4 and 1.8 times more than non anaemic women. The neonates of anemic woman also had 1.7 times increased risk of having low apgr scores at 1 min. Among anemic women there was 2.2 times greater risk of intrauterine fetal death than the non-anemic women. Regular antenatal care from first trimester has a vital role in assessing and managing maternal anemia timely and it directly affects the perinatal outcome. The patients with anemia have also higher risk of having low birth weight, preterm births and intra uterine fetal death. (author)

  7. NITRO MUSK BOUND TO CARP HEMOGLOBIN ...

    Science.gov (United States)

    Nitroaromatic compounds including synthetic nitro musks are important raw materials and intermediates in the synthesis of explosives, dyes, and pesticides, pharmaceutical and personal care-products (PPCPs). The nitro musks such as musk xylene (MX) and musk ketone (MK) are extensively used as fragrance ingredients in PPCPs and other commercial toiletries. Identification and quantification of a bound 4-amino-MX (4-AMX) metabolite as well as a 2- amino-MK (2-AMK) metabolite were carried out by gas chromatography-mass spectrometry' (GC/MS), with selected ion monitoring (SIM) in both the electron ionization (ElMS) and electron capture (EC) negative ion chemical ionization (NICIMS) modes. Detection of 4-AMX and 2-AMK occurred after the cysteine adducts in carp hemoglobin, derived from the nitroso metabolites, were released by alkaline hydrolysis. The released metabolites were extracted into n-hexane. The extract was preconcentrated by evaporation, and analyzed by GC-SIM-MS. A comparison between the El and EC approaches was made. EC NICIMS detected both metabolites whereas only 4-AMX was detected by ElMS. The EC NICIMS approach exhibited fewer matrix responses and provided a lower detection limit. Quantitation in both approaches was based on internal standard and a calibration plot. The research focused on in the subtasks is the development and application of state-of the-art technologies to meet the needs of the public, Office of Water, and ORD in the area of Water Q

  8. Noninvasive hemoglobin measurement using dynamic spectrum

    Science.gov (United States)

    Yi, Xiaoqing; Li, Gang; Lin, Ling

    2017-08-01

    Spectroscopy methods for noninvasive hemoglobin (Hgb) measurement are interfered by individual difference and particular weak signal. In order to address these problems, we have put forward a series of improvement methods based on dynamic spectrum (DS), including instrument design, spectrum extraction algorithm, and modeling approach. The instrument adopts light sources composed of eight laser diodes with the wavelength range from 600 nm to 1100 nm and records photoplethysmography signals at eight wavelengths synchronously. In order to simplify the optical design, we modulate the light sources with orthogonal square waves and design the corresponding demodulation algorithm, instead of adopting a beam-splitting system. A newly designed algorithm named difference accumulation has been proved to be effective in improving the accuracy of dynamic spectrum extraction. 220 subjects are involved in the clinical experiment. An extreme learning machine calibration model between the DS data and the Hgb levels is established. Correlation coefficient and root-mean-square error of prediction sets are 0.8645 and 8.48 g/l, respectively. The results indicate that the Hgb level can be derived by this approach noninvasively with acceptable precision and accuracy. It is expected to achieve a clinic application in the future.

  9. Spectroscopic and molecular docking techniques study of the interaction between oxymetholone and human serum albumin

    Energy Technology Data Exchange (ETDEWEB)

    Madrakian, Tayyebeh, E-mail: madrakian@basu.ac.ir; Bagheri, Habibollah; Afkhami, Abbas; Soleimani, Mohammad

    2014-11-15

    In this study, the binding of oxymetholone (OXM), a doping drug, to human serum albumin (HSA) was explored at pH 7.40 by spectroscopic methods including spectrofluorimetry, three dimensional excitation–emission matrix (3D EEM), UV–vis absorption, resonance rayleigh scattering (RRS) and molecular docking. The fluorescence results showed that there was a considerable quenching of the intrinsic fluorescence of HSA upon binding to OXM by static quenching mechanism. The Stern–Volmer quenching constants (K{sub SV}) between OXM and HSA at three different temperatures 295, 303, 308 K, were obtained as 4.63×10{sup 4}, 3.05×10{sup 4} and 1.49×10{sup 4} L mol{sup −1}, respectively. Furthermore this interaction was confirmed by UV–vis spectrophotometric and RRS techniques. The binding site number, n, apparent binding constant, K{sub b}, and corresponding thermodynamic parameters (ΔS, ΔH and ΔG) were measured at different temperatures. The Van der Waals and hydrogen-bond forces were found to stabilize OXM–HSA complex. The distance (r) between the donor and acceptor was obtained from Förster's theory of fluorescence resonance energy transfer (FRET) and found to be 1.67 nm. The 3D EEM showed that OXM slightly changes the secondary structure of HSA. Furthermore, the molecular docking was employed for identification of drug binding sites and interaction of OXM with amino acid residues. - Highlights: • The binding of OXM as a doping drug with HSA was studied by different techniques. • The binding constant of HSA–OXM was calculated. • The binding site of OXM on HSA was characterized with molecular docking. • The thermodynamic parameters were calculated according to fluorescence technique.

  10. Evans Syndrome Complicated by Intratubular Hemoglobin Cast Nephropathy

    Directory of Open Access Journals (Sweden)

    Iván González

    2017-01-01

    Full Text Available Evans syndrome (ES is a rare autoimmune disorder whose exact pathophysiology is unknown. It is characterized by the simultaneous or subsequent development of autoimmune hemolytic anemia (AIHA and immune thrombocytopenia (ITP. Intravascular hemolysis, with hemoglobinemia, is known to produce acute kidney injury; however, the development of intratubular hemoglobin casts (hemoglobin cast nephropathy in the setting of acute hemolysis is uncommon. Likewise, the association of ES and acute renal failure is equally uncommon. We present a case of a 7-year-old girl with ES who developed acute kidney injury in the setting of intravascular hemolysis and had widespread intratubular hemoglobin casts.

  11. Biophysical basis of hypoxic radioprotection by deoxygenated dextran-hemoglobin

    International Nuclear Information System (INIS)

    Wong, J.T.; Hill, R.P.

    1986-01-01

    Perfusion with deoxygenated dextran-hemoglobin provides an effective method for inducing hypoxic radioprotection of normal tissues during radiation treatment of tumors. In this study, the dependence of P50, the half-saturation pressure of oxygen binding to dextran-hemoglobin, was analyzed as a function of solution temperature and pH. The variation of attainable radioprotection with P50, and with the amount of collateral blood entering into the perfused region, was calculated. Upon perfusion of canine gracilis muscle with deoxygenated dextran-hemoglobin, a rapid onset of extensive venous hypoxia was observed

  12. Symbiotic and nonsymbiotic hemoglobin genes of Casuarina glauca

    DEFF Research Database (Denmark)

    Jacobsen-Lyon, K; Jensen, Erik Østergaard; Jørgensen, Jan-Elo

    1995-01-01

    Casuarina glauca has a gene encoding hemoglobin (cashb-nonsym). This gene is expressed in a number of plant tissues. Casuarina also has a second family of hemoglobin genes (cashb-sym) expressed at a high level in the nodules that Casuarina forms in a nitrogen-fixing symbiosis with the actinomycete...... of the Casuarina gene. The finding that the nonsymbiotic Casuarina gene is also correctly expressed in L. corniculatus suggests to us that a comparable non-symbiotic hemoglobin gene will be found in legume species. Udgivelsesdato: 1995-Feb...

  13. Demonstration of automated proximity and docking technologies

    Science.gov (United States)

    Anderson, Robert L.; Tsugawa, Roy K.; Bryan, Thomas C.

    An autodock was demonstrated using straightforward techniques and real sensor hardware. A simulation testbed was established and validated. The sensor design was refined with improved optical performance and image processing noise mitigation techniques, and the sensor is ready for production from off-the-shelf components. The autonomous spacecraft architecture is defined. The areas of sensors, docking hardware, propulsion, and avionics are included in the design. The Guidance Navigation and Control architecture and requirements are developed. Modular structures suitable for automated control are used. The spacecraft system manager functions including configuration, resource, and redundancy management are defined. The requirements for autonomous spacecraft executive are defined. High level decisionmaking, mission planning, and mission contingency recovery are a part of this. The next step is to do flight demonstrations. After the presentation the following question was asked. How do you define validation? There are two components to validation definition: software simulation with formal and vigorous validation, and hardware and facility performance validated with respect to software already validated against analytical profile.

  14. Combination of scoring schemes for protein docking

    Directory of Open Access Journals (Sweden)

    Schomburg Dietmar

    2007-08-01

    Full Text Available Abstract Background Docking algorithms are developed to predict in which orientation two proteins are likely to bind under natural conditions. The currently used methods usually consist of a sampling step followed by a scoring step. We developed a weighted geometric correlation based on optimised atom specific weighting factors and combined them with our previously published amino acid specific scoring and with a comprehensive SVM-based scoring function. Results The scoring with the atom specific weighting factors yields better results than the amino acid specific scoring. In combination with SVM-based scoring functions the percentage of complexes for which a near native structure can be predicted within the top 100 ranks increased from 14% with the geometric scoring to 54% with the combination of all scoring functions. Especially for the enzyme-inhibitor complexes the results of the ranking are excellent. For half of these complexes a near-native structure can be predicted within the first 10 proposed structures and for more than 86% of all enzyme-inhibitor complexes within the first 50 predicted structures. Conclusion We were able to develop a combination of different scoring schemes which considers a series of previously described and some new scoring criteria yielding a remarkable improvement of prediction quality.

  15. Reactive Path Planning Approach for Docking Robots in Unknown Environment

    Directory of Open Access Journals (Sweden)

    Peng Cui

    2017-01-01

    Full Text Available Autonomous robots need to be recharged and exchange information with the host through docking in the long-distance tasks. Therefore, feasible path is required in the docking process to guide the robot and adjust its pose. However, when there are unknown obstacles in the work area, it becomes difficult to determine the feasible path for docking. This paper presents a reactive path planning approach named Dubins-APF (DAPF to solve the path planning problem for docking in unknown environment with obstacles. In this proposed approach the Dubins curves are combined with the designed obstacle avoidance potential field to plan the feasible path. Firstly, an initial path is planned and followed according to the configurations of the robot and the docking station. Then when the followed path is evaluated to be infeasible, the intermediate configuration is calculated as well as the replanned path based on the obstacle avoidance potential field. The robot will be navigated to the docking station with proper pose eventually via the DAPF approach. The proposed DAPF approach is efficient and does not require the prior knowledge about the environment. Simulation results are given to validate the effectiveness and feasibility of the proposed approach.

  16. Interaction of promethazine and adiphenine to human hemoglobin: A comparative spectroscopic and computational analysis

    Science.gov (United States)

    Maurya, Neha; ud din Parray, Mehraj; Maurya, Jitendra Kumar; Kumar, Amit; Patel, Rajan

    2018-06-01

    The binding nature of amphiphilic drugs viz. promethazine hydrochloride (PMT) and adiphenine hydrochloride (ADP), with human hemoglobin (Hb) was unraveled by fluorescence, absorbance, time resolved fluorescence, fluorescence resonance energy transfer (FRET) and circular dichroism (CD) spectral techniques in combination with molecular docking and molecular dynamic simulation methods. The steady state fluorescence spectra indicated that both PMT and ADP quenches the fluorescence of Hb through static quenching mechanism which was further confirmed by time resolved fluorescence spectra. The UV-Vis spectroscopy suggested ground state complex formation. The activation energy (Ea) was observed more in the case of Hb-ADP than Hb-PMT interaction system. The FRET result indicates the high probability of energy transfer from β Trp37 residue of Hb to the PMT (r = 2.02 nm) and ADP (r = 2.33 nm). The thermodynamic data reveal that binding of PMT with Hb are exothermic in nature involving hydrogen bonding and van der Waal interaction whereas in the case of ADP hydrophobic forces play the major role and binding process is endothermic in nature. The CD results show that both PMT and ADP, induced secondary structural changes of Hb and unfold the protein by losing a large helical content while the effect is more pronounced with ADP. Additionally, we also utilized computational approaches for deep insight into the binding of these drugs with Hb and the results are well matched with our experimental results.

  17. New cholinesterase inhibitors for Alzheimer's disease: Structure Activity Studies (SARs) and molecular docking of isoquinolone and azepanone derivatives.

    Science.gov (United States)

    Bacalhau, Patrícia; San Juan, Amor A; Marques, Carolina S; Peixoto, Daniela; Goth, Albertino; Guarda, Cátia; Silva, Mara; Arantes, Sílvia; Caldeira, A Teresa; Martins, Rosário; Burke, Anthony J

    2016-08-01

    A library of isoquinolinone and azepanone derivatives were screened for both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity. The strategy adopted included (a) in vitro biological assays, against eel AChE (EeAChE) and equine serum BuChE (EqBuChE) in order to determine the compounds IC50 and their dose-response activity, consolidated by (b) molecular docking studies to evaluate the docking poses and interatomic interactions in the case of the hit compounds, validated by STD-NMR studies. Compound (1f) was identified as one of these hits with an IC50 of 89.5μM for EeAChE and 153.8μM for EqBuChE, (2a) was identified as a second hit with an IC50 of 108.4μM (EeAChE) and 277.8μM (EqBuChE). In order to gain insights into the binding mode and principle active site interactions of these molecules, (R)-(1f) along with 3 other analogues (also as the R-enantiomer) were docked into both RhAChE and hBuChE models. Galantamine was used as the benchmark. The docking study was validated by performing an STD-NMR study of (1f) with EeAChE using galantamine as the benchmark. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Hypoglycemic, hepatoprotective and molecular docking studies of 5-[(4-chlorophenoxy methyl]-1, 3, 4-oxadiazole-2-thiol

    Directory of Open Access Journals (Sweden)

    Naureen Shehzadi

    2018-05-01

    Full Text Available The present study aimed at the evaluation of anti-hyperglycemic and hepatoprotective potential of a new drug candidate, 5-[(4-chlorophenoxy methyl]-1,3,4-oxadiazole-2-thiol (OXCPM through in vitro and in vivo assays, respectively. The compound displayed excellent dose-dependent ɑ-amylase (28.0-92.0%, ɑ-glucosidase (40.3-93.1% and hemoglobin glycosylation (9.0%-54.9% inhibitory effects and promoted the uptake of glucose by the yeast cells (0.2 to 26.3%. The treatment of the isoniazid- and rifampicin- (p.o., 50 mg/kg of each intoxicated rats with OXCPM (100 mg/kg, p.o. resulted in restoring the normal serum levels of the non-enzymatic (total bilirubin, total protein and albumin and bringing about a remarkable decrease in the levels of enzymatic (alanine transaminases, aspartate transaminases and alkaline phosphatase biomarkers. The molecular docking studies indicated high binding affinity of the compound for hyperglycemia-related protein targets; fructose-1,6-bisphosphatase, beta2-adrenergic receptors and glucokinase. The results indicate that OXCPM may not only reduce hyperglycemia by enzyme inhibition but also the disease complications through protection of hemoglobin glycosylation and hepatic injury.

  19. Orion Handling Qualities During ISS Rendezvous and Docking

    Science.gov (United States)

    Hart, Jeremy J.; Stephens, J. P.; Spehar, P.; Bilimoria, K.; Foster, C.; Gonzalex, R.; Sullivan, K.; Jackson, B.; Brazzel, J.; Hart, J.

    2011-01-01

    The Orion spacecraft was designed to rendezvous with multiple vehicles in low earth orbit (LEO) and beyond. To perform the required rendezvous and docking task, Orion must provide enough control authority to perform coarse translational maneuvers while maintaining precision to perform the delicate docking corrections. While Orion has autonomous docking capabilities, it is expected that final approach and docking operations with the International Space Station (ISS) will initially be performed in a manual mode. A series of evaluations was conducted by NASA and Lockheed Martin at the Johnson Space Center to determine the handling qualities (HQ) of the Orion spacecraft during different docking and rendezvous conditions using the Cooper-Harper scale. This paper will address the specifics of the handling qualities methodology, vehicle configuration, scenarios flown, data collection tools, and subject ratings and comments. The initial Orion HQ assessment examined Orion docking to the ISS. This scenario demonstrates the Translational Hand Controller (THC) handling qualities of Orion. During this initial assessment, two different scenarios were evaluated. The first was a nominal docking approach to a stable ISS, with Orion initializing with relative position dispersions and a closing rate of approximately 0.1 ft/sec. The second docking scenario was identical to the first, except the attitude motion of the ISS was modeled to simulate a stress case ( 1 degree deadband per axis and 0.01 deg/sec rate deadband per axis). For both scenarios, subjects started each run on final approach at a docking port-to-port range of 20 ft. Subjects used the THC in pulse mode with cues from the docking camera image, window views, and range and range rate data displayed on the Orion display units. As in the actual design, the attitude of the Orion vehicle was held by the automated flight control system at 0.5 degree deadband per axis. Several error sources were modeled including Reaction

  20. 21 CFR 866.5470 - Hemoglobin immunological test system.

    Science.gov (United States)

    2010-04-01

    .... Measurements of free hemoglobin aid in the diagnosis of various hematologic disorders, such as sickle cell... blood cells), and leukemia (cancer of the blood-forming organs). (b) Classification. Class II...

  1. A nanocluster-based fluorescent sensor for sensitive hemoglobin detection.

    Science.gov (United States)

    Yang, Dongqin; Meng, Huijie; Tu, Yifeng; Yan, Jilin

    2017-08-01

    In this report, a fluorescence sensor for sensitive detection of hemoglobin was developed. Gold nanoclusters were first synthesized with bovine serum albumin. It was found that both hydrogen peroxide and hemoglobin could weakly quench the fluorescence from the gold nanoclusters, but when these two were applied onto the nanolcusters simultaneously, a much improved quenching was resulted. This enhancing effect was proved to come from the catalytic generation of hydroxyl radical by hemoglobin. Under an optimized condition, the quenching linearly related to the concentration of hemoglobin in the range of 1-250nM, and a limit of detection as low as 0.36nM could be obtained. This provided a sensitive means for the quantification of Hb. The sensor was then successfully applied for blood analyses with simple sample pretreatment. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Novel subunit structure observed for noncooperative hemoglobin from Urechis caupo.

    Science.gov (United States)

    Kolatkar, P R; Meador, W E; Stanfield, R L; Hackert, M L

    1988-03-05

    Tetrameric hemoglobin from the "fat innkeeper" worm Urechis caupo possesses a novel subunit arrangement having an "inside out" quaternary structure in that the G/H helices are located on the outer surface of the tetramer. A 5-A resolution crystal structure reveals that although the individual subunits are beta-like, having a distinct D helix and the general myoglobin fold, the subunit contacts are very different from those previously observed for hemoglobins. Furthermore, the hemoglobin from U. caupo is also quite different from the unusual hemoglobin tetramer from clam which also has its G/H helices on the outer surface but with the hemes in close proximity through E-F helical contacts (Royer, W. E., Jr., Love, W. E., and Fenderson, F. F. (1985) Nature 316, 277-280).

  3. The influence of socioeconomic status on the hemoglobin level and ...

    African Journals Online (AJOL)

    Conclusion: Poor socioeconomic status has an adverse effect on the nutritional status and hemoglobin of SCA patients. ... Date of Acceptance: 15-Mar-2011 ..... This study was designed to determine the relationship .... mobiles and devices.

  4. Hemoglobin as a factor in the control of tumor oxygenation

    International Nuclear Information System (INIS)

    Hirst, D.G.

    1987-01-01

    The concentration of hemoglobin in the blood has been shown to have a market effect on the radiosensitivity of human and animal tumors. Experimental studies in mice indicate that radiosensitivity is influenced by a change in the hemoglobin level rather than by the absolute concentration. This dependence may be exploited to therapeutic advantage. Recent studies of hemoglobin/oxygen affinity have shown that the concentration of 2,3 diphosphoglycerate (2,3 DPG) affects tumor sensitivity to X-rays. Increased 2,3 DPG levels increase radiosensitivity in several mouse tumors. The time dependence of this effect remains to be established. The effective application of these effects in man may depend on the development of drugs which produce changes in hemoglobin affinity without the need for blood transfusions. Several drugs are currently being investigated

  5. Manipulation of hemoglobin expression affects Arabidopsis shoot organogenesis

    DEFF Research Database (Denmark)

    Wang, Yaping; Elhiti, Mohamed; Hebelstrup, Kim

    2011-01-01

    Over the past few years non-symbiotic plant hemoglobins have been described in a variety of plant species where they fulfill several functions ranging from detoxification processes to basic aspects of plant growth and post-embryonic development. To date no information is available on the role...... of hemoglobins during invitro morphogenesis. Shoot organogenesis was induced in Arabidopsis lines constitutively expressing class 1, 2 and 3 hemoglobins (GLB1, 2 and 3) and lines in which the respective genes were either downregulated by RNAi (GLB1) or knocked out (GLB2 and GLB3). The process was executed......, 15, and 16), feed-back repressors of the cytokinin pathway, was repressed in both hemoglobin over-expressors whereas that of several Type-B ARRs (ARR2, 12, and 13), transcription activators of cytokinin-responsive genes, was induced. Such changes enhanced the sensitivity of the root explants...

  6. Lower versus Higher Hemoglobin Threshold for Transfusion in Septic Shock

    DEFF Research Database (Denmark)

    Holst, Lars B; Haase, Nicolai; Wetterslev, Jørn

    2014-01-01

    BACKGROUND: Blood transfusions are frequently given to patients with septic shock. However, the benefits and harms of different hemoglobin thresholds for transfusion have not been established. METHODS: In this multicenter, parallel-group trial, we randomly assigned patients in the intensive care...... unit (ICU) who had septic shock and a hemoglobin concentration of 9 g per deciliter or less to receive 1 unit of leukoreduced red cells when the hemoglobin level was 7 g per deciliter or less (lower threshold) or when the level was 9 g per deciliter or less (higher threshold) during the ICU stay...... were similar in the two intervention groups. CONCLUSIONS: Among patients with septic shock, mortality at 90 days and rates of ischemic events and use of life support were similar among those assigned to blood transfusion at a higher hemoglobin threshold and those assigned to blood transfusion...

  7. Direct electrochemistry of hemoglobin entrapped in dextran film on ...

    Indian Academy of Sciences (India)

    Administrator

    28. Li et al used single- walled carbon nanotube (SWCNT) and 1-hexyl-3- ... Electrochemistry of dextran/hemoglobin/carbon ionic liquid electrode. 273. 2.4 Procedures ..... used for the construction of H2O2 biosensor. Acknowledgement.

  8. Temperature-dependent enthalpy of oxygenation in Antarctic fish hemoglobins

    DEFF Research Database (Denmark)

    Fago, A.; Wells, R.M.G.; Weber, Roy E.

    1997-01-01

    The effect of temperature on the oxygen-binding properties of the hemoglobins of three cold-adapted Antarctic fish species, Dissostichus mawsoni, Pagothenia borchgrevinki and Trematomus, sp., has been investigated under different pH values and buffer conditions. A clear non linear van't Hoff plot...... (logP(50) vs 1/T) of D. mawsoni hemoglobin indicates that the enthalpy of oxygenation (slope of the plot) is temperature dependent and that at high temperatures oxygen-binding becomes less exothermic. Nearly linear relationships were found in the hemoglobins of the other two species. The data were...... oxygen binding. The degree of the temperature dependence of the heat of oxygenation observed in these hemoglobins seems to reflect the differences in their allosteric effects rather than a specific molecular adaptation to low temperatures. Moreover, this study indicates that the disagreement between...

  9. Receptor targeting of hemoglobin mediated by the haptoglobins

    DEFF Research Database (Denmark)

    Nielsen, Marianne Jensby; Moestrup, Søren Kragh

    2009-01-01

    Haptoglobin, the haptoglobin-hemoglobin receptor CD163, and the heme oxygenase-1 are proteins with a well-established function in the clearance and metabolism of "free" hemoglobin released during intravascular hemolysis. This scavenging system counteracts the potentially harmful oxidative and NO......-scavenging effects associated with "free" hemoglobin, and, furthermore, elicits an anti-inflammatory response. In the late primate evolution, haptoglobin variants with distinct functions have arisen, including haptoglobin polymers and the haptoglobin-related protein. The latter associates with a subspecies of high......-density lipoprotein (HDL) particles playing a crucial role in the innate immunity against certain trypanosome parasites. Recent studies have elucidated this fairly sophisticated immune defense mechanism that takes advantage of a trypanosomal haptoglobin-hemoglobin receptor evolved to supply the parasite with heme...

  10. Comparison of crystal and solution hemoglobin binding of selected antigelling agents and allosteric modifiers

    International Nuclear Information System (INIS)

    Mehanna, A.S.; Abraham, D.J.

    1990-01-01

    This paper details comprehensive binding studies (solution and X-ray) of human hemoglobin A with a group of halogenated carboxylic acids that were investigated as potential antisickling agents. It is, to our knowledge, the first study to compare solution and crystal binding for a series of compounds under similar high-salt conditions used for cocrystallization. The compounds include [(3,4-dichlorobenzyl)oxy]acetic acid, [(p-bromobenzyl)oxy]acetic acid, clofibric acid, and bezafibrate. The location and stereochemistry of binding sites have been established by X-ray crystallography, while the number of binding sites and affinity constants were measured by using equilibrium dialysis. The observed crystal structures are consistent with the binding observed in solution and that the number of binding sites is independent of salt concentration, while the binding constant increases with increasing salt concentration. The studies also reveal that relatively small changes in the chemical structure of a drug molecule can result in entirely different binding sites on the protein. Moreover, the X-ray studies provide a possible explanation for the multiplicity in function exhibited by these compounds as allosteric modulators and/or antisickling agents. Finally, the studies indicate that these compounds bind differently to the R and T states of hemoglobin, and observation of special significance to the original design of these agents

  11. A microcalorimetry and binding study on interaction of dodecyl trimethylammonium bromide with wigeon hemoglobin

    International Nuclear Information System (INIS)

    Bordbar, A.K.; Moosavi-Movahedi, A.A.; Amini, M.K.

    2003-01-01

    The thermodynamic parameters for the binding of dodecyl trimethylammonium bromide (DTAB) with wigeon hemoglobin (Hb) in aqueous solution at various pH and 27 deg. C have been measured by equilibrium dialysis and titration microcalorimetry techniques. The Scatchard plots represent unusual features at neutral and alkaline pH and specific binding at acidic pH. This leads us to analyze the binding data by fitting the data to the Hill equation for multiclasses of binding sites. The best fit was obtained with the equation for one class at acidic pH and two classes at neutral and alkaline pH. The thermodynamic analysis of the binding process shows that the strength of binding at neutral pH is more than these at other pH values. This can be related to the more accessible hydrophobic surface area of wigeon hemoglobin at this pH. The endothermic enthalpy data which was measured by microcalorimetry confirms the binding data analysis and represents the more regular and stable structure of wigeon hemoglobin at neutral pH

  12. Hemoglobin protein hollow shells fabricated through covalent layer-by-layer technique

    International Nuclear Information System (INIS)

    Duan Li; He Qiang; Yan Xuehai; Cui Yue; Wang Kewei; Li Junbai

    2007-01-01

    Hemoglobin (Hb) protein microcapsules held together by cross-linker, glutaraldehyde (GA), were successfully fabricated by covalent layer-by-layer (LbL) technique. The Schiff base reaction occurred on the colloid templates between the aldehyde groups of GA and free amino sites of Hb results in the formation of GA/Hb microcapsules after the removal of the templates. The structure of obtained monodisperse protein microcapsule was characterized by transmission electron microscopy (TEM) and confocal laser scanning microscopy (CLSM). The UV-Vis spectra measurements demonstrate the existence of Hb in the assembled capsules. Cyclic voltammetry (CV) and potential-controlled amperometric measurements (I-t curve) confirm that hemoglobin microcapsules after fabrication remain their heme electroactivity. Moreover, direct electron transfer process from protein to electrode surface was performed to detect the heme electrochemistry without using any mediator or promoter. The experiments of fluorescence recovery after photobleaching (FRAP) by CLSM demonstrate that the hemoglobin protein microcapsules have an improved permeability comparing to the conventional polyelectrolyte microcapsules

  13. Detection of anion-linked polymerization of the tetrameric hemoglobin from Scapharca inaequivalvis by 35Cl NMR spectroscopy

    International Nuclear Information System (INIS)

    Chiancone, E.; Univ. 'La Sapienza', Rome; Drakenberg, T.; Forsen, S.

    1988-01-01

    Ion binding to the hemoglobin components of Scaphara inaequivalvis has been measured directly in quadrupole relaxation experiments of 23 Na and 35 Cl. The dimeric and tetrameric hemoglobins interact weakly with sodium ions, but differ in their interaction with chloride ions. The dimeric hemoglobin binds chloride ions with low affinity, whereas the tetrameric protein has high affinity chloride binding sites. Binding of chloride ions to these high affinity sites brings about an oxygen-linked polymerization which manifests itself in an unusual dependence of the 35 Cl excess linewidth on the concentration of the anion. Polymerization is more pronounced in the deoxygenated than in the oxygenated derivative: in the former, it has been observed previously in sedimentation velocity experiments. The sensitivity of the 35 Cl excess linewidth on polymer formation indicates that the residence time of the transiently bound chloride on the tetrameric hemoglobin is not shorter than the correlation time of the molecule (2 X 10 -8 s -1 ). 17 refs.; 2 figs

  14. Effects of thyroid status on glycated hemoglobin

    Directory of Open Access Journals (Sweden)

    Rana Bhattacharjee

    2017-01-01

    Full Text Available Introduction: Glycated hemoglobin (HbA1c can be altered in different conditions. We hypothesize that HbA1c levels may change due to altered thyroid status, possibly due to changes in red blood cell (RBC turnover. Objectives: The objective of this study was to determine the effects of altered thyroid status on HbA1c levels in individuals without diabetes, with overt hyper- and hypo-thyroidism, and if present, whether such changes in HbA1c are reversed after achieving euthyroid state. Methods: Euglycemic individuals with overt hypo- or hyper-thyroidism were selected. Age- and sex-matched controls were recruited. Baseline HbA1c and reticulocyte counts (for estimation of RBC turnover were estimated in all the patients and compared. Thereafter, stable euthyroidism was achieved in a randomly selected subgroup and HbA1c and reticulocyte count was reassessed. HbA1c values and reticulocyte counts were compared with baseline in both the groups. Results: Hb A1c in patients initially selected was found to be significantly higher in hypothyroid group. HbA1c values in hyperthyroid patients were not significantly different from controls. HbA1c reduction and rise in reticulocyte count were significant in hypothyroid group following treatment without significant change in glucose level. Hb A1c did not change significantly following treatment in hyperthyroid group. The reticulocyte count, however, decreased significantly. Conclusion: Baseline HbA1c levels were found to be significantly higher in hypothyroid patients, which reduced significantly after achievement of euthyroidism without any change in glucose levels. Significant baseline or posttreatment change was not observed in hyperthyroid patients. Our study suggests that we should be cautious while interpreting HbA1c data in patients with hypothyroidism.

  15. Hemoglobin concentrations and associated factors in adolescentes from Recife, Brazil

    OpenAIRE

    Elisângela Barros Soares Mendonça; Lilian Ferreira Muniz; Ilma Kruze Grande de Arruda; Alcides da Silva Diniz

    2014-01-01

    OBJECTIVE: To estimate the prevalence of anemia and associated factors in adolescents from the city of Recife in Pernambuco state. METHODS: This is a cross-sectional study, involving a random sample of 256 adolescents of both genders, aged 13 to 18, whose hemoglobin concentrations were evaluated, along with their nutritional status and socioeconomic and demographic characteristics. RESULTS: The prevalence of inadequate hemoglobin concentrations was 10.2% [CI95%=6.7-14.5], reaching levels cons...

