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Sample records for induced fit docking

  1. Adaptive BP-Dock: An Induced Fit Docking Approach for Full Receptor Flexibility.

    Science.gov (United States)

    Bolia, Ashini; Ozkan, S Banu

    2016-04-25

    We present an induced fit docking approach called Adaptive BP-Dock that integrates perturbation response scanning (PRS) with the flexible docking protocol of RosettaLigand in an adaptive manner. We first perturb the binding pocket residues of a receptor and obtain a new conformation based on the residue response fluctuation profile using PRS. Next, we dock a ligand to this new conformation by RosettaLigand, where we repeat these steps for several iterations. We test this approach on several protein test sets including difficult unbound docking cases such as HIV-1 reverse transcriptase and HIV-1 protease. Adaptive BP-Dock results show better correlation with experimental binding affinities compared to other docking protocols. Overall, the results imply that Adaptive BP-Dock can easily capture binding induced conformational changes by simultaneous sampling of protein and ligand conformations. This can provide faster and efficient docking of novel targets for rational drug design.

  2. Rationalization of Activity Cliffs of a Sulfonamide Inhibitor of DNA Methyltransferases with Induced-Fit Docking

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    José L. Medina-Franco

    2014-02-01

    Full Text Available Inhibitors of human DNA methyltransferases (DNMT are of increasing interest to develop novel epi-drugs for the treatment of cancer and other diseases. As the number of compounds with reported DNMT inhibition is increasing, molecular docking is shedding light to elucidate their mechanism of action and further interpret structure–activity relationships. Herein, we present a structure-based rationalization of the activity of SW155246, a distinct sulfonamide compound recently reported as an inhibitor of human DNMT1 obtained from high-throughput screening. We used flexible and induce-fit docking to develop a binding model of SW155246 with a crystallographic structure of human DNMT1. Results were in excellent agreement with experimental information providing a three-dimensional structural interpretation of ‘activity cliffs’, e.g., analogues of SW155246 with a high structural similarity to the sulfonamide compound, but with no activity in the enzymatic assay.

  3. A comparison of various optimization algorithms of protein-ligand docking programs by fitness accuracy.

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    Guo, Liyong; Yan, Zhiqiang; Zheng, Xiliang; Hu, Liang; Yang, Yongliang; Wang, Jin

    2014-07-01

    In protein-ligand docking, an optimization algorithm is used to find the best binding pose of a ligand against a protein target. This algorithm plays a vital role in determining the docking accuracy. To evaluate the relative performance of different optimization algorithms and provide guidance for real applications, we performed a comparative study on six efficient optimization algorithms, containing two evolutionary algorithm (EA)-based optimizers (LGA, DockDE) and four particle swarm optimization (PSO)-based optimizers (SODock, varCPSO, varCPSO-ls, FIPSDock), which were implemented into the protein-ligand docking program AutoDock. We unified the objective functions by applying the same scoring function, and built a new fitness accuracy as the evaluation criterion that incorporates optimization accuracy, robustness, and efficiency. The varCPSO and varCPSO-ls algorithms show high efficiency with fast convergence speed. However, their accuracy is not optimal, as they cannot reach very low energies. SODock has the highest accuracy and robustness. In addition, SODock shows good performance in efficiency when optimizing drug-like ligands with less than ten rotatable bonds. FIPSDock shows excellent robustness and is close to SODock in accuracy and efficiency. In general, the four PSO-based algorithms show superior performance than the two EA-based algorithms, especially for highly flexible ligands. Our method can be regarded as a reference for the validation of new optimization algorithms in protein-ligand docking.

  4. Exertional and CrossFit-Induced Rhabdomyolysis.

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    Meyer, Michelle; Sundaram, Sneha; Schafhalter-Zoppoth, Ingeborg

    2017-07-14

    Few publications of exercise-induced rhabomyolysis currently exist in the medical literature besides case reports. However, this condition can be severe, resulting in hospitalization and IV fluid administration to prevent serious sequelae. This report describes a case of exercise-induced rhabdomyolysis caused by a CrossFit workout. A 31-year-old female presented with 2 days of bilateral upper extremity pain and soreness, which began 2 days after she completed a CrossFit workout. Workup revealed an elevated creatine phosphokinase (CPK) of 18 441 U/L, consistent with exercise-induced rhabdomyolysis, and elevated liver function tests and elevated D-dimer, although her renal function was normal. She was hospitalized for 2 days and treated with IV fluids. This case report demonstrates that CrossFit exercises can lead to rhabdomyolysis, highlighting a condition that may be underdiagnosed and underreported.

  5. Induced-fit Mechanism for Prolyl Endopeptidase

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    Li, Min; Chen, Changqing; Davies, David R.; Chiu, Thang K. (NIH); (LSU); (Chinese Aca. Sci.)

    2010-11-15

    Prolyl peptidases cleave proteins at proline residues and are of importance for cancer, neurological function, and type II diabetes. Prolyl endopeptidase (PEP) cleaves neuropeptides and is a drug target for neuropsychiatric diseases such as post-traumatic stress disorder, depression, and schizophrenia. Previous structural analyses showing little differences between native and substrate-bound structures have suggested a lock-and-key catalytic mechanism. We now directly demonstrate from seven structures of Aeromonus punctata PEP that the mechanism is instead induced fit: the native enzyme exists in a conformationally flexible opened state with a large interdomain opening between the {beta}-propeller and {alpha}/{beta}-hydrolase domains; addition of substrate to preformed native crystals induces a large scale conformational change into a closed state with induced-fit adjustments of the active site, and inhibition of this conformational change prevents substrate binding. Absolute sequence conservation among 28 orthologs of residues at the active site and critical residues at the interdomain interface indicates that this mechanism is conserved in all PEPs. This finding has immediate implications for the use of conformationally targeted drug design to improve specificity of inhibition against this family of proline-specific serine proteases.

  6. Dock10, a Cdc42 and Rac1 GEF, induces loss of elongation, filopodia, and ruffles in cervical cancer epithelial HeLa cells

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    Natalia Ruiz-Lafuente

    2015-07-01

    Full Text Available Dock10 is one of the three members of the Dock-D family of Dock proteins, a class of guanine nucleotide exchange factors (GEFs for Rho GTPases. Its homologs Dock9 and Dock11 are Cdc42 GEFs. Dock10 is required for maintenance of rounded morphology and amoeboid-type movement. Full-length isoforms of Dock10 have been recently cloned. Here, we address GTPase specificity and GEF activity of Dock10. In order of decreasing intensity, Dock10 interacted with nucleotide-free Rac1, Cdc42, and Rac3, and more weakly with Rac2, RhoF, and RhoG. Inducible expression of Dock10 in HeLa epithelial cells promoted GEF activity on Cdc42 and Rac1, and a morphologic change in two-dimensional culture consisting in loss of cell elongation, increase of filopodia, and ruffles. Area in contact with the substrate of cells that spread with non-elongated morphology was larger in cells expressing Dock10. Inducible expression of constitutively active mutants of Cdc42 and Rac1 in HeLa cells also induced loss of elongation. However, Cdc42 induced filopodia and contraction, and Rac1 induced membrane ruffles and flattening. When co-expressed with Dock10, Cdc42 potentiated filopodia, and Rac1 potentiated ruffles. These results suggest that Dock10 functions as a dual GEF for Cdc42 and Rac1, affecting cell morphology, spreading and actin cytoskeleton protrusions of adherent HeLa cells.

  7. Stress state in turbopump bearing induced by shrink fitting

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    Sims, P.; Zee, R.

    1991-01-01

    The stress generated by shrink fitting in bearing-like geometries is studied. The feasibility of using strain gages to determine the strain induced by shrink fitting process is demonstrated. Results from a ring with a uniform cross section reveal the validity of simple stress mechanics calculations for determining the stress state induced in this geometry by shrink fitting.

  8. Contrasted Fitness Costs of Docking and Antibacterial Constructs in the EE and EVida3 Strains Validates Two-Phase Anopheles gambiae Genetic Transformation System.

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    Doug Paton

    Full Text Available The deployment of transgenic mosquitoes carrying genes for refractoriness to malaria has long been seen as a futuristic scenario riddled with technical difficulties. The integration of anti-malarial effector genes and a gene-drive system into the mosquito genome without affecting mosquito fitness is recognized as critical to the success of this malaria control strategy. Here we conducted detailed fitness studies of two Anopheles gambiae s.s. transgenic lines recently developed using a two-phase targeted genetic transformation system. In replicated cage-invasion experiments, males and females of the EE Phase-1 docking strain and EVida3 Phase-2 strain loaded with an antimicrobial peptide (AMP expressed upon blood-feeding, were mixed with individuals of a recently-colonized strain of the Mopti chromosomal form. The experimental design enabled us to detect initial strain reproductive success differences, assortative mating and hybrid vigor that may characterize mosquito release situations. In addition, the potential fitness costs of the unloaded Phase-1 and loaded Phase-2 genetic constructs, independent of the strains' original genetic backgrounds, were estimated between the 1(st instar larvae, pupae and adult stages over 10 generations. The Phase-1 unloaded docking cassette was found to have significantly lower allelic fitness relative to the wild type allele during larval development. However, overall genotypic fitness was comparable to the wild type allele across all stages leading to stable equilibrium in all replicates. In contrast, the Phase-2 construct expressing EVida3 disappeared from all replicates within 10 generations due to lower fitness of hemi- and homozygous larvae, suggesting costly background AMP expression and/or of the DsRed2 marker. This is the first study to effectively partition independent fitness stage-specific determinants in unloaded and loaded transgenic strains of a Phase-1-2 transformation system. Critically, the high

  9. Contrasted Fitness Costs of Docking and Antibacterial Constructs in the EE and EVida3 Strains Validates Two-Phase Anopheles gambiae Genetic Transformation System.

    Science.gov (United States)

    Paton, Doug; Underhill, Anne; Meredith, Janet; Eggleston, Paul; Tripet, Frederic

    2013-01-01

    The deployment of transgenic mosquitoes carrying genes for refractoriness to malaria has long been seen as a futuristic scenario riddled with technical difficulties. The integration of anti-malarial effector genes and a gene-drive system into the mosquito genome without affecting mosquito fitness is recognized as critical to the success of this malaria control strategy. Here we conducted detailed fitness studies of two Anopheles gambiae s.s. transgenic lines recently developed using a two-phase targeted genetic transformation system. In replicated cage-invasion experiments, males and females of the EE Phase-1 docking strain and EVida3 Phase-2 strain loaded with an antimicrobial peptide (AMP) expressed upon blood-feeding, were mixed with individuals of a recently-colonized strain of the Mopti chromosomal form. The experimental design enabled us to detect initial strain reproductive success differences, assortative mating and hybrid vigor that may characterize mosquito release situations. In addition, the potential fitness costs of the unloaded Phase-1 and loaded Phase-2 genetic constructs, independent of the strains' original genetic backgrounds, were estimated between the 1(st) instar larvae, pupae and adult stages over 10 generations. The Phase-1 unloaded docking cassette was found to have significantly lower allelic fitness relative to the wild type allele during larval development. However, overall genotypic fitness was comparable to the wild type allele across all stages leading to stable equilibrium in all replicates. In contrast, the Phase-2 construct expressing EVida3 disappeared from all replicates within 10 generations due to lower fitness of hemi- and homozygous larvae, suggesting costly background AMP expression and/or of the DsRed2 marker. This is the first study to effectively partition independent fitness stage-specific determinants in unloaded and loaded transgenic strains of a Phase-1-2 transformation system. Critically, the high fitness of the

  10. Predicting protein conformational changes for unbound and homology docking: learning from intrinsic and induced flexibility.

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    Chen, Haoran; Sun, Yuanfei; Shen, Yang

    2017-03-01

    Predicting protein conformational changes from unbound structures or even homology models to bound structures remains a critical challenge for protein docking. Here we present a study directly addressing the challenge by reducing the dimensionality and narrowing the range of the corresponding conformational space. The study builds on cNMA-our new framework of partner- and contact-specific normal mode analysis that exploits encounter complexes and considers both intrinsic and induced flexibility. First, we established over a CAPRI (Critical Assessment of PRedicted Interactions) target set that the direction of conformational changes from unbound structures and homology models can be reproduced to a great extent by a small set of cNMA modes. In particular, homology-to-bound interface root-mean-square deviation (iRMSD) can be reduced by 40% on average with the slowest 30 modes. Second, we developed novel and interpretable features from cNMA and used various machine learning approaches to predict the extent of conformational changes. The models learned from a set of unbound-to-bound conformational changes could predict the actual extent of iRMSD with errors around 0.6 Å for unbound proteins in a held-out benchmark subset, around 0.8 Å for unbound proteins in the CAPRI set, and around 1 Å even for homology models in the CAPRI set. Our results shed new insights into origins of conformational differences between homology models and bound structures and provide new support for the low-dimensionality of conformational adjustment during protein associations. The results also provide new tools for ensemble generation and conformational sampling in unbound and homology docking. Proteins 2017; 85:544-556. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  11. In Pursuit of Fully Flexible Protein-Ligand Docking: Modeling the Bilateral Mechanism of Binding.

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    Henzler, Angela M; Rarey, Matthias

    2010-03-15

    Modern structure-based drug design aims at accounting for the intrinsic flexibility of therapeutic relevant targets. Over the last few years a considerable amount of docking approaches that encounter this challenging problem has emerged. Here we provide the readership with an overview of established methods for fully flexible protein-ligand docking and current developments in the field. All methods are based on one of two fundamental models which describe the dynamic behavior of proteins upon ligand binding. Methods for ensemble docking (ED) model the protein conformational change before the ligand is placed, whereas induced-fit docking (IFD) optimizes the protein structure afterwards. A third category of docking approaches is formed by recent approaches that follow both concepts. This categorization allows to comprehensively discover strengths and weaknesses of the individual processes and to extract information for their applicability in real world docking scenarios.

  12. Optimal strategies for virtual screening of induced-fit and flexible target in the 2015 D3R Grand Challenge

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    Ye, Zhaofeng; Baumgartner, Matthew P.; Wingert, Bentley M.; Camacho, Carlos J.

    2016-09-01

    Induced fit or protein flexibility can make a given structure less useful for docking and/or scoring. The 2015 Drug Design Data Resource (D3R) Grand Challenge provided a unique opportunity to prospectively test optimal strategies for virtual screening in these type of targets: heat shock protein 90 (HSP90), a protein with multiple ligand-induced binding modes; and mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), a kinase with a large flexible pocket. Using previously known co-crystal structures, we tested predictions from methods that keep the receptor structure fixed and used (a) multiple receptor/ligand co-crystals as binding templates for minimization or docking ("close"), (b) methods that align or dock to a single receptor ("cross"), and (c) a hybrid approach that chose from multiple bound ligands as initial templates for minimization to a single receptor ("min-cross"). Pose prediction using our "close" models resulted in average ligand RMSDs of 0.32 and 1.6 Å for HSP90 and MAP4K4, respectively, the most accurate models of the community-wide challenge. On the other hand, affinity ranking using our "cross" methods performed well overall despite the fact that a fixed receptor cannot model ligand-induced structural changes,. In addition, "close" methods that leverage the co-crystals of the different binding modes of HSP90 also predicted the best affinity ranking. Our studies suggest that analysis of changes on the receptor structure upon ligand binding can help select an optimal virtual screening strategy.

  13. Modulation of current through a nanopore induced by a charged globule: implications for DNA-docking

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    Chinappi, Mauro; Cecconi, Fabio; Marconi, Umberto Marini Bettolo; Melchionna, Simone

    2015-01-01

    The passage of DNA through a nanopore can be effectively decomposed into two distinct phases, docking and actual translocation. In experiments each phase is characterized by a distinct current signature which allows the discrimination of the two events. However, at low voltages a clear distinction of the two phases is lost. By using numerical simulations we clarify how the current signature associated to the docking events depends on the applied voltage. The simulations show that at small voltage the DNA globule enhances the pore conductance due to an enrichment of charge carriers. At high voltage, the globule drains substantial charge carriers from the pore region, thereby reducing the overall conductance. The results provide a new interpretation to the experimental data on conductance and show how docking interferes with the translocation signal, of potential interest for sequencing applications.

  14. Involvement of complexin 2 in docking, locking and unlocking of different SNARE complexes during sperm capacitation and induced acrosomal exocytosis.

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    Pei-Shiue J Tsai

    Full Text Available Acrosomal exocytosis (AE is an intracellular multipoint fusion reaction of the sperm plasma membrane (PM with the outer acrosomal membrane (OAM. This unique exocytotic event enables the penetration of the sperm through the zona pellucida of the oocyte. We previously observed a stable docking of OAM to the PM brought about by the formation of the trans-SNARE complex (syntaxin 1B, SNAP 23 and VAMP 3. By using electron microscopy, immunochemistry and immunofluorescence techniques in combination with functional studies and proteomic approaches, we here demonstrate that calcium ionophore-induced AE results in the formation of unilamellar hybrid membrane vesicles containing a mixture of components originating from the two fused membranes. These mixed vesicles (MV do not contain the earlier reported trimeric SNARE complex but instead possess a novel trimeric SNARE complex that contained syntaxin 3, SNAP 23 and VAMP 2, with an additional SNARE interacting protein, complexin 2. Our data indicate that the earlier reported raft and capacitation-dependent docking phenomenon between the PM and OAM allows a specific rearrangement of molecules between the two docked membranes and is involved in (1 recruiting SNAREs and complexin 2 in the newly formed lipid-ordered microdomains, (2 the assembly of a fusion-driving SNARE complex which executes Ca(2+-dependent AE, (3 the disassembly of the earlier reported docking SNARE complex, (4 the recruitment of secondary zona binding proteins at the zona interacting sperm surface. The possibility to study separate and dynamic interactions between SNARE proteins, complexin and Ca(2+ which are all involved in AE make sperm an ideal model for studying exocytosis.

  15. SnugDock: Paratope Structural Optimization during Antibody-Antigen Docking Compensates for Errors in Antibody Homology Models

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    Sircar, Aroop; Gray, Jeffrey J.