  16. Thalassemia and Hemoglobin E in Southern Thai Blood Donors

    OpenAIRE

    Nuinoon, Manit; Kruachan, Kwanta; Sengking, Warachaya; Horpet, Dararat; Sungyuan, Ubol

    2014-01-01

    Thalassemia and hemoglobin E (Hb E) are common in Thailand. Individuals with thalassemia trait usually have a normal hemoglobin concentration or mild anemia. Therefore, thalassemic individuals who have minimum acceptable Hb level may be accepted as blood donors. This study was aimed at determining the frequency of α-thalassemia 1 trait, β-thalassemia trait, and Hb E-related syndromes in Southern Thai blood donors. One hundred and sixteen voluntary blood donors, Southern Thailand origin, were ...

  17. Individualized Anemia Management Reduces Hemoglobin Variability in Hemodialysis Patients

    OpenAIRE

    Gaweda, Adam E.; Aronoff, George R.; Jacobs, Alfred A.; Rai, Shesh N.; Brier, Michael E.

    2013-01-01

    One-size-fits-all protocol-based approaches to anemia management with erythropoiesis-stimulating agents (ESAs) may result in undesired patterns of hemoglobin variability. In this single-center, double-blind, randomized controlled trial, we tested the hypothesis that individualized dosing of ESA improves hemoglobin variability over a standard population-based approach. We enrolled 62 hemodialysis patients and followed them over a 12-month period. Patients were randomly assigned to receive ESA ...

  18. Comparative study of bedside and laboratory measurements of hemoglobin.

    Science.gov (United States)

    Krenzischek, D A; Tanseco, F V

    1996-11-01

    The purpose of this study was to examine the effects of variations in technique on measurements of hemoglobin level done at the bedside and to compare these results with laboratory measurements of hemoglobin. In accordance with hospital policy, procedure, and protocol, various techniques were used to obtain samples of capillary and venous blood and of blood from arterial and central venous catheters. Levels of hemoglobin were measured at the bedside and in the laboratory, and the results were compared. The Johns Hopkins Hospital adult postanesthesia care unit. A total of 187 blood samples were obtained from 62 adults who had undergone general surgery. Group I comprised 20 subjects with capillary and venous blood samples. Group II comprised 21 subjects with arterial blood samples. Group III comprised 21 subjects with central venous blood samples. The results showed that the amount of blood to be discarded before obtaining samples of arterial and central venous blood need not be any larger than double the dead space of the catheter, and that shaking the blood sample for 10 seconds was sufficient to mix the sample before measurement of hemoglobin levels. Results of bedside and laboratory measurements of hemoglobin level were comparable. Bedside measurement of hemoglobin increases efficiency in patient care, decreases risk of blood-transmitted infection for staff, and decreases cost to the patient. However, the persons who perform the assay must be responsible in adhering to the standard of practice to minimize errors in the measurements.

  19. Cell volume regulation in hemoglobin CC and AA erythrocytes

    International Nuclear Information System (INIS)

    Berkowitz, L.R.; Orringer, E.P.

    1987-01-01

    Swelling hemoglobin CC erythrocytes stimulates a ouabain-insensitive K flux that restores original cell volume. Studies were performed with the K analog, 86 Rb. This volume regulatory pathway was characterized for its anion dependence, sensitivity to loop diuretics, and requirement for Na. The swelling-induced K flux was eliminated if intracellular chloride was replaced by nitrate and both swelling-activated K influx and efflux were partially inhibited by 1 mM furosemide or bumetanide. K influx in swollen hemoglobin CC cells was not diminished when Na in the incubation medium was replaced with choline, indicating Na independence of the swelling-induced flux. Identical experiments with hemoglobin AA cells also demonstrated a swelling-induced increase in K flux, but the magnitude and duration of this increase were considerably less than that seen with hemoglobin CC cells. The increased K flux in hemoglobin AA cells was likewise sensitive to anion replacement and to loop diuretics and did not require the presence of Na. These data indicate that a volume-activated K pathway with similar transport characteristics exists in both hemoglobin CC and AA red cells

  20. ARCADE small-scale docking mechanism for micro-satellites

    Science.gov (United States)

    Boesso, A.; Francesconi, A.

    2013-05-01

    The development of on-orbit autonomous rendezvous and docking (ARD) capabilities represents a key point for a number of appealing mission scenarios that include activities of on-orbit servicing, automated assembly of modular structures and active debris removal. As of today, especially in the field of micro-satellites ARD, many fundamental technologies are still missing or require further developments and micro-gravity testing. In this framework, the University of Padova, Centre of Studies and Activities for Space (CISAS), developed the Autonomous Rendezvous Control and Docking Experiment (ARCADE), a technology demonstrator intended to fly aboard a BEXUS stratospheric balloon. The goal was to design, build and test, in critical environment conditions, a proximity relative navigation system, a custom-made reaction wheel and a small-size docking mechanism. The ARCADE docking mechanism was designed against a comprehensive set of requirements and it can be classified as small-scale, central, gender mating and unpressurized. The large use of commercial components makes it low-cost and simple to be manufactured. Last, it features a good tolerance to off-nominal docking conditions and a by-design soft docking capability. The final design was extensively verified to be compliant with its requirements by means of numerical simulations and physical testing. In detail, the dynamic behaviour of the mechanism in both nominal and off-nominal conditions was assessed with the multibody dynamics analysis software MD ADAMS 2010 and functional tests were carried out within the fully integrated ARCADE experiment to ensure the docking system efficacy and to highlight possible issues. The most relevant results of the study will be presented and discussed in conclusion to this paper.

  1. Protein-protein docking with dynamic residue protonation states.

    Directory of Open Access Journals (Sweden)

    Krishna Praneeth Kilambi

    2014-12-01

    Full Text Available Protein-protein interactions depend on a host of environmental factors. Local pH conditions influence the interactions through the protonation states of the ionizable residues that can change upon binding. In this work, we present a pH-sensitive docking approach, pHDock, that can sample side-chain protonation states of five ionizable residues (Asp, Glu, His, Tyr, Lys on-the-fly during the docking simulation. pHDock produces successful local docking funnels in approximately half (79/161 the protein complexes, including 19 cases where standard RosettaDock fails. pHDock also performs better than the two control cases comprising docking at pH 7.0 or using fixed, predetermined protonation states. On average, the top-ranked pHDock structures have lower interface RMSDs and recover more native interface residue-residue contacts and hydrogen bonds compared to RosettaDock. Addition of backbone flexibility using a computationally-generated conformational ensemble further improves native contact and hydrogen bond recovery in the top-ranked structures. Although pHDock is designed to improve docking, it also successfully predicts a large pH-dependent binding affinity change in the Fc-FcRn complex, suggesting that it can be exploited to improve affinity predictions. The approaches in the study contribute to the goal of structural simulations of whole-cell protein-protein interactions including all the environmental factors, and they can be further expanded for pH-sensitive protein design.

  2. Improving Docking Performance Using Negative Image-Based Rescoring.

    Science.gov (United States)

    Kurkinen, Sami T; Niinivehmas, Sanna; Ahinko, Mira; Lätti, Sakari; Pentikäinen, Olli T; Postila, Pekka A

    2018-01-01

    Despite the large computational costs of molecular docking, the default scoring functions are often unable to recognize the active hits from the inactive molecules in large-scale virtual screening experiments. Thus, even though a correct binding pose might be sampled during the docking, the active compound or its biologically relevant pose is not necessarily given high enough score to arouse the attention. Various rescoring and post-processing approaches have emerged for improving the docking performance. Here, it is shown that the very early enrichment (number of actives scored higher than 1% of the highest ranked decoys) can be improved on average 2.5-fold or even 8.7-fold by comparing the docking-based ligand conformers directly against the target protein's cavity shape and electrostatics. The similarity comparison of the conformers is performed without geometry optimization against the negative image of the target protein's ligand-binding cavity using the negative image-based (NIB) screening protocol. The viability of the NIB rescoring or the R-NiB, pioneered in this study, was tested with 11 target proteins using benchmark libraries. By focusing on the shape/electrostatics complementarity of the ligand-receptor association, the R-NiB is able to improve the early enrichment of docking essentially without adding to the computing cost. By implementing consensus scoring, in which the R-NiB and the original docking scoring are weighted for optimal outcome, the early enrichment is improved to a level that facilitates effective drug discovery. Moreover, the use of equal weight from the original docking scoring and the R-NiB scoring improves the yield in most cases.

  3. Comparison of Hemoglobin Levels Before and After Hemodialysis and Their Effects on Erythropoietin Dosing and Cost

    OpenAIRE

    Sagheb; Fallahzadeh; Moaref; Fallahzadeh; Dormanesh

    2016-01-01

    Background Hemoglobin levels measured after hemodialysis, as compared to hemoglobin levels measured before hemodialysis, are suggested to be a more accurate reflection of the hemoglobin levels between hemodialysis sessions, and to be a better reference point for adjusting erythropoietin dosing. Objectives The aim of this study was to compare the hemoglobin levels before and after hemodialysis, to calculate the required erythropoie...

  4. Crystallization and preliminary X-ray structural studies of hemoglobin A2 and hemoglobin E, isolated from the blood samples of β-thalassemic patients

    International Nuclear Information System (INIS)

    Dasgupta, Jhimli; Sen, Udayaditya; Choudhury, Debi; Datta, Poppy; Chakrabarti, Abhijit; Chakrabarty, Sudipa Basu; Chakrabarty, Amit; Dattagupta, J.K.

    2003-01-01

    Hemoglobin A 2 (α 2 δ 2 ), a minor (2-3%) component of circulating red blood cells, acts as an anti-sickling agent and its elevated concentration in β-thalassemia is a useful clinical diagnostic. In β-thalassemia major, where there is a failure of β-chain production, HbA 2 acts as the predominant oxygen deliverer. Hemoglobin E, is another common abnormal hemoglobin, caused by splice site mutation in exon 1 of β globin gene, when combines with β-thalassemia, causes severe microcytic anemia. The purification, crystallization, and preliminary structural studies of HbA 2 and HbE are reported here. HbA 2 and HbE are purified by cation exchange column chromatography in presence of KCN from the blood samples of individuals suffering from β-thalassemia minor and Eβ-thalassemia. X-ray diffraction data of HbA 2 and HbE were collected upto 2.1 and 1.73 A, respectively. HbA 2 crystallized in space group P2 1 with unit cell parameters a=54.33 A, b=83.73 A, c=62.87 A, and β=99.80 degree sign whereas HbE crystallized in space group P2 1 2 1 2 1 with unit cell parameters a=60.89 A, b=95.81 A, and c=99.08 A. Asymmetric unit in each case contains one Hb tetramer in R 2 state

  5. GOMoDo: A GPCRs online modeling and docking webserver.

    Directory of Open Access Journals (Sweden)

    Massimo Sandal

    Full Text Available G-protein coupled receptors (GPCRs are a superfamily of cell signaling membrane proteins that include >750 members in the human genome alone. They are the largest family of drug targets. The vast diversity and relevance of GPCRs contrasts with the paucity of structures available: only 21 unique GPCR structures have been experimentally determined as of the beginning of 2013. User-friendly modeling and small molecule docking tools are thus in great demand. While both GPCR structural predictions and docking servers exist separately, with GOMoDo (GPCR Online Modeling and Docking, we provide a web server to seamlessly model GPCR structures and dock ligands to the models in a single consistent pipeline. GOMoDo can automatically perform template choice, homology modeling and either blind or information-driven docking by combining together proven, state of the art bioinformatic tools. The web server gives the user the possibility of guiding the whole procedure. The GOMoDo server is freely accessible at http://molsim.sci.univr.it/gomodo.

  6. Inspection by docking of nuclear-powered ship 'Mutsu'

    International Nuclear Information System (INIS)

    1989-01-01

    Japan Atomic Energy Research Institute carried out the docking and inspection of the nuclear-powered ship 'Mutsu' at Sekinehama Port, Mutsu City, Aomori Prefecture, from the middle of June to late in July, 1989. In this inspection, the Mutsu was mounted on a floating dock off the coast, the dock was towed by tugboats into the port and moored at the pier, and after completing the works in the dock, the dock was towed to the outside of the port, and the Mutsu was launched. The Mutsu was built as a nuclear power experiment ship, and length 130 m, breadth 19 m, depth 13.2 m, design draft at full load 6.9 m, 8242 GT. One PWR of 36 MWt and one steam turbine of 10000 ps are installed, and velocity is 16.5 knots. In September, 1974, after the first criticality, the leak of radioactivity occurred. The repair of shield and general inspection on safety were carried out in Sasebo Shipyard from August, 1980 to August, 1982. Thereafter, the Mutsu stayed in Ominato, but in January, 1988, after the completion of Sekinehama Port, the Mutsu was brought there. The Sekinehama Port, the test and inspection of the Mutsu carried out so far and the plan of hereafter are reported. (K.I.)

  7. GPU acceleration of Dock6's Amber scoring computation.

    Science.gov (United States)

    Yang, Hailong; Zhou, Qiongqiong; Li, Bo; Wang, Yongjian; Luan, Zhongzhi; Qian, Depei; Li, Hanlu

    2010-01-01

    Dressing the problem of virtual screening is a long-term goal in the drug discovery field, which if properly solved, can significantly shorten new drugs' R&D cycle. The scoring functionality that evaluates the fitness of the docking result is one of the major challenges in virtual screening. In general, scoring functionality in docking requires a large amount of floating-point calculations, which usually takes several weeks or even months to be finished. This time-consuming procedure is unacceptable, especially when highly fatal and infectious virus arises such as SARS and H1N1, which forces the scoring task to be done in a limited time. This paper presents how to leverage the computational power of GPU to accelerate Dock6's (http://dock.compbio.ucsf.edu/DOCK_6/) Amber (J. Comput. Chem. 25: 1157-1174, 2004) scoring with NVIDIA CUDA (NVIDIA Corporation Technical Staff, Compute Unified Device Architecture - Programming Guide, NVIDIA Corporation, 2008) (Compute Unified Device Architecture) platform. We also discuss many factors that will greatly influence the performance after porting the Amber scoring to GPU, including thread management, data transfer, and divergence hidden. Our experiments show that the GPU-accelerated Amber scoring achieves a 6.5× speedup with respect to the original version running on AMD dual-core CPU for the same problem size. This acceleration makes the Amber scoring more competitive and efficient for large-scale virtual screening problems.

  8. Identification of a haptoglobin-hemoglobin complex in the Alaskan Least Cisco (Coregonus sardinella).

    Science.gov (United States)

    Wahl, S M; Boger, J K; Michael, V; Duffy, L K

    1992-01-01

    The hemoglobin and a hemoglobin binding protein have been characterized in the Arctic fish (Coregonus sardinella). The evolutionary significance of the hemoglobin and plasma protein differences between fish and mammals is still unresolved. Blood samples from the Alaskan Least Cisco were separated into plasma and hemoglobin fractions and the proteins in these fractions were analyzed both by alkaline agarose gel electrophoresis, by isolelectric focusing, and by capillary electrophoresis. Staining the plasma proteins gels with o-dianisidine revealed hemoglobin containing protein complexes. A hemoglobin-containing band was observed in hemolyzed plasma which did not migrate with free hemoglobin, and is believed to be hemoglobin-haptoglobin complex. Size exclusion chromatography further characterized the hemoglobin as disassociating freely into dimers, and hemoglobin-haptoglobin complex having a molecular weight greater then 200,000 daltons.

  9. Alteration of the α1β2/α2β1 subunit interface contributes to the increased hemoglobin-oxygen affinity of high-altitude deer mice

    Energy Technology Data Exchange (ETDEWEB)

    Inoguchi, Noriko; Mizuno, Nobuhiro; Baba, Seiki; Kumasaka, Takashi; Natarajan, Chandrasekhar; Storz, Jay F.; Moriyama, Hideaki; Permyakov, Eugene A.

    2017-03-31

    Deer mice (Peromyscus maniculatus) that are native to high altitudes in the Rocky Mountains have evolved hemoglobins with an increased oxygen-binding affinity relative to those of lowland conspecifics. To elucidate the molecular mechanisms responsible for the evolved increase in hemoglobin-oxygen affinity, the crystal structure of the highland hemoglobin variant was solved and compared with the previously reported structure for the lowland variant. Highland hemoglobin yielded at least two crystal types, in which the longest axes were 507 and 230 Å. Using the smaller unit cell crystal, the structure was solved at 2.2 Å resolution. The asymmetric unit contained two tetrameric hemoglobin molecules. The analyses revealed that αPro50 in the highland hemoglobin variant promoted a stable interaction between αHis45 and heme that was not seen in the αHis50 lowland variant. The αPro50 mutation also altered the nature of atomic contacts at the α1β2/α2β1 intersubunit interfaces. These results demonstrate how affinity-altering changes in intersubunit interactions can be produced by mutations at structurally remote sites.

  10. Identification of potent inhibitors against snake venom metalloproteinase (SVMP) using molecular docking and molecular dynamics studies.

    Science.gov (United States)

    Chinnasamy, Sathishkumar; Chinnasamy, Selvakkumar; Nagamani, Selvaraman; Muthusamy, Karthikeyan

    2015-01-01

    Snake venom metalloproteinase (SVMP) (Echis coloratus (Carpet viper) is a multifunctional enzyme that is involved in producing several symptoms that follow a snakebite, such as severe local hemorrhage, nervous system effects and tissue necrosis. Because the three-dimensional (3D) structure of SVMP is not known, models were constructed, and the best model was selected based on its stereo-chemical quality. The stability of the modeled protein was analyzed through molecular dynamics (MD) simulation studies. Structure-based virtual screening was performed, and 15 potential molecules with the highest binding energies were selected. Further analysis was carried out with induced fit docking, Prime/MM-GBSA (ΔGBind calculations), quantum-polarized ligand docking, and density functional theory calculations. Further, the stability of the lead molecules in the SVMP-active site was examined using MD simulation. The results showed that the selected lead molecules were highly stable in the active site of SVMP. Hence, these molecules could potentially be selective inhibitors of SVMP. These lead molecules can be experimentally validated, and their backbone structural scaffold could serve as building blocks in designing drug-like molecules for snake antivenom.

  11. In silico molecular modeling and docking studies on the leishmanial tryparedoxin peroxidase

    Directory of Open Access Journals (Sweden)

    Ozal Mutlu

    2014-04-01

    Full Text Available Leishmaniasis is one of the most common form of neglected parasitic disease that affects about 350 million people worldwide. Leishmanias have a trypanothione mediated hydroperoxide metabolism to eliminate endogenous or exogenous oxidative agents. Both of 2-Cys peroxiredoxin (Prx and glutathione peroxidase type tryparedoxin peroxidase (Px are the terminal enzymes in the trypanothione dependent detoxification system. Therefore absence of trypanothione redox system in mammals and the sensitivity of trypanosomatids against oxidative stress, enzymes of this pathway are drug targets candidates. In this study, 3D structure of tryparedoxin peroxidase (2-Cys peroxiredoxin type from Leishmania donovani (LdTXNPx was described by homology modeling method based on the template of tryparedoxin peroxidase from Crithidia fasciculata and selected compounds were docked to the active site pocket. The quality of the 3D structure of the model was confirmed by various web based validation programs. When compared secondary and tertiary structure of the model, it showed a typical thioredoxin fold containing a central beta-sheet and three alpha-helices. Docking study showed that the selected compound 2 (CID 16073813 interacted with the active site amino acids and binding energy was -118.675 kcal/mol.

  12. Imidazole-containing farnesyltransferase inhibitors: 3D quantitative structure-activity relationships and molecular docking

    Science.gov (United States)

    Xie, Aihua; Odde, Srinivas; Prasanna, Sivaprakasam; Doerksen, Robert J.

    2009-07-01

    One of the most promising anticancer and recent antimalarial targets is the heterodimeric zinc-containing protein farnesyltransferase (FT). In this work, we studied a highly diverse series of 192 Abbott-initiated imidazole-containing compounds and their FT inhibitory activities using 3D-QSAR and docking, in order to gain understanding of the interaction of these inhibitors with FT to aid development of a rational strategy for further lead optimization. We report several highly significant and predictive CoMFA and CoMSIA models. The best model, composed of CoMFA steric and electrostatic fields combined with CoMSIA hydrophobic and H-bond acceptor fields, had r 2 = 0.878, q 2 = 0.630, and r pred 2 = 0.614. Docking studies on the statistical outliers revealed that some of them had a different binding mode in the FT active site based on steric bulk and available active site space, explaining why the predicted activities differed from the experimental activities.

  13. The narrow therapeutic window of glycated hemoglobin and assay variability.

    Science.gov (United States)

    Hosseini, S S; Bibler, I; Charles, M A

    1999-12-01

    Glycated hemoglobin is measured by a variety of assays, each of which has a unique normal level. Our purpose is to show that among the different assays available in the United States, using the same patient's blood sample, assay results may vary widely and may more or less easily achieve a glycated hemoglobin value within the normal range. The following assays were compared using the same patient's blood sample for each pair of assays: glycohemoglobin affinity assay (GHB Reader; Isolab, Akron, OH) versus gel electrophoresis assay (n = 76); Isolab versus ion capture assay (IMX; Abbott Laboratories, Irving, TX) (n = 57); monoclonal antibody assay (DCA2000; Bayer Diagnostics, Pittsburgh, PA) versus IMX (n = 100); and high-performance liquid chromatography (HPLC) assay (Bio-Rad Variant A1c; Bio-Rad Laboratories, Richmond, CA) versus IMX assay (n = 55). Our analyses indicate that a relative ranking can be established for the ease of achieving a normal glycated hemoglobin level. The ranking indicates that the most stringent or difficult assays for achieving a normal level are the Isolab and DCA2000 assays. The intermediate assays are the IMX and Bio-Rad Variant, and the easiest method for achieving a normal value is the gel electrophoresis assay. Our results indicate that various glycated hemoglobin assays vary widely and are associated with more or less difficulty for an individual patient to achieve a glycated hemoglobin level within the normal range. These results are especially significant with respect to (1) the clinically narrow therapeutic window of glycated hemoglobin values in type 1 diabetes to avoid rapidly advancing severe hypoglycemia rates and chronic microvascular complication rates, and (2) the glycated hemoglobin threshold for rapidly advancing macrovascular disease in both type 1 and type 2 patients.

  14. Propanil-induced methemoglobinemia and hemoglobin binding in the rat

    Energy Technology Data Exchange (ETDEWEB)

    McMillan, D.C.; McRae, T.A.; Hinson, J.A. (National Center for Toxicological Research, Jefferson, AR (USA))

    1990-09-15

    Administration of (ring-U-14C)propanil (3,4-dichloropropionanilide) to male Sprague-Dawley rats (30, 100, and 300 mg/kg, ip) increased the formation of methemoglobin at the two highest doses. Following a propanil dose of 100 mg/kg, methemoglobin formation attained a maximum level of 5% by 1.5 hr and declined to normal levels (approximately 2.5%) by 12 hr. Hemoglobin binding attained a maximum level of 50 pmol/mg protein by 12 hr, and remained constant for 24 hr. Following a propanil dose of 300 mg/kg, methemoglobin formation attained a maximum level of 24% by 4.5 hr, and declined to a level of 5% by 24 hr. Hemoglobin binding attained a maximum level of 425 pmol/mg protein by 12 hr, and remained constant for 24 hr. Hemoglobin binding was also detected at the lowest propanil dose (10 pmol/mg protein) even though methemoglobin formation was not observed. HPLC analysis of alkaline-treated hemoglobin from propanil-treated rats indicated the presence of one radiolabeled compound with the same HPLC retention time as 3,4-dichloraniline. These data are consistent with the concept that propanil is converted to N-hydroxy-3,4-dichloroaniline in the liver. Subsequently, this metabolite enters the erythrocyte and is oxidized by hemoglobin to 3,4-dichloronitrosobenzene with concomitant conversion of oxyhemoglobin to methemoglobin. The 3,4-dichloronitrosobenzene binds to cysteine residues on hemoglobin as the corresponding sulfinic acid amide adduct. These data suggest that human exposure to propanil may be monitored in the absence of observable toxicity by the analysis of propanil metabolites bound to hemoglobin.

  15. Expression and purification of recombinant hemoglobin in Escherichia coli.

    Directory of Open Access Journals (Sweden)

    Chandrasekhar Natarajan

    Full Text Available Recombinant DNA technologies have played a pivotal role in the elucidation of structure-function relationships in hemoglobin (Hb and other globin proteins. Here we describe the development of a plasmid expression system to synthesize recombinant Hbs in Escherichia coli, and we describe a protocol for expressing Hbs with low intrinsic solubilities. Since the α- and β-chain Hbs of different species span a broad range of solubilities, experimental protocols that have been optimized for expressing recombinant human HbA may often prove unsuitable for the recombinant expression of wildtype and mutant Hbs of other species.As a test case for our expression system, we produced recombinant Hbs of the deer mouse (Peromyscus maniculatus, a species that has been the subject of research on mechanisms of Hb adaptation to hypoxia. By experimentally assessing the combined effects of induction temperature, induction time and E. coli expression strain on the solubility of recombinant deer mouse Hbs, we identified combinations of expression conditions that greatly enhanced the yield of recombinant protein and which also increased the efficiency of post-translational modifications.Our protocol should prove useful for the experimental study of recombinant Hbs in many non-human animals. One of the chief advantages of our protocol is that we can express soluble recombinant Hb without co-expressing molecular chaperones, and without the need for additional reconstitution or heme-incorporation steps. Moreover, our plasmid construct contains a combination of unique restriction sites that allows us to produce recombinant Hbs with different α- and β-chain subunit combinations by means of cassette mutagenesis.

  16. Expression and purification of recombinant hemoglobin in Escherichia coli.

    Science.gov (United States)

    Natarajan, Chandrasekhar; Jiang, Xiaoben; Fago, Angela; Weber, Roy E; Moriyama, Hideaki; Storz, Jay F

    2011-01-01

    Recombinant DNA technologies have played a pivotal role in the elucidation of structure-function relationships in hemoglobin (Hb) and other globin proteins. Here we describe the development of a plasmid expression system to synthesize recombinant Hbs in Escherichia coli, and we describe a protocol for expressing Hbs with low intrinsic solubilities. Since the α- and β-chain Hbs of different species span a broad range of solubilities, experimental protocols that have been optimized for expressing recombinant human HbA may often prove unsuitable for the recombinant expression of wildtype and mutant Hbs of other species. As a test case for our expression system, we produced recombinant Hbs of the deer mouse (Peromyscus maniculatus), a species that has been the subject of research on mechanisms of Hb adaptation to hypoxia. By experimentally assessing the combined effects of induction temperature, induction time and E. coli expression strain on the solubility of recombinant deer mouse Hbs, we identified combinations of expression conditions that greatly enhanced the yield of recombinant protein and which also increased the efficiency of post-translational modifications. Our protocol should prove useful for the experimental study of recombinant Hbs in many non-human animals. One of the chief advantages of our protocol is that we can express soluble recombinant Hb without co-expressing molecular chaperones, and without the need for additional reconstitution or heme-incorporation steps. Moreover, our plasmid construct contains a combination of unique restriction sites that allows us to produce recombinant Hbs with different α- and β-chain subunit combinations by means of cassette mutagenesis.

  17. Plant hemoglobins: Important players at the crossroads between oxygen and nitric oxide

    DEFF Research Database (Denmark)

    Gupta, Kapuganti J; Hebelstrup, Kim; Mur, Luis A J

    2011-01-01

    Plant hemoglobins constitute a diverse group of hemeproteins and evolutionarily belong to three different classes. Class 1 hemoglobins possess an extremely high affinity to oxygen and their main function consists in scavenging of nitric oxide (NO) at very low oxygen levels. Class 2 hemoglobins have...... at high O2 concentrations. Depending on their physical properties, hemoglobins belong either to hexacoordinate non-symbiotic or pentacoordinate symbiotic groups. Plant hemoglobins are plausible targets for improving resistance to multiple stresses....

  18. Selection of aptamers specific for glycated hemoglobin and total hemoglobin using on-chip SELEX.

    Science.gov (United States)

    Lin, Hsin-I; Wu, Ching-Chu; Yang, Ching-Hsuan; Chang, Ko-Wei; Lee, Gwo-Bin; Shiesh, Shu-Chu

    2015-01-21

    Blood glycated hemoglobin (HbA1c) levels reflecting average glucose concentrations over the past three months are fundamental for the diagnosis, monitoring, and risk assessment of diabetes. It has been hypothesized that aptamers, which are single-stranded DNAs or RNAs that demonstrate high affinity to a large variety of molecules ranging from small drugs, metabolites, or proteins, could be used for the measurement of HbA1c. Aptamers are selected through an in vitro process called systematic evolution of ligands by exponential enrichment (SELEX), and they can be chemically synthesized with high reproducibility at relatively low costs. This study therefore aimed to select HbA1c- and hemoglobin (Hb)-specific single-stranded DNA aptamers using an on-chip SELEX protocol. A microfluidic SELEX chip was developed to continuously and automatically carry out multiple rounds of SELEX to screen specific aptamers for HbA1c and Hb. HbA1c and Hb were first coated onto magnetic beads. Following several rounds of selection and enrichment with a randomized 40-mer DNA library, specific oligonucleotides were selected. The binding specificity and affinity were assessed by competitive and binding assays. Using the developed microfluidic system, the incubation and partitioning times were greatly decreased, and the entire process was shortened dramatically. Both HbA1c- and Hb-specific aptamers selected by the microfluidic system showed high specificity and affinity (dissociation constant, Kd = 7.6 ± 3.0 nM and 7.3 ± 2.2 nM for HbA1c and Hb, respectively). With further refinements in the assay, these aptamers may replace the conventional antibodies for in vitro diagnostics applications in the near future.

  19. A non-docking intraoperative electron beam applicator system

    International Nuclear Information System (INIS)

    Palta, J.R.; Suntharalingam, N.

    1989-01-01

    A non-docking intraoperative radiation therapy electron beam applicator system for a linear accelerator has been designed to minimize the mechanical, electrical, and tumor visualization problems associated with a docking system. A number of technical innovations have been used in the design of this system. These include: (a) a new intraoperative radiation therapy cone design that gives a better dose uniformity in the treatment volume at all depths; (b) a collimation system which reduces the leakage radiation dose to tissues outside the intraoperative radiation therapy cone; (c) a non-docking system with a translational accuracy of 2 mm and a rotational accuracy of 0.5 degrees; and (d) a rigid clamping system for the cones. A comprehensive set of dosimetric characteristics of the intraoperative radiation therapy applicator system is presented

  20. Space Shuttle Program (SSP) Dual Docked Operations (DDO)

    Science.gov (United States)

    Sills, Joel W., Jr.; Bruno, Erica E.

    2016-01-01

    This document describes the concept definition, studies, and analysis results generated by the Space Shuttle Program (SSP), International Space Station (ISS) Program (ISSP), and Mission Operations Directorate for implementing Dual Docked Operations (DDO) during mated Orbiter/ISS missions. This work was performed over a number of years. Due to the ever increasing visiting vehicle traffic to and from the ISS, it became apparent to both the ISSP and the SSP that there would arise occasions where conflicts between a visiting vehicle docking and/or undocking could overlap with a planned Space Shuttle launch and/or during docked operations. This potential conflict provided the genesis for evaluating risk mitigations to gain maximum flexibility for managing potential visiting vehicle traffic to and from the ISS and to maximize launch and landing opportunities for all visiting vehicles.