    2010-01-01

    High resolution structures of antibody-antigen complexes are useful for analyzing the binding interface and to make rational choices for antibody engineering. When a crystallographic structure of a complex is unavailable, the structure must be predicted using computational tools. In this work, we illustrate a novel approach, named SnugDock, to predict high-resolution antibody-antigen complex structures by simultaneously structurally optimizing the antibody-antigen rigid-body positions, the relative orientation of the antibody light and heavy chains, and the conformations of the six complementarity determining region loops. This approach is especially useful when the crystal structure of the antibody is not available, requiring allowances for inaccuracies in an antibody homology model which would otherwise frustrate rigid-backbone docking predictions. Local docking using SnugDock with the lowest-energy RosettaAntibody homology model produced more accurate predictions than standard rigid-body docking. SnugDock can be combined with ensemble docking to mimic conformer selection and induced fit resulting in increased sampling of diverse antibody conformations. The combined algorithm produced four medium (Critical Assessment of PRediction of Interactions-CAPRI rating) and seven acceptable lowest-interface-energy predictions in a test set of fifteen complexes. Structural analysis shows that diverse paratope conformations are sampled, but docked paratope backbones are not necessarily closer to the crystal structure conformations than the starting homology models. The accuracy of SnugDock predictions suggests a new genre of general docking algorithms with flexible binding interfaces targeted towards making homology models useful for further high-resolution predictions. PMID:20098500

  16. DockingShop: A Tool for Interactive Molecular Docking

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    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.

  17. Combining docking and molecular dynamic simulations in drug design.

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    Alonso, Hernán; Bliznyuk, Andrey A; Gready, Jill E

    2006-09-01

    A rational approach is needed to maximize the chances of finding new drugs, and to exploit the opportunities of potential new drug targets emerging from genomic and proteomic initiatives, and from the large libraries of small compounds now readily available through combinatorial chemistry. Despite a shaky early history, computer-aided drug design techniques can now be effective in reducing costs and speeding up drug discovery. This happy outcome results from development of more accurate and reliable algorithms, use of more thoughtfully planned strategies to apply them, and greatly increased computer power to allow studies with the necessary reliability to be performed. Our review focuses on applications and protocols, with the main emphasis on critical analysis of recent studies where docking calculations and molecular dynamics (MD) simulations were combined to dock small molecules into protein receptors. We highlight successes to demonstrate what is possible now, but also point out drawbacks and future directions. The review is structured to lead the reader from the simpler to more compute-intensive methods. Thus, while inexpensive and fast docking algorithms can be used to scan large compound libraries and reduce their size, more accurate but expensive MD simulations can be applied when a few selected ligand candidates remain. MD simulations can be used: during the preparation of the protein receptor before docking, to optimize its structure and account for protein flexibility; for the refinement of docked complexes, to include solvent effects and account for induced fit; to calculate binding free energies, to provide an accurate ranking of the potential ligands; and in the latest developments, during the docking process itself to find the binding site and correctly dock the ligand a priori.

  18. MOLS 2.0: software package for peptide modeling and protein-ligand docking.

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    Paul, D Sam; Gautham, N

    2016-10-01

    We previously developed an algorithm to perform conformational searches of proteins and peptides, and to perform the docking of ligands to protein receptors. In order to identify optimal conformations and docked poses, this algorithm uses mutually orthogonal Latin squares (MOLS) to rationally sample the vast conformational (or docking) space, and then analyzes this relatively small sample using a variant of mean field theory. The conformational search part of the algorithm was denoted MOLS 1.0. The docking portion of the algorithm, which allows only "flexible ligand/rigid receptor" docking, was denoted MOLSDOCK. Both are FORTRAN-based command-line-only molecular docking computer programs, though a GUI was developed later for MOLS 1.0. Both the conformational search and the rigid receptor docking parts of the algorithm have been extensively validated. We have now further enhanced the capabilities of the program by incorporating "induced fit" side-chain receptor flexibility for docking peptide ligands. Benchmarking and extensive testing is now being carried out for the flexible receptor portion of the docking. Additionally, to make both the peptide conformational search and docking algorithms (the latter including both flexible ligand/rigid receptor and flexible ligand/flexible receptor techniques) more accessible to the research community, we have developed MOLS 2.0, which incorporates a new Java-based graphical user interface (GUI). Here, we give a detailed description of MOLS 2.0. The source code and binary for MOLS 2.0 are distributed free (under a GNU Lesser General Public License) to the scientific community. They are freely available for download at https://sourceforge.net/projects/mols2-0/files/ .

  19. Spectroscopic and molecular docking study on the interaction between salicylic acid and the induced disease-resistant protein OsAAA1 of rice

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    Chen, Ya H.; Dai, Kang; Zhang, Hua; Wu, Yun H.; Wang, Chun T.; Liu, Xue Q.; Liu, Xin Q.

    2017-02-01

    The interaction between salicylic acid (SA) and the induced disease-resistant protein OsAAA1 in rice was studied using spectroscopy and molecular docking. Ultraviolet (UV) absorption spectroscopy demonstrated an interaction between OsAAA1 protein and SA. Spectroscopy showed that this interaction was a dynamic quenching process. Synchronous fluorescence spectroscopy (SFS) further revealed that this interaction caused changes in the microenvironment of tyrosine and tryptophan and that the interaction site was closer to the tryptophan residue. The structural model of protein OsAAA1 was determined by homology modeling method, and the molecular docking simulation diagram of OsAAA1 with SA was obtained. These models, in combination with a Ramachandran plot analysis, showed amino acid residues ranging from position 240 to position 420 as the possible site interacting with SA. Among them, Gly389, Lys257 and Glu425 might be three key amino acids that can form hydrogen bonds with SA.

  20. Flexible CDOCKER: Development and application of a pseudo-explicit structure-based docking method within CHARMM.

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    Gagnon, Jessica K; Law, Sean M; Brooks, Charles L

    2016-03-30

    Protein-ligand docking is a commonly used method for lead identification and refinement. While traditional structure-based docking methods represent the receptor as a rigid body, recent developments have been moving toward the inclusion of protein flexibility. Proteins exist in an interconverting ensemble of conformational states, but effectively and efficiently searching the conformational space available to both the receptor and ligand remains a well-appreciated computational challenge. To this end, we have developed the Flexible CDOCKER method as an extension of the family of complete docking solutions available within CHARMM. This method integrates atomically detailed side chain flexibility with grid-based docking methods, maintaining efficiency while allowing the protein and ligand configurations to explore their conformational space simultaneously. This is in contrast to existing approaches that use induced-fit like sampling, such as Glide or Autodock, where the protein or the ligand space is sampled independently in an iterative fashion. Presented here are developments to the CHARMM docking methodology to incorporate receptor flexibility and improvements to the sampling protocol as demonstrated with re-docking trials on a subset of the CCDC/Astex set. These developments within CDOCKER achieve docking accuracy competitive with or exceeding the performance of other widely utilized docking programs.

  1. Involvement of Complexin 2 in Docking, Locking and Unlocking of Different SNARE Complexes during Sperm Capacitation and Induced Acrosomal Exocytosis.

    NARCIS (Netherlands)

    Tsai, P.S.; Brewis, I.A.; van Maaren, J.; Gadella, B.M.

    2012-01-01

    Acrosomal exocytosis (AE) is an intracellular multipoint fusion reaction of the sperm plasma membrane (PM) with the outer acrosomal membrane (OAM). This unique exocytotic event enables the penetration of the sperm through the zona pellucida of the oocyte. We previously observed a stable docking of O

  2. Mouse fat storage-inducing transmembrane protein 2 (FIT2) promotes lipid droplet accumulation in plants.

    Science.gov (United States)

    Cai, Yingqi; McClinchie, Elizabeth; Price, Ann; Nguyen, Thuy N; Gidda, Satinder K; Watt, Samantha C; Yurchenko, Olga; Park, Sunjung; Sturtevant, Drew; Mullen, Robert T; Dyer, John M; Chapman, Kent D

    2017-07-01

    Fat storage-inducing transmembrane protein 2 (FIT2) is an endoplasmic reticulum (ER)-localized protein that plays an important role in lipid droplet (LD) formation in animal cells. However, no obvious homologue of FIT2 is found in plants. Here, we tested the function of FIT2 in plant cells by ectopically expressing mouse (Mus musculus) FIT2 in Nicotiana tabacum suspension-cultured cells, Nicotiana benthamiana leaves and Arabidopsis thaliana plants. Confocal microscopy indicated that the expression of FIT2 dramatically increased the number and size of LDs in leaves of N. benthamiana and Arabidopsis, and lipidomics analysis and mass spectrometry imaging confirmed the accumulation of neutral lipids in leaves. FIT2 also increased seed oil content by ~13% in some stable, overexpressing lines of Arabidopsis. When expressed transiently in leaves of N. benthamiana or suspension cells of N. tabacum, FIT2 localized specifically to the ER and was often concentrated at certain regions of the ER that resembled ER-LD junction sites. FIT2 also colocalized at the ER with other proteins known to be involved in triacylglycerol biosynthesis or LD formation in plants, but not with ER resident proteins involved in electron transfer or ER-vesicle exit sites. Collectively, these results demonstrate that mouse FIT2 promotes LD accumulation in plants, a surprising functional conservation in the context of a plant cell given the apparent lack of FIT2 homologues in higher plants. These results suggest also that FIT2 expression represents an effective synthetic biology strategy for elaborating neutral lipid compartments in plant tissues for potential biofuel or bioproduct purposes. © 2016 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

  3. How to distinguish conformational selection and induced fit based on chemical relaxation rates

    CERN Document Server

    Paul, Fabian

    2016-01-01

    Protein binding often involves conformational changes. Important questions are whether a conformational change occurs prior to a binding event ('conformational selection') or after a binding event ('induced fit'), and how conformational transition rates can be obtained from experiments. In this article, we present general results for the chemical relaxation rates of conformational-selection and induced-fit binding processes that hold for all concentrations of proteins and ligands and, thus, go beyond the standard pseudo-first-order approximation of large ligand concentration. These results allow to distinguish conformational-selection from induced-fit processes - also in cases in which such a distinction is not possible under pseudo-first-order conditions - and to extract conformational transition rates of proteins from chemical relaxation data.

  4. Towards Al3+-Induced Manganese-Containing Superoxide Dismutase Inactivation and Conformational Changes: An Integrating Study with Docking Simulations

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    Jiang-Liu Yang

    2011-01-01

    Full Text Available Superoxide dismutase (SOD, EC 1.15.1.1 plays an important antioxidant defense role in skins exposed to oxygen. We studied the inhibitory effects of Al3+ on the activity and conformation of manganese-containing SOD (Mn-SOD. Mn-SOD was significantly inactivated by Al3+ in a dose-dependent manner. The kinetic studies showed that Al3+ inactivated Mn-SOD follows the first-order reaction. Al3+ increased the degree of secondary structure of Mn-SOD and also disrupted the tertiary structure of Mn-SOD, which directly resulted in enzyme inactivation. We further simulated the docking between Mn-SOD and Al3+ (binding energy for Dock 6.3: −14.07 kcal/mol and suggested that ASP152 and GLU157 residues were predicted to interact with Al3+, which are not located in the Mn-contained active site. Our results provide insight into the inactivation of Mn-SOD during unfolding in the presence of Al3+ and allow us to describe a ligand binding via inhibition kinetics combined with the computational prediction.

  5. SOS-induced DNA polymerases enhance long-term survival and evolutionary fitness

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    Yeiser, Bethany; Pepper, Evan D.; Goodman, Myron F.; Finkel, Steven E.

    2002-01-01

    Escherichia coli encodes three SOS-induced DNA polymerases: pol II, pol IV, and pol V. We show here that each of these polymerases confers a competitive fitness advantage during the stationary phase of the bacterial life cycle, in the absence of external DNA-damaging agents known to induce the SOS response. When grown individually, wild-type and SOS pol mutants exhibit indistinguishable temporal growth and death patterns. In contrast, when grown in competition with wild-type E. coli, mutants lacking one or more SOS polymerase suffer a severe reduction in fitness. These mutants also fail to express the “growth advantage in stationary phase” phenotype as do wild-type strains, instead expressing two additional new types of “growth advantage in stationary phase” phenotype. These polymerases contribute to survival by providing essential functions to ensure replication of the chromosome and by generating genetic diversity. PMID:12060704

  6. Activation ofβ2-Adrenergic Receptor Induced by Three Catecholamine Agonists: a Docking and Molecular Dynamics Study

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    ZHANG Rui; DONG Li-hua; LING Bao-ping; WANG Zhi-guo; LIU Yong-jun

    2012-01-01

    We studied the activation of β2-adrenergic receptor(β2AR) by norepinephrine,epinephrine and isoproterenol using docking and molecular dynamics(MD) simulation.The simulation was done on the assumption that β2AR was surrounded with explicit water and infinite lipid bilayer membrane at body temperature.So the result should be close to that under the physiological conditions.We calculated the structure of binding sites in β2AR for the three activators.We also simulated the change of the conformation ofβ2AR in the transmembrane regions(TMs),in the molecular switches,and in the conserved DRY(Aspartic acid,Arginine and Tyrosine) motif.This study provides detailed information concerning the structure ofβ2AR during activation process.

  7. MS-DOCK: accurate multiple conformation generator and rigid docking protocol for multi-step virtual ligand screening.

    Science.gov (United States)

    Sauton, Nicolas; Lagorce, David; Villoutreix, Bruno O; Miteva, Maria A

    2008-04-10

    The number of protein targets with a known or predicted tri-dimensional structure and of drug-like chemical compounds is growing rapidly and so is the need for new therapeutic compounds or chemical probes. Performing flexible structure-based virtual screening computations on thousands of targets with millions of molecules is intractable to most laboratories nor indeed desirable. Since shape complementarity is of primary importance for most protein-ligand interactions, we have developed a tool/protocol based on rigid-body docking to select compounds that fit well into binding sites. Here we present an efficient multiple conformation rigid-body docking approach, MS-DOCK, which is based on the program DOCK. This approach can be used as the first step of a multi-stage docking/scoring protocol. First, we developed and validated the Multiconf-DOCK tool that generates several conformers per input ligand. Then, each generated conformer (bioactives and 37970 decoys) was docked rigidly using DOCK6 with our optimized protocol into seven different receptor-binding sites. MS-DOCK was able to significantly reduce the size of the initial input library for all seven targets, thereby facilitating subsequent more CPU demanding flexible docking procedures. MS-DOCK can be easily used for the generation of multi-conformer libraries and for shape-based filtering within a multi-step structure-based screening protocol in order to shorten computation times.

  8. A Flexible Domain-Domain Hinge Promotes an Induced-fit Dominant Mechanism for the Loading of Guide-DNA into Argonaute Protein in Thermus thermophilus

    KAUST Repository

    Zhu, Lizhe

    2016-02-24

    Argonaute proteins (Ago) are core components of the RNA Induced Silencing Complex (RISC) that load and utilize small guide nucleic acids to silence mRNAs or cleave foreign DNAs. Despite the essential role of Ago in gene regulation and defense against virus, the molecular mechanism of guide-strand loading into Ago remains unclear. We explore such a mechanism in the bacterium Thermus thermophilus Ago (TtAgo), via a computational approach combining molecular dynamics, bias-exchange metadynamics, and protein-DNA docking. We show that apo TtAgo adopts multiple closed states that are unable to accommodate guide-DNA. Conformations able to accommodate the guide are beyond the reach of thermal fluctuations from the closed states. These results suggest an induced-fit dominant mechanism for guide-strand loading in TtAgo, drastically different from the two-step mechanism for human Ago 2 (hAgo2) identified in our previous study. Such a difference between TtAgo and hAgo2 is found to mainly originate from the distinct rigidity of their L1-PAZ hinge. Further comparison among known Ago structures from various species indicates that the L1-PAZ hinge may be flexible in general for prokaryotic Agos but rigid for eukaryotic Agos. © 2016 American Chemical Society.

  9. A Flexible Domain-Domain Hinge Promotes an Induced-fit Dominant Mechanism for the Loading of Guide-DNA into Argonaute Protein in Thermus thermophilus.

    Science.gov (United States)

    Zhu, Lizhe; Jiang, Hanlun; Sheong, Fu Kit; Cui, Xuefeng; Gao, Xin; Wang, Yanli; Huang, Xuhui

    2016-03-17

    Argonaute proteins (Ago) are core components of the RNA Induced Silencing Complex (RISC) that load and utilize small guide nucleic acids to silence mRNAs or cleave foreign DNAs. Despite the essential role of Ago in gene regulation and defense against virus, the molecular mechanism of guide-strand loading into Ago remains unclear. We explore such a mechanism in the bacterium Thermus thermophilus Ago (TtAgo), via a computational approach combining molecular dynamics, bias-exchange metadynamics, and protein-DNA docking. We show that apo TtAgo adopts multiple closed states that are unable to accommodate guide-DNA. Conformations able to accommodate the guide are beyond the reach of thermal fluctuations from the closed states. These results suggest an induced-fit dominant mechanism for guide-strand loading in TtAgo, drastically different from the two-step mechanism for human Ago 2 (hAgo2) identified in our previous study. Such a difference between TtAgo and hAgo2 is found to mainly originate from the distinct rigidity of their L1-PAZ hinge. Further comparison among known Ago structures from various species indicates that the L1-PAZ hinge may be flexible in general for prokaryotic Ago's but rigid for eukaryotic Ago's.

  10. Exercise-Induced Fitness Changes Correlate with Changes in Neural Specificity in Older Adults

    Science.gov (United States)

    Kleemeyer, Maike M.; Polk, Thad A.; Schaefer, Sabine; Bodammer, Nils C.; Brechtel, Lars; Lindenberger, Ulman

    2017-01-01

    Neural specificity refers to the degree to which neural representations of different stimuli can be distinguished. Evidence suggests that neural specificity, operationally defined as stimulus-related differences in functional magnetic resonance imaging (fMRI) activation patterns, declines with advancing adult age, and that individual differences in neural specificity are associated with individual differences in fluid intelligence. A growing body of literature also suggests that regular physical activity may help preserve cognitive abilities in old age. Based on this literature, we hypothesized that exercise-induced improvements in fitness would be associated with greater neural specificity among older adults. A total of 52 adults aged 59–74 years were randomly assigned to one of two aerobic-fitness training regimens, which differed in intensity. Participants in both groups trained three times a week on stationary bicycles. In the low-intensity (LI) group, the resistance was kept constant at a low level (10 Watts). In the high-intensity (HI) group, the resistance depended on participants’ heart rate and therefore typically increased with increasing fitness. Before and after the 6-month training phase, participants took part in a functional MRI experiment in which they viewed pictures of faces and buildings. We used multivariate pattern analysis (MVPA) to estimate the distinctiveness of neural activation patterns in ventral visual cortex (VVC) evoked by face or building stimuli. Fitness was also assessed before and after training. In line with our hypothesis, training-induced changes in fitness were positively associated with changes in neural specificity. We conclude that physical activity may protect against age-related declines in neural specificity. PMID:28360850

  11. Brain-derived neurotrophic factor (BDNF)-induced mitochondrial motility arrest and presynaptic docking contribute to BDNF-enhanced synaptic transmission.

    Science.gov (United States)

    Su, Bo; Ji, Yun-Song; Sun, Xu-lu; Liu, Xiang-Hua; Chen, Zhe-Yu

    2014-01-17

    Appropriate mitochondrial transport and distribution are essential for neurons because of the high energy and Ca(2+) buffering requirements at synapses. Brain-derived neurotrophic factor (BDNF) plays an essential role in regulating synaptic transmission and plasticity. However, whether and how BDNF can regulate mitochondrial transport and distribution are still unclear. Here, we find that in cultured hippocampal neurons, application of BDNF for 15 min decreased the percentage of moving mitochondria in axons, a process dependent on the activation of the TrkB receptor and its downstream PI3K and phospholipase-Cγ signaling pathways. Moreover, the BDNF-induced mitochondrial stopping requires the activation of transient receptor potential canonical 3 and 6 (TRPC3 and TRPC6) channels and elevated intracellular Ca(2+) levels. The Ca(2+) sensor Miro1 plays an important role in this process. Finally, the BDNF-induced mitochondrial stopping leads to the accumulation of more mitochondria at presynaptic sites. Mutant Miro1 lacking the ability to bind Ca(2+) prevents BDNF-induced mitochondrial presynaptic accumulation and synaptic transmission, suggesting that Miro1-mediated mitochondrial motility is involved in BDNF-induced mitochondrial presynaptic docking and neurotransmission. Together, these data suggest that mitochondrial transport and distribution play essential roles in BDNF-mediated synaptic transmission.

  12. International Docking Standardization NASA

    Science.gov (United States)

    Donahoe, Stanley; Lewis, J.; Carroll, M.; Le, T.

    2009-01-01

    This slide presentation reviews the different types of docking types. The objective is the pressurized vehicle connection and crew transfer. Androgynous Docking is defined as the joining or coming together of two free flying space vehicles with alike interfaces. Androgynous mating allows for collaboration between any two vehicles. The subsytems of an androgynous mating system are reviewed, including: Hard docking subsystems: latch system, tunnel housing, alignment system and seal.

  13. BP-Dock: a flexible docking scheme for exploring protein-ligand interactions based on unbound structures.

    Science.gov (United States)

    Bolia, Ashini; Gerek, Z Nevin; Ozkan, S Banu

    2014-03-24

    Molecular docking serves as an important tool in modeling protein-ligand interactions. However, it is still challenging to incorporate overall receptor flexibility, especially backbone flexibility, in docking due to the large conformational space that needs to be sampled. To overcome this problem, we developed a novel flexible docking approach, BP-Dock (Backbone Perturbation-Dock) that can integrate both backbone and side chain conformational changes induced by ligand binding through a multi-scale approach. In the BP-Dock method, we mimic the nature of binding-induced events as a first-order approximation by perturbing the residues along the protein chain with a small Brownian kick one at a time. The response fluctuation profile of the chain upon these perturbations is computed using the perturbation response scanning method. These response fluctuation profiles are then used to generate binding-induced multiple receptor conformations for ensemble docking. To evaluate the performance of BP-Dock, we applied our approach on a large and diverse data set using unbound structures as receptors. We also compared the BP-Dock results with bound and unbound docking, where overall receptor flexibility was not taken into account. Our results highlight the importance of modeling backbone flexibility in docking for recapitulating the experimental binding affinities, especially when an unbound structure is used. With BP-Dock, we can generate a wide range of binding site conformations realized in nature even in the absence of a ligand that can help us to improve the accuracy of unbound docking. We expect that our fast and efficient flexible docking approach may further aid in our understanding of protein-ligand interactions as well as virtual screening of novel targets for rational drug design.

  14. Exploring the selectivity of auto-inducer complex with LuxR using molecular docking, mutational studies and molecular dynamics simulations

    Science.gov (United States)

    Rajamanikandan, Sundaraj; Srinivasan, Pappu

    2017-03-01

    Bacteria communicate with one another using extracellular signaling molecules called auto-inducers (AHLs), a process termed as quorum sensing. The quorum sensing process allows bacteria to regulate various physiological activities. In this regard, quorum sensing master regulator LuxR from Vibrio harveyi represents an attractive therapeutic target for the development of novel anti-quorum sensing agents. Eventhough the binding of AHL complex with LuxR is evidenced in earlier reports, but their mode of binding is not clearly determined. Therefore, in the present work, molecular docking, in silico mutational studies, molecular dynamics simulations and free energy calculations were performed to understand the selectivity of AHL into the binding site of LuxR. The results revealed that Asn133 and Gln137 residues play a crucial role in recognizing AHL more effectively into the binding site of LuxR with good binding free energy. In addition to that, the carbonyl group presents in the lactone ring and amide group of AHL plays a vital role in the formation of hydrogen bond interactions with the protein. Further, structure based virtual screening was performed using ChemBridge database to screen potent lead molecules against LuxR. 4-benzyl-2-pyrrolidinone and N-[2(1-cyclohexen-1-yl) enthyl]-N'(2-ethoxyphenyl) were selected based on dock score, binding affinity and mode of interactions with the receptor. Furthermore, binding free energy, density functional theory and ADME prediction were performed to rank the lead molecules. Thus, the identified lead molecules can be used for the development of anti-quorum sensing drugs.

  15. Inducible expression eliminates the fitness cost of vancomycin resistance in enterococci.

    Science.gov (United States)

    Foucault, Marie-Laure; Depardieu, Florence; Courvalin, Patrice; Grillot-Courvalin, Catherine

    2010-09-28

    Inducible vancomycin resistance in enterococci is due to a sophisticated mechanism that combines synthesis of cell wall peptidoglycan precursors with low affinity for glycopeptides and elimination of the normal target precursors. Although this dual mechanism, which involves seven genes organized in two operons, is predicted to have a high fitness cost, resistant enterococci have disseminated worldwide. We have evaluated the biological cost of VanB-type resistance due to acquisition of conjugative transposon Tn1549 in Enterococcus faecium and Enterococcus faecalis. Because fitness was dependent on the integration site of Tn1549, an isogenic set of E. faecalis was constructed to determine the cost of inducible or constitutive expression of resistance or of carriage of Tn1549. A luciferase gene was inserted in the integrase gene of the transposon to allow differential quantification of the strains in cocultures and in the digestive tract of gnotobiotic mice. Both in vitro and in vivo, carriage of inactivated or inducible Tn1549 had no cost for the host in the absence of induction by vancomycin. In contrast, induced or constitutively resistant strains not only had reduced fitness but were severely impaired in colonization ability and dissemination among mice. These data indicate that tight regulation of resistance expression drastically reduces the biological cost associated with vancomycin resistance in Enterococcus spp. and accounts for the widespread dissemination of these strains. Our findings are in agreement with the observation that regulation of expression is common in horizontally acquired resistance and represents an efficient evolutionary pathway for resistance determinants to become selectively neutral.

  16. Two Cases of CrossFit®-Induced Rhabdomyolysis: A Rising Concern

    Directory of Open Access Journals (Sweden)

    Madhur Rathi

    2015-10-01

    Full Text Available ackground: The author reports the cases of two adult males who presented with severe rhabdomyolysis following identical CrossFit® workouts performed on the same day, at the same time and at the same location. Results: For both cases, symptoms of rhabdomyolysis disappeared upon discontinuation of the regime and within three days of aggressive hydration and rest. Patients made a complete recovery upon discharge. Conclusion: The rhabdomyolysis was attributed to the same excruciating workout both men underwent. Exertional rhabdomyolysis exemplified by the cases presented highlights a rising concern over the health consequences of the popular training program. CrossFit®-induced rhabdomyolysis is underrecognized and should be considered in patients presenting with signs and symptoms of rhabdomyolysis.

  17. Single-molecule FRET unveils induced-fit mechanism for substrate selectivity in flap endonuclease 1

    Science.gov (United States)

    Rashid, Fahad; Harris, Paul D; Zaher, Manal S; Sobhy, Mohamed A; Joudeh, Luay I; Yan, Chunli; Piwonski, Hubert; Tsutakawa, Susan E; Ivanov, Ivaylo; Tainer, John A; Habuchi, Satoshi; Hamdan, Samir M

    2017-01-01

    Human flap endonuclease 1 (FEN1) and related structure-specific 5’nucleases precisely identify and incise aberrant DNA structures during replication, repair and recombination to avoid genomic instability. Yet, it is unclear how the 5’nuclease mechanisms of DNA distortion and protein ordering robustly mediate efficient and accurate substrate recognition and catalytic selectivity. Here, single-molecule sub-millisecond and millisecond analyses of FEN1 reveal a protein-DNA induced-fit mechanism that efficiently verifies substrate and suppresses off-target cleavage. FEN1 sculpts DNA with diffusion-limited kinetics to test DNA substrate. This DNA distortion mutually ‘locks’ protein and DNA conformation and enables substrate verification with extreme precision. Strikingly, FEN1 never misses cleavage of its cognate substrate while blocking probable formation of catalytically competent interactions with noncognate substrates and fostering their pre-incision dissociation. These findings establish FEN1 has practically perfect precision and that separate control of induced-fit substrate recognition sets up the catalytic selectivity of the nuclease active site for genome stability. DOI: http://dx.doi.org/10.7554/eLife.21884.001 PMID:28230529

  18. Single-molecule FRET unveils induced-fit mechanism for substrate selectivity in flap endonuclease 1

    KAUST Repository

    Rashid, Fahad

    2017-02-23

    Human flap endonuclease 1 (FEN1) and related structure-specific 5\\'nucleases precisely identify and incise aberrant DNA structures during replication, repair and recombination to avoid genomic instability. Yet, it is unclear how the 5\\'nuclease mechanisms of DNA distortion and protein ordering robustly mediate efficient and accurate substrate recognition and catalytic selectivity. Here, single-molecule sub-millisecond and millisecond analyses of FEN1 reveal a protein-DNA induced-fit mechanism that efficiently verifies substrate and suppresses off-target cleavage. FEN1 sculpts DNA with diffusion-limited kinetics to test DNA substrate. This DNA distortion mutually \\'locks\\' protein and DNA conformation and enables substrate verification with extreme precision. Strikingly, FEN1 never misses cleavage of its cognate substrate while blocking probable formation of catalytically competent interactions with noncognate substrates and fostering their pre-incision dissociation. These findings establish FEN1 has practically perfect precision and that separate control of induced-fit substrate recognition sets up the catalytic selectivity of the nuclease active site for genome stability.

  19. Sexual harassment induces a temporary fitness cost but does not constrain the acquisition of environmental information in fruit flies.

    Science.gov (United States)

    Teseo, Serafino; Veerus, Liisa; Moreno, Céline; Mery, Frédéric

    2016-01-01

    Across animals, sexual harassment induces fitness costs for females and males. However, little is known about the cognitive costs involved, i.e. whether it constrains learning processes, which could ultimately affect an individual's fitness. Here we evaluate the acquisition of environmental information in groups of fruit flies challenged with various levels of male sexual harassment. We show that, although high sexual harassment induces a temporary fitness cost for females, all fly groups of both sexes exhibit similar levels of learning. This suggests that, in fruit flies, the fitness benefits of acquiring environmental information are not affected by the fitness costs of sexual harassment, and that selection may favour cognition even in unfavourable social contexts. Our study provides novel insights into the relationship between sexual conflicts and cognition and the evolution of female counterstrategies against male sexual harassment.

  20. Smart macrocyclic molecules: induced fit and ultrafast self-sorting inclusion behavior through dynamic covalent chemistry.

    Science.gov (United States)

    Han, Ji-Min; Pan, Jin-Long; Lei, Ting; Liu, Chenjiang; Pei, Jian

    2010-12-10

    A family of macrocycles with oligo(ethylene glycol) chains, 4O, 5O, and 6O, was developed to construct a series of new incorporated macrocycles through dynamic covalent chemistry. These flexible macrocycles exhibited excellent "self-sorting" abilities with diamine compounds, which depended on the "induced-fit" rule. For instance, the host macrocycles underwent conformational modulation to accommodate the diamine guests, affording [1+1] intramolecular addition compounds regardless of the flexibility of the diamine. These macrocycles folded themselves to fit various diamines with different chain length through modulation of the flexible polyether chain, and afforded intramolecular condensation products. However, if the chain of the diamine was too long and rigid, oligomers or polymers were obtained from the mixture of the macromolecule and the diamine. All results demonstrated that inclusion compounds involving conformationally suitable aromatic diamines were thermodynamically favorable candidates in the mixture due to the restriction of the macrocycle size. Furthermore, kinetic and thermodynamic studies of self-sorting behaviors of both mixed 4O-5O and 4O-6O systems were investigated in detail. Finally, theoretical calculations were also employed to further understand such self-sorting behavior, and indicated that the large enthalpy change of H(2)NArArNH(2)@4O is the driving force for the sorting behavior. Our system may provide a model to further understand the principle of biomolecules with high specificity due only to their conformational self-adjusting ability.

  1. Molecular docking using the molecular lipophilicity potential as hydrophobic descriptor: impact on GOLD docking performance.

    Science.gov (United States)

    Nurisso, Alessandra; Bravo, Juan; Carrupt, Pierre-Alain; Daina, Antoine

    2012-05-25

    GOLD is a molecular docking software widely used in drug design. In the initial steps of docking, it creates a list of hydrophobic fitting points inside protein cavities that steer the positioning of ligand hydrophobic moieties. These points are generated based on the Lennard-Jones potential between a carbon probe and each atom of the residues delimitating the binding site. To thoroughly describe hydrophobic regions in protein pockets and properly guide ligand hydrophobic moieties toward favorable areas, an in-house tool, the MLP filter, was developed and herein applied. This strategy only retains GOLD hydrophobic fitting points that match the rigorous definition of hydrophobicity given by the molecular lipophilicity potential (MLP), a molecular interaction field that relies on an atomic fragmental system based on 1-octanol/water experimental partition coefficients (log P(oct)). MLP computations in the binding sites of crystallographic protein structures revealed that a significant number of points considered hydrophobic by GOLD were actually polar according to the MLP definition of hydrophobicity. To examine the impact of this new tool, ligand-protein complexes from the Astex Diverse Set and the PDB bind core database were redocked with and without the use of the MLP filter. Reliable docking results were obtained by using the MLP filter that increased the quality of docking in nonpolar cavities and outperformed the standard GOLD docking approach.

  2. 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.

  3. 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.

  4. Effect of simulated microgravity on endocrine response to insulin-induced hypoglycemia in physically fit men.

    Science.gov (United States)

    Ksinantova, L; Koska, J; Kvetnansky, R; Marko, M; Hamar, D; Vigas, M

    2002-03-01

    Adaptation to microgravity is associated with alteration in some endocrine functions. In the present longitudinal study, the counterregulatory hormonal response to insulin-induced hypoglycemia (ITT, 0.1 IU/kg short acting insulin i. v.) was evaluated under simulated microgravity conditions in 15 physically fit subjects. ITT was performed at the beginning of the investigation, and again after completion of 6 weeks of endurance training and after a subsequent period of 4 days of head-down bed rest at a backward tilt of 6 degrees from the horizontal. Endurance training showed a significant increase in maximal aerobic capacity in previously well-trained subjects (increase by 12 %), as well as on attenuation of counterregulatory response of epinephrine to hypoglycemia. After 4 days of bed rest, basal concentrations of plasma norepinephrine was diminished (p < 0.002) and plasma renin activity was enhanced (p < 0.02). After bed rest, decreased responses of the two catecholamines (norepinephrine, p < 0.001; epinephrine, p < 0.001), growth hormone (p < 0.001), and cortisol (p < 0.05) were observed. Response of plasma renin activity after bed rest was increased (p < 0.01). This longitudinal study indicated that 4 days of bed rest in endurance-trained subjects induced increased response of PRA to hypoglycemia and attenuation of other counterregulatory neuroendocrine responses.

  5. High physical fitness is associated with reduction in basal- and exercise-induced inflammation.

    Science.gov (United States)

    Kleiven, Ø; Bjørkavoll-Bergseth, M; Melberg, T; Skadberg, Ø; Bergseth, R; Selvåg, J; Auestad, B; Aukrust, P; Aarsland, T; Ørn, S

    2017-03-17

    C-reactive protein (CRP) increases after strenuous exercise. It has been a concern that prolonged strenuous exercise may be harmful and induce a deleterious inflammatory response. The purpose of this study was to (a) assess and quantify the magnitude of CRP response following an endurance cycling competition in healthy middle-aged recreational cyclists. (b) Identify important determinants of this response. (c) Identify the relationship between CRP, myocardial damage (cardiac Troponin I (cTnI)), and myocardial strain (B-type natriuretic peptide [BNP]). (d) Identify the relationship between CRP and clinical events, defined as utilization of healthcare services or self-reported unusual discomfort. Race time was used as a measure of physical fitness. A total of 97 individuals (43±10 years of age, 74 [76%] males) were assessed prior to and 0, 3, and 24 hours following the 91-km mountain bike race "Nordsjørittet" (Sandnes, Norway, June 2013). There was a highly significant increase in CRP from baseline to 24 hours (0.9 (0.5-1.8) mg/L vs. 11.6 (6.0-17.5) mg/L (median[IQR]), Pfitness was associated with reduction in both basal- and exercise-induced CRP. No adverse relationship was found between high intensity physical exercise, CRP levels, and outcomes.