  1. Protein-Protein Docking in Drug Design and Discovery.

    Science.gov (United States)

    Kaczor, Agnieszka A; Bartuzi, Damian; Stępniewski, Tomasz Maciej; Matosiuk, Dariusz; Selent, Jana

    2018-01-01

    Protein-protein interactions (PPIs) are responsible for a number of key physiological processes in the living cells and underlie the pathomechanism of many diseases. Nowadays, along with the concept of so-called "hot spots" in protein-protein interactions, which are well-defined interface regions responsible for most of the binding energy, these interfaces can be targeted with modulators. In order to apply structure-based design techniques to design PPIs modulators, a three-dimensional structure of protein complex has to be available. In this context in silico approaches, in particular protein-protein docking, are a valuable complement to experimental methods for elucidating 3D structure of protein complexes. Protein-protein docking is easy to use and does not require significant computer resources and time (in contrast to molecular dynamics) and it results in 3D structure of a protein complex (in contrast to sequence-based methods of predicting binding interfaces). However, protein-protein docking cannot address all the aspects of protein dynamics, in particular the global conformational changes during protein complex formation. In spite of this fact, protein-protein docking is widely used to model complexes of water-soluble proteins and less commonly to predict structures of transmembrane protein assemblies, including dimers and oligomers of G protein-coupled receptors (GPCRs). In this chapter we review the principles of protein-protein docking, available algorithms and software and discuss the recent examples, benefits, and drawbacks of protein-protein docking application to water-soluble proteins, membrane anchoring and transmembrane proteins, including GPCRs.

  2. Behaviour of tail-docked lambs tested in isolation

    Directory of Open Access Journals (Sweden)

    Marchewka Joanna

    2016-12-01

    Full Text Available The aims of the current study were to detect behavioural indicators of pain of tail-docked sheep tested in isolation and to determine the relationship between behaviour and the pain levels to which they were exposed. Twenty-four female lambs, randomly assigned to four pens, had their tail docked with a rubber ring (TD; n = 6 without pain control procedures, TD with anaesthesia (TDA; n = 6 or TD with anaesthesia and analgesia (TDAA; n = 6. Additionally, six lambs handled but without tail docking or application of pain relief measures were used as the control (C. On the day prior (Day –1 to the TD and on days 1, 3 and 5 post-procedure, each lamb was individually removed from its group and underwent a 2.5 min open field test in a separate pen. Frequencies of behaviours such as rest, running, standing, walking and exploring were directly observed. Frequencies of exploratory climbs (ECs and abrupt climbs (ACs over the testing pen’s walls were video-recorded. Data were analysed using generalised linear mixed models with repeated measurements, including treatment and day as fixed effects and behaviour on Day –1 as a linear covariate. Control and TDAA lambs stood more frequently than TD lambs. TD lambs performed significantly more ACs compared to all other treatment groups. No other treatment effects were detected. A day effect was detected for all behaviours, while the EC frequency was highest for all tail-docked lambs on Day 5. Findings suggest that standing, ACs and ECs could be used as potential indicators of pain in isolated tail-docked lambs. However, differences in ECs between treatments only appeared 3 d after tail docking.

  3. X-ray diffraction study of the binding of the antisickling agent 12C79 to human hemoglobin

    International Nuclear Information System (INIS)

    Wireko, R.C.; Abraham, D.J.

    1991-01-01

    The hemoglobin binding site of the antisickling agent 12C79 has been determined by x-ray crystallography. 12C79 is recognized as one of the first molecules to reach clinical trials that was designed, de novo, from x-ray-determined atomic coordinates of a protein. Several previous attempts to verify the proposed Hb binding sites via crystallographic studies have failed. Using revised experimental procedures, the authors obtained 12C79-deoxhemoglobin crystals grown after reaction with oxyhemoglobin and cyanoborohydride reduction to stabilize the Schiff base linkage. The difference electron-density Fourier maps show that two 12C79 molecules bind covalently to both symmetry-related N-terminal amino groups of the hemoglobin α chains. This is in contrast to the original design that proposed the binding of one drug molecule that spans the molecular dyad to interact with both N-terminal α-amino groups

  4. [Hemoglobin variants in Colombian patients referred to discard hemoglobinopathies].

    Science.gov (United States)

    Romero-Sánchez, Consuelo; Gómez Gutiérrez, Alberto; Duarte, Yurani; Amazo, Constanza; Manosalva, Clara; Chila M, Lorena; Casas-Gómez, María Consuelo; Briceño Balcázar, Ignacio

    2015-10-01

    Oxygen transport is altered in hemoglobinopathies. To study the distribution of hemoglobinopathies in Andean subjects without African ancestry. We analyzed blood samples of 1,407 subjects aged 18 to 59 years (58% females), living in the central Andean region of Colombia, referred to discard hemoglobinopathies. The frequency and type of hemoglobinopathy was established by capillary and agarose gel electrophoresis. The frequency of hemoglobinopathies was 34.5% and higher among females. The structural variants found were: AS-heterozygous hemoglobin (8.1%), homozygous SS (3.7%), heterozygous SC (2.2%), AC heterozygotes (0.5%) and heterozygous AE (0.3%). Quantitative variants found were Hb A-Beta thalassemia (13.91%) and Hb H (0.06%), Beta-thalassemia heterozygotes C (0.88%), S-Beta thalassemia heterozygotes (6.07%) and compound heterozygous SC/Beta thalassemia (0.25%), with a persistence of fetal hemoglobin 0. Composite thalassemia was also found in 31%. All techniques showed good correlation and capillary electrophoresis demonstrated a greater detection of hemoglobin variants. The frequency of hemoglobin variants in the analyzed population was high, which is an important public health indicator. The most common hemoglobin variant was HbA/Increased structural Hb A2 and the mos frequent structural hemoglobinopathy was sickle cell trait. Capillary electrophoresis can discern any Hb variants present in the population.

  5. Placental morphology at different maternal hemoglobin levels: a histopathological study

    International Nuclear Information System (INIS)

    Kiran, N.; Zubair, A.; Malik, T.M.

    2015-01-01

    To evaluate the histopathological parameters of the placenta like weight, infarct and syncytial knots, at different maternal hemoglobin levels, in both qualitative and quantitative manner. Study design: Descriptive study Place and Duration of Study: Army Medical College, National University of Sciences and Technology in collaboration with Department of Obstetrics and Gynecology, Military Hospital, Rawalpindi, Pakistan, from December 2011 to November 2012. Patients and Methods: A total of 75 placentas were included, that were collected from full term mothers at the time of childbirth. Placental weight was taken without umbilical cord and gross placental infarcts were noted. Samples of placental tissue were taken and stained by haematoxylin and eosin (H and E). Microscopic study was done to evaluate placental infarcts and syncytial knots. Results: Mean placental weight at normal and low maternal hemoglobin was 581.67 ± 83.97g and 482.58 ± 104.74g respectively. Gross placental infarcts were found in all cases having low maternal hemoglobin concentration (60% cases). Syncytial knots were found in all placentas but they were considerably more at decreasing levels of maternal hemoglobin (19.79 ± 5.22). Conclusion: The present study showed decrease in placental weight, increase in placental infarcts and syncytial knot hyperplasia at low maternal hemoglobin concentration, displaying adaptive alterations. (author)

  6. Blood hemoglobin level and treatment outcome of early breast cancer

    International Nuclear Information System (INIS)

    Henke, M.; Sindlinger, F.; Ikenberg, H.; Gerds, T.; Schumacher, M.

    2004-01-01

    Background and purpose: to determine whether the blood hemoglobin concentration correlates with the prognosis of patients with early breast cancer and, if so, whether this is restricted to treatment modality. Patients and methods: data were collected retrospectively from patients with early breast cancer (T1,2 NO-2 MO) who underwent either breast-conserving surgery followed by adjuvant radiotherapy (BCS-RT; n = 96) or a modified radical mastectomy (MRM; n = 194). The effect of preoperative blood hemoglobin level, nodal status, histological grading and hormone receptor status on disease-free survival was determined for both treatment modalities using a cox regression model and visualized by kaplan-meier plots. Results: the blood hemoglobin concentration significantly correlated with disease-free survival of patients receiving BCS-RT (relative risk [RR]: 0.67 per g/dl; p = 0.007). This was independent of other known risk factors for breast cancer patients, as determined by multivariate analysis. By contrast, the blood hemoglobin level had no prognostic significance when patients were treated with MRM. Conclusion: blood hemoglobin concentration seems to affect the prognosis of patients with early breast cancer when a treatment schedule that includes radiotherapy is applied. Reduced radiosensitivity due to diminished tumor oxygenation may be the underlying cause. Confirmative trials and studies intended to elucidate the underlying mechanism are warranted. (orig.)

  7. The refractive index of human hemoglobin in the visible range

    International Nuclear Information System (INIS)

    Zhernovaya, O; Tuchin, V; Sydoruk, O; Douplik, A

    2011-01-01

    Because the refractive index of hemoglobin in the visible range is sensitive to the hemoglobin concentration, optical investigations of hemoglobin are important for medical diagnostics and treatment. Direct measurements of the refractive index are, however, challenging; few such measurements have previously been reported, especially in a wide wavelength range. We directly measured the refractive index of human deoxygenated and oxygenated hemoglobin for nine wavelengths between 400 and 700 nm for the hemoglobin concentrations up to 140 g l -1 . This paper analyzes the results and suggests a set of model functions to calculate the refractive index depending on the concentration. At all wavelengths, the measured values of the refractive index depended on the concentration linearly. Analyzing the slope of the lines, we determined the specific refraction increments, derived a set of model functions for the refractive index depending on the concentration, and compared our results with those available in the literature. Based on the model functions, we further calculated the refractive index at the physiological concentration within the erythrocytes of 320 g l -1 . The results can be used to calculate the refractive index in the visible range for arbitrary concentrations provided that the refractive indices depend on the concentration linearly.

  8. Biophysical Monitoring and dose response characteristics of irradiated hemoglobin

    International Nuclear Information System (INIS)

    Elshemey, W.M; Selim, N.S.; Desouky, O.

    2003-01-01

    The present work aims to move a step forward towards a deeper understanding of the scattering of x-ray, from lyophilized biological samples. Comparative study has been performed using LAXS and UV-visible spectrophotometry for monitoring the dose response characteristics of the hemoglobin molecule of irradiated blood. Blood samples were irradiated at doses ranging from 5 up to 100 Gy. Diluted hemoglobin solution was scanned in the UV- visible range (200-700 nm), and lyophilized hemoglobin was prepared for LAXS measurement. The radiation-induced changes in the hemoglobin structure have been evaluated. The LAXS profile of hemoglobin molecule is characterized by the presence of two peaks in the forward direction of scattering. These peaks were found to be sensitive to the variations in the molecular structure of a given sample. The obtained results suggest that the 1 s t peak, recorded at 4.65 o , is sensitive to the tertiary and quaternary structure of the globin part, while the major peak, recorded at 10.5 o , appeared to be related to its primary and secondary structure

  9. Post-transfusion hemoglobin values and patient blood management

    DEFF Research Database (Denmark)

    Moerman, Jan; Vermeulen, Edith; Van Mullem, Mia

    2018-01-01

    Objectives: The objective of this retrospective study was to evaluate the added value of communicating post-transfusion hemoglobin values to clinicians as a strategy to improve RBC utilization in a 500-bed hospital. Methods: The total number of RBC transfusions, the mean number of RBC units...... transfused per patient, the mean pre- and post-transfusion hemoglobin values, the ratio of patients transfused and the ratio of patients with a post-transfusion hemoglobin > 10.5 g/dL were calculated per service and per department for six months. The data were reported to each service and compared...... with the data of the department as peer group. The impact of this communication strategy was evaluated in the following six months. Results: In the six months pre-intervention, the mean post-transfusion hemoglobin value was 9.2 g/dL. Post-transfusion hemoglobin was > 10.5 g/dL in 13.4% of patients (112...

  10. Study of LAXS Profile of Hemoglobin from Irradiated Blood

    International Nuclear Information System (INIS)

    Selim, N.S.; Desouky, O.S.; Elshemey, W.M.

    2006-01-01

    The present work aims to move a step forward towards a deeper understanding of the scattering of x-ray, from lyophilized biological samples. Comparative study has been performed using low angle x-ray scattering (LAXS) and UV-visible spectrophotometry for monitoring the dose response characteristics of the hemoglobin molecule of irradiated blood. Blood samples were exposed to gamma rays, at doses ranging from 5 up to 100 Gy. Diluted hemoglobin solution was scanned in the UV-visible range (200-700 nm), and lyophilized hemoglobin was prepared for LAXS measurement. The radiation-induced changes in the hemoglobin structure have been evaluated. The LAXS profile of hemoglobin molecule is characterized by the presence of 2 peaks in the forward direction of scattering. These peaks were found to be sensitive to the variations in the molecular structure of a given sample. The obtained results suggest that the 1st peak, recorded at 4.65O (equivalent to momentum transfer, x= 0.526 nm-1), is sensitive to the tertiary and quaternary structure of the globin part, while the major peak, recorded at 10.5O (equivalent to momentum transfer, x= 1.189 nm-1), appeared to be related to its primary and secondary structure

  11. A microfluidic approach for hemoglobin detection in whole blood

    Science.gov (United States)

    Taparia, Nikita; Platten, Kimsey C.; Anderson, Kristin B.; Sniadecki, Nathan J.

    2017-10-01

    Diagnosis of anemia relies on the detection of hemoglobin levels in a blood sample. Conventional blood analyzers are not readily available in most low-resource regions where anemia is prevalent, so detection methods that are low-cost and point-of-care are needed. Here, we present a microfluidic approach to measure hemoglobin concentration in a sample of whole blood. Unlike conventional approaches, our microfluidic approach does not require hemolysis. We detect the level of hemoglobin in a blood sample optically by illuminating the blood in a microfluidic channel at a peak wavelength of 540 nm and measuring its absorbance using a CMOS sensor coupled with a lens to magnify the image onto the detector. We compare measurements in microchannels with channel heights of 50 and 115 μm and found the channel with the 50 μm height provided a better range of detection. Since we use whole blood and not lysed blood, we fit our data to an absorption model that includes optical scattering in order to obtain a calibration curve for our system. Based on this calibration curve and data collected, we can measure hemoglobin concentration within 1 g/dL for severe cases of anemia. In addition, we measured optical density for blood flowing at a shear rate of 500 s-1 and observed it did not affect the nonlinear model. With this method, we provide an approach that uses microfluidic detection of hemoglobin levels that can be integrated with other microfluidic approaches for blood analysis.

  12. Parallel Evolutionary Optimization Algorithms for Peptide-Protein Docking

    Science.gov (United States)

    Poluyan, Sergey; Ershov, Nikolay

    2018-02-01

    In this study we examine the possibility of using evolutionary optimization algorithms in protein-peptide docking. We present the main assumptions that reduce the docking problem to a continuous global optimization problem and provide a way of using evolutionary optimization algorithms. The Rosetta all-atom force field was used for structural representation and energy scoring. We describe the parallelization scheme and MPI/OpenMP realization of the considered algorithms. We demonstrate the efficiency and the performance for some algorithms which were applied to a set of benchmark tests.

  13. The conserved Phe GH5 of importance for hemoglobin intersubunit contact is mutated in gadoid fish

    Science.gov (United States)

    2014-01-01

    Background Functionality of the tetrameric hemoglobin molecule seems to be determined by a few amino acids located in key positions. Oxygen binding encompasses structural changes at the interfaces between the α1β2 and α2β1 dimers, but also subunit interactions are important for the oxygen binding affinity and stability. The latter packing contacts include the conserved Arg B12 interacting with Phe GH5, which is replaced by Leu and Tyr in the αA and αD chains, respectively, of birds and reptiles. Results Searching all known hemoglobins from a variety of gnathostome species (jawed vertebrates) revealed the almost invariant Arg B12 coded by the AGG triplet positioned at an exon-intron boundary. Rare substitutions of Arg B12 in the gnathostome β globins were found in pig, tree shrew and scaled reptiles. Phe GH5 is also highly conserved in the β globins, except for the Leu replacement in the β1 globin of five marine gadoid species, gilthead seabream and the Comoran coelacanth, while Cys and Ile were found in burbot and yellow croaker, respectively. Atlantic cod β1 globin showed a Leu/Met polymorphism at position GH5 dominated by the Met variant in northwest-Atlantic populations that was rarely found in northeast-Atlantic cod. Site-specific analyses identified six consensus codons under positive selection, including 122β(GH5), indicating that the amino acid changes identified at this position may offer an adaptive advantage. In fact, computational mutation analysis showed that the replacement of Phe GH5 with Leu or Cys decreased the number of van der Waals contacts essentially in the deoxy form that probably causes a slight increase in the oxygen binding affinity. Conclusions The almost invariant Arg B12 and the AGG codon seem to be important for the packing contacts and pre-mRNA processing, respectively, but the rare mutations identified might be beneficial. The Leu122β1(GH5)Met and Met55β1(D6)Val polymorphisms in Atlantic cod hemoglobin modify the

  14. An Investigation of Molecular Docking and Molecular Dynamic Simulation on Imidazopyridines as B-Raf Kinase Inhibitors

    Directory of Open Access Journals (Sweden)

    Huiding Xie

    2015-11-01

    Full Text Available In the recent cancer treatment, B-Raf kinase is one of key targets. Nowadays, a group of imidazopyridines as B-Raf kinase inhibitors have been reported. In order to investigate the interaction between this group of inhibitors and B-Raf kinase, molecular docking, molecular dynamic (MD simulation and binding free energy (ΔGbind calculation were performed in this work. Molecular docking was carried out to identify the key residues in the binding site, and MD simulations were performed to determine the detail binding mode. The results obtained from MD simulation reveal that the binding site is stable during the MD simulations, and some hydrogen bonds (H-bonds in MD simulations are different from H-bonds in the docking mode. Based on the obtained MD trajectories, ΔGbind was computed by using Molecular Mechanics Generalized Born Surface Area (MM-GBSA, and the obtained energies are consistent with the activities. An energetic analysis reveals that both electrostatic and van der Waals contributions are important to ΔGbind, and the unfavorable polar solvation contribution results in the instability of the inhibitor with the lowest activity. These results are expected to understand the binding between B-Raf and imidazopyridines and provide some useful information to design potential B-Raf inhibitors.

  15. Molecular dynamics modeling the synthetic and biological polymers interactions pre-studied via docking: anchors modified polyanions interference with the HIV-1 fusion mediator.

    Science.gov (United States)

    Tsvetkov, Vladimir B; Serbin, Alexander V

    2014-06-01

    In previous works we reported the design, synthesis and in vitro evaluations of synthetic anionic polymers modified by alicyclic pendant groups (hydrophobic anchors), as a novel class of inhibitors of the human immunodeficiency virus type 1 (HIV-1) entry into human cells. Recently, these synthetic polymers interactions with key mediator of HIV-1 entry-fusion, the tri-helix core of the first heptad repeat regions [HR1]3 of viral envelope protein gp41, were pre-studied via docking in terms of newly formulated algorithm for stepwise approximation from fragments of polymeric backbone and side-group models toward real polymeric chains. In the present article the docking results were verified under molecular dynamics (MD) modeling. In contrast with limited capabilities of the docking, the MD allowed of using much more large models of the polymeric ligands, considering flexibility of both ligand and target simultaneously. Among the synthesized polymers the dinorbornen anchors containing alternating copolymers of maleic acid were selected as the most representative ligands (possessing the top anti-HIV activity in vitro in correlation with the highest binding energy in the docking). To verify the probability of binding of the polymers with the [HR1]3 in the sites defined via docking, various starting positions of polymer chains were tried. The MD simulations confirmed the main docking-predicted priority for binding sites, and possibilities for axial and belting modes of the ligands-target interactions. Some newly MD-discovered aspects of the ligand's backbone and anchor units dynamic cooperation in binding the viral target clarify mechanisms of the synthetic polymers anti-HIV activity and drug resistance prevention.

  16. Scheduling trucks in cross docking systems with temporary storage and dock repeat truck holding pattern using genetic algorithm

    Directory of Open Access Journals (Sweden)

    Ehsan Ghobadian

    2013-02-01

    Full Text Available Cross docking is one of the most important issues in management of supply chains. In cross docking, different items delivered to a warehouse by inbound trucks are directly arranged and reorganized based on customer demands, routed and loaded into outbound trucks for delivery purposes to customers without virtually keeping them at the warehouse. If any item is kept in storage, it is normally for a short amount of time, say less than 24 hours. In this paper, we consider a special case of cross docking where there is temporary storage and implements genetic algorithm to solve the resulted problem for some realistic test problems. In our method, we first use some heuristics as initial solutions and then improve the final solution using genetic algorithm. The performance of the proposed model is compared with alternative solution strategy, the GRASP method.

  17. Technology Development of Automated Rendezvous and Docking/Capture Sensors and Docking Mechanism for the Asteroid Redirect Crewed Mission

    Science.gov (United States)

    Hinkel, Heather; Strube, Matthew; Zipay, John J.; Cryan, Scott

    2016-01-01

    This paper will describe the technology development efforts NASA has underway for Automated Rendezvous and Docking/Capture (AR&D/C) sensors and a docking mechanism and the challenges involved. The paper will additionally address how these technologies will be extended to other missions requiring AR&D/C whether robotic or manned. NASA needs AR&D/C sensors for both the robotic and crewed segments of the Asteroid Redirect Mission (ARM). NASA recently conducted a commonality assessment of the concept of operations for the robotic Asteroid Redirect Vehicle (ARV) and the crewed mission segment using the Orion spacecraft. The commonality assessment also considered several future exploration and science missions requiring an AR&D/C capability. Missions considered were asteroid sample return, satellite servicing, and planetary entry, descent, and landing. This assessment determined that a common sensor suite consisting of one or more visible wavelength cameras, a three-dimensional LIDAR along with long-wavelength infrared cameras for robustness and situational awareness could be used on each mission to eliminate the cost of multiple sensor developments and qualifications. By choosing sensor parameters at build-time instead of at design-time and, without having to requalify flight hardware, a specific mission can design overlapping bearing, range, relative attitude, and position measurement availability to suit their mission requirements with minimal non-recurring engineering costs. The resulting common sensor specification provides the union of all performance requirements for each mission and represents an improvement over the current systems used for AR&D/C today. These sensor specifications are tightly coupled to the docking system capabilities and requirements for final docking conditions. The paper will describe NASA's efforts to develop a standard docking system for use across NASA human spaceflight missions to multiple destinations. It will describe the current

  18. Hemoglobin is essential for normal growth of Arabidopsis organs

    DEFF Research Database (Denmark)

    Hebelstrup, Kim Henrik; Hunt, Peter; Dennis, Elizabeth

    2006-01-01

    In Arabidopsis thaliana, the class I hemoglobin AHb1 is transiently expressed in the hydathodes of leaves and in floral buds from young inflorescences. Nitric oxide (NO) accumulates to high levels in these organs when AHb1 is silenced, indicating an important role in metabolizing NO. AHb1-silenced...... lines are viable but show a mutant phenotype affecting the regions where AHb1 is expressed. Arabidopsis lines with an insertional knockout or overexpression of AHb2, a class II 3-on-3 hemoglobin, were generated. Seedlings overexpressing AHb2 show enhanced survival of hypoxic stress. The AHb2 knockout...... lines develop normally. However, when AHb2 knockout is combined with AHb1 silencing, seedlings die at an early vegetative stage suggesting that the two 3-on-3 hemoglobins, AHb1 and AHb2, together play an essential role for normal development of Arabidopsis seedlings. In conclusion, these results...

  19. Fluorometric and molecular docking investigation on the binding characteristics of SB202190 to human serum albumin

    Energy Technology Data Exchange (ETDEWEB)

    Nasruddin, Ahmad N.; Feroz, Shevin R. [Biomolecular Research Group, Biochemistry Programme, Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur (Malaysia); Mukarram, Abdul K. [Bioinformatics Programme, Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur (Malaysia); Mohamad, Saharuddin B. [Bioinformatics Programme, Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur (Malaysia); Centre of Research for Computational Sciences and Informatics for Biology, Bioindustry, Environment, Agriculture and Healthcare, Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur (Malaysia); Tayyab, Saad, E-mail: saadtayyab2004@yahoo.com [Biomolecular Research Group, Biochemistry Programme, Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur (Malaysia); Centre of Research for Computational Sciences and Informatics for Biology, Bioindustry, Environment, Agriculture and Healthcare, Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur (Malaysia)

    2016-06-15

    The interaction of SB202190, a p38 mitogen-activated protein kinase inhibitor with the main drug transporter in human circulation, human serum albumin (HSA) was studied using fluorescence spectroscopy and in silico docking methods. The association constant, K{sub a} of the binding reaction was determined to be 3.24±0.07×10{sup 4} M{sup −1} at 25 °C based on fluorescence quenching titration results. The values of enthalpy change and entropy change for the interaction were found as −8.54 kJ mol{sup −1} and 58.01 J mol{sup −1} K{sup −1}, respectively. Both thermodynamic data and docking results suggested the involvement of hydrophobic and van der Waals forces in the complex formation. Three-dimensional fluorescence data of SB202190–HSA complex demonstrated significant changes in the microenvironment around the protein fluorophores upon drug binding. Comparison of HSA thermograms obtained in the absence and the presence of SB202190 suggested improved protein thermal stability upon complexation with the drug. Competitive drug displacement results as well as modeling data concluded the preferred binding site of SB202190 on HSA as Sudlow's site I. - Highlights: • SB202190 interacts with HSA with moderate affinity. • Involvement of hydrophobic and van der Waals forces in SB202190 binding. • SB202190 binding results in microenvironmental changes around fluorophores. • Sudlow's site I is the preferred binding site of SB202190.

  20. Nitric Oxide in Plants: The Roles of Ascorbate and Hemoglobin

    Science.gov (United States)

    Wang, Xiaoguang; Hargrove, Mark S.

    2013-01-01

    Ascorbic acid and hemoglobins have been linked to nitric oxide metabolism in plants. It has been hypothesized that ascorbic acid directly reduces plant hemoglobin in support of NO scavenging, producing nitrate and monodehydroascorbate. In this scenario, monodehydroascorbate reductase uses NADH to reduce monodehydroascorbate back to ascorbate to sustain the cycle. To test this hypothesis, rates of rice nonsymbiotic hemoglobin reduction by ascorbate were measured directly, in the presence and absence of purified rice monodehydroascorbate reductase and NADH. Solution NO scavenging was also measured methodically in the presence and absence of rice nonsymbiotic hemoglobin and monodehydroascorbate reductase, under hypoxic and normoxic conditions, in an effort to gauge the likelihood of these proteins affecting NO metabolism in plant tissues. Our results indicate that ascorbic acid slowly reduces rice nonsymbiotic hemoglobin at a rate identical to myoglobin reduction. The product of the reaction is monodehydroascorbate, which can be efficiently reduced back to ascorbate in the presence of monodehydroascorbate reductase and NADH. However, our NO scavenging results suggest that the direct reduction of plant hemoglobin by ascorbic acid is unlikely to serve as a significant factor in NO metabolism, even in the presence of monodehydroascorbate reductase. Finally, the possibility that the direct reaction of nitrite/nitrous acid and ascorbic acid produces NO was measured at various pH values mimicking hypoxic plant cells. Our results suggest that this reaction is a likely source of NO as the plant cell pH drops below 7, and as nitrite concentrations rise to mM levels during hypoxia. PMID:24376554

  1. Independency of Fe ions in hemoglobin on immunomagnetic reduction assay

    Energy Technology Data Exchange (ETDEWEB)

    Yang, S.Y. [MagQu Co. Ltd., Sindian City, Taipei County 231, Taiwan (China); Institute of Electro-optical Science and Technology, National Taiwan Normal University, Taipei 116, Taiwan (China); Lan, C.B.; Chen, C.H. [Institute of Electro-optical Science and Technology, National Taiwan Normal University, Taipei 116, Taiwan (China); Horng, H.E. [Institute of Electro-optical Science and Technology, National Taiwan Normal University, Taipei 116, Taiwan (China)], E-mail: phyfv001@scc.ntnu.edu.tw; Hong, Chin-Yih [Department of Mechanical Engineering, Nan-Kai University of Technology, Nantau County, Taiwan (China)], E-mail: cyhong@nkut.edu.tw; Yang, H.C. [Department of Physics, National Taiwan University, Taipei 106, Taiwan (China)], E-mail: hcyang@phys.ntu.edu.tw; Lai, Y.K. [College of Life Sciences, National Tsing Hua University, Hsinchu City 300, Taiwan (China); Department of Bioresources, Da-Yeh University, Changhua 515, Taiwan (China); Lin, Y.H.; Teng, K.S. [Apex Biotechnology Co. Ltd., Hsinchu City 300, Taiwan (China)

    2009-10-15

    Immunomagnetic reduction (IMR), which involves measuring the reduction in the ac magnetic susceptibility of magnetic reagents, is due to the association between bio-functionalized magnetic nanoparticles and target bio-molecules. This has been demonstrated for assaying proteins in solutions free of Fe ions, such as serum. In this work, the validity of IMR assay for samples rich in Fe ions like hemoglobin (Hb) is investigated. According to the results, there is no magnetic signal contributed by Fe-ion-rich Hb. Furthermore, the results show a high sensitivity in assaying hemoglobin A1c (HbA1c) by using IMR.

  2. Independency of Fe ions in hemoglobin on immunomagnetic reduction assay

    International Nuclear Information System (INIS)

    Yang, S.Y.; Lan, C.B.; Chen, C.H.; Horng, H.E.; Hong, Chin-Yih; Yang, H.C.; Lai, Y.K.; Lin, Y.H.; Teng, K.S.

    2009-01-01

    Immunomagnetic reduction (IMR), which involves measuring the reduction in the ac magnetic susceptibility of magnetic reagents, is due to the association between bio-functionalized magnetic nanoparticles and target bio-molecules. This has been demonstrated for assaying proteins in solutions free of Fe ions, such as serum. In this work, the validity of IMR assay for samples rich in Fe ions like hemoglobin (Hb) is investigated. According to the results, there is no magnetic signal contributed by Fe-ion-rich Hb. Furthermore, the results show a high sensitivity in assaying hemoglobin A1c (HbA1c) by using IMR.

  3. Why are there two kinds of chain in tetrameric hemoglobins

    International Nuclear Information System (INIS)

    Ferreira, R.; Jacchieri, S.G.

    1981-01-01

    The homeotropic allosteric interactions responsible for the sigmoidal oxygen saturation curves of α 2 β 2 hemoglobins are shown to be larger than those of hypothetical hemoglobins obeying identical curves and built from equivalent chains, γ 4 . It is also shown that this ensures for the α 2 β 2 species a more dependable cooperativity, through a biologically significative temperature range. On the basis of these findings it is argued that the existence of two different globin chains is advantageous in an evolutionary sense. (Author) [pt

  4. Postoperative hemoglobin level in patients with femoral neck fracture

    OpenAIRE

    Nagra, Navraj; van Popta, Dmitri; Whiteside, Sigrid; Holt, Edward

    2018-01-01

    Objective: The aim of this study was to analyze the changes of hemoglobin levels in patients undergoing fixation for femoral neck fracture.Methods: Peroperative hemoglobin levels of patients who underwent either dynamic hip screw (DHS) fixation (n=74; mean age: 80 years) or hip hemiarthroplasty (n=104; mean age: 84 years) for femoral neck fracture was monitored.Results: There was a statistically and clinically significant mean drop of 31.1 g/L between the preoperative (D0) and postoperative D...

  5. Respiratory properties of blood and hemoglobin solutions from the piranha

    DEFF Research Database (Denmark)

    Wood, S.C.; Weber, Roy E.; Powers, D.