  6. 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...... relative pose information to assist the human operator during the docking phase. The closed loop and operator assistance performance of the system have been assessed using a test bench including human operator, navigation module and high fidelity visualization module. The tests performed verified...

  7. A New, Improved Hybrid Scoring Function for Molecular Docking and Scoring Based on AutoDock and AutoDock Vina.

    Science.gov (United States)

    Tanchuk, Vsevolod Yu; Tanin, Volodymyr O; Vovk, Andriy I; Poda, Gennady

    2016-04-01

    Automated docking is one of the most important tools for structure-based drug design that allows prediction of ligand binding poses and also provides an estimate of how well small molecules fit in the binding site of a protein. A new scoring function based on AutoDock and AutoDock Vina has been introduced. The new hybrid scoring function is a linear combination of the two scoring function components derived from a multiple linear regression fitting procedure. The scoring function was built on a training set of 2412 protein-ligand complexes from pdbbind database (www.pdbbind.org.cn, version 2012). A test set of 313 complexes that appeared in the 2013 version was used for validation purposes. The new hybrid scoring function performed better than the original functions, both on training and test sets of protein-ligand complexes, as measured by the non-parametric Pearson correlation coefficient, R, mean absolute error (MAE), and root-mean-square error (RMSE) between the experimental binding affinities and the docking scores. The function also gave one of the best results among more than 20 scoring functions tested on the core set of the pdbbind database. The new AutoDock hybrid scoring function will be implemented in modified version of AutoDock. © 2015 John Wiley & Sons A/S.

  8. Highly Flexible Protein-Peptide Docking Using CABS-Dock.

    Science.gov (United States)

    Ciemny, Maciej Paweł; Kurcinski, Mateusz; Kozak, Konrad Jakub; Kolinski, Andrzej; Kmiecik, Sebastian

    2017-01-01

    Protein-peptide molecular docking is a difficult modeling problem. It is even more challenging when significant conformational changes that may occur during the binding process need to be predicted. In this chapter, we demonstrate the capabilities and features of the CABS-dock server for flexible protein-peptide docking. CABS-dock allows highly efficient modeling of full peptide flexibility and significant flexibility of a protein receptor. During CABS-dock docking, the peptide folding and binding process is explicitly simulated and no information about the peptide binding site or its structure is used. This chapter presents a successful CABS-dock use for docking a potentially therapeutic peptide to a protein target. Moreover, simulation contact maps, a new CABS-dock feature, are described and applied to the docking test case. Finally, a tutorial for running CABS-dock from the command line or command line scripts is provided. The CABS-dock web server is available from http://biocomp.chem.uw.edu.pl/CABSdock/ .

  9. Reverse Induced Fit-Driven MAS-Downstream Transduction: Looking for Metabotropic Agonists.

    Science.gov (United States)

    Pernomian, Larissa; Gomes, Mayara Santos; de Paula da Silva, Carlos Henrique Tomich; Campos, Joaquin

    2017-09-11

    The protective effects assigned to MAS receptors activation have spurred a great interest in the development of MAS agonists for clinical purposes. However, the current bases that drive the design of these ligands preclude important concepts recently addressed for MAS activation. Emerging data confirmed that physiological concentrations of peptide MAS agonists induce an atypical signaling that does not reach the metabotropic efficacy of constitutive MAS activation. The canonical activation of MAS-coupled G proteins is only achieved by supraphysiological concentrations of peptide MAS agonists or physiological concentrations of chemically modified analogues. These pleiotropic differences are because of two overlapped but non-identical ligand binding domains (LBD): one non-metabotropic site that recognizes peptide agonists and one metabotropic domain that recognizes modified analogues. Accordingly, it is feasible that supraphysiological concentrations of peptide MAS agonists undergo to chemical modifications that make them suitable for binding to the metabotropic LBD. Recent advances on Receptor Theory confirmed that G protein-coupled receptor (GPCR) oligomerization enhances pharmacological parameters coupled to metabotropic signaling from GPCR ligands, including MAS agonists. For instance, the formation of GPCR-signalosome complex (higher order heteroligomers of GPCR involved in signaling crosstalk) makes the transduction of agonists a more adaptive signal. Considering the recent identification of MAS-signalosome, we postulate the reverse induced fit hypothesis in which MAS-signalosome would trigger chemical modifications required for agonists bind to the metabotropic MAS/LBD. In view of this hypothesis, we cover rational perspectives that consider this information for the development of novel metabotropic MAS agonists provided with constitutive efficacy at physiological concentrations. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  10. Molecular characterization of a family 5 glycoside hydrolase suggests an induced-fit enzymatic mechanism.

    Science.gov (United States)

    Liberato, Marcelo V; Silveira, Rodrigo L; Prates, Érica T; de Araujo, Evandro A; Pellegrini, Vanessa O A; Camilo, Cesar M; Kadowaki, Marco A; Neto, Mario de O; Popov, Alexander; Skaf, Munir S; Polikarpov, Igor

    2016-04-01

    Glycoside hydrolases (GHs) play fundamental roles in the decomposition of lignocellulosic biomaterials. Here, we report the full-length structure of a cellulase from Bacillus licheniformis (BlCel5B), a member of the GH5 subfamily 4 that is entirely dependent on its two ancillary modules (Ig-like module and CBM46) for catalytic activity. Using X-ray crystallography, small-angle X-ray scattering and molecular dynamics simulations, we propose that the C-terminal CBM46 caps the distal N-terminal catalytic domain (CD) to establish a fully functional active site via a combination of large-scale multidomain conformational selection and induced-fit mechanisms. The Ig-like module is pivoting the packing and unpacking motions of CBM46 relative to CD in the assembly of the binding subsite. This is the first example of a multidomain GH relying on large amplitude motions of the CBM46 for assembly of the catalytically competent form of the enzyme.

  11. Conformational Selection and Induced Fit for RNA Polymerase and RNA/DNA Hybrid Backtracked Recognition

    Directory of Open Access Journals (Sweden)

    Haifeng eChen

    2015-11-01

    Full Text Available RNA polymerase catalyzes transcription with a high fidelity. If DNA/RNA mismatch or DNA damage occurs downstream, a backtracked RNA polymerase can proofread this situation. However, the backtracked mechanism is still poorly understood. Here we have performed multiple explicit-solvent molecular dynamics (MD simulations on bound and apo DNA/RNA hybrid to study backtracked recognition. MD simulations at room temperature suggest that specific electrostatic interactions play key roles in the backtracked recognition between the polymerase and DNA/RNA hybrid. Kinetics analysis at high temperature shows that bound and apo DNA/RNA hybrid unfold via a two-state process. Both kinetics and free energy landscape analyses indicate that bound DNA/RNA hybrid folds in the order of DNA/RNA contracting, the tertiary folding and polymerase binding. The predicted Φ-values suggest that C7, G9, dC12, dC15 and dT16 are key bases for the backtracked recognition of DNA/RNA hybrid. The average RMSD values between the bound structures and the corresponding apo ones and Kolmogorov-Smirnov (KS P test analyses indicate that the recognition between DNA/RNA hybrid and polymerase might follow an induced fit mechanism for DNA/RNA hybrid and conformation selection for polymerase. Furthermore, this method could be used to relative studies of specific recognition between nucleic acid and protein.

  12. Kinetic studies of yeast polyA polymerase indicate an induced fit mechanism for nucleotide specificity.

    Science.gov (United States)

    Balbo, Paul B; Meinke, Gretchen; Bohm, Andrew

    2005-05-31

    Polyadenylate polymerase (PAP) catalyzes the synthesis of 3'-polyadenylate tails onto mRNA. A comprehensive steady-state kinetic analysis of PAP was conducted which included initial velocity studies of the forward and reverse reactions, inhibition studies, and the use of alternative substrates. The reaction (A(n) + ATP A(n+1) + PP(i)) is adequately described by a rapid equilibrium random mechanism. Several thermodynamic parameters for the reaction were determined or calculated, including the overall equilibrium constant (K(eq) = 84) and the apparent equilibrium constant of the internal step (K(int) = 4) which involves the rate-determining interconversion of central complexes. A large (100-fold) difference in Vmax accounts for nucleotide specificity (ATP vs CTP), despite an only 3-fold difference in Km. Comparison of the sulfur elemental effect on Vmax for ATP and CTP suggests that the chemical step is rate-determining for both reactions. Comparison of the sulfur elemental effect on Vmax/Km revealed differences in the mechanism by which either nucleotide is incorporated. Consistent with these data, an induced fit mechanism for nucleotide specificity is proposed whereby PAP couples a uniform binding mechanism, which selects for ATP, with a ground-state destabilization mechanism, which serves to accelerate the velocity for the correct substrate.

  13. Ubiquitin dynamics in complexes reveal molecular recognition mechanisms beyond induced fit and conformational selection.

    Directory of Open Access Journals (Sweden)

    Jan H Peters

    Full Text Available Protein-protein interactions play an important role in all biological processes. However, the principles underlying these interactions are only beginning to be understood. Ubiquitin is a small signalling protein that is covalently attached to different proteins to mark them for degradation, regulate transport and other functions. As such, it interacts with and is recognised by a multitude of other proteins. We have conducted molecular dynamics simulations of ubiquitin in complex with 11 different binding partners on a microsecond timescale and compared them with ensembles of unbound ubiquitin to investigate the principles of their interaction and determine the influence of complex formation on the dynamic properties of this protein. Along the main mode of fluctuation of ubiquitin, binding in most cases reduces the conformational space available to ubiquitin to a subspace of that covered by unbound ubiquitin. This behaviour can be well explained using the model of conformational selection. For lower amplitude collective modes, a spectrum of zero to almost complete coverage of bound by unbound ensembles was observed. The significant differences between bound and unbound structures are exclusively situated at the binding interface. Overall, the findings correspond neither to a complete conformational selection nor induced fit scenario. Instead, we introduce a model of conformational restriction, extension and shift, which describes the full range of observed effects.

  14. Implicit ligand theory: rigorous binding free energies and thermodynamic expectations from molecular docking.

    Science.gov (United States)

    Minh, David D L

    2012-09-14

    A rigorous formalism for estimating noncovalent binding free energies and thermodynamic expectations from calculations in which receptor configurations are sampled independently from the ligand is derived. Due to this separation, receptor configurations only need to be sampled once, facilitating the use of binding free energy calculations in virtual screening. Demonstrative calculations on a host-guest system yield good agreement with previous free energy calculations and isothermal titration calorimetry measurements. Implicit ligand theory provides guidance on how to improve existing molecular docking algorithms and insight into the concepts of induced fit and conformational selection in noncovalent macromolecular recognition.

  15. Using AutoDock for ligand-receptor docking.

    Science.gov (United States)

    Morris, Garrett M; Huey, Ruth; Olson, Arthur J

    2008-12-01

    This unit describes how to set up and analyze ligand-protein docking calculations using AutoDock and the graphical user interface, AutoDockTools (ADT). The AutoDock scoring function is a subset of the AMBER force field that treats molecules using the United Atom model. The unit uses an X-ray crystal structure of Indinavir bound to HIV-1 protease taken from the Protein Data Bank (UNIT 1.9) and shows how to prepare the ligand and receptor for AutoGrid, which computes grid maps needed by AutoDock. Indinavir is prepared for AutoDock, adding the polar hydrogens, and partial charges, and defining the rotatable bonds that will be explored during the docking. The input files for AutoGrid and AutoDock are created, and then the grid map calculation run, followed by the docking calculation in AutoDock. Finally, this unit describes some of the ways the results can be analyzed using AutoDockTools. Copyright 2008 by John Wiley & Sons, Inc.

  16. Multiple factors confer specific Cdc42 and Rac protein activation by dedicator of cytokinesis (DOCK) nucleotide exchange factors.

    Science.gov (United States)

    Kulkarni, Kiran; Yang, Jing; Zhang, Ziguo; Barford, David

    2011-07-15

    DOCK (dedicator of cytokinesis) guanine nucleotide exchange factors (GEFs) activate the Rho-family GTPases Rac and Cdc42 to control cell migration, morphogenesis, and phagocytosis. The DOCK A and B subfamilies activate Rac, whereas the DOCK D subfamily activates Cdc42. Nucleotide exchange is catalyzed by a conserved DHR2 domain (DOCK(DHR2)). Although the molecular basis for DOCK(DHR2)-mediated GTPase activation has been elucidated through structures of a DOCK9(DHR2)-Cdc42 complex, the factors determining recognition of specific GTPases are unknown. To understand the molecular basis for DOCK-GTPase specificity, we have determined the crystal structure of DOCK2(DHR2) in complex with Rac1. DOCK2(DHR2) and DOCK9(DHR2) exhibit similar tertiary structures and homodimer interfaces and share a conserved GTPase-activating mechanism. Multiple structural differences between DOCK2(DHR2) and DOCK9(DHR2) account for their selectivity toward Rac1 and Cdc42. Key determinants of selectivity of Cdc42 and Rac for their cognate DOCK(DHR2) are a Phe or Trp residue within β3 (residue 56) and the ability of DOCK proteins to exploit differences in the GEF-induced conformational changes of switch 1 dependent on a divergent residue at position 27. DOCK proteins, therefore, differ from DH-PH GEFs that select their cognate GTPases through recognition of structural differences within the β2/β3 strands.

  17. Cell-Dock: high-performance protein-protein docking.

    Science.gov (United States)

    Pons, Carles; Jiménez-González, Daniel; González-Álvarez, Cecilia; Servat, Harald; Cabrera-Benítez, Daniel; Aguilar, Xavier; Fernández-Recio, Juan

    2012-09-15

    The application of docking to large-scale experiments or the explicit treatment of protein flexibility are part of the new challenges in structural bioinformatics that will require large computer resources and more efficient algorithms. Highly optimized fast Fourier transform (FFT) approaches are broadly used in docking programs but their optimal code implementation leaves hardware acceleration as the only option to significantly reduce the computational cost of these tools. In this work we present Cell-Dock, an FFT-based docking algorithm adapted to the Cell BE processor. We show that Cell-Dock runs faster than FTDock with maximum speedups of above 200×, while achieving results of similar quality. The source code is released under GNU General Public License version 2 and can be downloaded from http://mmb.pcb.ub.es/~cpons/Cell-Dock. djimenez@ac.upc.edu or juanf@bsc.es Supplementary data are available at Bioinformatics online.

  18. Characterization of MxFIT, an iron deficiency induced transcriptional factor in Malus xiaojinensis.

    Science.gov (United States)

    Yin, Lili; Wang, Yi; Yuan, Mudan; Zhang, Xinzhong; Xu, Xuefeng; Han, Zhenhai

    2014-02-01

    Iron deficiency often results in nutritional disorder in fruit trees. Transcription factors play an important role in the regulation of iron uptake. In this study, we isolated an iron deficiency response transcription factor gene, MxFIT, from an iron-efficient apple genotype of Malus xiaojinensis. MxFIT encoded a basic helix-loop-helix protein and contained a 966 bp open reading frame. MxFIT protein was targeted to the nucleus in onion epidermal cells and showed strong transcriptional activation in yeast cells. Spatiotemporal expression analysis revealed that MxFIT was up-regulated in roots under iron deficiency at both mRNA and protein levels, while almost no expression was detected in leaves irrespective of iron supply. Ectopic expression of MxFIT resulted in enhanced iron deficiency responses in Arabidopsis under iron deficiency and stronger resistance to iron deficiency. Thus, MxFIT might be involved in iron uptake and plays an important role in iron deficiency response.

  19. Quantum Chemical Calculations and Molecular Docking Studies of Some NSAID Drugs (Aceclofenac, Salicylic Acid, and Piroxicam as 1PGE Inhibitors

    Directory of Open Access Journals (Sweden)

    S. Suresh

    2016-01-01

    Full Text Available The molecular structure of the three compounds Aceclofenac (I, Salicylic Acid (II, and Piroxicam (III has been determined using Gaussian 03W program with B3LYP method using 6-311++G (d,p basis set calculations. The molecular structures were fully optimized with atomic numbering scheme adopted in the study. To understand the mode of binding and molecular interaction, the docking studies of compounds Aceclofenac (I, Salicylic Acid (II, and Piroxicam (III have been carried out with prostaglandin H2 synthase-1 (1PGE as target using induced fit docking. The molecular docking results show that the interactions and energy for Aceclofenac, Salicylic Acid, and Piroxicam show the best results when docked with prostaglandin H2 synthase-1 (1PGE. The hydrogen bonding interactions of compound I (Aceclofenac are prominent with Arginine moiety, those of compound II (Salicylic Acid are prominent with Tyrosine and Serine moieties, and compound III (Piroxicam shows such interaction with Tyrosine and Arginine moieties. These interactions of prostaglandin H2 synthase-1 (1PGE with substrates are responsible for governing COX-1 inhibitor potency which in turn is a direct measure of the potency of the drug.

  20. 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.

  1. An Automated Strategy for Binding-Pose Selection and Docking Assessment in Structure-Based Drug Design.

    Science.gov (United States)

    Ballante, Flavio; Marshall, Garland R

    2016-01-25

    Molecular docking is a widely used technique in drug design to predict the binding pose of a candidate compound in a defined therapeutic target. Numerous docking protocols are available, each characterized by different search methods and scoring functions, thus providing variable predictive capability on a same ligand-protein system. To validate a docking protocol, it is necessary to determine a priori the ability to reproduce the experimental binding pose (i.e., by determining the docking accuracy (DA)) in order to select the most appropriate docking procedure and thus estimate the rate of success in docking novel compounds. As common docking programs use generally different root-mean-square deviation (RMSD) formulas, scoring functions, and format results, it is both difficult and time-consuming to consistently determine and compare their predictive capabilities in order to identify the best protocol to use for the target of interest and to extrapolate the binding poses (i.e., best-docked (BD), best-cluster (BC), and best-fit (BF) poses) when applying a given docking program over thousands/millions of molecules during virtual screening. To reduce this difficulty, two new procedures called Clusterizer and DockAccessor have been developed and implemented for use with some common and "free-for-academics" programs such as AutoDock4, AutoDock4(Zn), AutoDock Vina, DOCK, MpSDockZn, PLANTS, and Surflex-Dock to automatically extrapolate BD, BC, and BF poses as well as to perform consistent cluster and DA analyses. Clusterizer and DockAccessor (code available over the Internet) represent two novel tools to collect computationally determined poses and detect the most predictive docking approach. Herein an application to human lysine deacetylase (hKDAC) inhibitors is illustrated.

  2. Spacecraft rendezvous and docking

    DEFF Research Database (Denmark)

    Jørgensen, John Leif

    1999-01-01

    procedures. The method described generates, based on a single camera and a priory information about the target vehicle and orbit data, all necessary guidance information for closed-loop autonomous navigation, from first detection at far distance, to a close up a hold point. Furthermore, the system provide...... 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...

  3. Reduced Cardiorespiratory Fitness after Stroke: Biological Consequences and Exercise-Induced Adaptations

    Directory of Open Access Journals (Sweden)

    Sandra A. Billinger

    2012-01-01

    Full Text Available Evidence from several studies consistently shows decline in cardiorespiratory (CR fitness and physical function after disabling stroke. The broader implications of such a decline to general health may be partially understood through negative poststroke physiologic adaptations such as unilateral muscle fiber type shifts, impaired hemodynamic function, and decrements in systemic metabolic status. These physiologic changes also interrelate with reductions in activities of daily living (ADLs, community ambulation, and exercise tolerance, causing a perpetual cycle of worsening disability and deteriorating health. Fortunately, initial evidence suggests that stroke participants retain the capacity to adapt physiologically to an exercise training stimulus. However, despite this evidence, exercise as a therapeutic intervention continues to be clinically underutilized in the general stroke population. Far more research is needed to fully comprehend the consequences of and remedies for CR fitness impairments after stroke. The purpose of this brief review is to describe some of what is currently known about the physiological consequences of CR fitness decline after stroke. Additionally, there is an overview of the evidence supporting exercise interventions for improving CR fitness, and associated aspects of general health in this population.

  4. Induced fungal resistance to insect grazing: reciprocal fitness consequences and fungal gene expression in the Drosophila-Aspergillus model system.

    Directory of Open Access Journals (Sweden)

    Silvia Caballero Ortiz

    Full Text Available BACKGROUND: Fungi are key dietary resources for many animals. Fungi, in consequence, have evolved sophisticated physical and chemical defences for repelling and impairing fungivores. Expression of such defences may entail costs, requiring diversion of energy and nutrients away from fungal growth and reproduction. Inducible resistance that is mounted after attack by fungivores may allow fungi to circumvent the potential costs of defence when not needed. However, no information exists on whether fungi display inducible resistance. We combined organism and fungal gene expression approaches to investigate whether fungivory induces resistance in fungi. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that grazing by larval fruit flies, Drosophila melanogaster, induces resistance in the filamentous mould, Aspergillus nidulans, to subsequent feeding by larvae of the same insect. Larval grazing triggered the expression of various putative fungal resistance genes, including the secondary metabolite master regulator gene laeA. Compared to the severe pathological effects of wild type A. nidulans, which led to 100% insect mortality, larval feeding on a laeA loss-of-function mutant resulted in normal insect development. Whereas the wild type fungus recovered from larval grazing, larvae eradicated the chemically deficient mutant. In contrast, mutualistic dietary yeast, Saccharomyces cerevisiae, reached higher population densities when exposed to Drosophila larval feeding. CONCLUSIONS/SIGNIFICANCE: Our study presents novel evidence that insect grazing is capable of inducing resistance to further grazing in a filamentous fungus. This phenotypic shift in resistance to fungivory is accompanied by changes in the expression of genes involved in signal transduction, epigenetic regulation and secondary metabolite biosynthesis pathways. Depending on reciprocal insect-fungus fitness consequences, fungi may be selected for inducible resistance to maintain high fitness in

  5. A phase transition induces chaos in a predator-prey ecosystem with a dynamic fitness landscape.

    Directory of Open Access Journals (Sweden)

    William Gilpin

    2017-07-01

    Full Text Available In many ecosystems, natural selection can occur quickly enough to influence the population dynamics and thus future selection. This suggests the importance of extending classical population dynamics models to include such eco-evolutionary processes. Here, we describe a predator-prey model in which the prey population growth depends on a prey density-dependent fitness landscape. We show that this two-species ecosystem is capable of exhibiting chaos even in the absence of external environmental variation or noise, and that the onset of chaotic dynamics is the result of the fitness landscape reversibly alternating between epochs of stabilizing and disruptive selection. We draw an analogy between the fitness function and the free energy in statistical mechanics, allowing us to use the physical theory of first-order phase transitions to understand the onset of rapid cycling in the chaotic predator-prey dynamics. We use quantitative techniques to study the relevance of our model to observational studies of complex ecosystems, finding that the evolution-driven chaotic dynamics confer community stability at the "edge of chaos" while creating a wide distribution of opportunities for speciation during epochs of disruptive selection-a potential observable signature of chaotic eco-evolutionary dynamics in experimental studies.

  6. Flexible Ligand Docking Using Differential Evolution

    DEFF Research Database (Denmark)

    Thomsen, René

    2003-01-01

    evolution algorithm (DE) is applied to the docking problem using the AutoDock program. The introduced DockDE algorithm is compared with the Lamarckian GA (LGA) provided with AutoDock, and the DockEA previously found to outperform the LGA. The comparison is performed on a suite of six commonly used docking...... problems. In conclusion, the introduced DockDE outperformed the other algorithms on all problems. Further, the DockDE showed remarkable performance in terms of convergence speed and robustness regarding the found solution....

  7. DockingApp: a user friendly interface for facilitated docking simulations with AutoDock Vina

    Science.gov (United States)

    Di Muzio, Elena; Toti, Daniele; Polticelli, Fabio

    2017-02-01

    Molecular docking is a powerful technique that helps uncover the structural and energetic bases of the interaction between macromolecules and substrates, endogenous and exogenous ligands, and inhibitors. Moreover, this technique plays a pivotal role in accelerating the screening of large libraries of compounds for drug development purposes. The need to promote community-driven drug development efforts, especially as far as neglected diseases are concerned, calls for user-friendly tools to allow non-expert users to exploit the full potential of molecular docking. Along this path, here is described the implementation of DockingApp, a freely available, extremely user-friendly, platform-independent application for performing docking simulations and virtual screening tasks using AutoDock Vina. DockingApp sports an intuitive graphical user interface which greatly facilitates both the input phase and the analysis of the results, which can be visualized in graphical form using the embedded JMol applet. The application comes with the DrugBank set of more than 1400 ready-to-dock, FDA-approved drugs, to facilitate virtual screening and drug repurposing initiatives. Furthermore, other databases of compounds such as ZINC, available also in AutoDock format, can be readily and easily plugged in.

  8. DockingApp: a user friendly interface for facilitated docking simulations with AutoDock Vina.

    Science.gov (United States)

    Di Muzio, Elena; Toti, Daniele; Polticelli, Fabio

    2017-02-01

    Molecular docking is a powerful technique that helps uncover the structural and energetic bases of the interaction between macromolecules and substrates, endogenous and exogenous ligands, and inhibitors. Moreover, this technique plays a pivotal role in accelerating the screening of large libraries of compounds for drug development purposes. The need to promote community-driven drug development efforts, especially as far as neglected diseases are concerned, calls for user-friendly tools to allow non-expert users to exploit the full potential of molecular docking. Along this path, here is described the implementation of DockingApp, a freely available, extremely user-friendly, platform-independent application for performing docking simulations and virtual screening tasks using AutoDock Vina. DockingApp sports an intuitive graphical user interface which greatly facilitates both the input phase and the analysis of the results, which can be visualized in graphical form using the embedded JMol applet. The application comes with the DrugBank set of more than 1400 ready-to-dock, FDA-approved drugs, to facilitate virtual screening and drug repurposing initiatives. Furthermore, other databases of compounds such as ZINC, available also in AutoDock format, can be readily and easily plugged in.

  9. DockingApp: a user friendly interface for facilitated docking simulations with AutoDock Vina

    Science.gov (United States)

    Di Muzio, Elena; Toti, Daniele; Polticelli, Fabio

    2017-01-01

    Molecular docking is a powerful technique that helps uncover the structural and energetic bases of the interaction between macromolecules and substrates, endogenous and exogenous ligands, and inhibitors. Moreover, this technique plays a pivotal role in accelerating the screening of large libraries of compounds for drug development purposes. The need to promote community-driven drug development efforts, especially as far as neglected diseases are concerned, calls for user-friendly tools to allow non-expert users to exploit the full potential of molecular docking. Along this path, here is described the implementation of DockingApp, a freely available, extremely user-friendly, platform-independent application for performing docking simulations and virtual screening tasks using AutoDock Vina. DockingApp sports an intuitive graphical user interface which greatly facilitates both the input phase and the analysis of the results, which can be visualized in graphical form using the embedded JMol applet. The application comes with the DrugBank set of more than 1400 ready-to-dock, FDA-approved drugs, to facilitate virtual screening and drug repurposing initiatives. Furthermore, other databases of compounds such as ZINC, available also in AutoDock format, can be readily and easily plugged in.

  10. Unraveling the degradation of artificial amide bonds in nylon oligomer hydrolase: from induced-fit to acylation processes.

    Science.gov (United States)

    Baba, Takeshi; Boero, Mauro; Kamiya, Katsumasa; Ando, Hiroyuki; Negoro, Seiji; Nakano, Masayoshi; Shigeta, Yasuteru

    2015-02-14

    To elucidate how the nylon oligomer hydrolase (NylB) acquires its peculiar degradation activity towards non-biological amide bonds, we inspected the underlying enzymatic processes going from the induced-fit upon substrate binding to acylation. Specifically we investigated the mutational effects of two mutants, Y170F and D181G, indicated in former experiments as crucial systems because of their specific amino acid residues. Therefore, by adopting first-principles molecular dynamics complemented with metadynamics we provide a detailed insight into the underlying acylation mechanism. Our results show that while in the wild type (WT) the Tyr170 residue points the NH group towards the proton-acceptor site of an artificial amide bond, hence ready to react, in the Y170F this does not occur. The reason is ascribed to the absence of Tyr170 in the mutant, which is replaced by phenylalanine, which is unable to form hydrogen bond with the amide bond; thus, resulting in an increase in the activation barrier of more than 10 kcal mol(-1). Nonetheless, despite the lack of hydrogen bonding between the Y170F and the substrate, the highest free energy barrier for the induced-fit is similar to that of WT. This seems to suggest that in the induced-fit process, kinetics is little affected by the mutation. On the basis of additional structural homology analyses on the enzymes of the same family, we suggest that natural selection is responsible for the development of the peculiar hydrolytic activity of Arthrobacter sp. KI72.

  11. OMV docking simulator

    Science.gov (United States)

    Teoh, W.; Hawkins, J.

    1988-01-01

    The Boeing Orbital Maneuvering Vehicle (OMV) Docking and Proximity Operation System (DAPOS) was completed. The system constructed involves the use of four separate processors. Appropriate software was developed that drives each of these four processors. The hand controller logic coordinates all the activities in the control station, and communicates with the OMV mathematical model. The state vector generated by the model is in turn transmitted to the control station as well as the POLY 2000 (via the ALCYON host computer) for real time graphics generation. The OMV characteristics are stored in a data file which may be easily updated and modified without disturbing the software, thereby making the system very flexible. The current system supports two types of hand controllers. The system was flown by several volunteers, some of whom are airplane pilots. A user manual is also enclosed.

  12. Altered Competitive Fitness, Antimicrobial Susceptibility, and Cellular Morphology in a Triclosan-Induced Small-Colony Variant of Staphylococcus aureus.

    Science.gov (United States)

    Forbes, Sarah; Latimer, Joe; Bazaid, Abdulrahman; McBain, Andrew J

    2015-08-01

    Staphylococcus aureus can produce small-colony variants (SCVs) that express various phenotypes. While their significance is unclear, SCV propagation may be influenced by relative fitness, antimicrobial susceptibility, and the underlying mechanism. We have investigated triclosan-induced generation of SCVs in six S. aureus strains, including methicillin-resistant S. aureus (MRSA). Parent strains (P0) were repeatedly passaged on concentration gradients of triclosan using a solid-state exposure system to generate P10. P10 was subsequently passaged without triclosan to generate X10. Susceptibility to triclosan and 7 antibiotics was assessed at all stages. For S. aureus ATCC 6538, SCVs were further characterized by determining microbicide susceptibility and competitive fitness. Cellular morphology was examined using electron microscopy, and protein expression was evaluated through proteomics. Triclosan susceptibility in all SCVs (which could be generated from 4/6 strains) was markedly decreased, while antibiotic susceptibility was significantly increased in the majority of cases. An SCV of S. aureus ATCC 6538 exhibited significantly increased susceptibility to all tested microbicides. Cross-wall formation was impaired in this bacterium, while expression of FabI, a target of triclosan, and IsaA, a lytic transglycosylase involved in cell division, was increased. The P10 SCV was 49% less fit than P0. In summary, triclosan exposure of S. aureus produced SCVs in 4/6 test bacteria, with decreased triclosan susceptibility but with generally increased antibiotic susceptibility. An SCV derived from S. aureus ATCC 6538 showed reduced competitive fitness, potentially due to impaired cell division. In this SCV, increased FabI expression could account for reduced triclosan susceptibility, while IsaA may be upregulated in response to cell division defects.

  13. Evaluation of docking calculations on X-ray structures using CONSENSUS-DOCK.

    Science.gov (United States)

    Okamoto, Masako; Masuda, Yoshiaki; Muroya, Ayumu; Yasuno, Kazuhiro; Takahashi, Osamu; Furuya, Toshio

    2010-12-01

    We are participating in the challenge of identifying active compounds for target proteins using structure-based virtual screening (SBVS). We use an in-house customized docking program, CONSENSUS-DOCK, which is a customized version of the DOCK4 program in which three scoring functions (DOCK4, FlexX and PMF) and consensus scoring have been implemented. This paper compares the docking calculation results obtained using CONSENSUS-DOCK and DOCK4, and demonstrates that CONSENSUS-DOCK produces better results than DOCK4 for major X-ray structures obtained from the Protein Data Bank (PDB).

  14. Dock3 overexpression and p38 MAPK inhibition synergistically stimulate neuroprotection and axon regeneration after optic nerve injury.

    Science.gov (United States)

    Semba, Kentaro; Namekata, Kazuhiko; Kimura, Atsuko; Harada, Chikako; Katome, Takashi; Yoshida, Hiroshi; Mitamura, Yoshinori; Harada, Takayuki

    2014-10-03

    The dedicator of cytokinesis 3 (Dock3) is an atypical guanine nucleotide exchange factor that is predominantly expressed in the CNS. Dock3 exerts neuroprotective effects and stimulates optic nerve regeneration. The p38 mitogen-activated protein kinase acts downstream of apoptosis signal-regulating kinase 1 (ASK1) signaling and plays an important role in neural cell death. We assessed a therapeutic efficacy of Dock3 stimulation and p38 inhibition in retinal degeneration induced by optic nerve injury (ONI). In vivo retinal imaging using optical coherence tomography revealed that ONI-induced retinal degeneration was ameliorated in SB203580 (a p38 inhibitor)-treated WT mice and PBS-treated Dock3 overexpressing (Dock3 Tg) mice, and SB203580 further stimulated retinal protection in Dock3 Tg mice. In addition, SB203580 increased the number of regenerating axons after ONI in both WT and Dock3 Tg mice. ONI-induced phosphorylation of ASK1, p38 and the N-methyl-d-aspartate receptor 2B subunit were suppressed in the retina of Dock3 Tg mice. Inhibition of the ASK1 pathway in Dock3 Tg mice suggests that Dock3 may have an antioxidant-like property. These results indicate that overexpression of Dock3 and pharmacological interruption of p38 have synergistic effects for both neuroprotection and axon regeneration, thus combined application may be beneficial for the treatment of ONI. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  15. 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.

  16. A protocol for CABS-dock protein-peptide docking driven by side-chain contact information.

    Science.gov (United States)

    Kurcinski, Mateusz; Blaszczyk, Maciej; Ciemny, Maciej Pawel; Kolinski, Andrzej; Kmiecik, Sebastian

    2017-08-18

    The characterization of protein-peptide interactions is a challenge for computational molecular docking. Protein-peptide docking tools face at least two major difficulties: (1) efficient sampling of large-scale conformational changes induced by binding and (2) selection of the best models from a large set of predicted structures. In this paper, we merge an efficient sampling technique with external information about side-chain contacts to sample and select the best possible models. In this paper we test a new protocol that uses information about side-chain contacts in CABS-dock protein-peptide docking. As shown in our recent studies, CABS-dock enables efficient modeling of large-scale conformational changes without knowledge about the binding site. However, the resulting set of binding sites and poses is in many cases highly diverse and difficult to score. As we demonstrate here, information about a single side-chain contact can significantly improve the prediction accuracy. Importantly, the imposed constraints for side-chain contacts are quite soft. Therefore, the developed protocol does not require precise contact information and ensures large-scale peptide flexibility in the broad contact area. The demonstrated protocol provides the extension of the CABS-dock method that can be practically used in the structure prediction of protein-peptide complexes guided by the knowledge of the binding interface.