    1979-01-01

    1. Respiratory properties of piranha blood are distinguished from those of other fish primarily by the high CO2 buffering capacity (?HCO3/-?pH= 19.6mmol/l for oxygenated blood and 39.1 mmol/l for deoxygenated blood). 2. The concentration of nucleoside triphosphates (NTP) and the half-saturation t......) lowered the oxygen affinity of purified hemoglobin solutions, accounting for the size-dependent correlation ofP50 and NTP concentration in whole blood. 5. While similar in concentration in red cells, GTP is more potent than ATP as an allosteric modifier of hemoglobin function....

  6. Is Routine Ordering of Both Hemoglobin and Hematocrit Justifiable?

    Science.gov (United States)

    Addison, David J.

    1966-01-01

    In order to assess the value of routine simultaneous hemoglobin and hematocrit determinations, paired determinations in the following groups were studied: (1) 360 consecutive pairs from the hematology laboratory, (2) 95 pairs on general medical patients, (3) 43 pairs on 10 patients with upper gastrointestinal hemorrhage, and (4) 62 pairs on 10 patients with burns. These values were plotted on scatter diagrams. In the 560 pairs only three disparate determinations were found. It is concluded that, in most clinical situations, determination of the hemoglobin or the hematocrit as a screening procedure provides as much useful information as the simultaneous determination of both. PMID:5296947

  7. Solvated protein-protein docking using Kyte-Doolittle-based water preferences

    NARCIS (Netherlands)

    Kastritis, P.; Visscher, K.M.; van Dijk, A.D.J.; Bonvin, A.M.J.J.

    2013-01-01

    HADDOCK is one of the few docking programs that can explicitly account for water molecules in the docking process. Its solvated docking protocol starts from hydrated molecules and a fraction of the resulting interfacial waters is subsequently removed in a biased Monte Carlo procedure based on

  8. Solvated protein-protein docking using Kyte-Doolittle-based water preferences

    NARCIS (Netherlands)

    Kastritis, Panagiotis L.; Visscher, Koen M.; van Dijk, Aalt D.J.; Bonvin, Alexandre M.J.J.

    HADDOCK is one of the few docking programs that can explicitly account for water molecules in the docking process. Its solvated docking protocol starts from hydrated molecules and a fraction of the resulting interfacial waters is subsequently removed in a biased Monte Carlo procedure based on

  9. More tail lesions among undocked than tail docked pigs in a conventional herd

    DEFF Research Database (Denmark)

    Lahrmann, H. P.; Busch, M. E.; D'Eath, R. B.

    2017-01-01

    The vast majority of piglets reared in the European Union (EU) and worldwide is tail docked to reduce the risk of being tail bitten, even though EU animal welfare legislation bans routine tail docking. Many conventional herds experience low levels of tail biting among tail docked pigs, however...

  10. China Accomplished Its First Space Rendezvous and Docking

    Institute of Scientific and Technical Information of China (English)

    Chen Xiaoli

    2011-01-01

    At 1:36 am on November 3,China's Shenzhou 8 unmanned spaceship and Tiangong 1 space lab spacecraft accomplished the country's first space docking procedure and coupling in space at more than 343km above Earth's surface,marking a great leap in China's space program.

  11. Complete cDNA sequence coding for human docking protein

    Energy Technology Data Exchange (ETDEWEB)

    Hortsch, M; Labeit, S; Meyer, D I

    1988-01-11

    Docking protein (DP, or SRP receptor) is a rough endoplasmic reticulum (ER)-associated protein essential for the targeting and translocation of nascent polypeptides across this membrane. It specifically interacts with a cytoplasmic ribonucleoprotein complex, the signal recognition particle (SRP). The nucleotide sequence of cDNA encoding the entire human DP and its deduced amino acid sequence are given.

  12. Synthesis, biological evaluation and molecular docking studies of ...

    African Journals Online (AJOL)

    Synthesis, biological evaluation and molecular docking studies of Mannich bases derived from 1, 3, 4-oxadiazole- 2-thiones as potential urease inhibitors. ... Mannich bases (5-17) were subjected to in silico screening as urease inhibitors, using crystal structure of urease (Protein Data Bank ID: 5FSE) as a model enzyme.

  13. Optimization of Spacecraft Rendezvous and Docking using Interval Analysis

    NARCIS (Netherlands)

    Van Kampen, E.; Chu, Q.P.; Mulder, J.A.

    2010-01-01

    This paper applies interval optimization to the fixed-time multiple impulse rendezvous and docking problem. Current methods for solving this type of optimization problem include for example genetic algorithms and gradient based optimization. Unlike these methods, interval methods can guarantee that

  14. Molecular Dynamics and Docking of Biphenyl: A Potential ...

    African Journals Online (AJOL)

    Purpose: To develop a new drug that inhibits viral attachment and entry for the treatment of HIV/AIDS patients. Methods: Two Protein Databank (PDB) crystal structures of HIV-1 gp120-CD4 complexes, namely, 1RZK and 1G9N, were mutated at amino acid position 43 to a biphenylalanine (biPhe-43) residue. FireDock web ...

  15. SKATE: a docking program that decouples systematic sampling from scoring.

    Science.gov (United States)

    Feng, Jianwen A; Marshall, Garland R

    2010-11-15

    SKATE is a docking prototype that decouples systematic sampling from scoring. This novel approach removes any interdependence between sampling and scoring functions to achieve better sampling and, thus, improves docking accuracy. SKATE systematically samples a ligand's conformational, rotational and translational degrees of freedom, as constrained by a receptor pocket, to find sterically allowed poses. Efficient systematic sampling is achieved by pruning the combinatorial tree using aggregate assembly, discriminant analysis, adaptive sampling, radial sampling, and clustering. Because systematic sampling is decoupled from scoring, the poses generated by SKATE can be ranked by any published, or in-house, scoring function. To test the performance of SKATE, ligands from the Asetex/CDCC set, the Surflex set, and the Vertex set, a total of 266 complexes, were redocked to their respective receptors. The results show that SKATE was able to sample poses within 2 A RMSD of the native structure for 98, 95, and 98% of the cases in the Astex/CDCC, Surflex, and Vertex sets, respectively. Cross-docking accuracy of SKATE was also assessed by docking 10 ligands to thymidine kinase and 73 ligands to cyclin-dependent kinase. 2010 Wiley Periodicals, Inc.

  16. Synthesis, anti-microbial activity and molecular docking studies on ...

    Indian Academy of Sciences (India)

    Molecular structures of triazolylcoumarins 1–8. method and are ... organic layer was washed with water (100 mL) and sat- ... (0.5mmol) in a mixture of THF and water (1:1) solution. ..... for docking studies with the target DNA gyrase B (PDB.

  17. Synthesis and molecular docking of new hydrazones derived from ...

    African Journals Online (AJOL)

    Synthesis and molecular docking of new hydrazones derived from ethyl isonipecotate and their biological activities. A Munir, Aziz-ur Rehman, M.A. Abbasi, S.Z. Siddiqui, A Nasir, S.G. Khan, S Rasool, S.A.A. Shah ...

  18. Tail docking in dogs: can attitude change be achieved?

    Science.gov (United States)

    Bennett, P; Perini, E

    2003-05-01

    The debate about tail docking in domestic dogs continues to rage in many developed countries and attitudes expressed by different community groups remain diametrically opposed. Veterinary associations and welfare organisations typically want the practice banned, while many breeders and pure-bred dog associations just as vigorously oppose the introduction of anti-docking legislation. In recent years, much data have been accumulated concerning the welfare implications of tail docking. A recent evaluation of this literature suggests that the practice has little to recommend it and that, in the absence of reasonable case-by-case justification, it may constitute an unacceptable abuse of a sentient species. Given this situation, it is difficult to understand why many canine interest groups, presumably representing those people who care most about the welfare of companion dogs, should continue to hold such strong attitudes in favour of tail docking. In this review we attempt to explain why different community groups might espouse strong but opposing attitudes, despite having access to the same information. We argue that the theory of cognitive dissonance, popular among social psychologists, may provide a useful framework within which to understand, and attempt to alter, attitudes that persist even though they appear contrary to available empirical evidence.

  19. β-lactoglobulin's conformational requirements for ligand binding at the calyx and the dimer interphase: a flexible docking study.

    Directory of Open Access Journals (Sweden)

    Lenin Domínguez-Ramírez

    Full Text Available β-lactoglobulin (BLG is an abundant milk protein relevant for industry and biotechnology, due significantly to its ability to bind a wide range of polar and apolar ligands. While hydrophobic ligand sites are known, sites for hydrophilic ligands such as the prevalent milk sugar, lactose, remain undetermined. Through the use of molecular docking we first, analyzed the known fatty acid binding sites in order to dissect their atomistic determinants and second, predicted the interaction sites for lactose with monomeric and dimeric BLG. We validated our approach against BLG structures co-crystallized with ligands and report a computational setup with a reduced number of flexible residues that is able to reproduce experimental results with high precision. Blind dockings with and without flexible side chains on BLG showed that: i 13 experimentally-determined ligands fit the calyx requiring minimal movement of up to 7 residues out of the 23 that constitute this binding site. ii Lactose does not bind the calyx despite conformational flexibility, but binds the dimer interface and an alternate Site C. iii Results point to a probable lactolation site in the BLG dimer interface, at K141, consistent with previous biochemical findings. In contrast, no accessible lysines are found near Site C. iv lactose forms hydrogen bonds with residues from both monomers stabilizing the dimer through a claw-like structure. Overall, these results improve our understanding of BLG's binding sites, importantly narrowing down the calyx residues that control ligand binding. Moreover, our results emphasize the importance of the dimer interface as an insufficiently explored, biologically relevant binding site of particular importance for hydrophilic ligands. Furthermore our analyses suggest that BLG is a robust scaffold for multiple ligand-binding, suitable for protein design, and advance our molecular understanding of its ligand sites to a point that allows manipulation to control

  20. Extramedullary hematopoiesis presented as cytopenia and massive paraspinal masses leading to cord compression in a patient with hereditary persistence of fetal hemoglobin

    OpenAIRE

    Katchi, Tasleem; Kolandaivel, Krishna; Khattar, Pallavi; Farooq, Taliya; Islam, Humayun; Liu, Delong

    2016-01-01

    Background Extramedullary hematopoeisis (EMH) can occur in various physiological and pathologic states. The spleen is the most common site of EMH. Case presentation We report a case with hereditary persistence of fetal hemoglobin with extramedullary hematopoiesis presented as cord compression and cytopenia secondary to multi-paraspinal masses. Conclusion Treatment can be a challenge. Relapse is a possibility.

  1. Extramedullary hematopoiesis presented as cytopenia and massive paraspinal masses leading to cord compression in a patient with hereditary persistence of fetal hemoglobin.

    Science.gov (United States)

    Katchi, Tasleem; Kolandaivel, Krishna; Khattar, Pallavi; Farooq, Taliya; Islam, Humayun; Liu, Delong

    2016-01-01

    Extramedullary hematopoeisis (EMH) can occur in various physiological and pathologic states. The spleen is the most common site of EMH. We report a case with hereditary persistence of fetal hemoglobin with extramedullary hematopoiesis presented as cord compression and cytopenia secondary to multi-paraspinal masses. Treatment can be a challenge. Relapse is a possibility.

  2. Caffeine and sulfadiazine interact differently with human serum albumin: A combined fluorescence and molecular docking study

    Science.gov (United States)

    Islam, Mullah Muhaiminul; Sonu, Vikash K.; Gashnga, Pynsakhiat Miki; Moyon, N. Shaemningwar; Mitra, Sivaprasad

    2016-01-01

    The interaction and binding behavior of the well-known drug sulfadiazine (SDZ) and psychoactive stimulant caffeine (CAF) with human serum albumin (HSA) was monitored by in vitro fluorescence titration and molecular docking calculations under physiological condition. The quenching of protein fluorescence on addition of CAF is due to the formation of protein-drug complex in the ground state; whereas in case of SDZ, the experimental results were explained on the basis of sphere of action model. Although both these compounds bind preferentially in Sudlow's site 1 of the protein, the association constant is approximately two fold higher in case of SDZ (∼4.0 × 104 M-1) in comparison with CAF (∼9.3 × 102 M-1) and correlates well with physico-chemical properties like pKa and lipophilicity of the drugs. Temperature dependent fluorescence study reveals that both SDZ and CAF bind spontaneously with HSA. However, the binding of SDZ with the protein is mainly governed by the hydrophobic forces in contrast with that of CAF; where, the interaction is best explained in terms of electrostatic mechanism. Molecular docking calculation predicts the binding of these drugs in different location of sub-domain IIA in the protein structure.

  3. Coumarin structure as a lead scaffold for antibacterial agents - molecular docking

    Directory of Open Access Journals (Sweden)

    Veselinović, J.B.

    2016-12-01

    Full Text Available Coumarins owe their class name to “Coumarou”, the vernacular name of the tonka bean (Dipteryx odorata Willd, Fabaceae, from which coumarin was isolated in 1820. Many molecules based on the coumarin structure have been synthesized utilizing innovative synthetic techniques. Various synthetic routes have led to interesting derivatives including the furanocoumarins, pyranocoumarins and coumarinsulfamates which have been found to be useful in photochemotherapy, antitumor and anti-HIV therapy, as stimulants for central nervous system, antiinflammatory therapy, as anti-coagulants, etc. One of important pharmacological activity of coumarin molecules is their potential as antibacterial agents since they show inhibitory activity toward isoleucyl-transfer RNA (tRNA synthetase. In the presented research molecular docking studies of selected coumarin compounds inside isoleucyltransfer RNA (tRNA synthetase active site were performed. Molecular docking scores of all studied compounds were obtained through score functions. Presented results indicate that from all studied coumarin compounds the strongest interactions with studied enzyme has 7,8-dihydroxy-4-phenyl coumarin followed by 5,7-dihydroxy-4-phenyl coumarin. Presented results are in accordance with in vitro obtained results for their antibacterial activity. Presented findings suggest that 4-phenyl hydroxycoumarins may be considered as good molecular templates for potential antibacterial agents and can be used for further chemical modifications for improving their antibacterial activity.

  4. Spectrofluoremetric and molecular docking study on the interaction of bisdemethoxycurcumin with bovine β-casein nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Mehranfar, Fahimeh [Department of Chemistry, University of Isfahan, Isfahan 81746-73441 (Iran, Islamic Republic of); Bordbar, Abdol-Khalegh, E-mail: bordbar@chem.ui.ac.ir [Department of Chemistry, University of Isfahan, Isfahan 81746-73441 (Iran, Islamic Republic of); Keyhanfar, Mehrnaz; Behbahani, Mandana [Faculty of Advanced Sciences and Technologies, Department of Biotechnology, University of Isfahan, Isfahan, 81746-73441 (Iran, Islamic Republic of)

    2013-11-15

    The interaction of bisdemethoxycurcumin (BDMC), as one of the main active component of turmeric (Curcuma longa L.), with bovine β-casein nanoparticle, as an efficient drug carrier system, was investigated using steady-state fluorescence spectroscopy and molecular docking calculations. Results of fluorescence quenching experiments, Forster energy transfer measurements and molecular docking calculations suggested that BDMC bind to the hydrophobic core of β-casein via formation of 3 hydrogen bonds and several vander Waals contacts that represented the encapsulation of BDMC in β-casein micelle nanoparticles. The binding parameters including number of substantive binding sites and the binding constants were evaluated by fluorescence quenching method. Additionally, the cytotoxicity of free BDMC and BDMC-β-casein complex in human breast cancer cell line MCF7 was evaluated in vitro. The study revealed the higher cytotoxic effects of encapsulated BDMC on MCF7 cells compared to equal dose of free BDMC. -- Highlights: • BDMC binds to the hydrophobic core of β-casein. • The effective encapsulation of BDMC in β-casein micelle nanoparticles was shown. • Enhanced cytotoxicity was observed for encapsulated BDMC in β-casein nanoparticles.

  5. In Silico Design of Human IMPDH Inhibitors Using Pharmacophore Mapping and Molecular Docking Approaches

    Directory of Open Access Journals (Sweden)

    Rui-Juan Li

    2015-01-01

    Full Text Available Inosine 5′-monophosphate dehydrogenase (IMPDH is one of the crucial enzymes in the de novo biosynthesis of guanosine nucleotides. It has served as an attractive target in immunosuppressive, anticancer, antiviral, and antiparasitic therapeutic strategies. In this study, pharmacophore mapping and molecular docking approaches were employed to discover novel Homo sapiens IMPDH (hIMPDH inhibitors. The Güner-Henry (GH scoring method was used to evaluate the quality of generated pharmacophore hypotheses. One of the generated pharmacophore hypotheses was found to possess a GH score of 0.67. Ten potential compounds were selected from the ZINC database using a pharmacophore mapping approach and docked into the IMPDH active site. We find two hits (i.e., ZINC02090792 and ZINC00048033 that match well the optimal pharmacophore features used in this investigation, and it is found that they form interactions with key residues of IMPDH. We propose that these two hits are lead compounds for the development of novel hIMPDH inhibitors.

  6. Study on the interaction of catalase with pesticides by flow injection chemiluminescence and molecular docking.

    Science.gov (United States)

    Tan, Xijuan; Wang, Zhuming; Chen, Donghua; Luo, Kai; Xiong, Xunyu; Song, Zhenghua

    2014-08-01

    The interaction mechanisms of catalase (CAT) with pesticides (including organophosphates: disulfoton, isofenphos-methyl, malathion, isocarbophos, dimethoate, dipterex, methamidophos and acephate; carbamates: carbaryl and methomyl; pyrethroids: fenvalerate and deltamethrin) were first investigated by flow injection (FI) chemiluminescence (CL) analysis and molecular docking. By homemade FI-CL model of lg[(I0-I)/I]=lgK+nlg[D], it was found that the binding processes of pesticides to CAT were spontaneous with the apparent binding constants K of 10(3)-10(5) L mol(-1) and the numbers of binding sites about 1.0. The binding abilities of pesticides to CAT followed the order: fenvalerate>deltamethrin>disulfoton>isofenphos-methyl>carbaryl>malathion>isocarbophos>dimethoate>dipterex>acephate>methomyl>methamidophos, which was generally similar to the order of determination sensitivity of pesticides. The thermodynamic parameters revealed that CAT bound with hydrophobic pesticides by hydrophobic interaction force, and with hydrophilic pesticides by hydrogen bond and van der Waals force. The pesticides to CAT molecular docking study showed that pesticides could enter into the cavity locating among the four subdomains of CAT, giving the specific amino acid residues and hydrogen bonds involved in CAT-pesticides interaction. It was also found that the lgK values of pesticides to CAT increased regularly with increasing lgP, Mr, MR and MV, suggesting that the hydrophobicity and steric property of pesticide played essential roles in its binding to CAT. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. Spectrofluoremetric and molecular docking study on the interaction of bisdemethoxycurcumin with bovine β-casein nanoparticles

    International Nuclear Information System (INIS)

    Mehranfar, Fahimeh; Bordbar, Abdol-Khalegh; Keyhanfar, Mehrnaz; Behbahani, Mandana

    2013-01-01

    The interaction of bisdemethoxycurcumin (BDMC), as one of the main active component of turmeric (Curcuma longa L.), with bovine β-casein nanoparticle, as an efficient drug carrier system, was investigated using steady-state fluorescence spectroscopy and molecular docking calculations. Results of fluorescence quenching experiments, Forster energy transfer measurements and molecular docking calculations suggested that BDMC bind to the hydrophobic core of β-casein via formation of 3 hydrogen bonds and several vander Waals contacts that represented the encapsulation of BDMC in β-casein micelle nanoparticles. The binding parameters including number of substantive binding sites and the binding constants were evaluated by fluorescence quenching method. Additionally, the cytotoxicity of free BDMC and BDMC-β-casein complex in human breast cancer cell line MCF7 was evaluated in vitro. The study revealed the higher cytotoxic effects of encapsulated BDMC on MCF7 cells compared to equal dose of free BDMC. -- Highlights: • BDMC binds to the hydrophobic core of β-casein. • The effective encapsulation of BDMC in β-casein micelle nanoparticles was shown. • Enhanced cytotoxicity was observed for encapsulated BDMC in β-casein nanoparticles

  8. Tail Docking and Ear Cropping Dogs: Public Awareness and Perceptions.

    Directory of Open Access Journals (Sweden)

    Katelyn E Mills

    Full Text Available Tail docking and ear cropping are two surgical procedures commonly performed on many dog breeds. These procedures are classified as medically unnecessary surgeries whose purpose is primarily cosmetic. Available attitude research surrounding these controversial practices has been limited to surveys of veterinarians and dog breeders familiar with both practices. The aim of this project was to: 1 assess public awareness of tail docking and ear cropping, 2 determine whether physical alteration of a dog affects how the dog, and 3 owner are perceived. In Experiment 1 awareness was measured using a combination of both explicit and implicit measures. We found that 42% of participants (n = 810 were unable to correctly explain the reason why tail docked and ear cropped dogs had short ears and tails. Similarly, an implicit measure of awareness ('nature vs nurture task', found that the majority of participants believed short tails and erect ears were a consequence of genetics rather than something the owner or breeder had done. The results obtained in Experiment 2 (n = 392 provide evidence that ear cropped and tail docked dogs are perceived differently than an identical dog in its 'natural' state. Modified dogs were perceived as being more aggressive, more dominant, less playful and less attractive than natural dogs. Experiment 3 (n = 410 is the first evidence that owners of modified dogs are perceived as being more aggressive, more narcissistic, less playful, less talkative and less warm compared to owners of natural dogs. Taken together, these results suggest that although a significant proportion of subjects appear unaware of the practices of tail docking and ear cropping in dogs, these procedures have significant impacts on how modified dogs and their owners are perceived by others.

  9. Tail Docking and Ear Cropping Dogs: Public Awareness and Perceptions.

    Science.gov (United States)

    Mills, Katelyn E; Robbins, Jesse; von Keyserlingk, Marina A G

    2016-01-01

    Tail docking and ear cropping are two surgical procedures commonly performed on many dog breeds. These procedures are classified as medically unnecessary surgeries whose purpose is primarily cosmetic. Available attitude research surrounding these controversial practices has been limited to surveys of veterinarians and dog breeders familiar with both practices. The aim of this project was to: 1) assess public awareness of tail docking and ear cropping, 2) determine whether physical alteration of a dog affects how the dog, and 3) owner are perceived. In Experiment 1 awareness was measured using a combination of both explicit and implicit measures. We found that 42% of participants (n = 810) were unable to correctly explain the reason why tail docked and ear cropped dogs had short ears and tails. Similarly, an implicit measure of awareness ('nature vs nurture task'), found that the majority of participants believed short tails and erect ears were a consequence of genetics rather than something the owner or breeder had done. The results obtained in Experiment 2 (n = 392) provide evidence that ear cropped and tail docked dogs are perceived differently than an identical dog in its 'natural' state. Modified dogs were perceived as being more aggressive, more dominant, less playful and less attractive than natural dogs. Experiment 3 (n = 410) is the first evidence that owners of modified dogs are perceived as being more aggressive, more narcissistic, less playful, less talkative and less warm compared to owners of natural dogs. Taken together, these results suggest that although a significant proportion of subjects appear unaware of the practices of tail docking and ear cropping in dogs, these procedures have significant impacts on how modified dogs and their owners are perceived by others.

  10. Re-docking scheme for generating near-native protein complexes by assembling residue interaction fingerprints.

    Directory of Open Access Journals (Sweden)

    Nobuyuki Uchikoga

    Full Text Available Interaction profile method is a useful method for processing rigid-body docking. After the docking process, the resulting set of docking poses could be classified by calculating similarities among them using these interaction profiles to search for near-native poses. However, there are some cases where the near-native poses are not included in this set of docking poses even when the bound-state structures are used. Therefore, we have developed a method for generating near-native docking poses by introducing a re-docking process. We devised a method for calculating the profile of interaction fingerprints by assembling protein complexes after determining certain core-protein complexes. For our analysis, we used 44 bound-state protein complexes selected from the ZDOCK benchmark dataset ver. 2.0, including some protein pairs none of which generated near-native poses in the docking process. Consequently, after the re-docking process we obtained profiles of interaction fingerprints, some of which yielded near-native poses. The re-docking process involved searching for possible docking poses in a restricted area using the profile of interaction fingerprints. If the profile includes interactions identical to those in the native complex, we obtained near-native docking poses. Accordingly, near-native poses were obtained for all bound-state protein complexes examined here. Application of interaction fingerprints to the re-docking process yielded structures with more native interactions, even when a docking pose, obtained following the initial docking process, contained only a small number of native amino acid interactions. Thus, utilization of the profile of interaction fingerprints in the re-docking process yielded more near-native poses.

  11. Re-docking scheme for generating near-native protein complexes by assembling residue interaction fingerprints.

    Science.gov (United States)

    Uchikoga, Nobuyuki; Matsuzaki, Yuri; Ohue, Masahito; Hirokawa, Takatsugu; Akiyama, Yutaka

    2013-01-01

    Interaction profile method is a useful method for processing rigid-body docking. After the docking process, the resulting set of docking poses could be classified by calculating similarities among them using these interaction profiles to search for near-native poses. However, there are some cases where the near-native poses are not included in this set of docking poses even when the bound-state structures are used. Therefore, we have developed a method for generating near-native docking poses by introducing a re-docking process. We devised a method for calculating the profile of interaction fingerprints by assembling protein complexes after determining certain core-protein complexes. For our analysis, we used 44 bound-state protein complexes selected from the ZDOCK benchmark dataset ver. 2.0, including some protein pairs none of which generated near-native poses in the docking process. Consequently, after the re-docking process we obtained profiles of interaction fingerprints, some of which yielded near-native poses. The re-docking process involved searching for possible docking poses in a restricted area using the profile of interaction fingerprints. If the profile includes interactions identical to those in the native complex, we obtained near-native docking poses. Accordingly, near-native poses were obtained for all bound-state protein complexes examined here. Application of interaction fingerprints to the re-docking process yielded structures with more native interactions, even when a docking pose, obtained following the initial docking process, contained only a small number of native amino acid interactions. Thus, utilization of the profile of interaction fingerprints in the re-docking process yielded more near-native poses.

  12. A docking study of enhanced intracellular survival protein from Mycobacterium tuberculosis with human DUSP16/MKP-7

    International Nuclear Information System (INIS)

    Yoon, Hye-Jin; Kim, Kyoung Hoon; Yang, Jin Kuk; Suh, Se Won; Kim, Hyunsik; Jang, Soonmin

    2013-01-01

    A docking study of Mtb Eis with its substrate DUSP16/MKP-7 was performed. The docking model suggests dissociation of hexameric Mtb Eis into dimers or monomers. The intracellular pathogen Mycobacterium tuberculosis (Mtb) causes tuberculosis, and one of its secreted effector proteins, called enhanced intracellular survival (Eis) protein, enhances its survival in macrophages. Mtb Eis activates JNK-specific dual-specificity protein phosphatase 16 (DUSP16)/mitogen-activated protein kinase phosphatase-7 (MKP-7) through the acetylation on Lys55, thus inactivating JNK by dephosphorylation. Based on the recently reported crystal structure of Mtb Eis, a docking model for the binding of Mtb Eis to DUSP16/MKP-7 was generated. In the docking model, the substrate helix containing Lys55 of DUSP16/MKP-7 fits nicely into the active-site cleft of Mtb Eis; the twisted β-sheet of Eis domain II embraces the substrate helix from one side. Most importantly, the side-chain of Lys55 is inserted toward acetyl-CoA and the resulting distance is 4.6 Å between the NZ atom of Lys55 and the carbonyl carbon of the acetyl group in acetyl-CoA. The binding of Mtb Eis and DUSP16/MKP-7 is maintained by strong electrostatic interactions. The active-site cleft of Mtb Eis has a negatively charged surface formed by Asp25, Glu138, Asp286, Glu395 and the terminal carboxylic group of Phe396. In contrast, DUSP16/MKP-7 contains five basic residues, Lys52, Lys55, Arg56, Arg57 and Lys62, which point toward the negatively charged surface of the active-site pocket of Mtb Eis. Thus, the current docking model suggests that the binding of DUSP16/MKP-7 to Mtb Eis should be established by charge complementarity in addition to a very favorable geometric arrangement. The suggested mode of binding requires the dissociation of the hexameric Mtb Eis into dimers or monomers. This study may be useful for future studies aiming to develop inhibitors of Mtb Eis as a new anti-tuberculosis drug candidate

  13. A docking study of enhanced intracellular survival protein from Mycobacterium tuberculosis with human DUSP16/MKP-7

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Hye-Jin, E-mail: yoonhj@snu.ac.kr; Kim, Kyoung Hoon [Seoul National University, Seoul 151-747 (Korea, Republic of); Yang, Jin Kuk [Soongsil University, Seoul 156-743 (Korea, Republic of); Suh, Se Won [Seoul National University, Seoul 151-747 (Korea, Republic of); Seoul National University, Seoul 151-747 (Korea, Republic of); Kim, Hyunsik; Jang, Soonmin, E-mail: yoonhj@snu.ac.kr [Sejong University, Seoul 143-747 (Korea, Republic of)

    2013-11-01

    A docking study of Mtb Eis with its substrate DUSP16/MKP-7 was performed. The docking model suggests dissociation of hexameric Mtb Eis into dimers or monomers. The intracellular pathogen Mycobacterium tuberculosis (Mtb) causes tuberculosis, and one of its secreted effector proteins, called enhanced intracellular survival (Eis) protein, enhances its survival in macrophages. Mtb Eis activates JNK-specific dual-specificity protein phosphatase 16 (DUSP16)/mitogen-activated protein kinase phosphatase-7 (MKP-7) through the acetylation on Lys55, thus inactivating JNK by dephosphorylation. Based on the recently reported crystal structure of Mtb Eis, a docking model for the binding of Mtb Eis to DUSP16/MKP-7 was generated. In the docking model, the substrate helix containing Lys55 of DUSP16/MKP-7 fits nicely into the active-site cleft of Mtb Eis; the twisted β-sheet of Eis domain II embraces the substrate helix from one side. Most importantly, the side-chain of Lys55 is inserted toward acetyl-CoA and the resulting distance is 4.6 Å between the NZ atom of Lys55 and the carbonyl carbon of the acetyl group in acetyl-CoA. The binding of Mtb Eis and DUSP16/MKP-7 is maintained by strong electrostatic interactions. The active-site cleft of Mtb Eis has a negatively charged surface formed by Asp25, Glu138, Asp286, Glu395 and the terminal carboxylic group of Phe396. In contrast, DUSP16/MKP-7 contains five basic residues, Lys52, Lys55, Arg56, Arg57 and Lys62, which point toward the negatively charged surface of the active-site pocket of Mtb Eis. Thus, the current docking model suggests that the binding of DUSP16/MKP-7 to Mtb Eis should be established by charge complementarity in addition to a very favorable geometric arrangement. The suggested mode of binding requires the dissociation of the hexameric Mtb Eis into dimers or monomers. This study may be useful for future studies aiming to develop inhibitors of Mtb Eis as a new anti-tuberculosis drug candidate.

  14. Calorimetric and spectroscopic properties of small globular proteins (bovine serum albumin, hemoglobin) after free radical generation

    International Nuclear Information System (INIS)

    Farkas, N.; Belagyi, J.; Lorinczy, D.