  17. DOCK 6: Impact of new features and current docking performance.

    Science.gov (United States)

    Allen, William J; Balius, Trent E; Mukherjee, Sudipto; Brozell, Scott R; Moustakas, Demetri T; Lang, P Therese; Case, David A; Kuntz, Irwin D; Rizzo, Robert C

    2015-06-05

    This manuscript presents the latest algorithmic and methodological developments to the structure-based design program DOCK 6.7 focused on an updated internal energy function, new anchor selection control, enhanced minimization options, a footprint similarity scoring function, a symmetry-corrected root-mean-square deviation algorithm, a database filter, and docking forensic tools. An important strategy during development involved use of three orthogonal metrics for assessment and validation: pose reproduction over a large database of 1043 protein-ligand complexes (SB2012 test set), cross-docking to 24 drug-target protein families, and database enrichment using large active and decoy datasets (Directory of Useful Decoys [DUD]-E test set) for five important proteins including HIV protease and IGF-1R. Relative to earlier versions, a key outcome of the work is a significant increase in pose reproduction success in going from DOCK 4.0.2 (51.4%) → 5.4 (65.2%) → 6.7 (73.3%) as a result of significant decreases in failure arising from both sampling 24.1% → 13.6% → 9.1% and scoring 24.4% → 21.1% → 17.5%. Companion cross-docking and enrichment studies with the new version highlight other strengths and remaining areas for improvement, especially for systems containing metal ions. The source code for DOCK 6.7 is available for download and free for academic users at http://dock.compbio.ucsf.edu/. © 2015 Wiley Periodicals, Inc.

  18. Vortex-Induced Vibration of a Circular Cylinder Fitted with a Single Spanwise Tripwire

    Science.gov (United States)

    Vaziri, Ehsan; Ekmekci, Alis

    2016-11-01

    A spanwise tripwire can be used to alter the coherence and strength of the vortex shedding from cylindrical structures. While this has been well-documented for cylinders in stationary state, there exists a lack of understanding regarding the control induced by spanwise tripwires for cylinders undergoing vortex-induced vibration (VIV). The current experimental research investigates the consequences of spanwise tripping on VIV of a cylinder. Experiments are conducted in a recirculating water tunnel at a Reynolds number of 10,000. The test setup allows the rigid test cylinder to have one-degree-of-freedom vibration in the cross-flow direction as a result of fluid forcing. To measure the cylinder motion, a high-resolution laser displacement sensor is used. The tripwire diameter to cylinder diameter ratio is fixed at 6.1%. Various angular positions of tripwire are studied ranging from 40 to 90 degrees. It is shown that the tripwire location controls the pattern, amplitude, frequency, and mid-position of oscillations significantly. Different oscillation modes are classified based on the observed oscillation pattern, amplitude and frequency. Oscillation amplitude can be reduced by 61% with respect to the amplitude of a clean cylinder undergoing VIV under the same flow condition.

  19. Induced fit and equilibrium dynamics for high catalytic efficiency in ferredoxin-NADP(H) reductases.

    Science.gov (United States)

    Paladini, Darío H; Musumeci, Matías A; Carrillo, Néstor; Ceccarelli, Eduardo A

    2009-06-23

    Ferredoxin-NADP(H) reductase (FNR) is a FAD-containing protein that catalyzes the reversible transfer of electrons between NADP(H) and ferredoxin or flavodoxin. This enzyme participates in the redox-based metabolism of plastids, mitochondria, and bacteria. Plastidic plant-type FNRs are very efficient reductases in supporting photosynthesis. They have a strong preference for NADP(H) over NAD(H), consistent with the main physiological role of NADP(+) photoreduction. In contrast, FNRs from organisms with heterotrophic metabolisms or anoxygenic photosynthesis display turnover rates that are up to 100-fold lower than those of their plastidic and cyanobacterial counterparts. With the aim of elucidating the mechanisms by which plastidic enzymes achieve such high catalytic efficiencies and NADP(H) specificity, we investigated the manner in which the NADP(H) nicotinamide enters and properly binds to the catalytic site. Analyzing the interaction of different nucleotides, substrate analogues, and aromatic compounds with the wild type and the mutant Y308S-FNR from pea, we found that the interaction of the 2'-P-AMP moiety from NADP(+) induces a change that favors the interaction of the nicotinamide, thereby facilitating the catalytic process. Furthermore, the main role of the terminal tyrosine, Y308, is to destabilize the interaction of the nicotinamide with the enzyme, inducing product release and favoring discrimination of the nucleotide substrate. We determined that this function can be replaced by the addition of aromatic compounds that freely diffuse in solution and establish a dynamic equilibrium, reversing the effect of the mutation in the Y308S-FNR mutant.

  20. Information entropy-based fitting of the disease trajectory of brain ischemia-induced vascular cognitive impairment

    Institute of Scientific and Technical Information of China (English)

    Lin Liu; Ju Huo; Ying Zhao; Yu Tian

    2012-01-01

    The present study investigated the disease trajectory of vascular cognitive impairment using the entropy of information in a neural network mathematical simulation based on the free radical and excitatory amino acids theories.Glutamate, malondialdehyde, and inducible nitric oxide synthase content was significantly elevated, but acetylcholine, catalase, superoxide dismutase, glutathione peroxidase and constitutive nitric oxide synthase content was significantly decreased in our vascular cognitive impairment model.The fitting curves for each factor were obtained using Matlab software.Nineteen, 30 and 49 days post ischemia were the main output time frames of the influence of these seven factors.Our results demonstrated that vascular cognitive impairment involves multiple factors.These factors include excitatory amino acid toxicity and nitric oxide toxicity.These toxicities disrupt the dynamic equilibrium of the production and removal of oxygen free radicals after cerebral ischemia, reducing the ability to clear oxygen free radicals and worsening brain injury.

  1. Fitness declines towards range limits and local adaptation to climate affect dispersal evolution during climate‐induced range shifts

    DEFF Research Database (Denmark)

    Hargreaves, Anna; Bailey, Susan; Laird, Robert

    2015-01-01

    Dispersal ability will largely determine whether species track their climatic niches during climate change, a process especially important for populations at contracting (low-latitude/low-elevation) range limits that otherwise risk extinction. We investigate whether dispersal evolution at contrac......Dispersal ability will largely determine whether species track their climatic niches during climate change, a process especially important for populations at contracting (low-latitude/low-elevation) range limits that otherwise risk extinction. We investigate whether dispersal evolution...... at contracting range limits is facilitated by two processes that potentially enable edge populations to experience and adjust to the effects of climate deterioration before they cause extinction: (i) climate-induced fitness declines towards range limits and (ii) local adaptation to a shifting climate gradient...

  2. Exercise- and methylcholine-induced sweating responses in older and younger men: effect of heat acclimation and aerobic fitness

    Science.gov (United States)

    Inoue, Y.; Havenith, George; Kenney, W. Larry; Loomis, Joseph L.; Buskirk, Elsworth R.

    The purpose of this investigation was to examine the effects of aging and aerobic fitness on exercise- and methylcholine-induced sweating responses during heat acclimation. Five younger [Y group - age: 23+/-1 (SEM) years; maximal oxygen consumption (V.O2max): 47+/-3 ml.kg-1.min-1], four highly fit older (HO group - 63+/-3 years; 48+/-4 ml.kg-1.min-1) and five normally fit older men (NO group - 67+/-3 years; 30+/-1 ml.kg-1.min-1) who were matched for height, body mass and percentage fat, were heat acclimated by daily cycle exercise ( 35% V.O2max for 90 min) in a hot (43°C, 30% RH) environment for 8 days. The heat acclimation regimen increased performance time, lowered final rectal temperature (Tre) and percentage maximal heart rate (%HRmax), improved thermal comfort and decreased sweat sodium concentration similarly in all groups. Although total body sweating rates (M.sw) during acclimation were significantly greater in the Y and HO groups than in the NO group (Prates (m.sw) on chest, back, forearm and thigh changed in all groups by the acclimation. The HO group presented greater forearm m.sw (30-90 min) values and the Y group had greater back and thigh m.sw (early in exercise) values, compared to the other groups (PHO>NO, and on the forearm Y=HO>NO. No group differences were observed for activated sweat gland density at any site. The SGO at the respective sites increased in the post-acclimation test regardless of group (Pincrease was lower in the NO (Pexercised at the same relative exercise intensity. Furthermore, the changes induced by acclimation appear associated with an age-related decrease in V.O2max. However methylcholine-activated SGO and the magnitude of improvement of SGO with acclimation are related not only to V.O2max but also to aging, suggesting that sensitivity to cholinergic stimulation decreases with aging.

  3. Fitness Effects of Network Non-Linearity Induced by Gene Expression Noise

    Science.gov (United States)

    Ray, Christian; Cooper, Tim; Balazsi, Gabor

    2012-02-01

    In the non-equilibrium dynamics of growing microbial cells, metabolic enzymes can create non-linearities in metabolite concentration because of non-linear degradation (utilization): an enzyme can saturate in the process of metabolite utilization. Increasing metabolite production past the saturation point then results in an ultrasensitive metabolite response. If the production rate of a metabolite depends on a second enzyme or other protein-mediated process, uncorrelated gene expression noise can thus cause transient metabolite concentration bursts. Such bursts are physiologically unnecessary and may represent a source of selection against the ultrasensitive switch, especially if the fluctuating metabolic intermediate is toxic. Selection may therefore favor correlated gene expression fluctuations for enzymes in the same pathway, such as by same-operon membership in bacteria. Using a modified experimental lac operon system, we are undertaking a combined theoretical-experimental approach to demonstrate that (i) the lac operon has an implicit ultrasensitive switch that we predict is avoided by gene expression correlations induced by same-operon membership; (ii) bacterial growth rates are sensitive to crossing the ultrasensitive threshold. Our results suggest that correlations in intrinsic gene expression noise are exploited by evolution to ameliorate the detrimental effects of nonlinearities in metabolite concentrations.

  4. Critical role for hematopoietic cell kinase (Hck)-mediated phosphorylation of Gab1 and Gab2 docking proteins in interleukin 6-induced proliferation and survival of multiple myeloma cells.

    Science.gov (United States)

    Podar, Klaus; Mostoslavsky, Gustavo; Sattler, Martin; Tai, Yu-Tzu; Hayashi, Toshiaki; Catley, Laurence P; Hideshima, Teru; Mulligan, Richard C; Chauhan, Dharminder; Anderson, Kenneth C

    2004-05-14

    Interleukin-6 (LI-6) is a known growth and survival factor in multiple myeloma via activation of extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling cascade. In this report we show that Grb2-associated binder (Gab) family adapter proteins Gab1 and Gab2 are expressed by multiple myeloma cells; and that interleukin-6 induces their tyrosine phosphorylation and association with downstream signaling molecules. We further demonstrate that these events are Src family tyrosine kinase-dependent and specifically identify the role of hematopoietic cell kinase (Hck) as a new Gab family adapter protein kinase. Conversely, inhibition of Src family tyrosine kinases by the pyrazolopyrimidine PP2, as in kinase-inactive Hck mutants, significantly reduces IL-6-triggered activation of extracellular signal-regulated kinase and AKT-1, leading to significant reduction of multiple myeloma cell proliferation and survival. Taken together, these results delineate a key role for Hck-mediated phosphorylation of Gab1 and Gab2 docking proteins in IL-6-induced proliferation and survival of multiple myeloma cells and identify tyrosine kinases and downstream adapter proteins as potential new therapeutic targets in multiple myeloma.

  5. Trapping conformational states along ligand-binding dynamics of peptide deformylase: the impact of induced fit on enzyme catalysis.

    Directory of Open Access Journals (Sweden)

    Sonia Fieulaine

    2011-05-01

    Full Text Available For several decades, molecular recognition has been considered one of the most fundamental processes in biochemistry. For enzymes, substrate binding is often coupled to conformational changes that alter the local environment of the active site to align the reactive groups for efficient catalysis and to reach the transition state. Adaptive substrate recognition is a well-known concept; however, it has been poorly characterized at a structural level because of its dynamic nature. Here, we provide a detailed mechanism for an induced-fit process at atomic resolution. We take advantage of a slow, tight binding inhibitor-enzyme system, actinonin-peptide deformylase. Crystal structures of the initial open state and final closed state were solved, as well as those of several intermediate mimics captured during the process. Ligand-induced reshaping of a hydrophobic pocket drives closure of the active site, which is finally "zipped up" by additional binding interactions. Together with biochemical analyses, these data allow a coherent reconstruction of the sequence of events leading from the encounter complex to the key-lock binding state of the enzyme. A "movie" that reconstructs this entire process can be further extrapolated to catalysis.

  6. Computation of currents induced by ELF electric fields in anisotropic human tissues using the Finite Integration Technique (FIT

    Directory of Open Access Journals (Sweden)

    V. C. Motrescu

    2005-01-01

    Full Text Available In the recent years, the task of estimating the currents induced within the human body by environmental electromagnetic fields has received increased attention from scientists around the world. While important progress was made in this direction, the unpredictable behaviour of living biological tissue made it difficult to quantify its reaction to electromagnetic fields and has kept the problem open. A successful alternative to the very difficult one of performing measurements is that of computing the fields within a human body model using numerical methods implemented in a software code. One of the difficulties is represented by the fact that some tissue types exhibit an anisotropic character with respect to their dielectric properties. Our work consists of computing currents induced by extremely low frequency (ELF electric fields in anisotropic muscle tissues using in this respect, a human body model extended with muscle fibre orientations as well as an extended version of the Finite Integration Technique (FIT able to compute fully anisotropic dielectric properties.

  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. DINC: a new AutoDock-based protocol for docking large ligands.

    Science.gov (United States)

    Dhanik, Ankur; McMurray, John S; Kavraki, Lydia E

    2013-01-01

    Using the popular program AutoDock, computer-aided docking of small ligands with 6 or fewer rotatable bonds, is reasonably fast and accurate. However, docking large ligands using AutoDock's recommended standard docking protocol is less accurate and computationally slow. In our earlier work, we presented a novel AutoDock-based incremental protocol (DINC) that addresses the limitations of AutoDock's standard protocol by enabling improved docking of large ligands. Instead of docking a large ligand to a target protein in one single step as done in the standard protocol, our protocol docks the large ligand in increments. In this paper, we present three detailed examples of docking using DINC and compare the docking results with those obtained using AutoDock's standard protocol. We summarize the docking results from an extended docking study that was done on 73 protein-ligand complexes comprised of large ligands. We demonstrate not only that DINC is up to 2 orders of magnitude faster than AutoDock's standard protocol, but that it also achieves the speed-up without sacrificing docking accuracy. We also show that positional restraints can be applied to the large ligand using DINC: this is useful when computing a docked conformation of the ligand. Finally, we introduce a webserver for docking large ligands using DINC. Docking large ligands using DINC is significantly faster than AutoDock's standard protocol without any loss of accuracy. Therefore, DINC could be used as an alternative protocol for docking large ligands. DINC has been implemented as a webserver and is available at http://dinc.kavrakilab.org. Applications such as therapeutic drug design, rational vaccine design, and others involving large ligands could benefit from DINC and its webserver implementation.

  9. 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

  10. Unusually strong binding to the DNA minor groove by a highly twisted benzimidazole diphenylether: induced fit and bound water.

    Science.gov (United States)

    Tanious, Farial A; Laine, William; Peixoto, Paul; Bailly, Christian; Goodwin, Kristie D; Lewis, Mark A; Long, Eric C; Georgiadis, Millie M; Tidwell, Richard R; Wilson, W David

    2007-06-12

    RT29 is a dicationic diamidine derivative that does not obey the classical "rules" for shape and functional group placement that are expected to result in strong binding and specific recognition of the DNA minor groove. The compound contains a benzimidazole diphenyl ether core that is flanked by the amidine cations. The diphenyl ether is highly twisted and gives the entire compound too much curvature to fit well to the shape of the minor groove. DNase I footprinting, fluorescence intercalator displacement studies, and circular dichroism spectra, however, indicate that the compound is an AT specific minor groove binding agent. Even more surprisingly, quantitative biosensor-surface plasmon resonance and isothermal titration calorimetric results indicate that the compound binds with exceptional strength to certain AT sequences in DNA with a large negative enthalpy of binding. Crystallographic results for the DNA complex of RT29 compared to calculated results for the free compound show that the compound undergoes significant conformational changes to enhance its minor groove interactions. In addition, a water molecule is incorporated directly into the complex to complete the compound-DNA interface, and it forms an essential link between the compound and base pair edges at the floor of the minor groove. The calculated DeltaCp value for complex formation is substantially less than the experimentally observed value, which supports the idea of water being an intrinsic part of the complex with a major contribution to the DeltaCp value. Both the induced fit conformational changes of the compound and the bound water are essential for strong binding to DNA by RT29.

  11. Automated docking of flexible ligands: applications of AutoDock.

    Science.gov (United States)

    Goodsell, D S; Morris, G M; Olson, A J

    1996-01-01

    AutoDock is a suite of C programs used to predict the bound conformations of a small, flexible ligand to a macromolecular target of known structure. The technique combines simulated annealing for conformation searching with a rapid grid-based method of energy evaluation. This paper reviews recent applications of the technique and describes the enhancements included in the current release.