    2003-01-01

    Mild oxidation of -SH-containing proteins (serum albumin, hemoglobin) by Ce(IV)-ions in the presence of the spin trap phenyl-tert-butylnitrone (PBN) resulted in the appearance of strongly immobilized nitroxide free radicals which evidences the formation of thiyl radicals on the thiol site of the proteins. In hydroxyl free radical generating system a fraction of strongly immobilized nitroxide radicals was also detected in these proteins, which implies that the oxidation of a fraction of the thiol groups was also involved in the free radical reaction. According to the differential scanning calorimetry (DSC) experiments the melting processes of the proteins were calorimetrically irreversible, therefore the two-state kinetic model was used to evaluate the experiments. The results support the view that site-specific interaction of SH-containing proteins with hydroxyl and thiyl free radicals is able to modify the internal dynamics of proteins and affect the conformation of large molecules

  15. The effect of ionizing radiation on hemoglobin synthesis

    Energy Technology Data Exchange (ETDEWEB)

    Lipinski, S

    1972-01-01

    The effect of ionizing radiation on hemoglobin synthesis was studied and its effect on the quality of protein was discovered. The biological effects due to the changes in the structure of protein were also observed. The results of the experiments are presented.

  16. Recombinant bacterial hemoglobin alters metabolism of Aspergillus niger

    DEFF Research Database (Denmark)

    Hofmann, Gerald; Diano, Audrey; Nielsen, Jens

    2009-01-01

    , the fungus will produce various by-products like organic acids and polyols. In order to circumvent this problem we here study the effects of the expression of a bacterial hemoglobin protein on the metabolism of A. niger. We integrated the vgb gene from Vitreoscilla sp. into the genome at the pyrA locus...

  17. Relationship of Hemoglobin to Arterial Oxygen Desaturation during Aeromedical Evacuation

    Science.gov (United States)

    2015-04-02

    2. REPORT TYPE Special Report 3. DATES COVERED (From – To) September 2012 – September 2014 4. TITLE AND SUBTITLE Relationship of Hemoglobin to...pressurized pulsatile, and hydrosurgery debridement methods for removing bacteria from fracture implants. Orthopedics. 2012; 35(7):e1046-e1050. 11. Burns TC

  18. Hemoglobin is essential for normal growth of Arabidopsis organs

    DEFF Research Database (Denmark)

    Hebelstrup, Kim Henrik; Hunt, Peter; Dennis, Elizabeth

    2006-01-01

    In Arabidopsis thaliana, the class I hemoglobin AHb1 is transiently expressed in the hydathodes of leaves and in floral buds from young inflorescences. Nitric oxide (NO) accumulates to high levels in these organs when AHb1 is silenced, indicating an important role in metabolizing NO. AHb1-silence...... suggests that 3-on-3 hemoglobins apart from a role in hypoxic stress play a general role under non-stressed conditions where they are essential for normal development by controlling the level of NO which tends to accumulate in floral buds and leaf hydathodes of plants......In Arabidopsis thaliana, the class I hemoglobin AHb1 is transiently expressed in the hydathodes of leaves and in floral buds from young inflorescences. Nitric oxide (NO) accumulates to high levels in these organs when AHb1 is silenced, indicating an important role in metabolizing NO. AHb1-silenced...... lines are viable but show a mutant phenotype affecting the regions where AHb1 is expressed. Arabidopsis lines with an insertional knockout or overexpression of AHb2, a class II 3-on-3 hemoglobin, were generated. Seedlings overexpressing AHb2 show enhanced survival of hypoxic stress. The AHb2 knockout...

  19. Effect of some high consumption spices on hemoglobin glycation.

    Science.gov (United States)

    Naderi, G H; Dinani, Narges J; Asgary, S; Taher, M; Nikkhoo, N; Boshtam, M

    2014-01-01

    Formation of glycation products is major factor responsible in complications of diabetes. Worldwide trend is toward the use of natural additives in reducing the complications of diseases. Therefore, there is a growing interest in natural antiglycation found in plants. Herbs and spices are one of the most important targets to search for natural antiglycation from the point of view of safety. This study investigated the ability of some of the spices to inhibit glycation process in a hemoglobin/glucose model system and compared their potency with each other. For this subject the best concentration and time to incubate glucose with hemoglobin was investigated. Then the glycosylation degree of hemoglobin in the presence of extracts by the three concentrations 0.25, 0.5 and 1 μg/ml was measured colorimetrically at 520 nm. Results represent that some of extracts such as wild caraway, turmeric, cardamom and black pepper have inhibitory effects on hemoglobin glycation. But some of the extracts such as anise and saffron have not only inhibitory effects but also aggravated this event and have proglycation properties. In accordance with the results obtained we can conclude that wild caraway, turmeric, cardamom and black pepper especially wild caraway extracts are potent antiglycation agents, which can be of great value in the preventive glycation-associated complications in diabetes.

  20. A Review on hematology and hemoglobin of fish

    Directory of Open Access Journals (Sweden)

    Ebru YILMAZ

    2015-01-01

    Full Text Available Determination of hematological parameters of fish living in natüre helps to recognize population and to determinate of pollutants in the aquatic environment. In this review, hematological parameters of fish, fish hemoglobin and the Bohr effect were given information.

  1. Influence of hemoglobin on non-invasive optical bilirubin sensing

    Science.gov (United States)

    Jiang, Jingying; Gong, Qiliang; Zou, Da; Xu, Kexin

    2012-03-01

    Since the abnormal metabolism of bilirubin could lead to diseases in the human body, especially the jaundice which is harmful to neonates. Traditional invasive measurements are difficult to be accepted by people because of pain and infection. Therefore, the real-time and non-invasive measurement of bilirubin is of great significance. However, the accuracy of currently transcutaneous bilirubinometry(TcB) is generally not high enough, and affected by many factors in the human skin, mostly by hemoglobin. In this talk, absorption spectra of hemoglobin and bilirubin have been collected and analyzed, then the Partial Least Squares (PLS) models have been built. By analyzing and comparing the Correlation and Root Mean Square Error of Prediction(RMSEP), the results show that the Correlation of bilirubin solution model is larger than that of the mixture solution added with hemoglobin, and its RMSEP value is smaller than that of mixture solution. Therefore, hemoglobin has influences on the non-invasive optical bilirubin sensing. In next step, it is necessary to investigate how to eliminate the influence.

  2. Glycated Hemoglobin Measurement and Prediction of Cardiovascular Disease

    DEFF Research Database (Denmark)

    Di Angelantonio, Emanuele; Gao, Pei; Khan, Hassan

    2014-01-01

    IMPORTANCE: The value of measuring levels of glycated hemoglobin (HbA1c) for the prediction of first cardiovascular events is uncertain. OBJECTIVE: To determine whether adding information on HbA1c values to conventional cardiovascular risk factors is associated with improvement in prediction of c...

  3. 21 CFR 864.7470 - Glycosylated hemoglobin assay.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Glycosylated hemoglobin assay. 864.7470 Section 864.7470 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Hematology Kits and Packages § 864.7470...

  4. 21 CFR 864.7415 - Abnormal hemoglobin assay.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Abnormal hemoglobin assay. 864.7415 Section 864.7415 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Hematology Kits and Packages § 864.7415 Abnormal...

  5. 21 CFR 864.5620 - Automated hemoglobin system.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Automated hemoglobin system. 864.5620 Section 864.5620 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Automated and Semi-Automated Hematology Devices § 864...

  6. 21 CFR 864.7500 - Whole blood hemoglobin assays.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Whole blood hemoglobin assays. 864.7500 Section 864.7500 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Hematology Kits and Packages § 864.7500 Whole...

  7. 21 CFR 864.7440 - Electrophoretic hemoglobin analysis system.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Electrophoretic hemoglobin analysis system. 864.7440 Section 864.7440 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Hematology Kits and Packages § 864...

  8. The influence of socioeconomic status on the hemoglobin level and ...

    African Journals Online (AJOL)

    Materials and Methods: This is a cross-sectional study involving 100 children with SCA and 100 age-, sex-, and social class-matched controls that fulfilled the inclusion criteria. Social class was assessed using educational attainment and occupation of parents. Hemoglobin concentration was determined using the ...

  9. A Microplate Assay for the Determination of Hemoglobin Concentration

    National Research Council Canada - National Science Library

    Frenchik, Michael D; McFaul, Steve J; Tsonev, Latchezar I

    2004-01-01

    ... (NaOH), and converts all hemoglobin species, including COHb, to AHD within 5 min. Both protocols are carried out in cuvettes, and are, therefore, time intensive and difficult to manage when many samples are quantified. This impedes acquisition of triplicate values for each sample necessary to improve accuracy and determine statistical significance.

  10. Expression and purification of recombinant hemoglobin in Escherichia coli

    DEFF Research Database (Denmark)

    Natarajan, Chandrasekhar; Jiang, Xiaoben; Fago, Angela

    2011-01-01

    BACKGROUND: Recombinant DNA technologies have played a pivotal role in the elucidation of structure-function relationships in hemoglobin (Hb) and other globin proteins. Here we describe the development of a plasmid expression system to synthesize recombinant Hbs in Escherichia coli, and we describe...

  11. Importance of hemoglobin concentration to exercise: acute manipulations

    DEFF Research Database (Denmark)

    Calbet, José A L; Lundby, Carsten; Koskolou, Maria

    2006-01-01

    An acute reduction of blood hemoglobin concentration ([Hb]), even when the circulating blood volume is maintained, results in lower (.)V(O(2)(max) and endurance performance, due to the reduction of the oxygen carrying capacity of blood. Conversely, an increase of [Hb] is associated with enhanced...

  12. Myth or reality : Hematocrit and hemoglobin differ in trauma

    NARCIS (Netherlands)

    Nijboer, Johanna M. M.; van der Horst, Iwan C. C.; Hendriks, Herman G. D.; ten Duis, Hendrik-Jan; Nijsten, Maarten W. N.

    Background: Estimating blood loss in trauma patients usually involves the determination of hematocrit (Ht) or hemoglobin (Hb). However, in trauma patients, a poorly substantiated habit exists to determine both Ht and Hb in assessing acute blood loss. This suggests that Ht and Hb provide different

  13. Prediction models for hemoglobin deferral in whole blood donors

    NARCIS (Netherlands)

    Baart, A.M.

    2013-01-01

    Each year, a relevant proportion of the invited blood donors is eventually deferred from donation because of low hemoglobin (Hb) levels. Deferrals are meant to protect donors from developing iron deficiency anemia after a blood donation, however, they may increase the risk of donor lapse, even

  14. Direct electrochemistry of hemoglobin entrapped in dextran film on ...

    Indian Academy of Sciences (India)

    Direct electrochemistry of hemoglobin (Hb) entrapped in the dextran (De) film on the surface of a room temperature ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate (BMIMPF6) modified carbon paste electrode (CILE) has been investigated. UV-Vis and FT-IR spectroscopy showed that Hb retained its native ...

  15. Relationships between hemoglobin A1c and spot glucose ...

    African Journals Online (AJOL)

    Background: Glycosylated hemoglobin, HbA1c is the most acceptable measure of chronic glycemia. It is not widely available and/or affordable in Nigeria. The mean of the monthly fasting plasma glucose (MFPG) of the preceding 3 months is often used as surrogate for assessing chronic glycemia. Objective: To determine the ...

  16. Routine hemoglobin electrophoresis for pediatric surgery day case ...

    African Journals Online (AJOL)

    Background: Hemoglobin electrophoresis (HBE) is a part of the preoperative routine requested by anesthetists. However, the prevalence of hemoglobinopathy in the population is low. This study aims to determine the clinical risk factors for hemoglobinopathies and propose clinical guidelines for preoperative screening of ...

  17. Hemoglobin, Growth, and Attention of Infants in Southern Ethiopia

    Science.gov (United States)

    Aubuchon-Endsley, Nicki L.; Grant, Stephanie L.; Berhanu, Getenesh; Thomas, David G.; Schrader, Sarah E.; Eldridge, Devon; Kennedy, Tay; Hambidge, Michael

    2011-01-01

    Male and female infants from rural Ethiopia were tested to investigate relations among hemoglobin (Hb), anthropometry, and attention. A longitudinal design was used to examine differences in attention performance from 6 (M = 24.9 weeks, n = 89) to 9 months of age (M = 40.6 weeks, n = 85), differences hypothesized to be related to changes in iron…

  18. Ultrasonic processing for recovery of chicken erythrocyte hemoglobin

    Science.gov (United States)

    Hemoglobin from chicken blood has been shown to be a good substitute for synthetic polymeric flocculants. One stage of processing the blood entails breaking open the cells and releasing the cytoplasmic contents; in the present study, we investigate the use of ultrasonic processing at this stage. Was...

  19. The Relationship Between Hemoglobin Level and Intellectual Function.

    Science.gov (United States)

    Munro, Nancy

    In a study to learn whether or not poor nutrition, as indicated by low hemoglobin levels, affects intelligence and behavior, 113 Head Start children in Missoula, Montana took part. Group testing with the Lorge Thorndike Intelligence Test and individual testing with the Wechsler and Primary Scale of Intelligence or Wechsler Intelligence Scale for…

  20. Human macrophage hemoglobin-iron metabolism in vitro

    International Nuclear Information System (INIS)

    Custer, G.; Balcerzak, S.; Rinehart, J.

    1982-01-01

    An entirely in vitro technique was employed to characterize hemoglobin-iron metabolism by human macrophages obtained by culture of blood monocytes and pulmonary alveolar macrophages. Macrophages phagocytized about three times as many erythrocytes as monocytes and six times as many erythrocytes as pulmonary alveolar macrophages. The rate of subsequent release of 59 Fe to the extracellular transferrin pool was two- to fourfold greater for macrophages as compared to the other two cell types. The kinetics of 59 Fe-transferrin release were characterized by a relatively rapid early phase (hours 1-4) followed by a slow phase (hours 4-72) for all three cell types. Intracellular movement of iron was characterized by a rapid shift from hemoglobin to ferritin that was complete with the onset of the slow phase of extracellular release. A transient increase in 59 Fe associated with an intracellular protein eluting with transferrin was also observed within 1 hour after phagocytosis. The process of hemoglobin-iron release to extracellular transferrin was inhibited at 4 degrees C but was unaffected by inhibitory of protein synthesis, glycolysis, microtubule function, and microfilament function. These data emphasize the rapidity of macrophage hemoglobin iron metabolism, provide a model for characterization of this process in vitro, and in general confirm data obtained utilizing in vivo animal models

  1. Computational docking, molecular dynamics simulation and subsite structure analysis of a maltogenic amylase from Bacillus lehensis G1 provide insights into substrate and product specificity.

    Science.gov (United States)

    Manas, Nor Hasmaliana Abdul; Bakar, Farah Diba Abu; Illias, Rosli Md

    2016-06-01

    Maltogenic amylase (MAG1) from Bacillus lehensis G1 displayed the highest hydrolysis activity on β-cyclodextrin (β-CD) to produce maltose as a main product and exhibited high transglycosylation activity on malto-oligosaccharides with polymerization degree of three and above. These substrate and product specificities of MAG1 were elucidated from structural point of view in this study. A three-dimensional structure of MAG1 was constructed using homology modeling. Docking of β-CD and malto-oligosaccharides was then performed in the MAG1 active site. An aromatic platform in the active site was identified which is responsible in substrate recognition especially in determining the enzyme's preference toward β-CD. Molecular dynamics (MD) simulation showed MAG1 structure is most stable when docked with β-CD and least stable when docked with maltose. The docking analysis and MD simulation showed that the main subsites for substrate stabilization in the active site are -2, -1, +1 and +2. A bulky residue, Trp359 at the +2 subsite was identified to cause steric interference to the bound linear malto-oligosaccharides thus prevented it to occupy subsite +3, which can only be reached by a highly bent glucose molecule such as β-CD. The resulted modes of binding from docking simulation show a good correlation with the experimentally determined hydrolysis pattern. The subsite structure generated from this study led to a possible mode of action that revealed how maltose was mainly produced during hydrolysis. Furthermore, maltose only occupies subsite +1 and +2, therefore could not be hydrolyzed or transglycosylated by the enzyme. This important knowledge has paved the way for a novel structure-based molecular design for modulation of its catalytic activities. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. No dry dock: safely strategy for avoiding unplanned dry dock and reducing safety, health and environment risks

    Energy Technology Data Exchange (ETDEWEB)

    Constantinis, Danny A.; Brett, David E. [EM and I Alliance, Cheshire (United Kingdom)

    2012-07-01

    There are currently over 150 operational FPUs with an expected increase of a further 100 units in the next 5 years. This results from several factors: increasing demand for hydrocarbons; new reserves in deep water; pipeline infrastructure is not required and FPU design fits many field requirements. FPUs are increasingly chosen for large, deep water, longer life developments. Units are bigger and more complex. Regulators and oil majors are imposing more stringent integrity requirements to protect against safety, environmental and operational risks related to loss of containment and loss of hull structure integrity which could lead to HSE risks, increased costs and production losses which would become particularly onerous should the unit have to dry dock. There are a number of other important components the context of asset integrity, e.g. mooring and sub sea systems, but these are outside the scope of this paper. The 'No Dry dock....Safely' approach is based on the principle of Criticality Based Integrity which identifies components whose integrity is critical to avoiding incidents and the risk of dry docking. Once critical components are identified the challenge is to establish integrity status and maintain fitness-for-service. Various JIPs e.g. the Hull Inspection Techniques and Strategies are looking at best practice inspection methodologies. The industry is progressing ways of maintaining and repairing critical items without going to dry dock. The challenges include coating maintenance, structural and pressure system repairs. Advances in cathodic protection and coating maintenance strategies are proving successful as are techniques for carrying out major structural repairs. The 'No Dry dock...Safely' methodology is a proven solution and case histories have been included. Technological advances will further improve integrity in the industry. There is no reason why FPUs cannot be kept on station and in production for 25 years or more whilst

  3. Iron metabolism mutant hbd mice have a deletion in Sec15l1, which has homology to a yeast gene for vesicle docking.

    Science.gov (United States)

    White, Robert A; Boydston, Leigh A; Brookshier, Terri R; McNulty, Steven G; Nsumu, Ndona N; Brewer, Brandon P; Blackmore, Krista

    2005-12-01

    Defects in iron absorption and utilization lead to iron deficiency and anemia. While iron transport by transferrin receptor-mediated endocytosis is well understood, it is not completely clear how iron is transported from the endosome to the mitochondria where heme is synthesized. We undertook a positional cloning project to identify the causative mutation for the hemoglobin-deficit (hbd) mouse mutant, which suffers from a microcytic, hypochromic anemia apparently due to defective iron transport in the endocytosis cycle. As shown by previous studies, reticulocyte iron accumulation in homozygous hbd/hbd mice is deficient despite normal binding of transferrin to its receptor and normal transferrin uptake in the cell. We have identified a strong candidate gene for hbd, Sec15l1, a homologue to yeast SEC15, which encodes a key protein in vesicle docking. The hbd mice have an exon deletion in Sec15l1, which is the first known mutation of a SEC gene homologue in mammals.

  4. The subunit structure of the extracellular hemoglobin of Biomphalaria glabrata

    International Nuclear Information System (INIS)

    Arndt, Marcio H.L.; Naves, Cristiani F.; Xavier, Luciana P.; Santoro, Marcelo M.

    1997-01-01

    Full text. The hemoglobin of Biomphalaria glabrata was purified to homogeneity by a two step purification protocol using a gel filtration column (Superose 6 HR/Pharmacia ) followed by an anion exchange chromatography (MONO-Q Sepharose/Pharmacia). The dissociation products were analysed by a 5 - 15 % Polyacrylamide gel electrophoresis containing Sodium Dodecyl Sulfate (SDS-PAGE) giving a band of 270 K Daltons and a band of 180 K Daltons after reduction with β-mercaptoethanol. The same profile was obtained in a 3.5 % Agarose gel electrophoresis containing SDS (SDS-AGE) showing additional bands of higher molecular weight. These bands were proposed to be monomers, dimers and trimers and, after reduction in a Bidimensional SDS-AGE, the proposed monomers and dimers were decomposed in two and four bands that were interpreted as 1 - 4 chains. The hemoglobin was digested by four different proteases ( Thrombin, Trypsin, Chymotrypsin and Subtilisin ) showing several equivalent fragments with molecular weights multiples of its minimum molecular weight ( 17.7 K Daltons). The circular dichroism spectrum of the protein showed a characteristic high α-helix content. We proposed that this hemoglobin is a pentamer of approx. 360 K Daltons subunits each formed by two 180 K Daltons chains linked in pairs by disulfide bridges and each of these chains comprises ten Heme binding domains. These data were compared to other Planorbidae extracellular hemoglobins. Up to now, the quaternary structure of this hemoglobin (shape and disposition of the subunits) is unknown. It is intended to elucidate its structure by Small Angle X-Ray Scattering in Brazilian National Laboratory of Synchrotron Light (LNLS). (author)

  5. Hemoglobin Kinetics and Long-term Prognosis in Heart Failure.

    Science.gov (United States)

    Díez-López, Carles; Lupón, Josep; de Antonio, Marta; Zamora, Elisabet; Domingo, Mar; Santesmases, Javier; Troya, Maria-Isabel; Boldó, Maria; Bayes-Genis, Antoni

    2016-09-01

    The influence of hemoglobin kinetics on outcomes in heart failure has been incompletely established. Hemoglobin was determined at the first visit and at 6 months. Anemia was defined according to World Health Organization criteria (hemoglobin < 13g/dL for men and hemoglobin < 12g/dL for women). Patients were classified relative to their hemoglobin values as nonanemic (both measurements normal), transiently anemic (anemic at the first visit but not at 6 months), newly anemic (nonanemic initially but anemic at 6 months), or permanently anemic (anemic in both measurements). A total of 1173 consecutive patients (71.9% men, mean age 66.8±12.2 years) were included in the study. In all, 476 patients (40.6%) were considered nonanemic, 170 (14.5%) had transient anemia, 147 (12.5%) developed new-onset anemia, and 380 (32.4%) were persistently anemic. During a follow-up of 3.7±2.8 years after the 6-month visit, 494 patients died. On comprehensive multivariable analyses, anemia (P < .001) and the type of anemia (P < .001) remained as independent predictors of all-cause mortality. Compared with patients without anemia, patients with persistent anemia (hazard ratio [HR] = 1.62; 95% confidence interval [95%CI], 1.30-2.03; P < .001) and new-onset anemia (HR = 1.39; 95%CI, 1.04-1.87, P = .03) had higher mortality, and even transient anemia showed a similar trend, although without reaching statistical significance (HR = 1.31; 95%CI, 0.97-1.77, P = .075). Anemia, especially persistent and of new-onset, and to a lesser degree, transient anemia, is deleterious in heart failure. Copyright © 2016 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

  6. Anemia and hemoglobin levels among Indigenous Xavante children, Central Brazil.

    Science.gov (United States)

    Ferreira, Aline Alves; Santos, Ricardo Ventura; Souza, July Anne Mendonça de; Welch, James R; Coimbra, Carlos E A

    2017-01-01

    To evaluate the prevalence of anemia, mean hemoglobin levels, and the main nutritional, demographic, and socioeconomic factors among Xavante children in Mato Grosso State, Brazil. A survey was conducted with children under 10 years of age in two indigenous Xavante communities within the Pimentel Barbosa Indigenous Reserve. Hemoglobin concentration levels, anthropometric measurements, and socioeconomic/demographic data were collected by means of clinical measurements and structured interviews. The cut-off points recommended by the World Health Organization were used for anemia classification. Linear regression analyses with hemoglobin as the outcome and Poisson regression with robust variance and with the presence or absence of anemia as outcomes were performed (95%CI). Lower mean hemoglobin values were observed in children under 2 years of age, without a significant difference between sexes. Anemia was observed among 50.8% of children overall, with the highest prevalence among children under 2 years of age (77.8%). Age of the child was inversely associated with the occurrence of anemia (adjusted PR = 0.60; 95%CI 0.38-0.95) and mean hemoglobin values increased significantly with age. Greater height-for-age z-score values reduced the probability of having anemia by 1.8 times (adjusted PR = 0.59; 95%CI 0.34-1.00). Presence of another child with anemia within the household increased the probability of the occurrence of anemia by 52.9% (adjusted PR = 1.89; 95%CI 1.16-3.09). Elevated levels of anemia among Xavante children reveal a disparity between this Indigenous population and the national Brazilian population. Results suggest that anemia is determined by complex and variable relationships between socioeconomic, sociodemographic, and biological factors.

  7. A microfluidic approach for hemoglobin detection in whole blood

    Directory of Open Access Journals (Sweden)

    Nikita Taparia

    2017-10-01

    Full Text Available Diagnosis of anemia relies on the detection of hemoglobin levels in a blood sample. Conventional blood analyzers are not readily available in most low-resource regions where anemia is prevalent, so detection methods that are low-cost and point-of-care are needed. Here, we present a microfluidic approach to measure hemoglobin concentration in a sample of whole blood. Unlike conventional approaches, our microfluidic approach does not require hemolysis. We detect the level of hemoglobin in a blood sample optically by illuminating the blood in a microfluidic channel at a peak wavelength of 540 nm and measuring its absorbance using a CMOS sensor coupled with a lens to magnify the image onto the detector. We compare measurements in microchannels with channel heights of 50 and 115 μm and found the channel with the 50 μm height provided a better range of detection. Since we use whole blood and not lysed blood, we fit our data to an absorption model that includes optical scattering in order to obtain a calibration curve for our system. Based on this calibration curve and data collected, we can measure hemoglobin concentration within 1 g/dL for severe cases of anemia. In addition, we measured optical density for blood flowing at a shear rate of 500 s-1 and observed it did not affect the nonlinear model. With this method, we provide an approach that uses microfluidic detection of hemoglobin levels that can be integrated with other microfluidic approaches for blood analysis.

  8. Rational design of methicillin resistance staphylococcus aureus inhibitors through 3D-QSAR, molecular docking and molecular dynamics simulations.

    Science.gov (United States)

    Ballu, Srilata; Itteboina, Ramesh; Sivan, Sree Kanth; Manga, Vijjulatha

    2018-04-01

    Staphylococcus aureus is a gram positive bacterium. It is the leading cause of skin and respiratory infections, osteomyelitis, Ritter's disease, endocarditis, and bacteraemia in the developed world. We employed combined studies of 3D QSAR, molecular docking which are validated by molecular dynamics simulations and in silico ADME prediction have been performed on Isothiazoloquinolones inhibitors against methicillin resistance Staphylococcus aureus. Three-dimensional quantitative structure-activity relationship (3D-QSAR) study was applied using comparative molecular field analysis (CoMFA) with Q 2 of 0.578, R 2 of 0.988, and comparative molecular similarity indices analysis (CoMSIA) with Q 2 of 0.554, R 2 of 0.975. The predictive ability of these model was determined using a test set of molecules that gave acceptable predictive correlation (r 2 Pred) values 0.55 and 0.57 of CoMFA and CoMSIA respectively. Docking, simulations were employed to position the inhibitors into protein active site to find out the most probable binding mode and most reliable conformations. Developed models and Docking methods provide guidance to design molecules with enhanced activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Docking Studies, Synthesis and Biological Evaluation of β-aryl-β-hydroxy Propanoic Acids for Anti-inflammatory Activity.

    Science.gov (United States)

    Savic, Jelena; Dilber, Sanda; Milenkovic, Marina; Kotur-Stevuljevic, Jelena; Markovic, Bojan; Vladimirov, Sote; Brboric, Jasmina

    2017-01-01

    Nonsteriodal anti-inflammatory drugs (NSAIDs) are numerous and widely used for more than 60 years, but there is still a strong need for developing novel selective NSAIDs. The need is justified by the fact that nonselective NSAIDs can produce serious gastric side effects and that some of the selective NSAID are withdrawn due to their cardiotoxic side effects. Eight β-hydroxy-β-arylpropanoic acids, which belong to the arylpropanoic acid class of compounds, structurally similar to some nonsteroidal anti-inflammatory drugs (NSAIDs), were docked into 3D catalytic site of both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Seven out of those eight acids were synthesized using already published modification of Reformatsky reaction additionally optimized by increasing temperature. Synthesized compounds were tested in vivo in order to elucidate anti-inflammatory activity, gastric tolerability and impact on liver function of rats. Results of docking studies have indicated that all compounds have potential to selectively inhibit COX-2 isoform, but that the compounds containing polar substituents on phenyl ring are better inhibitors. Results of carrageenan-induced rat paw oedema test have shown that all compounds exhibit dose dependence and good gastric tolerability and none of the tested compounds have shown negative effect on liver function compared to ibuprofen. The compound containing polar nitro group in para position has shown the best docking results, anti-inflammatory activity, low hepatotoxicity and good gastric tolerability. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  10. Genetic hemoglobin disorders rather than iron deficiency are a major predictor of hemoglobin concentration in women of reproductive age in rural prey Veng, Cambodia.

    Science.gov (United States)

    Karakochuk, Crystal D; Whitfield, Kyly C; Barr, Susan I; Lamers, Yvonne; Devlin, Angela M; Vercauteren, Suzanne M; Kroeun, Hou; Talukder, Aminuzzaman; McLean, Judy; Green, Timothy J

    2015-01-01

    Anemia is common in Cambodian women. Potential causes include micronutrient deficiencies, genetic hemoglobin disorders, inflammation, and disease. We aimed to investigate factors associated with anemia (low hemoglobin concentration) in rural Cambodian women (18-45 y) and to investigate the relations between hemoglobin disorders and other iron biomarkers. Blood samples were obtained from 450 women. A complete blood count was conducted, and serum and plasma were analyzed for ferritin, soluble transferrin receptor (sTfR), folate, vitamin B-12, retinol binding protein (RBP), C-reactive protein (CRP), and α1 acid glycoprotein (AGP). Hemoglobin electrophoresis and multiplex polymerase chain reaction were used to determine the prevalence and type of genetic hemoglobin disorders. Overall, 54% of women had a genetic hemoglobin disorder, which included 25 different genotypes (most commonly, hemoglobin E variants and α(3.7)-thalassemia). Of the 420 nonpregnant women, 29.5% had anemia (hemoglobin 8.3 mg/L), hemoglobin disorders, respectively. There was no biochemical evidence of vitamin A deficiency (RBP 5 mg/L) and 26% (AGP >1 g/L) of nonpregnant women, respectively. By using an adjusted linear regression model, the strongest predictors of hemoglobin concentration were hemoglobin E homozygous disorder and pregnancy status. Other predictors were 2 other heterozygous traits (hemoglobin E and Constant Spring), parity, RBP, log ferritin, and vitamin B-12. Multiple biomarkers for anemia and iron deficiency were significantly influenced by the presence of hemoglobin disorders, hence reducing their diagnostic sensitivity. Further investigation of the unexpectedly low prevalence of IDA in Cambodian women is warranted. © 2015 American Society for Nutrition.

  11. FET immunosensor for hemoglobin A1c using a gold nanofilm grown by a seed-mediated technique and covered with mixed self-assembled monolayers

    International Nuclear Information System (INIS)

    Xue, Q.; Bian, C.; Tong, J.; Sun, J.; Zhang, H.; Xia, S.