  12. 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

  13. Docking of Secretory Vesicles Is Syntaxin Dependent

    Science.gov (United States)

    de Wit, Heidi; Cornelisse, L. Niels; Toonen, Ruud F.G.; Verhage, Matthijs

    2006-01-01

    Secretory vesicles dock at the plasma membrane before they undergo fusion. Molecular docking mechanisms are poorly defined but believed to be independent of SNARE proteins. Here, we challenged this hypothesis by acute deletion of the target SNARE, syntaxin, in vertebrate neurons and neuroendocrine cells. Deletion resulted in fusion arrest in both systems. No docking defects were observed in synapses, in line with previous observations. However, a drastic reduction in morphologically docked secretory vesicles was observed in chromaffin cells. Syntaxin-deficient chromaffin cells showed a small reduction in total and plasma membrane staining for the docking factor Munc18-1, which appears insufficient to explain the drastic reduction in docking. The sub-membrane cortical actin network was unaffected by syntaxin deletion. These observations expose a docking role for syntaxin in the neuroendocrine system. Additional layers of regulation may have evolved to make syntaxin redundant for docking in highly specialized systems like synaptic active zones. PMID:17205130

  14. Docking of secretory vesicles is syntaxin dependent.

    Directory of Open Access Journals (Sweden)

    Heidi de Wit

    Full Text Available Secretory vesicles dock at the plasma membrane before they undergo fusion. Molecular docking mechanisms are poorly defined but believed to be independent of SNARE proteins. Here, we challenged this hypothesis by acute deletion of the target SNARE, syntaxin, in vertebrate neurons and neuroendocrine cells. Deletion resulted in fusion arrest in both systems. No docking defects were observed in synapses, in line with previous observations. However, a drastic reduction in morphologically docked secretory vesicles was observed in chromaffin cells. Syntaxin-deficient chromaffin cells showed a small reduction in total and plasma membrane staining for the docking factor Munc18-1, which appears insufficient to explain the drastic reduction in docking. The sub-membrane cortical actin network was unaffected by syntaxin deletion. These observations expose a docking role for syntaxin in the neuroendocrine system. Additional layers of regulation may have evolved to make syntaxin redundant for docking in highly specialized systems like synaptic active zones.

  15. ZINC FINGER OF ARABIDOPSIS THALIANA12 (ZAT12) Interacts with FER-LIKE IRON DEFICIENCY-INDUCED TRANSCRIPTION FACTOR (FIT) Linking Iron Deficiency and Oxidative Stress Responses.

    Science.gov (United States)

    Le, Cham Thi Tuyet; Brumbarova, Tzvetina; Ivanov, Rumen; Stoof, Claudia; Weber, Eva; Mohrbacher, Julia; Fink-Straube, Claudia; Bauer, Petra

    2016-01-01

    Plants grown under iron (Fe)-deficient conditions induce a set of genes that enhance the efficiency of Fe uptake by the roots. In Arabidopsis (Arabidopsis thaliana), the central regulator of this response is the basic helix-loop-helix transcription factor FER-LIKE IRON DEFICIENCY-INDUCED TRANSCRIPTION FACTOR (FIT). FIT activity is regulated by protein-protein interactions, which also serve to integrate external signals that stimulate and possibly inhibit Fe uptake. In the search of signaling components regulating FIT function, we identified ZINC FINGER OF ARABIDOPSIS THALIANA12 (ZAT12), an abiotic stress-induced transcription factor. ZAT12 interacted with FIT, dependent on the presence of the ethylene-responsive element-binding factor-associated amphiphilic repression motif. ZAT12 protein was found expressed in the root early differentiation zone, where its abundance was modulated in a root layer-specific manner. In the absence of ZAT12, FIT expression was upregulated, suggesting a negative effect of ZAT12 on Fe uptake. Consistently, zat12 loss-of-function mutants had higher Fe content than the wild type at sufficient Fe. We found that under Fe deficiency, hydrogen peroxide (H2O2) levels were enhanced in a FIT-dependent manner. FIT protein, in turn, was stabilized by H2O2 but only in the presence of ZAT12, showing that H2O2 serves as a signal for Fe deficiency responses. We propose that oxidative stress-induced ZAT12 functions as a negative regulator of Fe acquisition. A model where H2O2 mediates the negative regulation of plant responses to prolonged stress might be applicable to a variety of stress conditions.

  16. Subjective analysis of exercise-induced changes in back dimensions of the horse: The influence of saddle-fit, rider skill and work quality.

    Science.gov (United States)

    Greve, Line; Murray, Rachel; Dyson, Sue

    2015-10-01

    Recommendations concerning saddle-fit are empirical rather than based on scientific information. A saddle needs to fit the horse in motion, but there has been no investigation of whether the thoracolumbar region changes in dimensions in association with exercise. The objectives of this study were to quantify exercise-induced back dimension changes and to describe the association with work quality, saddle-fit and rider skill. Sixty-three sports horses in regular work were assessed prospectively in a non-random, cross-sectional survey. Thoracolumbar dimensions/symmetries were measured at predetermined sites before and immediately after a 30 min exercise period; widths for two levels at each site were measured and the shape-ratio calculated. The work quality and rider skill were graded and the presence of lameness and saddle-fit were recorded. Descriptive statistics, univariable and multivariable mixed-effect linear regression were performed to assess the relationship between horse-saddle-rider factors and changes in back dimensions. The mean back width after ridden exercise was greater compared with before exercise. Mean changes were greater in horses working correctly vs. those not working correctly, in those with correctly-fitting vs. ill-fitting saddles, and in horses ridden by good > moderately > poorly skilled riders. Back-width changes were significantly associated with saddle-fit. The back dimensions of horses working correctly change transiently with work. If a saddle does not fit properly before exercise, this increase in size does not occur. Saddle-fit should be assessed both before and after exercise to ensure correct fit.

  17. Molecular docking guided structure based design of symmetrical N,N'-disubstituted urea/thiourea as HIV-1 gp120-CD4 binding inhibitors.

    Science.gov (United States)

    Sivan, Sree Kanth; Vangala, Radhika; Manga, Vijjulatha

    2013-08-01

    Induced fit molecular docking studies were performed on BMS-806 derivatives reported as small molecule inhibitors of HIV-1 gp120-CD4 binding. Comprehensive study of protein-ligand interactions guided in identification and design of novel symmetrical N,N'-disubstituted urea and thiourea as HIV-1 gp120-CD4 binding inhibitors. These molecules were synthesized in aqueous medium using microwave irradiation. Synthesized molecules were screened for their inhibitory ability by HIV-1 gp120-CD4 capture enzyme-linked immunosorbent assay (ELISA). Designed compounds were found to inhibit HIV-1 gp120-CD4 binding in micromolar (0.013-0.247 μM) concentrations.

  18. Molecular Docking, Molecular Dynamics Simulations, Computational Screening to Design Quorum Sensing Inhibitors Targeting LuxP of Vibrio harveyi and Its Biological Evaluation.

    Science.gov (United States)

    Rajamanikandan, Sundaraj; Jeyakanthan, Jeyaraman; Srinivasan, Pappu

    2017-01-01

    Quorum sensing (QS) plays an important role in the biofilm formation, production of virulence factors and stress responses in Vibrio harveyi. Therefore, interrupting QS is a possible approach to modulate bacterial behavior. In the present study, three docking protocols, such as Rigid Receptor Docking (RRD), Induced Fit Docking (IFD), and Quantum Polarized Ligand Docking (QPLD) were used to elucidate the binding mode of boronic acid derivatives into the binding pocket of LuxP protein in V. harveyi. Among the three docking protocols, IFD accurately predicted the correct binding mode of the studied inhibitors. Molecular dynamics (MD) simulations of the protein-ligand complexes indicates that the inter-molecular hydrogen bonds formed between the protein and ligand complex remains stable during the simulation time. Pharmacophore and shape-based virtual screening were performed to find selective and potent compounds from ChemBridge database. Five hit compounds were selected and subjected to IFD and MD simulations to validate the binding mode. In addition, enrichment calculation was performed to discriminate and separate active compounds from the inactive compounds. Based on the computational studies, the potent Bicyclo [2.2.1] hept-5-ene-2,3-dicarboxylic acid-2,6-dimethylpyridine 1-oxide (ChemBridge_5144368) was selected for in vitro assays. The compound exhibited dose dependent inhibition in bioluminescence and also inhibits biofilm formation in V. harveyi to the level of 64.25 %. The result from the study suggests that ChemBridge_5144368 could serve as an anti-quorum sensing molecule for V. harveyi.

  19. Glycolic acid inhibits enzymatic, hemorrhagic and edema-inducing activities of BaP1, a P-I metalloproteinase from Bothrops asper snake venom: insights from docking and molecular modeling.

    Science.gov (United States)

    Pereañez, Jaime Andrés; Patiño, Arley Camilo; Rey-Suarez, Paola; Núñez, Vitelbina; Henao Castañeda, Isabel Cristina; Rucavado, Alexandra

    2013-09-01

    Glycolic acid (GA) (2-Hydroxyethanoic acid) is widely used as chemical peeling agent in Dermatology and, more recently, as a therapeutic and cosmetic compound in the field of skin care and disease treatment. In this work we tested the inhibitory ability of glycolic acid on the enzymatic, hemorrhagic and edema-inducing activities of BaP1, a P-I metalloproteinase from Bothrops asper venom, which induces a variety of toxic actions. Glycolic acid inhibited the proteolytic activity of BaP1 on azocasein, with an IC₅₀ of 1.67 mM. The compound was also effective at inhibiting the hemorrhagic activity of BaP1 in skin and muscle in experiments involving preincubation of enzyme and inhibitor prior to injection. When BaP1 was injected i.m. and then, at the same site, different concentrations of glycolic acid were administered at either 0 or 5 min, 7 mM solutions of the inhibitor partially abrogated hemorrhagic activity when administered at 0 min. Moreover, glycolic acid inhibited, in a concentration-dependent manner, edema-forming activity of BaP1 in the footpad. In order to have insights on the mode of action of glycolic acid, UV-vis and intrinsic fluorescence studies were performed. Results of these assays suggest that glycolic acid interacts directly with BaP1 and chelates the Zn²⁺ ion at the active site. These findings were supported by molecular docking results, which suggested that glycolic acid forms hydrogen bonds with residues Glu143, Arg110 and Ala111 of the enzyme. Additionally, molecular modeling results suggest that the inhibitor chelates Zn²⁺, with a distance of 3.58 Å, and may occupy part of substrate binding cleft of BaP1. Our results suggest that glycolic acid is a candidate for the development of inhibitors to be used in snakebite envenomation.

  20. Vehicle routing with cross-docking

    DEFF Research Database (Denmark)

    Wen, Min; Larsen, Jesper; Clausen, Jens

    2009-01-01

    Over the past decade, cross-docking has emerged as an important material handling technology in transportation. A variation of the well-known Vehicle Routing Problem (VRP), the VRP with Cross-Docking (VRPCD) arises in a number of logistics planning contexts. This paper addresses the VRPCD, where...... 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...

  1. New Spectral Fitting Method for Full-Spectrum Solar-Induced Chlorophyll Fluorescence Retrieval Based on Principal Components Analysis

    Directory of Open Access Journals (Sweden)

    Xinjie Liu

    2015-08-01

    Full Text Available The full-spectrum Solar-Induced chlorophyll Fluorescence (SIF within the 650-800 nm spectral region can provide important information regarding physiological and biochemical activities in vegetation. This paper proposes a new Full-spectrum Spectral Fitting Method (F-SFM for the retrieval of SIF spectra based on Principal Components Analysis (PCA. Using F-SFM, both the full-spectrum reflectance and SIF within the 650-800 nm region were modeled by PCA based on a training dataset simulated by the Soil Canopy Observation, Photochemistry and Energy fluxes (SCOPE model, and the weighting coefficients of the principal components were estimated by the least-squares fitting method. An iterative process was employed to improve the accuracy of the estimation of the reflectance. In each iteration, the SIF spectra retrieved from the last run were removed from the total upwelling radiance to minimize the small contribution of the SIF to the apparent reflectance outside the absorption bands. Then, the F-SFM algorithm was tested using both simulated and field-measured data with different Spectral Resolutions (SRs and Signal-to-Noise Ratios (SNRs. For data with an SR of 0.3 nm and without noise, the Relative Root Mean Square Error (RRMSE was less than 14% within the spectral region that was studied, and the peak-value ratio (SIF735/SIF685 was accurately estimated with an RRMSE of 3.56%. In addition, the F-SFM algorithm proved less sensitive to the SR than the three-band Fraunhofer Line Discrimination (3 FLD and improved FLD (iFLD methods. In the case of the field spectral data with SRs of 3 nm and 0.3 nm, the double-peak shape and the diurnal variation trend of the SIF spectra could be reasonably reconstructed by F-SFM, and the retrieved SIF values at the O2-A and O2-B bands were consistent with those retrieved by 3FLD from data with a high SR (0.3 nm and SNR (1000. Therefore, the F-SFM method can provide full-spectrum SIF information with high accuracy even at

  2. A combinatorial scoring function for protein-RNA docking.

    Science.gov (United States)

    Zhang, Zhao; Lu, Lin; Zhang, Yue; Hua Li, Chun; Wang, Cun Xin; Zhang, Xiao Yi; Tan, Jian Jun

    2017-04-01

    Protein-RNA docking is still an open question. One of the main challenges is to develop an effective scoring function that can discriminate near-native structures from the incorrect ones. To solve the problem, we have constructed a knowledge-based residue-nucleotide pairwise potential with secondary structure information considered for nonribosomal protein-RNA docking. Here we developed a weighted combined scoring function RpveScore that consists of the pairwise potential and six physics-based energy terms. The weights were optimized using the multiple linear regression method by fitting the scoring function to L_rmsd for the bound docking decoys from Benchmark II. The scoring functions were tested on 35 unbound docking cases. The results show that the scoring function RpveScore including all terms performs best. Also RpveScore was compared with the statistical mechanics-based method derived potential ITScore-PR, and the united atom-based statistical potentials QUASI-RNP and DARS-RNP. The success rate of RpveScore is 71.6% for the top 1000 structures and the number of cases where a near-native structure is ranked in top 30 is 25 out of 35 cases. For 32 systems (91.4%), RpveScore can find the binding mode in top 5 that has no lower than 50% native interface residues on protein and nucleotides on RNA. Additionally, it was found that the long-range electrostatic attractive energy plays an important role in distinguishing near-native structures from the incorrect ones. This work can be helpful for the development of protein-RNA docking methods and for the understanding of protein-RNA interactions. RpveScore program is available to the public at http://life.bjut.edu.cn/kxyj/kycg/2017116/14845362285362368_1.html Proteins 2017; 85:741-752. © 2016 Wiley Periodicals, Inc.

  3. Fitness club

    CERN Multimedia

    Fitness club

    2011-01-01

    General fitness Classes Enrolments are open for general fitness classes at CERN taking place on Monday, Wednesday, and Friday lunchtimes in the Pump Hall (building 216). There are shower facilities for both men and women. It is possible to pay for 1, 2 or 3 classes per week for a minimum of 1 month and up to 6 months. Check out our rates and enrol at: http://cern.ch/club-fitness Hope to see you among us! CERN Fitness Club fitness.club@cern.ch  

  4. Comprehensive evaluation of ten docking programs on a diverse set of protein-ligand complexes: the prediction accuracy of sampling power and scoring power.

    Science.gov (United States)

    Wang, Zhe; Sun, Huiyong; Yao, Xiaojun; Li, Dan; Xu, Lei; Li, Youyong; Tian, Sheng; Hou, Tingjun

    2016-05-14

    As one of the most popular computational approaches in modern structure-based drug design, molecular docking can be used not only to identify the correct conformation of a ligand within the target binding pocket but also to estimate the strength of the interaction between a target and a ligand. Nowadays, as a variety of docking programs are available for the scientific community, a comprehensive understanding of the advantages and limitations of each docking program is fundamentally important to conduct more reasonable docking studies and docking-based virtual screening. In the present study, based on an extensive dataset of 2002 protein-ligand complexes from the PDBbind database (version 2014), the performance of ten docking programs, including five commercial programs (LigandFit, Glide, GOLD, MOE Dock, and Surflex-Dock) and five academic programs (AutoDock, AutoDock Vina, LeDock, rDock, and UCSF DOCK), was systematically evaluated by examining the accuracies of binding pose prediction (sampling power) and binding affinity estimation (scoring power). Our results showed that GOLD and LeDock had the best sampling power (GOLD: 59.8% accuracy for the top scored poses; LeDock: 80.8% accuracy for the best poses) and AutoDock Vina had the best scoring power (rp/rs of 0.564/0.580 and 0.569/0.584 for the top scored poses and best poses), suggesting that the commercial programs did not show the expected better performance than the academic ones. Overall, the ligand binding poses could be identified in most cases by the evaluated docking programs but the ranks of the binding affinities for the entire dataset could not be well predicted by most docking programs. However, for some types of protein families, relatively high linear correlations between docking scores and experimental binding affinities could be achieved. To our knowledge, this study has been the most extensive evaluation of popular molecular docking programs in the last five years. It is expected that our work

  5. Docking studies on DNA intercalators.

    Science.gov (United States)

    Gilad, Yocheved; Senderowitz, Hanoch

    2014-01-27

    DNA is an important target for the treatment of multiple pathologies, most notably cancer. In particular, DNA intercalators have often been used as anticancer drugs. However, despite their relevance to drug discovery, only a few systematic computational studies were performed on DNA-intercalator complexes. In this work we have analyzed ligand binding sites preferences in 63 high resolution DNA-intercalator complexes available in the PDB and found that ligands bind preferentially between G and C and between the C and A base pairs (70% and 11%, respectively). Next, we examined the ability of AUTODOCK to accurately dock ligands into preformed intercalation sites. Following the optimization of the docking protocol, AUTODOCK was able to generate conformations with RMSD values AUTODOCK was able to successfully distinguish between the intercalation site and the minor groove site. However, in all cases the crystal structures and poses tightly clustered around it had a lower score than the best scoring poses suggesting a potential scoring problem with AUTODOCK. A close examination of all cases where the top ranked pose had an RMSD value >2.00 Å suggests that AUTODOCK may overemphasize the hydrogen bonding term. A decision tree was built to identify ligands which are likely to be accurately docked based on their characteristics. This analysis revealed that AUTODOCK performs best for intercalators characterized by a large number of aromatic rings, low flexibility, high molecular weight, and a small number of hydrogen bond acceptors. Finally, for canonical B-DNA structures (where preformed sites are unavailable), we demonstrated that intercalation sites could be formed by inserting an anthracene moiety between the (anticipated) site-flanking base pairs and by relaxing the structure using either energy minimization or preferably molecular dynamics simulations. Such sites were suitable for the docking of different intercalators by AUTODOCK.

  6. 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.