    2012-01-01

    A micro FET-based immunosensor was developed for the determination of hemoglobin-A1c (HbA1c). The HbA1c/hemoglobin ratio is an important index in diabetes control. The sensor was fabricated by Complementary Metal-Oxide-Semiconductor Transistor (CMOS) and Micro Electronic Mechanical System (MEMS) techniques. The antibodies were immobilized via mixed self-assembled monolayers (SAMs) on a gold nanofilm. The nanofilm was deposited on a gold electrode by seed-mediated growth and gave a uniform and well distributed coverage. Nonspecific sites and interferences by noise were eliminated by covering the AuNPs with mixed SAMs. Compared to the immunosensor fabricated via the mixed SAMs method without gold nanofilm, the immunosensor displays a more than 2-fold sensitivity. The immunosensor is capable of detecting HbA1c and hemoglobin in hemolyzed and diluted whole blood, and results showed good agreement with the established clinical method. (author)

  12. MR Imaging-derived Oxygen-Hemoglobin Dissociation Curves and Fetal-Placental Oxygen-Hemoglobin Affinities.

    Science.gov (United States)

    Avni, Reut; Golani, Ofra; Akselrod-Ballin, Ayelet; Cohen, Yonni; Biton, Inbal; Garbow, Joel R; Neeman, Michal

    2016-07-01

    Purpose To generate magnetic resonance (MR) imaging-derived, oxygen-hemoglobin dissociation curves and to map fetal-placental oxygen-hemoglobin affinity in pregnant mice noninvasively by combining blood oxygen level-dependent (BOLD) T2* and oxygen-weighted T1 contrast mechanisms under different respiration challenges. Materials and Methods All procedures were approved by the Weizmann Institutional Animal Care and Use Committee. Pregnant mice were analyzed with MR imaging at 9.4 T on embryonic days 14.5 (eight dams and 58 fetuses; imprinting control region ICR strain) and 17.5 (21 dams and 158 fetuses) under respiration challenges ranging from hyperoxia to hypoxia (10 levels of oxygenation, 100%-10%; total imaging time, 100 minutes). A shorter protocol with normoxia to hyperoxia was also performed (five levels of oxygenation, 20%-100%; total imaging time, 60 minutes). Fast spin-echo anatomic images were obtained, followed by sequential acquisition of three-dimensional gradient-echo T2*- and T1-weighted images. Automated registration was applied to align regions of interest of the entire placenta, fetal liver, and maternal liver. Results were compared by using a two-tailed unpaired Student t test. R1 and R2* values were derived for each tissue. MR imaging-based oxygen-hemoglobin dissociation curves were constructed by nonlinear least square fitting of 1 minus the change in R2*divided by R2*at baseline as a function of R1 to a sigmoid-shaped curve. The apparent P50 (oxygen tension at which hemoglobin is 50% saturated) value was derived from the curves, calculated as the R1 scaled value (x) at which the change in R2* divided by R2*at baseline scaled (y) equals 0.5. Results The apparent P50 values were significantly lower in fetal liver than in maternal liver for both gestation stages (day 14.5: 21% ± 5 [P = .04] and day 17.5: 41% ± 7 [P hemoglobin dissociation curves with a shorter protocol that excluded the hypoxic periods was demonstrated. Conclusion MR imaging

  13. Characterization and Expression of the Lucina pectinata Oxygen and Sulfide Binding Hemoglobin Genes

    Science.gov (United States)

    López-Garriga, Juan; Cadilla, Carmen L.

    2016-01-01

    The clam Lucina pectinata lives in sulfide-rich muds and houses intracellular symbiotic bacteria that need to be supplied with hydrogen sulfide and oxygen. This clam possesses three hemoglobins: hemoglobin I (HbI), a sulfide-reactive protein, and hemoglobin II (HbII) and III (HbIII), which are oxygen-reactive. We characterized the complete gene sequence and promoter regions for the oxygen reactive hemoglobins and the partial structure and promoters of the HbI gene from Lucina pectinata. We show that HbI has two mRNA variants, where the 5’end had either a sequence of 96 bp (long variant) or 37 bp (short variant). The gene structure of the oxygen reactive Hbs is defined by having 4-exons/3-introns with conservation of intron location at B12.2 and G7.0 and the presence of pre-coding introns, while the partial gene structure of HbI has the same intron conservation but appears to have a 5-exon/ 4-intron structure. A search for putative transcription factor binding sites (TFBSs) was done with the promoters for HbII, HbIII, HbI short and HbI long. The HbII, HbIII and HbI long promoters showed similar predicted TFBSs. We also characterized MITE-like elements in the HbI and HbII gene promoters and intronic regions that are similar to sequences found in other mollusk genomes. The gene expression levels of the clam Hbs, from sulfide-rich and sulfide-poor environments showed a significant decrease of expression in the symbiont-containing tissue for those clams in a sulfide-poor environment, suggesting that the sulfide concentration may be involved in the regulation of these proteins. Gene expression evaluation of the two HbI mRNA variants indicated that the longer variant is expressed at higher levels than the shorter variant in both environments. PMID:26824233

  14. 1H and 31P nuclear magnetic resonance investigation of the interaction between 2,3-diphosphoglycerate and human normal adult hemoglobin.

    Science.gov (United States)

    Russu, I M; Wu, S S; Bupp, K A; Ho, N T; Ho, C

    1990-04-17

    High-resolution 1H and 31P nuclear magnetic resonance spectroscopy has been used to investigate the binding of 2,3-diphosphoglycerate to human normal adult hemoglobin and the molecular interactions involved in the allosteric effect of the 2,3-diphosphoglycerate molecule on hemoglobin. Individual hydrogen ion NMR titration curves have been obtained for 22-26 histidyl residues of hemoglobin and for each phosphate group of 2,3-diphosphoglycerate with hemoglobin in both the deoxy and carbonmonoxy forms. The results indicate that 2,3-diphosphoglycerate binds to deoxyhemoglobin at the central cavity between the two beta chains and the binding involves the beta 2-histidyl residues. Moreover, the results suggest that the binding site of 2,3-diphosphoglycerate to carbonmonoxyhemoglobin contains the same (or at least some of the same) amino acid residues responsible for binding in the deoxy form. As a result of the specific interactions with 2,3-diphosphoglycerate, the beta 2-histidyl residues make a significant contribution to the alkaline Bohr effect under these experimental conditions (up to 0.5 proton/Hb tetramer). 2,3-Diphosphoglycerate also affects the individual hydrogen ion equilibria of several histidyl residues located away from the binding site on the surface of the hemoglobin molecule, and, possibly, in the heme pockets. These results give the first experimental demonstration that long-range electrostatic and/or conformational effects of the binding could play an important role in the allosteric effect of 2,3-diphosphoglycerate on hemoglobin.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. Mechanism of the Enhancement of the Bohr Effect in Mammalian Hemoglobins by Diphosphoglycerate

    Science.gov (United States)

    Riggs, Austen

    1971-01-01

    The number of protons released from several mammalian hemoglobins as a consequence of oxygenation is greater in the presence of low concentrations of 2,3-diphosphoglycerate than in its absence. A mechanism for this enhancement of proton release is proposed. The basis of this mechanism is that 2,3-diphosphoglycerate binds primarily between the protonated α-NH2 terminal groups of the two β chains in deoxyhemoglobin. This binding will shift the ionization equilibria in favor of the protonation of the deoxyhemoglobin. Partial release of 2,3-diphosphoglycerate upon oxygenation of the hemoglobin is then accompanied by a release of protons. The apparent enthalpy of diphosphoglycerate binding appears to be close to zero. The previously reported temperature dependence appears to be due entirely to the associated protonation reaction. If only a single diphosphoglycerate binding site is assumed, the intrinsic association constant is estimated to be 3.9 × 105 M-1 for deoxyhemoglobin and 1.05 × 104 M-1 for oxyhemoglobin at 20°C in 0.1 M NaCl. PMID:5289365

  16. Mechanism of the enhancement of the Bohr effect in mammalian hemoglobins by diphosphoglycerate.

    Science.gov (United States)

    Riggs, A

    1971-09-01

    The number of protons released from several mammalian hemoglobins as a consequence of oxygenation is greater in the presence of low concentrations of 2,3-diphosphoglycerate than in its absence. A mechanism for this enhancement of proton release is proposed. The basis of this mechanism is that 2,3-diphosphoglycerate binds primarily between the protonated alpha-NH(2) terminal groups of the two beta chains in deoxyhemoglobin. This binding will shift the ionization equilibria in favor of the protonation of the deoxyhemoglobin. Partial release of 2,3-diphosphoglycerate upon oxygenation of the hemoglobin is then accompanied by a release of protons. The apparent enthalpy of diphosphoglycerate binding appears to be close to zero. The previously reported temperature dependence appears to be due entirely to the associated protonation reaction. If only a single diphosphoglycerate binding site is assumed, the intrinsic association constant is estimated to be 3.9 x 10(5) M(-1) for deoxyhemoglobin and 1.05 x 10(4) M(-1) for oxyhemoglobin at 20 degrees C in 0.1 M NaCl.

  17. Crystal structure of hemoglobin from the maned wolf (Chrysocyon brachyurus) using synchrotron radiation.

    Science.gov (United States)

    Fadel, Valmir; Canduri, Fernanda; Olivieri, Johnny R; Smarra, André L S; Colombo, Marcio F; Bonilla-Rodriguez, Gustavo O; de Azevedo, Walter F

    2003-12-01

    Crystal structure of hemoglobin isolated from the Brazilian maned wolf (Chrysocyon brachyurus) was determined using standard molecular replacement technique and refined using maximum-likelihood and simulated annealing protocols to 1.87A resolution. Structural and functional comparisons between hemoglobins from the Chrysocyon brachyurus and Homo sapiens are discussed, in order to provide further insights in the comparative biochemistry of vertebrate hemoglobins.

  18. Hemoglobin A1c (HbA1c) Test: MedlinePlus Lab Test Information

    Science.gov (United States)

    ... page: https://medlineplus.gov/labtests/hemoglobina1chba1ctest.html Hemoglobin A1c (HbA1c) Test To use the sharing features on this page, please enable JavaScript. What is a hemoglobin A1c (HbA1c) test? A hemoglobin A1c (HbA1c) test measures ...

  19. Hemoglobin levels in persons with depressive and/or anxiety disorders

    NARCIS (Netherlands)

    Lever-van Milligen, Bianca A.; Vogelzangs, Nicole; Smit, Johannes H.; Penninx, Brenda W. J. H.

    Objective: Both low and high hemoglobin levels lead to more physical diseases, and both are linked to mortality. Low hemoglobin, often classified as anemia, has also been linked to more depressive symptoms, but whether both hemoglobin extremes are associated with depressive disorder and potentially

  20. Enzymatic Activity Enhancement of Non-Covalent Modified Superoxide Dismutase and Molecular Docking Analysis

    Directory of Open Access Journals (Sweden)

    Fa-Jun Song

    2012-03-01

    Full Text Available The enzyme activity of superoxide dismutase was improved in the pyrogallol autoxidation system by about 27%, after interaction between hydroxypropyl-β-cyclo- dextrin and superoxide dismutase. Fluorescence spectrometry was used to study the interaction between hydroxypropyl-β-cyclodextrin and superoxide dismutase at different temperatures. By doing this, it can be found that these interactions increase fluorescence sensitivity. In the meantime, the synchronous fluorescence intensity revealed the interaction sites to be close to the tryptophan (Trp and tyrosine (Tyr residues of superoxide dismutase. Furthermore, molecular docking was applied to explore the binding mode between the ligands and the receptor. This suggested that HP-β-CD interacted with the B ring, G ring and the O ring and revealed that the lysine (Lys residues enter the nanocavity. It was concluded that the HP-β-CD caused specific conformational changes in SOD by non-covalent modification.

  1. Enzyme Inhibitory and Molecular Docking Studies on Some Organic Molecules of Natural Occurrence

    International Nuclear Information System (INIS)

    Abbasi, M. A.; Hussain, G.; Rehman, A. U.; Shahwar, D.; Mohyuddin, A.; Ashraf, M.; Rahman, J.; Lodhi, M. A.; Khan, F. A.

    2016-01-01

    In the present study, in vitro enzyme inhibitory studies on cinchonidine (1), cinchonine (2), quinine (3), noscapine (narcotine, 4) and santonine (5) were carried out. The various enzymes included in the study were lipoxygenase, xanthine oxidase, acetyl cholinesterase, butyryl cholinesterase and protease. The results revealed that 2, 3, and 4 were moderate active against lipoxygenase and xanthine oxidase enzymes. The molecule 3 possessed weak activity against butyryl cholinesterase enzyme while remaining molecules were inactive against this enzyme. However, all these compounds were inactive against acetyl cholinestrase and protease enzymes. The synthesized compounds were computationally docked into the active site of lipoxygenase enzyme. The compounds 3 and 4 showed decent interactions, hence strengthening the observed results. (author)

  2. Molecular docking of Glycine max and Medicago truncatula ureases with urea; bioinformatics approaches.

    Science.gov (United States)

    Filiz, Ertugrul; Vatansever, Recep; Ozyigit, Ibrahim Ilker

    2016-03-01

    Urease (EC 3.5.1.5) is a nickel-dependent metalloenzyme catalyzing the hydrolysis of urea into ammonia and carbon dioxide. It is present in many bacteria, fungi, yeasts and plants. Most species, with few exceptions, use nickel metalloenzyme urease to hydrolyze urea, which is one of the commonly used nitrogen fertilizer in plant growth thus its enzymatic hydrolysis possesses vital importance in agricultural practices. Considering the essentiality and importance of urea and urease activity in most plants, this study aimed to comparatively investigate the ureases of two important legume species such as Glycine max (soybean) and Medicago truncatula (barrel medic) from Fabaceae family. With additional plant species, primary and secondary structures of 37 plant ureases were comparatively analyzed using various bioinformatics tools. A structure based phylogeny was constructed using predicted 3D models of G. max and M. truncatula, whose crystallographic structures are not available, along with three additional solved urease structures from Canavalia ensiformis (PDB: 4GY7), Bacillus pasteurii (PDB: 4UBP) and Klebsiella aerogenes (PDB: 1FWJ). In addition, urease structures of these species were docked with urea to analyze the binding affinities, interacting amino acids and atom distances in urease-urea complexes. Furthermore, mutable amino acids which could potentially affect the protein active site, stability and flexibility as well as overall protein stability were analyzed in urease structures of G. max and M. truncatula. Plant ureases demonstrated similar physico-chemical properties with 833-878 amino acid residues and 89.39-90.91 kDa molecular weight with mainly acidic (5.15-6.10 pI) nature. Four protein domain structures such as urease gamma, urease beta, urease alpha and amidohydro 1 characterized the plant ureases. Secondary structure of plant ureases also demonstrated conserved protein architecture, with predominantly α-helix and random coil structures. In

  3. The interaction between 4-aminoantipyrine and bovine serum albumin: Multiple spectroscopic and molecular docking investigations

    International Nuclear Information System (INIS)

    Teng Yue; Liu Rutao; Li Chao; Xia Qing; Zhang Pengjun

    2011-01-01

    4-Aminoantipyrine (AAP) is widely used in the pharmaceutical industry, in biochemical experiments and in environmental monitoring. AAP as an aromatic pollutant in the environment poses a great threat to human health. To evaluate the toxicity of AAP at the protein level, the effects of AAP on bovine serum albumin (BSA) were investigated by multiple spectroscopic techniques and molecular modeling. After the inner filter effect was eliminated, the experimental results showed that AAP effectively quenched the intrinsic fluorescence of BSA via static quenching. The number of binding sites, the binding constant, the thermodynamic parameters and binding subdomain were measured, and indicated that AAP could spontaneously bind with BSA on subdomain IIIA through electrostatic forces. Molecular docking results revealed that AAP interacted with the Glu 488 and Glu 502 residues of BSA. Furthermore, the conformation of BSA was demonstrably changed in the presence of AAP. The skeletal structure of BSA loosened, exposing internal hydrophobic aromatic ring amino acids and peptide strands to the solution.

  4. 4-Aminoquinoline-pyrimidine hybrids: synthesis, antimalarial activity, heme binding and docking studies.

    Science.gov (United States)

    Kumar, Deepak; Khan, Shabana I; Tekwani, Babu L; Ponnan, Prija; Rawat, Diwan S

    2015-01-07

    A series of novel 4-aminoquinoline-pyrimidine hybrids has been synthesized and evaluated for their antimalarial activity. Several compounds showed promising in vitro antimalarial activity against both CQ-sensitive and CQ-resistant strains with high selectivity index. All the compounds were found to be non-toxic to the mammalian cell lines. Selected compound 7g exhibited significant suppression of parasitemia in the in vivo assay. The heme binding studies were conducted to determine the mode of action of these hybrid molecules. These compounds form a stable 1:1 complex with hematin suggesting that heme may be one of the possible targets of these hybrids. The interaction of these conjugate hybrids was also investigated by the molecular docking studies in the binding site of PfDHFR. The pharmacokinetic property analysis of best active compounds was also studied using ADMET prediction. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  5. Molecular Docking Studies and Anti-Tyrosinase Activity of Thai Mango Seed Kernel Extract

    Directory of Open Access Journals (Sweden)

    Patchreenart Saparpakorn

    2009-01-01

    Full Text Available The alcoholic extract from seed kernels of Thai mango (Mangifera indica L. cv. ‘Fahlun’ (Anacardiaceae and its major phenolic principle (pentagalloylglucopyranose exhibited potent, dose-dependent inhibitory effects on tyrosinase with respect to L-DOPA. Molecular docking studies revealed that the binding orientations of the phenolic principles were in the tyrosinase binding pocket and their orientations were located in the hydrophobic binding pocket surrounding the binuclear copper active site. The results indicated a possible mechanism for their anti-tyrosinase activity which may involve an ability to chelate the copper atoms which are required for the catalytic activity of tyrosinase.

  6. Sensor-based automated docking of large waste canisters

    International Nuclear Information System (INIS)

    Drotning, W.D.

    1990-01-01

    Sensor-based programmable robots have the potential to speed up remote manipulation operations while protecting operators from exposure to radiation. Conventional master/slave manipulators have proven to be very slow in performing precision remote operations. In addition, inadvertent collisions of remotely manipulated objects with their environment increase the hazards associated with remote handling. This paper describes the development of a robotic system for the sensor-based automated remote manipulation and precision docking of large payloads. Computer vision and proximity sensing are used to control the precision docking of a large object with a passive target cavity. Specifically, a container of nuclear spent fuel on a transport vehicle is mated with an emplacement door on a vertical storage borehole at a waste repository

  7. TECHNIQUES OF EVALUATION OF HEMOGLOBIN OXYGEN SATURATION IN CLINICAL OPHTHALMOLOGY

    Directory of Open Access Journals (Sweden)

    S. Yu. Petrov

    2016-01-01

    Full Text Available Oxygen content in body fluids and tissues is an important indicator of life support functions. A number of ocular pathologies, e.g. glaucoma, are of presumable vascular origin which means altered blood supply and oxygen circulation. Most oxygen is transported in the blood in the association with hemoglobin. When passing through the capillaries, hemoglobin releases oxygen, converting from oxygenated form to deoxygenated form. This process is accompanied by the changes in spectral characteristics of hemoglobin which result in different colors of arterial and venous blood. Photometric technique for the measurement of oxygen saturation in blood is based on the differences in light absorption by different forms of hemoglobin. The measurement of saturation is called oximetry. Pulse oximetry with assessment of tissue oxygenation is the most commonly used method in medicine. The degree of hemoglobin oxygen saturation in the eye blood vessels is the most accessible for noninvasive studies during ophthalmoscopy and informative. Numerous studies showed the importance of this parameter for the diagnosis of retinopathy of various genesis, metabolic status analysis in hyperglycemia, diagnosis and control of treatment of glaucoma and other diseases involving alterations in eye blood supply. The specific method for evaluation of oxygen concentration is the measurement of pressure of oxygen dissolved in the blood, i.e. partial pressure of oxygen. In ophthalmological practice, this parameter is measured in anterior chamber fluid evaluating oxygen level for several ophthalmopathies including different forms of glaucoma, for instillations of hypotensive eye drops as well as in vitreous body near to the optic disc under various levels of intraocular pressure. Currently, monitoring of oxygen saturation in retinal blood vessels, i.e. retinal oximetry, is well developed. This technique is based on the assessment of light absorption by blood depending on

  8. Evaluation of non cyanide methods for hemoglobin estimation

    Directory of Open Access Journals (Sweden)

    Vinaya B Shah

    2011-01-01

    Full Text Available Background: The hemoglobincyanide method (HiCN method for measuring hemoglobin is used extensively worldwide; its advantages are the ready availability of a stable and internationally accepted reference standard calibrator. However, its use may create a problem, as the waste disposal of large volumes of reagent containing cyanide constitutes a potential toxic hazard. Aims and Objective: As an alternative to drabkin`s method of Hb estimation, we attempted to estimate hemoglobin by other non-cyanide methods: alkaline hematin detergent (AHD-575 using Triton X-100 as lyser and alkaline- borax method using quarternary ammonium detergents as lyser. Materials and Methods: The hemoglobin (Hb results on 200 samples of varying Hb concentrations obtained by these two cyanide free methods were compared with a cyanmethemoglobin method on a colorimeter which is light emitting diode (LED based. Hemoglobin was also estimated in one hundred blood donors and 25 blood samples of infants and compared by these methods. Statistical analysis used was Pearson`s correlation coefficient. Results: The response of the non cyanide method is linear for serially diluted blood samples over the Hb concentration range from 3gm/dl -20 gm/dl. The non cyanide methods has a precision of + 0.25g/dl (coefficient of variation= (2.34% and is suitable for use with fixed wavelength or with colorimeters at wavelength- 530 nm and 580 nm. Correlation of these two methods was excellent (r=0.98. The evaluation has shown it to be as reliable and reproducible as HiCN for measuring hemoglobin at all concentrations. The reagents used in non cyanide methods are non-biohazardous and did not affect the reliability of data determination and also the cost was less than HiCN method. Conclusions: Thus, non cyanide methods of Hb estimation offer possibility of safe and quality Hb estimation and should prove useful for routine laboratory use. Non cyanide methods is easily incorporated in hemobloginometers

  9. Patterns of glycemic control using glycosylated hemoglobin in diabetics

    Directory of Open Access Journals (Sweden)

    Arunpreet Singh Kahlon

    2011-01-01

    Full Text Available Aim : Till now estimation of blood glucose is the highly effective method for diagnosing diabetes mellitus but it provides a short-term picture of control. More evidence is required to prove that plasma glucose and glycosylated hemoglobin levels together gives a better estimate of glycemic control and compliance with treatment. Indian diabetes risk score (IDRS is a simplified screening tool for identifying undiagnosed diabetic subjects, requires minimum time, and effort and can help to considerably reduce the costs of screening. Objective : To study patterns of glycemic control using glycosylated hemoglobin in diabetic patients. To find out correlation between levels of plasma glucose and glycosylated hemoglobin in diabetics and to calculate IDRS of the study population. Materials and Methods : A cross sectional study was conducted among 300 known diabetic patients attending outpatient department of a rural medical college in Haryana, India. Following standard procedures and protocols FPG and glycosylated hemoglobin were measured to find out a pattern of glycemic control in them after taking their written and informed consent. A correlation between the levels of glycosylated hemoglobin and fasting blood glucose was also calculated. These patients were made to fill a performa and their demographic and clinical risk factors were noted and based on this, their IDRS was calculated. This was done to validate the IDRS in Indian rural population. Results : Fifty-two percent of the population had fasting plasma glucose level between 125-150 mg/dl, 21% had this level between 151-175 mg/dl. Thirteen percent of the study subjects had HbA1C between 6.5-7.5, more than half (57.3% had this value between 7.5-8.5, 12% and 18% had values between 8.5-9.5 and 9.5-10.5, respectively. Twelve percent of the participants had HbA1C level higher than 10.5. Correlation of fasting plasma glucose level and HbA1C was also studied and found that correlation coefficient came

  10. Patterns of glycemic control using glycosylated hemoglobin in diabetics.

    Science.gov (United States)

    Kahlon, Arunpreet Singh; Pathak, Rambha

    2011-07-01

    Till now estimation of blood glucose is the highly effective method for diagnosing diabetes mellitus but it provides a short-term picture of control. More evidence is required to prove that plasma glucose and glycosylated hemoglobin levels together gives a better estimate of glycemic control and compliance with treatment. Indian diabetes risk score (IDRS) is a simplified screening tool for identifying undiagnosed diabetic subjects, requires minimum time, and effort and can help to considerably reduce the costs of screening. To study patterns of glycemic control using glycosylated hemoglobin in diabetic patients. To find out correlation between levels of plasma glucose and glycosylated hemoglobin in diabetics and to calculate IDRS of the study population. A cross sectional study was conducted among 300 known diabetic patients attending outpatient department of a rural medical college in Haryana, India. Following standard procedures and protocols FPG and glycosylated hemoglobin were measured to find out a pattern of glycemic control in them after taking their written and informed consent. A correlation between the levels of glycosylated hemoglobin and fasting blood glucose was also calculated. These patients were made to fill a performa and their demographic and clinical risk factors were noted and based on this, their IDRS was calculated. This was done to validate the IDRS in Indian rural population. Fifty-two percent of the population had fasting plasma glucose level between 125-150 mg/dl, 21% had this level between 151-175 mg/dl. Thirteen percent of the study subjects had HbA1C between 6.5-7.5, more than half (57.3%) had this value between 7.5-8.5, 12% and 18% had values between 8.5-9.5 and 9.5-10.5, respectively. Twelve percent of the participants had HbA1C level higher than 10.5. Correlation of fasting plasma glucose level and HbA1C was also studied and found that correlation coefficient came out to be .311. This correlation was found to be statistically

  11. A comparative modeling and molecular docking study on Mycobacterium tuberculosis targets involved in peptidoglycan biosynthesis.

    Science.gov (United States)

    Fakhar, Zeynab; Naiker, Suhashni; Alves, Claudio N; Govender, Thavendran; Maguire, Glenn E M; Lameira, Jeronimo; Lamichhane, Gyanu; Kruger, Hendrik G; Honarparvar, Bahareh

    2016-11-01

    An alarming rise of multidrug-resistant Mycobacterium tuberculosis strains and the continuous high global morbidity of tuberculosis have reinvigorated the need to identify novel targets to combat the disease. The enzymes that catalyze the biosynthesis of peptidoglycan in M. tuberculosis are essential and noteworthy therapeutic targets. In this study, the biochemical function and homology modeling of MurI, MurG, MraY, DapE, DapA, Alr, and Ddl enzymes of the CDC1551 M. tuberculosis strain involved in the biosynthesis of peptidoglycan cell wall are reported. Generation of the 3D structures was achieved with Modeller 9.13. To assess the structural quality of the obtained homology modeled targets, the models were validated using PROCHECK, PDBsum, QMEAN, and ERRAT scores. Molecular dynamics simulations were performed to calculate root mean square deviation (RMSD) and radius of gyration (Rg) of MurI and MurG target proteins and their corresponding templates. For further model validation, RMSD and Rg for selected targets/templates were investigated to compare the close proximity of their dynamic behavior in terms of protein stability and average distances. To identify the potential binding mode required for molecular docking, binding site information of all modeled targets was obtained using two prediction algorithms. A docking study was performed for MurI to determine the potential mode of interaction between the inhibitor and the active site residues. This study presents the first accounts of the 3D structural information for the selected M. tuberculosis targets involved in peptidoglycan biosynthesis.

  12. Spectroscopic characterization and docking studies of ZnO nanoparticle modified with BSA

    International Nuclear Information System (INIS)

    Ledesma, Ana E.; Chemes, Doly María; Frías, María de los Angeles; Guauque Torres, Maria del Pilar

    2017-01-01

    Highlights: • The ZnO NPs have synthesized at moderate temperature and conjugated with BSA to elucidate the characteristics of best binding site in the protein cavity. • The Docking studies have successfully applied to identify the amino acids residues involved in the interaction. • The cytotoxicity of ZnO NPs and ZnO-BSA NPs and esterase-like activity of the protein have evaluated, with very promising results for medical applications. - Abstract: Nanoparticles (NP) into a biological environment are an interesting topic for diagnosis and therapy in applications for medicine or environment and the knowledge about this interaction is important from the perspective of safe use of nanomaterials. In the current study, we characterized the type of interaction and the orientation of bovine serum albumin (BSA) adsorbed on ZnO nanoparticle surfaces as a function of size, using molecular docking. To probe experimentally different theoretical hypothesis about the interaction, ZnO-NPs were prepared in aqueous solution, and then were bioconjugated with BSA. Transmission electron microscopy (TEM) and Raman spectroscopy confirm the spherical shape of NP and the irreversible adsorption of BSA on NP surface. Raman and Infrared spectroscopy (FTIR) reveal that BSA interaction with ZnO nanoparticle produced a conformational rearrangement into protein, observing changes in Tyr and Trp environment, a minor percentage of α-helix structure and a more extended chain. The fluorescence analysis demonstrated that when BSA concentration higher than 30 μM is used the signal due to the self-oligomerization of protein overlaps with the ZnO nanoparticle emission. The results predicted that the most probable interaction site is near to domain IB and IIA and ionic interactions are the major responsible for the binding. Thermal stability studies reveals that the denaturalization temperature of BSA increase from 57 °C to 65 °C in presence of ZnO NP and their esterase-like activity was

  13. Spectroscopic characterization and docking studies of ZnO nanoparticle modified with BSA

    Energy Technology Data Exchange (ETDEWEB)

    Ledesma, Ana E., E-mail: anael@unse.edu.ar [CITSE-UNSE, CONICET, FCEyT, RN 9, km 1125, 4206 Santiago del Estero (Argentina); Chemes, Doly María [INQUINOA, UNT, CONICET, FBQyF, San Lorenzo 456, San Miguel de Tucumán CPA T4000ILI, Tucumán (Argentina); Frías, María de los Angeles [Laboratory of Biointerphases and Biomimetic Systems, (CITSE) National University of Santiago del Estero and CONICET, 4206, RN 9- Km 1125, Santiago del Estero (Argentina); Guauque Torres, Maria del Pilar [CITSE-UNSE, CONICET, FCEyT, RN 9, km 1125, 4206 Santiago del Estero (Argentina)

    2017-08-01

    Highlights: • The ZnO NPs have synthesized at moderate temperature and conjugated with BSA to elucidate the characteristics of best binding site in the protein cavity. • The Docking studies have successfully applied to identify the amino acids residues involved in the interaction. • The cytotoxicity of ZnO NPs and ZnO-BSA NPs and esterase-like activity of the protein have evaluated, with very promising results for medical applications. - Abstract: Nanoparticles (NP) into a biological environment are an interesting topic for diagnosis and therapy in applications for medicine or environment and the knowledge about this interaction is important from the perspective of safe use of nanomaterials. In the current study, we characterized the type of interaction and the orientation of bovine serum albumin (BSA) adsorbed on ZnO nanoparticle surfaces as a function of size, using molecular docking. To probe experimentally different theoretical hypothesis about the interaction, ZnO-NPs were prepared in aqueous solution, and then were bioconjugated with BSA. Transmission electron microscopy (TEM) and Raman spectroscopy confirm the spherical shape of NP and the irreversible adsorption of BSA on NP surface. Raman and Infrared spectroscopy (FTIR) reveal that BSA interaction with ZnO nanoparticle produced a conformational rearrangement into protein, observing changes in Tyr and Trp environment, a minor percentage of α-helix structure and a more extended chain. The fluorescence analysis demonstrated that when BSA concentration higher than 30 μM is used the signal due to the self-oligomerization of protein overlaps with the ZnO nanoparticle emission. The results predicted that the most probable interaction site is near to domain IB and IIA and ionic interactions are the major responsible for the binding. Thermal stability studies reveals that the denaturalization temperature of BSA increase from 57 °C to 65 °C in presence of ZnO NP and their esterase-like activity was

  14. PEPSI-Dock: a detailed data-driven protein–protein interaction potential accelerated by polar Fourier correlation

    OpenAIRE

    Neveu , Emilie; Ritchie , David; Popov , Petr; Grudinin , Sergei

    2016-01-01

    International audience; Motivation: Docking prediction algorithms aim to find the native conformation of a complex of proteins from knowledge of their unbound structures. They rely on a combination of sampling and scoring methods, adapted to different scales. Polynomial Expansion of Protein Structures and Interactions for Docking (PEPSI-Dock) improves the accuracy of the first stage of the docking pipeline , which will sharpen up the final predictions. Indeed, PEPSI-Dock benefits from the pre...

  15. Rigid Body Energy Minimization on Manifolds for Molecular Docking.

    Science.gov (United States)

    Mirzaei, Hanieh; Beglov, Dmitri; Paschalidis, Ioannis Ch; Vajda, Sandor; Vakili, Pirooz; Kozakov, Dima

    2012-11-13

    Virtually all docking methods include some local continuous minimization of an energy/scoring function in order to remove steric clashes and obtain more reliable energy values. In this paper, we describe an efficient rigid-body optimization algorithm that, compared to the most widely used algorithms, converges approximately an order of magnitude faster to conformations with equal or slightly lower energy. The space of rigid body transformations is a nonlinear manifold, namely, a space which locally resembles a Euclidean space. We use a canonical parametrization of the manifold, called the exponential parametrization, to map the Euclidean tangent space of the manifold onto the manifold itself. Thus, we locally transform the rigid body optimization to an optimization over a Euclidean space where basic optimization algorithms are applicable. Compared to commonly used methods, this formulation substantially reduces the dimension of the search space. As a result, it requires far fewer costly function and gradient evaluations and leads to a more efficient algorithm. We have selected the LBFGS quasi-Newton method for local optimization since it uses only gradient information to obtain second order information about the energy function and avoids the far more costly direct Hessian evaluations. Two applications, one in protein-protein docking, and the other in protein-small molecular interactions, as part of macromolecular docking protocols are presented. The code is available to the community under open source license, and with minimal effort can be incorporated into any molecular modeling package.

  16. An autonomous rendezvous and docking system using cruise missile technologies

    Science.gov (United States)

    Jones, Ruel Edwin

    1991-01-01

    In November 1990 the Autonomous Rendezvous & Docking (AR&D) system was first demonstrated for members of NASA's Strategic Avionics Technology Working Group. This simulation utilized prototype hardware from the Cruise Missile and Advanced Centaur Avionics systems. The object was to show that all the accuracy, reliability and operational requirements established for a space craft to dock with Space Station Freedom could be met by the proposed system. The rapid prototyping capabilities of the Advanced Avionics Systems Development Laboratory were used to evaluate the proposed system in a real time, hardware in the loop simulation of the rendezvous and docking reference mission. The simulation permits manual, supervised automatic and fully autonomous operations to be evaluated. It is also being upgraded to be able to test an Autonomous Approach and Landing (AA&L) system. The AA&L and AR&D systems are very similar. Both use inertial guidance and control systems supplemented by GPS. Both use an Image Processing System (IPS), for target recognition and tracking. The IPS includes a general purpose multiprocessor computer and a selected suite of sensors that will provide the required relative position and orientation data. Graphic displays can also be generated by the computer, providing the astronaut / operator with real-time guidance and navigation data with enhanced video or sensor imagery.

  17. DOCK8 is critical for the survival and function of NKT cells.

    Science.gov (United States)

    Crawford, Greg; Enders, Anselm; Gileadi, Uzi; Stankovic, Sanda; Zhang, Qian; Lambe, Teresa; Crockford, Tanya L; Lockstone, Helen E; Freeman, Alexandra; Arkwright, Peter D; Smart, Joanne M; Ma, Cindy S; Tangye, Stuart G; Goodnow, Christopher C; Cerundolo, Vincenzo; Godfrey, Dale I; Su, Helen C; Randall, Katrina L; Cornall, Richard J

    2013-09-19

    Patients with the dedicator of cytokinesis 8 (DOCK8) immunodeficiency syndrome suffer from recurrent viral and bacterial infections, hyper-immunoglobulin E levels, eczema, and greater susceptibility to cancer. Because natural killer T (NKT) cells have been implicated in these diseases, we asked if these cells were affected by DOCK8 deficiency. Using a mouse model, we found that DOCK8 deficiency resulted in impaired NKT cell development, principally affecting the formation and survival of long-lived, differentiated NKT cells. In the thymus, DOCK8-deficient mice lack a terminally differentiated subset of NK1.1(+) NKT cells expressing the integrin CD103, whereas in the liver, DOCK8-deficient NKT cells express reduced levels of the prosurvival factor B-cell lymphoma 2 and the integrin lymphocyte function-associated antigen 1. Although the initial NKT cell response to antigen is intact in the absence of DOCK8, their ongoing proliferative and cytokine responses are impaired. Importantly, a similar defect in NKT cell numbers was detected in DOCK8-deficient humans, highlighting the relevance of the mouse model. In conclusion, our data demonstrate that DOCK8 is required for the development and survival of mature NKT cells, consistent with the idea that DOCK8 mediates survival signals within a specialized niche. Accordingly, impaired NKT cell numbers and function are likely to contribute to the susceptibility of DOCK8-deficient patients to recurrent infections and malignant disease.

  18. DOCK8 is critical for the survival and function of NKT cells

    Science.gov (United States)

    Crawford, Greg; Enders, Anselm; Gileadi, Uzi; Stankovic, Sanda; Zhang, Qian; Lambe, Teresa; Crockford, Tanya L.; Lockstone, Helen E.; Freeman, Alexandra; Arkwright, Peter D.; Smart, Joanne M.; Ma, Cindy S.; Tangye, Stuart G.; Goodnow, Christopher C.; Cerundolo, Vincenzo; Godfrey, Dale I.; Su, Helen C.; Randall, Katrina L.

    2013-01-01

    Patients with the dedicator of cytokinesis 8 (DOCK8) immunodeficiency syndrome suffer from recurrent viral and bacterial infections, hyper–immunoglobulin E levels, eczema, and greater susceptibility to cancer. Because natural killer T (NKT) cells have been implicated in these diseases, we asked if these cells were affected by DOCK8 deficiency. Using a mouse model, we found that DOCK8 deficiency resulted in impaired NKT cell development, principally affecting the formation and survival of long-lived, differentiated NKT cells. In the thymus, DOCK8-deficient mice lack a terminally differentiated subset of NK1.1+ NKT cells expressing the integrin CD103, whereas in the liver, DOCK8-deficient NKT cells express reduced levels of the prosurvival factor B-cell lymphoma 2 and the integrin lymphocyte function-associated antigen 1. Although the initial NKT cell response to antigen is intact in the absence of DOCK8, their ongoing proliferative and cytokine responses are impaired. Importantly, a similar defect in NKT cell numbers was detected in DOCK8-deficient humans, highlighting the relevance of the mouse model. In conclusion, our data demonstrate that DOCK8 is required for the development and survival of mature NKT cells, consistent with the idea that DOCK8 mediates survival signals within a specialized niche. Accordingly, impaired NKT cell numbers and function are likely to contribute to the susceptibility of DOCK8-deficient patients to recurrent infections and malignant disease. PMID:23929855

  19. A New Approach for Flexible Molecular Docking Based on Swarm Intelligence

    Directory of Open Access Journals (Sweden)

    Yi Fu

    2015-01-01

    Full Text Available Molecular docking methods play an important role in the field of computer-aided drug design. In the work, on the basis of the molecular docking program AutoDock, we present QLDock as a tool for flexible molecular docking. For the energy evaluation, the algorithm uses the binding free energy function that is provided by the AutoDock 4.2 tool. The new search algorithm combines the features of a quantum-behaved particle swarm optimization (QPSO algorithm and local search method of Solis and Wets for solving the highly flexible protein-ligand docking problem. We compute the interaction of 23 protein-ligand complexes and compare the results with those of the QDock and AutoDock programs. The experimental results show that our approach leads to substantially lower docking energy and higher docking precision in comparison to Lamarckian genetic algorithm and QPSO algorithm alone. QPSO-ls algorithm was able to identify the correct binding mode of 74% of the complexes. In comparison, the accuracy of QPSO and LGA is 52% and 61%, respectively. This difference in performance rises with increasing complexity of the ligand. Thus, the novel algorithm QPSO-ls may be used to dock ligand with many rotatable bonds with high accuracy.

  20. Vitreoscilla hemoglobin promotes Salecan production by Agrobacterium sp. ZX09.

    Science.gov (United States)

    Chen, Yun-mei; Xu, Hai-yang; Wang, Yang; Zhang, Jian-fa; Wang, Shi-ming

    2014-11-01

    Salecan is a novel exopolysaccharide produced by the strain Agrobacterium sp. ZX09, and it is composed of only glucose monomers. The unique chemical composition and excellent physicochemical properties make Salecan a promising material for applications in coagulation, lubrication, protection against acute liver injury, and alleviating constipation. In this study, we cloned the Vitreoscilla hemoglobin gene into a broad-host-range plasmid pCM158. Without antibiotic selection, there was negligible loss of the plasmid in the host Agrobacterium sp. ZX09 after one passage of cultivation. The expression of Vitreoscilla hemoglobin was demonstrated by carbon monoxide (CO) difference spectrum. The engineered strain Agrobacterium sp. ZX09 increased Salecan yield by 30%. The other physiological changes included its elevated respiration rate and cellular invertase activity.

  1. Hemoglobin concentrations and associated factors in adolescentes from Recife, Brazil

    Directory of Open Access Journals (Sweden)

    Elisângela Barros Soares Mendonça

    2014-10-01

    Full Text Available OBJECTIVE: To estimate the prevalence of anemia and associated factors in adolescents from the city of Recife in Pernambuco state. METHODS: This is a cross-sectional study, involving a random sample of 256 adolescents of both genders, aged 13 to 18, whose hemoglobin concentrations were evaluated, along with their nutritional status and socioeconomic and demographic characteristics. RESULTS: The prevalence of inadequate hemoglobin concentrations was 10.2% [CI95%=6.7-14.5], reaching levels considered as mild anemia (9 g/dL 0.05, nor with socioeconomic or demographic characteristics (p>0.05. CONCLUSION: Although the prevalence of anemia was low and classified as a mild health problem, preventive nutrition education involving the dissemination of healthy eating habits in schools and encouraging the consumption of iron-rich foods are strongly recommended.

  2. Reticulocyte hemoglobin content (MCHr) in the detection of iron deficiency.

    Science.gov (United States)

    Urrechaga Igartua, Eloísa; Hoffmann, Johannes J M L; Izquierdo-Álvarez, Silvia; Escanero, Jesús F

    2017-09-01

    Blood hemoglobin (Hb) concentration within the reference interval does not exclude iron deficiency (ID): individuals with normal stores lose iron during a long period before their Hb falls below of the level that is defined as anemia. The process entails a decrease of storage iron, shown by serum ferritin below reference range, followed by iron depletion, eventually leading to iron restricted erythropoiesis; consequence of an imbalance between erythropoietic iron requirements and too low supply is a reduction of Hb synthesis in reticulocytes. We study the potential utility of mean reticulocyte hemoglobin content (MCHr), reported by CELL-DYN Sapphire (Abbott Diagnostics) analyzer, in the detection of ID in non-anemic adults. 207 patients with Hb within the reference range were enrolled. ID was defined as Hb>120g/L (women), >130g/L (men) and serum ferritin iron deficient adults. Copyright © 2016 Elsevier GmbH. All rights reserved.

  3. Does Erythropoietin Cause Hemoglobin Variability- Is It ‘Normal’?

    OpenAIRE

    Gupta, Ashwani K; David, Waseem

    2014-01-01

    Hemoglobin variability (Hb-var) in patients with chronic kidney disease has been stipulated to be a result of exogenous treatment with erythropoiesis stimulating agents (ESA) and has been related to mortality in dialysis patients. We hypothesized the existence of Hb-var independent of ESA administration and compared it to that in healthy adults using data from the Scripps-Kaiser and NHANES III databases. We studied the Hb-var in 1571 peritoneal dialysis patients which included 116 patients no...

  4. Optical Spectra of Hemoglobin Taken from Alcohol Dependent Humans

    OpenAIRE

    Dudok K.; Dudok T.; Vlokh I.; Vlokh R.

    2005-01-01

    Optical spectra of CNMetHb and CNMetHb-Coomassi G-250, taken from the blood of humans with alcohol dependence, are studied in the spectral range of 450–750nm. The shifts in the spectral absorption maxima of CNMetHb-Coomassi G-250 complexes are observed for the diseased persons with alcohol dependence. The obtained results show that the hemoglobin structure of alcohol dependent humans is changed.

  5. Oxygenation properties and isoform diversity of snake hemoglobins

    DEFF Research Database (Denmark)

    Storz, Jay F.; Natarajan, Chandrasekhar; Moriyama, Hideaki

    2015-01-01

    Available data suggest that snake hemoglobins (Hbs) are characterized by a combination of unusual structural and functional properties relative to the Hbs of other amniote vertebrates, including oxygenation-linked tetramer- dimer dissociation. However, standardized comparative data are lacking fo...... isoform of the South American rattlesnake is homologous to the minor HbD of other amniotes and, contrary to the pattern of Hb isoform differentiation in birds and turtles, exhibits a lower O2 affinity than the HbA isoform....

  6. The Determinants of Hemoglobin Variability in Hemodialysis Patients

    OpenAIRE

    Tomanoski Vasilije; Gjorgjievska Gordana; Zvezdakovska Jasminka; Krecova Vasiliki; Andonoski Aleksandar; Nakovska Margarita; Muharemi Serjat; Kliseski Tode; Janakievska Pavlina; Ristoska Katerina; Veliu Ramazan; Vasileva Liljana; Jovanov Toni; Mehmedi-Veseli Kaltrina; Ferati Beane

    2016-01-01

    Introduction. Factors that have been reported to affect erythropoietin (EPO) responsiveness in hemodialysis (HD) patients include iron deficiency, chronic inflammation, secondary hyperparathyroidism, malnutrition and inadequate HD dose. The aim of the study was to analyze the deteminants of hemoglobin variability in HD patients. Methods. The study encompassed 526 patients (197 F and 329 M). According to HD vintage at the beginning of the study the patients were divided into two groups: group-...

  7. Lower versus higher hemoglobin threshold for transfusion in septic shock.

    Science.gov (United States)

    Holst, Lars B; Haase, Nicolai; Wetterslev, Jørn; Wernerman, Jan; Guttormsen, Anne B; Karlsson, Sari; Johansson, Pär I; Aneman, Anders; Vang, Marianne L; Winding, Robert; Nebrich, Lars; Nibro, Helle L; Rasmussen, Bodil S; Lauridsen, Johnny R M; Nielsen, Jane S; Oldner, Anders; Pettilä, Ville; Cronhjort, Maria B; Andersen, Lasse H; Pedersen, Ulf G; Reiter, Nanna; Wiis, Jørgen; White, Jonathan O; Russell, Lene; Thornberg, Klaus J; Hjortrup, Peter B; Müller, Rasmus G; Møller, Morten H; Steensen, Morten; Tjäder, Inga; Kilsand, Kristina; Odeberg-Wernerman, Suzanne; Sjøbø, Brit; Bundgaard, Helle; Thyø, Maria A; Lodahl, David; Mærkedahl, Rikke; Albeck, Carsten; Illum, Dorte; Kruse, Mary; Winkel, Per; Perner, Anders

    2014-10-09

    Blood transfusions are frequently given to patients with septic shock. However, the benefits and harms of different hemoglobin thresholds for transfusion have not been established. In this multicenter, parallel-group trial, we randomly assigned patients in the intensive care unit (ICU) who had septic shock and a hemoglobin concentration of 9 g per deciliter or less to receive 1 unit of leukoreduced red cells when the hemoglobin level was 7 g per deciliter or less (lower threshold) or when the level was 9 g per deciliter or less (higher threshold) during the ICU stay. The primary outcome measure was death by 90 days after randomization. We analyzed data from 998 of 1005 patients (99.3%) who underwent randomization. The two intervention groups had similar baseline characteristics. In the ICU, the lower-threshold group received a median of 1 unit of blood (interquartile range, 0 to 3) and the higher-threshold group received a median of 4 units (interquartile range, 2 to 7). At 90 days after randomization, 216 of 502 patients (43.0%) assigned to the lower-threshold group, as compared with 223 of 496 (45.0%) assigned to the higher-threshold group, had died (relative risk, 0.94; 95% confidence interval, 0.78 to 1.09; P=0.44). The results were similar in analyses adjusted for risk factors at baseline and in analyses of the per-protocol populations. The numbers of patients who had ischemic events, who had severe adverse reactions, and who required life support were similar in the two intervention groups. Among patients with septic shock, mortality at 90 days and rates of ischemic events and use of life support were similar among those assigned to blood transfusion at a higher hemoglobin threshold and those assigned to blood transfusion at a lower threshold; the latter group received fewer transfusions. (Funded by the Danish Strategic Research Council and others; TRISS ClinicalTrials.gov number, NCT01485315.).

  8. A retrospective study on fourteen year hemoglobin genotype ...

    African Journals Online (AJOL)

    This suggests the possibility of many other residents in the capital city of Ondo state carrying the abnormal forms of hemoglobin genotype, and calling for more efforts in the area of genetic counseling. The gene frequencies of A, S, and C were 0.91, 0.08 and 0.01, respectively. The prevalence of HbAA in this study has been ...

  9. Molecular docking and 3D-QSAR studies on triazolinone and pyridazinone, non-nucleoside inhibitor of HIV-1 reverse transcriptase.

    Science.gov (United States)

    Sivan, Sree Kanth; Manga, Vijjulatha

    2010-06-01

    Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are allosteric inhibitors of the HIV-1 reverse transcriptase. Recently a series of Triazolinone and Pyridazinone were reported as potent inhibitors of HIV-1 wild type reverse transcriptase. In the present study, docking and 3D quantitative structure activity relationship (3D QSAR) studies involving comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on 31 molecules. Ligands were built and minimized using Tripos force field and applying Gasteiger-Hückel charges. These ligands were docked into protein active site using GLIDE 4.0. The docked poses were analyzed; the best docked poses were selected and aligned. CoMFA and CoMSIA fields were calculated using SYBYL6.9. The molecules were divided into training set and test set, a PLS analysis was performed and QSAR models were generated. The model showed good statistical reliability which is evident from the r2 nv, q2 loo and r2 pred values. The CoMFA model provides the most significant correlation of steric and electrostatic fields with biological activities. The CoMSIA model provides a correlation of steric, electrostatic, acceptor and hydrophobic fields with biological activities. The information rendered by 3D QSAR model initiated us to optimize the lead and design new potential inhibitors.

  10. Improvements in or relating to antibodies active against human hemoglobin Asub(1C)

    International Nuclear Information System (INIS)

    Javid, J.; Cerami, A.; Koenig, R.J.; Pettis, P.K.

    1980-01-01

    A method is described for preparing an antibody against human hemoglobin Asub(1c) which is substantially free of cross-reactivity against the human hemoglobins A 0 , Asub(1a) and Asub(1b). The antibodies are collected from cats, goats or sheep following injections of purified hemoglobin Asub(1c) antigen since these animals do not naturally produce hemoglobin Asub(1c). A radioimmunoassay method is also described whereby these antibodies are used to determine the quantity of hemoglobin Asub(1c) in blood samples. This is a useful technique in the diagnosis of diabetes mellitus. (U.K.)

  11. Concurrent measurement of cellular turbidity and hemoglobin to evaluate the antioxidant activity of plants.

    Science.gov (United States)

    Bellik, Yuva; Iguer-Ouada, Mokrane

    2016-01-01

    In past decades, a multitude of analytical methods for measuring antioxidant activity of plant extracts has been developed. However, when using methods to determine hemoglobin released from human erythrocytes treated with ginger extracts, we found hemoglobin concentrations were significantly higher than in untreated control samples. This suggests in the presence of antioxidants that measuring hemoglobin alone is not sufficient to determine hemolysis. We show concurrent measurement of erythrocyte concentration and hemoglobin is essential in such assays, and describe a new protocol based on simultaneous measurement of cellular turbidity and hemoglobin. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Effect of ethanol of the radiation sensitivity of human hemoglobin

    International Nuclear Information System (INIS)

    Szweda-Lewandowska, Z.; Puchala, M.

    1981-01-01

    Radiation sensitivity of oxy-, deoxy-, and methemoglobin (HbOs, Hbbj, and MetHb) in water solutions containing 0.2 M ethanol and in ethanol-free solutions was compared. Radiation sensitivity was estimated on the basis of changes in absorbance at the Soret band (a = 430 nm for deoxyhemoglobin), changes in the absorbance ration Avqv/Avwt determined after conversion of irradiated preparations to methemoglobin, and changes in the value of parameters describing the reaction of hemoglobin oxygenation. The protection coefficient p of hemoglobin by ethanol (ratio of a change in the absence of ethanol to that in its presence) calculated from changes in absorbance at the Soret band equaled about 1.5 at a 4-Mrad dose in all bases except MetHb irradiated in air for which p was much higher (about 3.2). The protection coefficient p' calculated from Dtx values for changes in Avchemically bondv/Avwt equaled 2.2 for HbOs, and 2.8 for MetHb for preparations irradiated in air; p' = 1.7 for Hbbj and 1.8 for MetHb for preparations irradiated under argon. On the basis of these results, the role of /sup ./OH radicals and oxygen in the radiation damage of hemoglobin is discussed

  13. Hydrogen-tritium exchange survey of allosteric effects in hemoglobin

    International Nuclear Information System (INIS)

    Englander, J.J.; Englander, S.W.

    1987-01-01

    The oxy and deoxy forms of hemoglobin display major differences in H-exchange behavior. Hydrogen-tritium exchange experiments on hemoglobin were performed in the low-resolution mode to observe the dependence of these differences on pH (Bohr effect), organic phosphates, and salt. Unlike a prior report, increasing pH was found to decrease the oxy-deoxy difference monotonically, in general accordance with the alkaline Bohr effect. A prior report that the H-exchange difference between oxy- and deoxyhemoglobin vanishes at pH 9, and thus appears to reflect the Bohr effect alone, was found to be due to the borate buffer used, which at high pH tends to abolish the oxy-deoxy difference in a limited region of the H-exchange curve. Effects on hemoglobin H exchange due to organic phosphates parallel the differential binding of these agents (inositol hexaphosphate more than diphosphoglycerate, deoxy more than oxy, at low pH more than at high pH). Added salt slows H exchange of deoxyhemoglobin and has no effect on the oxy form. These results display the sensitivity of simple H-exchange measurements for finding and characterizing effects on structure and dynamics that may occur anywhere in the protein and help to define conditions for higher resolution approaches that can localize the changes observed

  14. Pitfalls in the biological diagnosis of common hemoglobin disorders.

    Science.gov (United States)

    Wajcman, Henri; Moradkhani, Kamran

    2015-01-01

    In West-European countries, hemoglobin disorders are no more rare diseases. Programs for diagnosis of heterozygous carriers have been established to prevent cases with major sickle cell disease or thalassemias. These studies have been done essentially by high performance liquid chromatography on cation-exchange columns and electrophoresis (mostly capillary electrophoresis). They have been done through systematic population studies or premarital diagnosis. We describe in this work the frequent or rare pitfalls encountered, which led to false negative or positive diagnosis both in the field of sickle cell disease and thalassemias. In the absence of a well identified hemoglobin disorder in the proband's family, it is a rule that the use of a single test is insufficient to identify formally HbS. The presence of HbS could also be masked by another hemoglobin abnormality. The sole measurement of HbA2 level is insufficient to characterize a thalassemic trait: this level needs always to be interpreted considering RBC parameters and iron metabolic status. In difficult cases, the definitive answer may require a family study and/or a molecular genetic characterization.

  15. Carbon monoxide reduces near-infrared spectroscopy determined 'total' hemoglobin

    DEFF Research Database (Denmark)

    Niemann, Mads J; Sørensen, Henrik; Siebenmann, Christoph

    2017-01-01

    with CO (1.5 mL kg-1) was added to the circuit. Two NIRS systems (NIRO-200NX and INVOS-5100) assessed ScO2 as the ratio of oxygenated to deoxygenated hemoglobin, while venous blood samples were analyzed for carboxyhemoglobin (COHb). After CO/O2 rebreathing COHb increased to 8.7% (IQR; 7.9-9.4; p = .004...... to normoxia (68.9 ± 6.9%; p hemoglobin decreased (by 19.7 μM (median; IQR 2.8-34.8; p = .016) and 37.3 μM (30.8-46.6; p = .004), respectively) during inhalation of CO/O2 compared...... to inhalation of O2. Therefore, NIRO-200NX determined 'total' hemoglobin (sum of O2Hb and HHb) decreased (by 62.1 μM; 44.5-78.2; p = .001). In conclusion, exposure to CO did not increase MCAVmean, and neither NIRO-200NX nor INVOS-5100 detected a change in ScO2 when CO was added to inhalation of oxygen...

  16. Characterization of trypsin-derived peptides acrylamide-adducted hemoglobin

    International Nuclear Information System (INIS)

    Springer, D.L.; Goheen, S.C.; Edmonds, C.G.; McCulloch, M.; Sylvester, D.M.; Sander, C.; Bull, R.J.

    1991-01-01

    Even though there are a number of sources for human exposure to acrylamide, reliable biomarkers of exposure are not available. In an effort to develop such a biomarker, the authors are characterizing peptides derived from trypsin digests of acrylamide-adducted hemoglobin. For this, radiolabeled acrylamide was incubated with this, radiolabeled acrylamide was incubated with purified human hemoglobin (Ao) and decomposition products removed by dialysis. When the adducted hemoglobin was separated by reverse-phase HPLC, radioactivity eluted with the α and β subunits, suggesting covalent binding. Digestion of individual subunits with trypsin followed by reverse phase HPLC, indicated that most of the radioactivity associated with the α subunit co-eluted with a single peptide. Similar results were observed for the β subunit except that significant amounts of radioactivity eluted with the solvent front, suggesting that radioactivity was released by trypsin digestion. Currently, these preparation are under further characterization by electrospray ionization mass spectrometry. This approach will aid in the identification of the adducted will aid in the identification of the adducted peptide and subsequent preparation of an acrylamide-specific antibody

  17. Structural and functional properties of hemoglobins from unicellular organisms as revealed by resonance Raman spectroscopy.

    Science.gov (United States)

    Egawa, Tsuyoshi; Yeh, Syun-Ru

    2005-01-01

    Hemoglobins have been discovered in organisms from virtually all kingdoms. Their presence in unicellular organisms suggests that the gene for hemoglobin is very ancient and that the hemoglobins must have functions other than oxygen transport, in view of the fact that O2 delivery is a diffusion-controlled process in these organisms. Based on sequence alignment, three groups of hemoglobins have been characterized in unicellular organisms. The group-one hemoglobins, termed truncated hemoglobins, consist of proteins with 110-140 amino acid residues and a novel two-over-two alpha-helical sandwich motif. The group-two hemoglobins, termed flavohemoglobins, consist of a hemoglobin domain, with a classical three-over-three alpha-helical sandwich motif, and a flavin-containing reductase domain that is covalently attached to it. The group-three hemoglobins consist of myoglobin-like proteins that have high sequence homology and structural similarity to the hemoglobin domain of flavohemoglobins. In this review, recent resonance Raman studies of each group of these proteins are presented. Their implications are discussed in the context of the structural and functional properties of these novel hemoglobins.

  18. Hemoglobin isoform differentiation and allosteric regulation of oxygen binding in the turtle, Trachemys scripta

    DEFF Research Database (Denmark)

    Damsgaard, Christian; Storz, Jay F.; Hoffmann, Federico G.

    2013-01-01

    When freshwater turtles acclimatize to winter hibernation, there is a gradual transition from aerobic to anaerobic metabolism, which may require adjustments of blood O2 transport before turtles become anoxic. Here, we report the effects of protons, anionic cofactors, and temperature on the O2......-binding properties of isolated hemoglobin (Hb) isoforms, HbA and HbD, in the turtle Trachemys scripta. We determined the primary structures of the constituent subunits of the two Hb isoforms, and we related the measured functional properties to differences in O2 affinity between untreated hemolysates from...... turtles that were acclimated to normoxia and anoxia. Our data show that HbD has a consistently higher O2 affinity compared with HbA, whereas Bohr and temperature effects, as well as thiol reactivity, are similar. Although sequence data show amino acid substitutions at two known β-chain ATP-binding site...

  19. Fasting serum glucose and glycosylated hemoglobin level in obesity.

    Science.gov (United States)

    Das, R K; Nessa, A; Hossain, M A; Siddiqui, N I; Hussain, M A

    2014-04-01

    Obesity is a condition in which the body fat stores are increased to an extent which impairs health and leads to serious health consequences. The amount of body fat is difficult to measure directly, and is usually determined from an indirect measure - the body mass index (BMI). Increased BMI in obese persons is directly associated with an increase in metabolic disease, such as type 2 diabetes mellitus. This Analytical cross sectional study was undertaken to assess the relation between obesity and glycemic control of body by measuring fasting serum glucose and glycosylated hemoglobin. This study was carried out in the Department of Physiology, Mymensingh Medical College, Mymensingh from 1st July 2011 to 30th June 2012 on 120 equally divided male and female persons within the age range of 25 to 55 years. Age more than 55 years and less than 25 years and diagnosed case of Hypothyroidism, Cushing's syndrome, polycystic ovary, Antipsychotic drug user and regular steroid users were excluded. Non probability purposive type of sampling technique was used for selecting the study subjects. Measurement of body mass index was done as per procedure. Fasting serum glucose was estimated by glucose oxidase method and Glycosylated hemoglobin by Boronate Affinity method. Statistical analysis was done by SPSS (version 17.0). Data were expressed as Mean±SE and statistical significance of difference among the groups were calculated by unpaired student's 't' test and Pearson's correlation coefficient tests were done as applicable. The Mean±SE of fasting serum glucose was significant at 1% level (P value obese group of BMI. There was no significant difference of glycosylated hemoglobin level between control and study groups. But there was positive correlation within each group. Fasting serum glucose also showed a bit stronger positive correlation with BMI. Both obese male and female persons showed higher levels of fasting serum glucose and glycosylated hemoglobin. The observed positive

  20. MOLA: a bootable, self-configuring system for virtual screening using AutoDock4/Vina on computer clusters

    Directory of Open Access Journals (Sweden)

    Abreu Rui MV

    2010-10-01

    Full Text Available Abstract Background Virtual screening of small molecules using molecular docking has become an important tool in drug discovery. However, large scale virtual screening is time demanding and usually requires dedicated computer clusters. There are a number of software tools that perform virtual screening using AutoDock4 but they require access to dedicated Linux computer clusters. Also no software is available for performing virtual screening with Vina using computer clusters. In this paper we present MOLA, an easy-to-use graphical user interface tool that automates parallel virtual screening using AutoDock4 and/or Vina in bootable non-dedicated computer clusters. Implementation MOLA automates several tasks including: ligand preparation, parallel AutoDock4/Vina jobs distribution and result analysis. When the virtual screening project finishes, an open-office spreadsheet file opens with the ligands ranked by binding energy and distance to the active site. All results files can automatically be recorded on an USB-flash drive or on the hard-disk drive using VirtualBox. MOLA works inside a customized Live CD GNU/Linux operating system, developed by us, that bypass the original operating system installed on the computers used in the cluster. This operating system boots from a CD on the master node and then clusters other computers as slave nodes via ethernet connections. Conclusion MOLA is an ideal virtual screening tool for non-experienced users, with a limited number of multi-platform heterogeneous computers available and no access to dedicated Linux computer clusters. When a virtual screening project finishes, the computers can just be restarted to their original operating system. The originality of MOLA lies on the fact that, any platform-independent computer available can he added to the cluster, without ever using the computer hard-disk drive and without interfering with the installed operating system. With a cluster of 10 processors, and a

  1. Molecular docking for thrombolytic activity of some isolated compounds from Clausena lansium.

    Directory of Open Access Journals (Sweden)

    Arkajyoti Paul

    2017-03-01

    Full Text Available Clausena lansium (Family- Rutaceae is commonly known as wampee, is found in fallow lands throughout Bangladesh. Our aim of the study to performed molecular docking studies to identify potential binding affinities of the phytocompounds from Clausena lansium, namely Clausemarin B, Clausenaline C, Clausenaline E, Murrayanine, vanillic acid and Xanthotoxol for searching of lead molecule for thrombolytic activity. A wide range of docking score found during molecular docking by Schrodinger. Clausemarin B , Clausenaline C , Clausenaline E, Murrayanine , vanillic acid and Xanthotoxol showed the docking score -6.926, -4.041, -4.889 , -4.356, -3.007 and -5.816 respectively. Among all the compounds Clausemarin B showed the best docking score. So, Clausemarin B is the best compounds for thrombolytic activity, as it possessed the best value in Molecular docking. Further in vivo investigation need to identify the thrombolytic activity of isolated compounds from Clausena lansium.

  2. Modeling hemoglobin and hemoglobin:haptoglobin complex clearance in a non-rodent species–pharmacokinetic and therapeutic implications

    OpenAIRE

    Boretti, Felicitas S.; Baek, Jin Hyen; Palmer, Andre F.; Schaer, Dominik J.; Buehler, Paul W.

    2014-01-01

    Background: Haptoglobin (Hp) prevents hemoglobin (Hb) extravasation and attenuates Hb induced tissue oxidation and vasoconstriction. Small animal models such as mouse, rat and guinea pig appear to demonstrate proof-of-concept for Hb neutralization by Hp in diverse pre-clinical conditions. However, these species differ significantly from humans in the clearance of Hb:Hp and demonstrate long persistence of circulating Hb:Hp complexes. Objective: The focus of this study is to understand Hb:Hp...

  3. Oxygen entry through multiple pathways in T-state human hemoglobin.

    Science.gov (United States)

    Takayanagi, Masayoshi; Kurisaki, Ikuo; Nagaoka, Masataka

    2013-05-23

    The heme oxygen (O2) binding site of human hemoglobin (HbA) is buried in the interior of the protein, and there is a debate over the O2 entry pathways from solvent to the binding site. As a first step to understand HbA O2 binding process at the atomic level, we detected all significant multiple O2 entry pathways from solvent to the binding site in the α and β subunits of the T-state tetramer HbA by utilizing ensemble molecular dynamics (MD) simulation. By executing 128 independent 8 ns MD trajectories in O2-rich aqueous solvent, we simulated the O2 entry processes and obtained 141 and 425 O2 entry events in the α and β subunits of HbA, respectively. We developed the intrinsic pathway identification by clustering method to achieve a persuasive visualization of the multiple entry pathways including both the shapes and relative importance of each pathway. The rate constants of O2 entry estimated from the MD simulations correspond to the experimentally observed values, suggesting that O2 ligands enter the binding site through multiple pathways. The obtained multiple pathway map can be utilized for future detailed analysis of HbA O2 binding process.

  4. Hemoglobin redux: combining neutron and X-ray diffraction with mass spectrometry to analyse the quaternary state of oxidized hemoglobins

    Energy Technology Data Exchange (ETDEWEB)

    Mueser, Timothy C., E-mail: timothy.mueser@utoledo.edu; Griffith, Wendell P. [Department of Chemistry, University of Toledo, Toledo, OH 43606 (United States); Kovalevsky, Andrey Y. [Bioscience Division, MS M888, Los Alamos National Laboratory, Los Alamos, NM 87545 (United States); Guo, Jingshu; Seaver, Sean [Department of Chemistry, University of Toledo, Toledo, OH 43606 (United States); Langan, Paul [Department of Chemistry, University of Toledo, Toledo, OH 43606 (United States); Bioscience Division, MS M888, Los Alamos National Laboratory, Los Alamos, NM 87545 (United States); Hanson, B. Leif [Department of Chemistry, University of Toledo, Toledo, OH 43606 (United States)

    2010-11-01

    X-ray and neutron diffraction studies of cyanomethemoglobin are being used to evaluate the structural waters within the dimer–dimer interface involved in quaternary-state transitions. Improvements in neutron diffraction instrumentation are affording the opportunity to re-examine the structures of vertebrate hemoglobins and to interrogate proton and solvent position changes between the different quaternary states of the protein. For hemoglobins of unknown primary sequence, structural studies of cyanomethemoglobin (CNmetHb) are being used to help to resolve sequence ambiguity in the mass spectra. These studies have also provided additional structural evidence for the involvement of oxidized hemoglobin in the process of erythrocyte senescence. X-ray crystal studies of Tibetan snow leopard CNmetHb have shown that this protein crystallizes in the B state, a structure with a more open dyad, which possibly has relevance to RBC band 3 protein binding and erythrocyte senescence. R-state equine CNmetHb crystal studies elaborate the solvent differences in the switch and hinge region compared with a human deoxyhemoglobin T-state neutron structure. Lastly, comparison of histidine protonation between the T and R state should enumerate the Bohr-effect protons.

  5. Identification of STAT1 and STAT3 specific inhibitors using comparative virtual screening and docking validation.

    Directory of Open Access Journals (Sweden)

    Malgorzata Szelag

    Full Text Available Signal transducers and activators of transcription (STATs facilitate action of cytokines, growth factors and pathogens. STAT activation is mediated by a highly conserved SH2 domain, which interacts with phosphotyrosine motifs for specific STAT-receptor contacts and STAT dimerization. The active dimers induce gene transcription in the nucleus by binding to a specific DNA-response element in the promoter of target genes. Abnormal activation of STAT signaling pathways is implicated in many human diseases, like cancer, inflammation and auto-immunity. Searches for STAT-targeting compounds, exploring the phosphotyrosine (pTyr-SH2 interaction site, yielded many small molecules for STAT3 but sparsely for other STATs. However, many of these inhibitors seem not STAT3-specific, thereby questioning the present modeling and selection strategies of SH2 domain-based STAT inhibitors. We generated new 3D structure models for all human (hSTATs and developed a comparative in silico docking strategy to obtain further insight into STAT-SH2 cross-binding specificity of a selection of previously identified STAT3 inhibitors. Indeed, by primarily targeting the highly conserved pTyr-SH2 binding pocket the majority of these compounds exhibited similar binding affinity and tendency scores for all STATs. By comparative screening of a natural product library we provided initial proof for the possibility to identify STAT1 as well as STAT3-specific inhibitors, introducing the 'STAT-comparative binding affinity value' and 'ligand binding pose variation' as selection criteria. In silico screening of a multi-million clean leads (CL compound library for binding of all STATs, likewise identified potential specific inhibitors for STAT1 and STAT3 after docking validation. Based on comparative virtual screening and docking validation, we developed a novel STAT inhibitor screening tool that allows identification of specific STAT1 and STAT3 inhibitory compounds. This could increase our

  6. Structural and dynamical aspects of Streptococcus gordonii FabH through molecular docking and MD simulations.

    Science.gov (United States)

    Shamim, Amen; Abbasi, Sumra Wajid; Azam, Syed Sikander

    2015-07-01

    β-Ketoacyl-ACP-synthase III (FabH or KAS III) has become an attractive target for the development of new antibacterial agents which can overcome the multidrug resistance. Unraveling the fatty acid biosynthesis (FAB) metabolic pathway and understanding structural coordinates of FabH will provide valuable insights to target Streptococcus gordonii for curing oral infection. In this study, we designed inhibitors against therapeutic target FabH, in order to block the FAB pathway. As compared to other targets, FabH has more interactions with other proteins, located on the leading strand with higher codon adaptation index value and associated with lipid metabolism category of COG. Current study aims to gain in silico insights into the structural and dynamical aspect of S. gordonii FabH via molecular docking and molecular dynamics (MD) simulations. The FabH protein is catalytically active in dimerization while it can lock in monomeric state. Current study highlights two residues Pro88 and Leu315 that are close to each other by dimerization. The active site of FabH is composed of the catalytic triad formed by residues Cys112, His249, and Asn279 in which Cys112 is involved in acetyl transfer, while His249 and Asn279 play an active role in decarboxylation. Docking analysis revealed that among the studied compounds, methyl-CoA disulfide has highest GOLD score (82.75), binding affinity (-11 kcal/mol) and exhibited consistently better interactions. During MD simulations, the FabH structure remained stable with the average RMSD value of 1.7 Å and 1.6 Å for undocked protein and docked complex, respectively. Further, crucial hydrogen bonding of the conserved catalytic triad for exhibiting high affinity between the FabH protein and ligand is observed by RDF analysis. The MD simulation results clearly demonstrated that binding of the inhibitor with S. gordonii FabH enhanced the structure and stabilized the dimeric FabH protein. Therefore, the inhibitor has the potential to become

  7. Flavonoids-Rich Orthosiphon stamineus Extract as New Candidate for Angiotensin I-Converting Enzyme Inhibition: A Molecular Docking Study.

    Science.gov (United States)

    Shafaei, Armaghan; Sultan Khan, Md Shamsuddin; F A Aisha, Abdalrahim; Abdul Majid, Amin Malik Shah; Hamdan, Mohammad Razak; Mordi, Mohd Nizam; Ismail, Zhari

    2016-11-09

    This study aims to evaluate the in vitro angiotensin-converting enzyme (ACE) inhibition activity of different extracts of Orthosiphon stamineus (OS) leaves and their main flavonoids, namely rosmarinic acid (RA), sinensetin (SIN), eupatorin (EUP) and 3'-hydroxy-5,6,7,4'-tetramethoxyflavone (TMF). Furthermore, to identify possible mechanisms of action based on structure-activity relationships and molecular docking. The in vitro ACE inhibition activity relied on determining hippuric acid (HA) formation from ACE-specific substrate (hippuryl-histidyl-leucine (HHL)) by the action of ACE enzyme. A High Performance Liquid Chromatography method combined with UV detection was developed and validated for measurement the concentration of produced HA. The chelation ability of OS extract and its reference compounds was evaluated by tetramethylmurexide reagent. Furthermore, molecular docking study was performed by LeadIT-FlexX : BioSolveIT's LeadIT program. OS ethanolic extract (OS-E) exhibited highest inhibition and lowest IC 50 value (45.77 ± 1.17 µg/mL) against ACE compared to the other extracts. Among the tested reference compounds, EUP with IC 50 15.35 ± 4.49 µg/mL had highest inhibition against ACE and binding ability with Zn (II) (56.03% ± 1.26%) compared to RA, TMF and SIN. Molecular docking studies also confirmed that flavonoids inhibit ACE via interaction with the zinc ion and this interaction is stabilized by other interactions with amino acids in the active site. In this study, we have demonstrated that changes in flavonoids active core affect their capacity to inhibit ACE. Moreover, we showed that ACE inhibition activity of flavonoids compounds is directly related to their ability to bind with zinc ion in the active site of ACE enzyme. It was also revealed that OS extract contained high amount of flavonoids other than RA, TMF, SIN and EUP. As such, application of OS extract is useful as inhibitors of ACE.

  8. Binding interaction of ramipril with bovine serum albumin (BSA): Insights from multi-spectroscopy and molecular docking methods.

    Science.gov (United States)

    Shi, Jie-Hua; Pan, Dong-Qi; Jiang, Min; Liu, Ting-Ting; Wang, Qi

    2016-11-01

    The binding interaction between a typical angiotensin-converting enzyme inhibitor (ACEI), ramipril, and a transport protein, bovine serum albumin (BSA), was studied in vitro using UV-vis absorption spectroscopy, steady-state fluorescence spectroscopic titration, synchronous fluorescence spectroscopy, three dimensional fluorescence spectroscopy, circular dichroism and molecular docking under the imitated physiological conditions (pH=7.4). The experimental results suggested that the intrinsic fluorescence of BSA was quenched by ramipril thought a static quenching mechanism, indicating that the stable ramipril-BSA complex was formed by the intermolecular interaction. The number of binding sites (n) and binding constant of ramipril-BSA complex were about 1 and 3.50×10 4 M -1 at 298K, respectively, suggesting that there was stronger binding interaction of ramipril with BSA. The thermodynamic parameters together with molecular docking study revealed that both van der Waal's forces and hydrogen bonding interaction dominated the formation of the ramipril-BSA complex and the binding interaction of BSA with ramipril is enthalpy-driven processes due to |ΔH°|>|TΔS°| and ΔG°<0. The spatial distance between ramipril and BSA was calculated to be 3.56nm based on Förster's non-radiative energy transfer theory. The results of the competitive displacement experiments and molecular docking confirmed that ramipril inserted into the subdomain IIA (site I) of BSA, resulting in a slight change in the conformation of BSA but BSA still retained its secondary structure α-helicity. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. 1H and 31P nuclear magnetic resonance investigation of the interaction between 2,3-diphosphoglycerate and human normal adult hemoglobin

    International Nuclear Information System (INIS)

    Russu, I.M.; Wu, S.S.; Bupp, K.A.; Ho, N.T.; Ho, C.

    1990-01-01

    High-resolution 1 H and 31 P nuclear magnetic resonance spectroscopy has been used to investigate the binding of 2,3-diphosphoglycerate to human normal adult hemoglobin and the molecular interactions involved in the allosteric effect of the 2,3-diphosphoglycerate molecule on hemoglobin. Individual hydrogen ion NMR titration curves have been obtained for 22-26 histidyl residues of hemoglobin and for each phosphate group of 2,3-diphosphoglycerate with hemoglobin in both the deoxy and carbonmonoxy forms. The results indicate that 2,3-diphosphoglycerate binds to deoxyhemoglobin at the central cavity between the two β chains and the binding involves the β2-histidyl residues. Moreover, the results suggest that the binding site of 2,3-diphosphoglycerate to carbonmonoxyhemoglobin contains the same (or at least some of the same) amino acid residues responsible for binding in the deoxy form. As a result of the specific interactions with 2,3-diphosphoglycerate, the β2-histidyl residues make a significant contribution to the alkaline Bohr effect under these experimental conditions. These results give the first experimental demonstration that long-range electrostatic and/or conformation effects of the binding could play an important role in the allosteric effect of 2,3-diphosphoglycerate on hemoglobin. The 31 P nuclear magnetic resonance titration data for each phosphate group of 2,3-diphosphoglycerate have been used to calculate the pK values of the phosphate groups in 2,3-diphosphoglycerate bound to deoxy- and carbon-monoxyhemoglobin and the proton uptake by 2,3-diphosphoglycerate upon ligand binding to hemoglobin

  10. Stability and Application of Reactive Nitrogen and Oxygen Species-Induced Hemoglobin Modifications in Dry Blood Spots As Analyzed by Liquid Chromatography Tandem Mass Spectrometry.

    Science.gov (United States)

    Chen, Hauh-Jyun Candy; Fan, Chih-Huang; Yang, Ya-Fen

    2016-12-19

    Dried blood spot (DBS) is an emerging microsampling technique for the bioanalysis of small molecules, including fatty acids, metabolites, drugs, and toxicants. DBS offers many advantages as a sample format including easy sample collection and cheap sample shipment. Hemoglobin adducts have been recognized as a suitable biomarker for monitoring chemical exposure. We previously reported that certain modified peptides in hemoglobin derived from reactive chlorine, nitrogen, and oxygen species are associated with factors including smoking, diabetes mellitus, and aging. However, the stability of these oxidation-induced modifications of hemoglobin remains unknown and whether they can be formed artifactually during storage of DBS. To answer these questions, globin extracted from the DBS cards was analyzed, and the stability of the modifications was evaluated. After storage of the DBS cards at 4 °C or room temperature up to 7 weeks, we isolated globin from a quarter of the spot every week. The extents of 11 sites and types of post-translational modifications (PTMs), including nitration and nitrosylation of tyrosine and oxidation of cysteine and methionine residues, in human hemoglobin were measured in the trypsin digest by nanoflow liquid chromatography-nanospray ionization tandem mass spectrometry (nanoLC-NSI/MS/MS) using selected reaction monitoring. The extents of all these PTMs are stable within 14 days when stored on DBS at room temperature and at 4 °C, while those from direct extraction of fresh blood are stable for at least 8 weeks when stored as an aqueous solution at -20 °C. Extraction of globin from a DBS card is of particular importance for hemolytic blood samples. To our knowledge, this is the first report on the stability of oxidative modifications of hemoglobin on DBSs, which are stable for 14 days under ambient conditions (room temperature, in air). Therefore, it is feasible and convenient to analyze these hemoglobin modifications from DBSs in studies

  11. Current hemoglobin levels are more predictive of disease progression than hemoglobin measured at baseline in patients receiving antiretroviral treatment for HIV type 1 infection

    DEFF Research Database (Denmark)

    Kowalska, Justyna D; Mocroft, Amanda; Blaxhult, Anders

    2007-01-01

    The role of hemoglobin levels as an independent prognostic marker of progression to AIDS and/or death in HIV-infected patients starting combination antiretroviral therapy (cART) was investigated. A total of 2,579 patients from the EuroSIDA cohort with hemoglobin, CD4 cell count, and HIV RNA viral...

  12. Biallelic loss-of-function variants in DOCK3 cause muscle hypotonia, ataxia, and intellectual disability.

    Science.gov (United States)

    Helbig, K L; Mroske, C; Moorthy, D; Sajan, S A; Velinov, M

    2017-10-01

    DOCK3 encodes the dedicator of cytokinesis 3 protein, a member of the DOCK180 family of proteins that are characterized by guanine-nucleotide exchange factor activity. DOCK3 is expressed exclusively in the central nervous system and plays an important role in axonal outgrowth and cytoskeleton reorganization. Dock3 knockout mice exhibit motor deficiencies with abnormal ataxic gait and impaired learning. We report 2 siblings with biallelic loss-of-function variants in DOCK3. Diagnostic whole-exome sequencing (WES) and chromosomal microarray were performed on a proband with severe developmental disability, hypotonia, and ataxic gait. Testing was also performed on the proband's similarly affected brother. A paternally inherited 458 kb deletion in chromosomal region 3p21.2 disrupting the DOCK3 gene was identified in both affected siblings. WES identified a nonsense variant c.382C>G (p.Gln128*) in the DOCK3 gene (NM_004947) on the maternal allele in both siblings. Common features in both affected individuals include severe developmental disability, ataxic gait, and severe hypotonia, which recapitulates the Dock3 knockout mouse phenotype. We show that complete DOCK3 deficiency in humans leads to developmental disability with significant hypotonia and gait ataxia, probably due to abnormal axonal development. © 2017 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Homology modelling and docking analysis of L-lactate dehydrogenase from Streptococcus thermopilus

    Directory of Open Access Journals (Sweden)

    Vukić Vladimir R.

    2016-01-01

    Full Text Available The aim of this research was to create a three-dimensional model of L-lactate dehydrogenase from the main yoghurt starter culture - Streptococcus thermopilus, to analyse its structural features and investigate substrate binding in the active site. NCBI BlastP was used against the Protein Data Bank database in order to identify the template for construction of homology models. Multiple sequence alignment was performed using the program MUSCULE within the UGENE 1.11.3 program. Homology models were constructed using the program Modeller v. 9.17. The obtained 3D model was verified by Ramachandran plots. Molecular docking simulations were performed using the program Surflex-Dock. The highest sequence similarity was observed with L-lactate dehydrogenase from Lactobacillus casei subsp. casei, with 69% identity. Therefore, its structure (PDB ID: 2ZQY:A was selected as a modelling template for homology modelling. Active residues are by sequence similarity predicted: S. thermophilus - HIS181 and S. aureus - HIS179. Binding energy of pyruvate to L-lactate dehydrogenase of S. thermopilus was - 7.874 kcal/mol. Pyruvate in L-lactate dehydrogenase of S. thermopilus makes H bonds with catalytic HIS181 (1.9 Å, as well as with THR235 (3.6 Å. Although our results indicate similar position of substrates between L-lactate dehydrogenase of S. thermopilus and S. aureus, differences in substrate distances and binding energy values could influence the reaction rate. Based on these results, the L-lactate dehydrogenase model proposed here could be used as a guide for further research, such as transition states of the reaction through molecular dynamics. [Projekat Ministarstva nauke Republike Srbije, br. III 46009

  14. Synthesis, Pharmacological Profile and Docking Studies of New Sulfonamides Designed as Phosphodiesterase-4 Inhibitors.

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    Isabelle Karine da Costa Nunes

    Full Text Available Prior investigations showed that increased levels of cyclic AMP down-regulate lung inflammatory changes, stimulating the interest in phosphodiesterase (PDE4 as therapeutic target. Here, we described the synthesis, pharmacological profile and docking properties of a novel sulfonamide series (5 and 6a-k designed as PDE4 inhibitors. Compounds were screened for their selectivity against the four isoforms of human PDE4 using an IMAP fluorescence polarized protocol. The effect on allergen- or LPS-induced lung inflammation and airway hyper-reactivity (AHR was studied in A/J mice, while the xylazine/ketamine-induced anesthesia test was employed as a behavioral correlate of emesis in rodents. As compared to rolipram, the most promising screened compound, 6a (LASSBio-448 presented a better inhibitory index concerning PDE4D/PDE4A or PDE4D/PDE4B. Accordingly, docking analyses of the putative interactions of LASSBio-448 revealed similar poses in the active site of PDE4A and PDE4C, but slight unlike orientations in PDE4B and PDE4D. LASSBio-448 (100 mg/kg, oral, 1 h before provocation, inhibited allergen-induced eosinophil accumulation in BAL fluid and lung tissue samples. Under an interventional approach, LASSBio-448 reversed ongoing lung eosinophilic infiltration, mucus exacerbation, peribronchiolar fibrosis and AHR by allergen provocation, in a mechanism clearly associated with blockade of pro-inflammatory mediators such as IL-4, IL-5, IL-13 and eotaxin-2. LASSBio-448 (2.5 and 10 mg/kg also prevented inflammation and AHR induced by LPS. Finally, the sulfonamide derivative was shown to be less pro-emetic than rolipram and cilomilast in the assay employed. These findings suggest that LASSBio-448 is a new PDE4 inhibitor with marked potential to prevent and reverse pivotal pathological features of diseases characterized by lung inflammation, such as asthma.

  15. Antimalarial activity of potential inhibitors of Plasmodium falciparum lactate dehydrogenase enzyme selected by docking studies.

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    Julia Penna-Coutinho

    Full Text Available The Plasmodium falciparum lactate dehydrogenase enzyme (PfLDH has been considered as a potential molecular target for antimalarials due to this parasite's dependence on glycolysis for energy production. Because the LDH enzymes found in P. vivax, P. malariae and P. ovale (pLDH all exhibit ∼90% identity to PfLDH, it would be desirable to have new anti-pLDH drugs, particularly ones that are effective against P. falciparum, the most virulent species of human malaria. Our present work used docking studies to select potential inhibitors of pLDH, which were then tested for antimalarial activity against P. falciparum in vitro and P. berghei malaria in mice. A virtual screening in DrugBank for analogs of NADH (an essential cofactor to pLDH and computational studies were undertaken, and the potential binding of the selected compounds to the PfLDH active site was analyzed using Molegro Virtual Docker software. Fifty compounds were selected based on their similarity to NADH. The compounds with the best binding energies (itraconazole, atorvastatin and posaconazole were tested against P. falciparum chloroquine-resistant blood parasites. All three compounds proved to be active in two immunoenzymatic assays performed in parallel using monoclonals specific to PfLDH or a histidine rich protein (HRP2. The IC(50 values for each drug in both tests were similar, were lowest for posaconazole (<5 µM and were 40- and 100-fold less active than chloroquine. The compounds reduced P. berghei parasitemia in treated mice, in comparison to untreated controls; itraconazole was the least active compound. The results of these activity trials confirmed that molecular docking studies are an important strategy for discovering new antimalarial drugs. This approach is more practical and less expensive than discovering novel compounds that require studies on human toxicology, since these compounds are already commercially available and thus approved for human use.

  16. Clinical, hematological and genetic data of a cohort of children with hemoglobin SD

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    Paulo do Val Rezende

    Full Text Available ABSTRACT INTRODUCTION: The hemoglobin FSD is very uncommon in newborn screening programs for sickle cell disease. In the program of Minas Gerais, Brazil, the clinical course of children with hemoglobin SD was observed to be heterogeneous. The objective of this study was to estimate the incidence (1999-2012 and to describe the natural history of a cohort of newborns with hemoglobin SD. METHODS: Isoelectric focusing was the primary method used in newborn screening. Polymerase chain reaction-restriction fragment length polymorphism and gene sequencing were used to identify mutant alleles and for haplotyping. Gap-polymerase chain reaction was used to detect alpha-thalassemia. RESULTS: Eleven cases of hemoglobin S/D-Punjab and eight of Hb S-Korle Bu were detected. Other variants with hemoglobin D mobility were not identified. All hemoglobin D-Punjab and hemoglobin Korle Bu alleles were associated with haplotype I. Among the children with hemoglobin S/D-Punjab, there were four with the ßS CAR haplotype, six with the Benin haplotype, and one atypical. Results of laboratory tests for hemoglobin S/D-Punjab and hemoglobin S-Korle Bu were: hemoglobin 8.0 and 12.3 g/dL (p-value <0.001, leukocyte count 13.9 × 109/L and 10.5 × 109/L (p-value = 0.003, reticulocytes 7.5% and 1.0% (p-value <0.001, hemoglobin F concentration 16.1% and 6.9% (p-value = 0.001 and oxygen saturation 91.9% and 97% (p-value = 0.002, respectively. Only hemoglobin S/D-Punjab children had acute pain crises and needed blood transfusions or hydroxyurea. Those with the Benin ßS haplotype had higher total hemoglobin and hemoglobin F concentrations compared to the CAR haplotype. Transcranial Doppler was normal in all children. CONCLUSION: The clinical course and blood cell counts of children with hemoglobin S/D-Punjab were very similar to those of hemoglobin SS children. In contrast, children with hemoglobin S-Korle Bu had clinical course and blood cell counts like children with the sickle

  17. Prediction of N-Methyl-D-Aspartate Receptor GluN1-Ligand Binding Affinity by a Novel SVM-Pose/SVM-Score Combinatorial Ensemble Docking Scheme.

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    Leong, Max K; Syu, Ren-Guei; Ding, Yi-Lung; Weng, Ching-Feng

    2017-01-06

    The glycine-binding site of the N-methyl-D-aspartate receptor (NMDAR) subunit GluN1 is a potential pharmacological target for neurodegenerative disorders. A novel combinatorial ensemble docking scheme using ligand and protein conformation ensembles and customized support vector machine (SVM)-based models to select the docked pose and to predict the docking score was generated for predicting the NMDAR GluN1-ligand binding affinity. The predicted root mean square deviation (RMSD) values in pose by SVM-Pose models were found to be in good agreement with the observed values (n = 30, r 2  = 0.928-0.988,  = 0.894-0.954, RMSE = 0.002-0.412, s = 0.001-0.214), and the predicted pK i values by SVM-Score were found to be in good agreement with the observed values for the training samples (n = 24, r 2  = 0.967,  = 0.899, RMSE = 0.295, s = 0.170) and test samples (n = 13, q 2  = 0.894, RMSE = 0.437, s = 0.202). When subjected to various statistical validations, the developed SVM-Pose and SVM-Score models consistently met the most stringent criteria. A mock test asserted the predictivity of this novel docking scheme. Collectively, this accurate novel combinatorial ensemble docking scheme can be used to predict the NMDAR GluN1-ligand binding affinity for facilitating drug discovery.

  18. Molecular modeling-driven approach for identification of Janus kinase 1 inhibitors through 3D-QSAR, docking and molecular dynamics simulations.

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    Itteboina, Ramesh; Ballu, Srilata; Sivan, Sree Kanth; Manga, Vijjulatha

    2017-10-01

    Janus kinase 1 (JAK 1) belongs to the JAK family of intracellular nonreceptor tyrosine kinase. JAK-signal transducer and activator of transcription (JAK-STAT) pathway mediate signaling by cytokines, which control survival, proliferation and differentiation of a variety of cells. Three-dimensional quantitative structure activity relationship (3 D-QSAR), molecular docking and molecular dynamics (MD) methods was carried out on a dataset of Janus kinase 1(JAK 1) inhibitors. Ligands were constructed and docked into the active site of protein using GLIDE 5.6. Best docked poses were selected after analysis for further 3 D-QSAR analysis using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methodology. Employing 60 molecules in the training set, 3 D-QSAR models were generate that showed good statistical reliability, which is clearly observed in terms of r 2 ncv and q 2 loo values. The predictive ability of these models was determined using a test set of 25 molecules that gave acceptable predictive correlation (r 2 Pred ) values. The key amino acid residues were identified by means of molecular docking, and the stability and rationality of the derived molecular conformations were also validated by MD simulation. The good consonance between the docking results and CoMFA/CoMSIA contour maps provides helpful clues about the reasonable modification of molecules in order to design more efficient JAK 1 inhibitors. The developed models are expected to provide some directives for further synthesis of highly effective JAK 1 inhibitors.

  19. Bio-inspired algorithms applied to molecular docking simulations.

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    Heberlé, G; de Azevedo, W F

    2011-01-01

    Nature as a source of inspiration has been shown to have a great beneficial impact on the development of new computational methodologies. In this scenario, analyses of the interactions between a protein target and a ligand can be simulated by biologically inspired algorithms (BIAs). These algorithms mimic biological systems to create new paradigms for computation, such as neural networks, evolutionary computing, and swarm intelligence. This review provides a description of the main concepts behind BIAs applied to molecular docking simulations. Special attention is devoted to evolutionary algorithms, guided-directed evolutionary algorithms, and Lamarckian genetic algorithms. Recent applications of these methodologies to protein targets identified in the Mycobacterium tuberculosis genome are described.

  20. Structure and stability of human hemoglobin microparticles prepared with a double emulsion technique.

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    Cedrati, N; Bonneaux, F; Labrude, P; Maincent, P

    1997-09-01

    Hemoglobin solutions can be used as blood substitutes but they present some disadvantages often due to their rapid removal from the bloodstream after injection. A possible way of overcoming this problem is to trap hemoglobin inside particles. This study deals with the preparation, structure and stability of poly(lactic acid) and ethylcellulose microparticles containing human hemoglobin obtained with a double emulsion technique. We investigated the manufacturing process of these particles in order to increase the encapsulation ratio of hemoglobin. For this purpose, some parameters involved in the procedure were optimized, such as hemoglobin concentration and duration of stirring: hemoglobin loading increases with its concentration in the preparation and well-defined stirring time avoids a leakage of hemoglobin. Hemoglobin concentration, surfactant concentration i.e. poly(vinylic alcohol), amounts of polymer and solvent (methylene chloride), duration and speed of stirring. The microparticles were prepared with satisfactory yields (60 to 73%). They were spherical and their mean size was lower than 200 microns. The functional properties of entrapped hemoglobin were studied. The encapsulation did not alter hemoglobin and the oxygen affinity of the hemoglobin remained unmodified (P50 about 13.9 mm Hg in a Bis-Tris buffer pH 7.4 at 37 degrees C). Moreover, only low levels of methemoglobin could be detected (less than 3%). Besides, about 90% of encapsulated hemoglobin could be released from microparticles, with a speed related to the internal structure of the particles. The prepared microparticles were stored during one month at +4 degrees C. No degradation of the particle structure occurred and the functional properties of hemoglobin were preserved. These particles could provide a potential source of oxygen in the field of biotechnologies but any application for a transfusional purpose would first require a drastic reduction in particle size.