  7. Fitness Club

    CERN Multimedia

    Fitness Club

    2011-01-01

    The CERN Fitness Club is organising Zumba Classes on the first Wednesday of each month, starting 7 September (19.00 – 20.00). What is Zumba®? It’s an exhilarating, effective, easy-to-follow, Latin-inspired, calorie-burning dance fitness-party™ that’s moving millions of people toward joy and health. Above all it’s great fun and an excellent work out. Price: 22 CHF/person Sign-up via the following form: https://espace.cern.ch/club-fitness/Lists/Zumba%20Subscription/NewForm.aspx For more info: fitness.club@cern.ch

  8. Exercise-induced improvements in cardiorespiratory fitness and heart rate response to exercise are impaired in overweight/obese postmenopausal women

    Directory of Open Access Journals (Sweden)

    Emmanuel Gomes Ciolac

    2011-01-01

    Full Text Available OBJECTIVE: The purpose of this study was to compare the heart rate response to exercise and the exercise-induced improvements in muscle strength, cardiorespiratory fitness and heart rate response between normal-weight and overweight/obese postmenopausal women. METHODS: Sedentary women (n = 155 were divided into normal-weight (n = 79; BMI 25 kg/m²; 58.3 + 8.6 years groups, and have their 1-repetition maximum strength (adjusted for body mass, cardiorespiratory fitness and heart rate response to a graded exercise test compared before and after 12 months of a three times-per-week exercise-training program. RESULTS: Overweight/obese women displayed decreased upper and lower extremity muscle strengths, decreased cardiorespiratory fitness, and lower peak and reserve heart rates compared to normal-weight women. After follow-up, both groups improved their upper (32.9% and 41.5% in normal-weight and overweight/obese women, respectively and lower extremity(49.5% and 47.8% in normal-weight and overweight/obese women, respectively muscle strength. However, only normal-weight women improved their cardiorespiratory fitness (6.6% and recovery heart rate (5 bpm. Resting, reserve and peak heart rates did not change in either group. CONCLUSIONS: Overweight/obese women displayed impaired heart rate response to exercise. Both groups improved muscle strength, but only normal-weight women improved cardiorespiratory fitness and heart rate response to exercise. These results suggest that exercise-induced improvements in cardiorespiratory fitness and heart rate response to exercise may be impaired in overweight/obese postmenopausal women.

  9. Exercise-induced improvements in cardiorespiratory fitness and heart rate response to exercise are impaired in overweight/obese postmenopausal women.

    Science.gov (United States)

    Ciolac, Emmanuel Gomes; Greve, Júlia Maria D'Andréa

    2011-01-01

    The purpose of this study was to compare the heart rate response to exercise and the exercise-induced improvements in muscle strength, cardiorespiratory fitness and heart rate response between normal-weight and overweight/obese postmenopausal women. Sedentary women (n = 155) were divided into normal-weight (n = 79; BMI 25 kg/m(2); 58.3 ± 8.6 years) groups, and have their 1-repetition maximum strength (adjusted for body mass), cardiorespiratory fitness and heart rate response to a graded exercise test compared before and after 12 months of a three times-per-week exercise-training program. Overweight/obese women displayed decreased upper and lower extremity muscle strengths, decreased cardiorespiratory fitness, and lower peak and reserve heart rates compared to normal-weight women. After follow-up, both groups improved their upper (32.9% and 41.5% in normal-weight and overweight/obese women, respectively) and lower extremity(49.5% and 47.8% in normal-weight and overweight/obese women, respectively) muscle strength. However, only normal-weight women improved their cardiorespiratory fitness (6.6%) and recovery heart rate (5 bpm). Resting, reserve and peak heart rates did not change in either group. Overweight/obese women displayed impaired heart rate response to exercise. Both groups improved muscle strength, but only normal-weight women improved cardiorespiratory fitness and heart rate response to exercise. These results suggest that exercise-induced improvements in cardiorespiratory fitness and heart rate response to exercise may be impaired in overweight/obese postmenopausal women.

  10. Scoring functions for AutoDock.

    Science.gov (United States)

    Hill, Anthony D; Reilly, Peter J

    2015-01-01

    Automated docking allows rapid screening of protein-ligand interactions. A scoring function composed of a force field and linear weights can be used to compute a binding energy from a docked atom configuration. For different force fields or types of molecules, it may be necessary to train a custom scoring function. This chapter describes the data and methods one must consider in developing a custom scoring function for use with AutoDock.

  11. Development of robotics facility docking test hardware

    Science.gov (United States)

    Loughead, T. E.; Winkler, R. V.

    1984-01-01

    Design and fabricate test hardware for NASA's George C. Marshall Space Flight Center (MSFC) are reported. A docking device conceptually developed was fabricated, and two docking targets which provide high and low mass docking loads were required and were represented by an aft 61.0 cm section of a Hubble space telescope (ST) mockup and an upgrading of an existing multimission modular spacecraft (MSS) mockup respectively. A test plan is developed for testing the hardware.

  12. 36 CFR 13.1122 - Bartlett Cove Public Use Dock.

    Science.gov (United States)

    2010-07-01

    ... 36 Parks, Forests, and Public Property 1 2010-07-01 2010-07-01 false Bartlett Cove Public Use Dock... Bartlett Cove § 13.1122 Bartlett Cove Public Use Dock. (a) Docking, tying down, or securing aircraft is prohibited except at the designated aircraft float at the Bartlett Cove Public Use Dock. Docking, tying down...

  13. "Shrink-to-fit" superhydrophobicity: thermally-induced microscale wrinkling of thin hydrophobic multilayers fabricated on flexible shrink-wrap substrates.

    Science.gov (United States)

    Manna, Uttam; Carter, Matthew C D; Lynn, David M

    2013-06-11

    An approach to the design of flexible superhydrophobic surfaces based on thermally induced wrinkling of thin, hydrophobic polymer multilayers on heat-shrinkable polymer films is reported. This approach exploits shrinking processes common to "heat-shrink" plastics, and can thus be used to create "shrink-to-fit" superhydrophobic coatings on complex surfaces, manipulate the dimensions and densities of patterned features, and promote heat-activated repair of full-thickness defects.

  14. Extensive fitness and human cooperation.

    Science.gov (United States)

    van Hateren, J H

    2015-12-01

    Evolution depends on the fitness of organisms, the expected rate of reproducing. Directly getting offspring is the most basic form of fitness, but fitness can also be increased indirectly by helping genetically related individuals (such as kin) to increase their fitness. The combined effect is known as inclusive fitness. Here it is argued that a further elaboration of fitness has evolved, particularly in humans. It is called extensive fitness and it incorporates producing organisms that are merely similar in phenotype. The evolvability of this mechanism is illustrated by computations on a simple model combining heredity and behaviour. Phenotypes are driven into the direction of high fitness through a mechanism that involves an internal estimate of fitness, implicitly made within the organism itself. This mechanism has recently been conjectured to be responsible for producing agency and goals. In the model, inclusive and extensive fitness are both implemented by letting fitness increase nonlinearly with the size of subpopulations of similar heredity (for the indirect part of inclusive fitness) and of similar phenotype (for the phenotypic part of extensive fitness). Populations implementing extensive fitness outcompete populations implementing mere inclusive fitness. This occurs because groups with similar phenotype tend to be larger than groups with similar heredity, and fitness increases more when groups are larger. Extensive fitness has two components, a direct component where individuals compete in inducing others to become like them and an indirect component where individuals cooperate and help others who are already similar to them.

  15. LigDockCSA: protein-ligand docking using conformational space annealing.

    Science.gov (United States)

    Shin, Woong-Hee; Heo, Lim; Lee, Juyong; Ko, Junsu; Seok, Chaok; Lee, Jooyoung

    2011-11-30

    Protein-ligand docking techniques are one of the essential tools for structure-based drug design. Two major components of a successful docking program are an efficient search method and an accurate scoring function. In this work, a new docking method called LigDockCSA is developed by using a powerful global optimization technique, conformational space annealing (CSA), and a scoring function that combines the AutoDock energy and the piecewise linear potential (PLP) torsion energy. It is shown that the CSA search method can find lower energy binding poses than the Lamarckian genetic algorithm of AutoDock. However, lower-energy solutions CSA produced with the AutoDock energy were often less native-like. The loophole in the AutoDock energy was fixed by adding a torsional energy term, and the CSA search on the refined energy function is shown to improve the docking performance. The performance of LigDockCSA was tested on the Astex diverse set which consists of 85 protein-ligand complexes. LigDockCSA finds the best scoring poses within 2 Å root-mean-square deviation (RMSD) from the native structures for 84.7% of the test cases, compared to 81.7% for AutoDock and 80.5% for GOLD. The results improve further to 89.4% by incorporating the conformational entropy. Copyright © 2011 Wiley Periodicals, Inc.

  16. From Binding-Induced Dynamic Effects in SH3 Structures to Evolutionary Conserved Sectors

    OpenAIRE

    Ana Zafra Ruano; Elisa Cilia; Couceiro, José R.; Javier Ruiz Sanz; Joost Schymkowitz; Frederic Rousseau; Irene Luque; Tom Lenaerts

    2016-01-01

    Src Homology 3 domains are ubiquitous small interaction modules known to act as docking sites and regulatory elements in a wide range of proteins. Prior experimental NMR work on the SH3 domain of Src showed that ligand binding induces long-range dynamic changes consistent with an induced fit mechanism. The identification of the residues that participate in this mechanism produces a chart that allows for the exploration of the regulatory role of such domains in the activity of the encompassing...

  17. The Impact of BIB Spiraling-Induced Missing Data Patterns on Goodness-of-Fit Tests in Factor Analysis.

    Science.gov (United States)

    Kaplan, David

    1995-01-01

    This article considers the impact of missing data arising from balanced incomplete block (BIB) spiraled designs on the chi-square goodness-of-fit test in factor analysis. The new approach is shown to outperform the pairwise available case method for continuous variables and to be comparatively better for dichotomous variables. (SLD)

  18. 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.

  19. Fitness Club

    CERN Multimedia

    Fitness Club

    2012-01-01

    Open to All: http://cern.ch/club-fitness  fitness.club@cern.ch Boxing Your supervisor makes your life too tough ! You really need to release the pressure you've been building up ! Come and join the fit-boxers. We train three times a week in Bd 216, classes for beginners and advanced available. Visit our website cern.ch/Boxing General Fitness Escape from your desk with our general fitness classes, to strengthen your heart, muscles and bones, improve you stamina, balance and flexibility, achieve new goals, be more productive and experience a sense of well-being, every Monday, Wednesday and Friday lunchtime, Tuesday mornings before work and Thursday evenings after work – join us for one of our monthly fitness workshops. Nordic Walking Enjoy the great outdoors; Nordic Walking is a great way to get your whole body moving and to significantly improve the condition of your muscles, heart and lungs. It will boost your energy levels no end. Pilates A body-conditioning technique de...

  20. Binding-affinity predictions of HSP90 in the D3R Grand Challenge 2015 with docking, MM/GBSA, QM/MM, and free-energy simulations

    Science.gov (United States)

    Misini Ignjatović, Majda; Caldararu, Octav; Dong, Geng; Muñoz-Gutierrez, Camila; Adasme-Carreño, Francisco; Ryde, Ulf

    2016-09-01

    We have estimated the binding affinity of three sets of ligands of the heat-shock protein 90 in the D3R grand challenge blind test competition. We have employed four different methods, based on five different crystal structures: first, we docked the ligands to the proteins with induced-fit docking with the Glide software and calculated binding affinities with three energy functions. Second, the docked structures were minimised in a continuum solvent and binding affinities were calculated with the MM/GBSA method (molecular mechanics combined with generalised Born and solvent-accessible surface area solvation). Third, the docked structures were re-optimised by combined quantum mechanics and molecular mechanics (QM/MM) calculations. Then, interaction energies were calculated with quantum mechanical calculations employing 970-1160 atoms in a continuum solvent, combined with energy corrections for dispersion, zero-point energy and entropy, ligand distortion, ligand solvation, and an increase of the basis set to quadruple-zeta quality. Fourth, relative binding affinities were estimated by free-energy simulations, using the multi-state Bennett acceptance-ratio approach. Unfortunately, the results were varying and rather poor, with only one calculation giving a correlation to the experimental affinities larger than 0.7, and with no consistent difference in the quality of the predictions from the various methods. For one set of ligands, the results could be strongly improved (after experimental data were revealed) if it was recognised that one of the ligands displaced one or two water molecules. For the other two sets, the problem is probably that the ligands bind in different modes than in the crystal structures employed or that the conformation of the ligand-binding site or the whole protein changes.

  1. Binding-affinity predictions of HSP90 in the D3R Grand Challenge 2015 with docking, MM/GBSA, QM/MM, and free-energy simulations.

    Science.gov (United States)

    Misini Ignjatović, Majda; Caldararu, Octav; Dong, Geng; Muñoz-Gutierrez, Camila; Adasme-Carreño, Francisco; Ryde, Ulf

    2016-09-01

    We have estimated the binding affinity of three sets of ligands of the heat-shock protein 90 in the D3R grand challenge blind test competition. We have employed four different methods, based on five different crystal structures: first, we docked the ligands to the proteins with induced-fit docking with the Glide software and calculated binding affinities with three energy functions. Second, the docked structures were minimised in a continuum solvent and binding affinities were calculated with the MM/GBSA method (molecular mechanics combined with generalised Born and solvent-accessible surface area solvation). Third, the docked structures were re-optimised by combined quantum mechanics and molecular mechanics (QM/MM) calculations. Then, interaction energies were calculated with quantum mechanical calculations employing 970-1160 atoms in a continuum solvent, combined with energy corrections for dispersion, zero-point energy and entropy, ligand distortion, ligand solvation, and an increase of the basis set to quadruple-zeta quality. Fourth, relative binding affinities were estimated by free-energy simulations, using the multi-state Bennett acceptance-ratio approach. Unfortunately, the results were varying and rather poor, with only one calculation giving a correlation to the experimental affinities larger than 0.7, and with no consistent difference in the quality of the predictions from the various methods. For one set of ligands, the results could be strongly improved (after experimental data were revealed) if it was recognised that one of the ligands displaced one or two water molecules. For the other two sets, the problem is probably that the ligands bind in different modes than in the crystal structures employed or that the conformation of the ligand-binding site or the whole protein changes.

  2. 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 examin...

  3. [Noise exposure in a dry dock].

    Science.gov (United States)

    Atzeri, S; Vacca, L

    1997-01-01

    Personal monitoring of noise exposure was conducted in a small dry dock, where mainly tug-boats and high sea fishing-boats are refitted. Manual tools were the prevalent noise sources. Noise exposure could be affected and amplified by factors extraneous to workers' tasks. The workers might be employed in different jobs simultaneously also in confined and small areas, and were mainly involved in non-routine tasks. Six different tasks were investigated: dry-dock supervisor, welder/ship-wrights, painters, electricians, woodworkers and unskilled workers. The number of workers employed in the tasks, with the exclusion of the supervisor, might change from day to day according to the particular work phase carried out on the boat. Daily personal exposure was measured using Larson Davis mod. 700 integrating sound level meters. The all shift time history of short equivalent continuous sound level with 10 s integrating time was collected for each selected worker. A 1/2 inch microphone was attached to the helmet at a distance of 11 +/- 1 cm from the right outer ear. Measurements were repeated over 13 days and randomly distributed over about four months. The number of data-points collected was nine for the supervisor, twenty-seven for the welders, eighteen for the painters, twelve for the electricians, six for the woodworkers and eleven for the unskilled workers. Ranges of the daily noise exposure level were from 15 to 30 dBA for all tasks, with the exclusion of the woodworkers. The time histories relative to workers grouped in the same task were matched to verify the correlation. The daily exposure levels derived from correlated samples were substituted by their arithmetic mean. The analysis of variance applied to experimental distributions of daily exposure for four of the welders indicates that the difference of means (p > 0.3) is not significant. A similar conclusion is reached for painters when only this task is considered. If we take into account the exposures of painters

  4. 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.

  5. The Drosophila DOCK family protein sponge is involved in differentiation of R7 photoreceptor cells.

    Science.gov (United States)

    Eguchi, Koichi; Yoshioka, Yasuhide; Yoshida, Hideki; Morishita, Kazushige; Miyata, Seiji; Hiai, Hiroshi; Yamaguchi, Masamitsu

    2013-08-15

    The Drosophila sponge (spg)/CG31048 gene belongs to the dedicator of cytokinesis (DOCK) family genes that are conserved in a wide variety of species. DOCK family members are known as DOCK1-DOCK11 in mammals. Although DOCK1 and DOCK2 involve neurite elongation and immunocyte differentiation, respectively, the functions of other DOCK family members are not fully understood. Spg is a Drosophila homolog of mammalian DOCK3 and DOCK4. Specific knockdown of spg by the GMR-GAL4 driver in eye imaginal discs induced abnormal eye morphology in adults. To mark the photoreceptor cells in eye imaginal discs, we used a set of enhancer trap strains that express lacZ in various sets of photoreceptor cells. Immunostaining with anti-Spg antibodies and anti-lacZ antibodies revealed that Spg is localized mainly in R7 photoreceptor cells. Knockdown of spg by the GMR-GAL4 driver reduced signals of R7 photoreceptor cells, suggesting involvement of Spg in R7 cell differentiation. Furthermore, immunostaining with anti-dpERK antibodies showed the level of activated ERK signal was reduced extensively by knockdown of spg in eye discs, and both the defects in eye morphology and dpERK signals were rescued by over-expression of the Drosophila raf gene, a component of the ERK signaling pathway. Furthermore, the Duolink in situ Proximity Ligation Assay method detected interaction signals between Spg and Rap1 in and around the plasma membrane of the eye disc cells. Together, these results indicate Spg positively regulates the ERK pathway that is required for R7 photoreceptor cell differentiation and the regulation is mediated by interaction with Rap1 during development of the compound eye. Copyright © 2013 Elsevier Inc. All rights reserved.

  6. Computational protein-ligand docking and virtual drug screening with the AutoDock suite.

    Science.gov (United States)

    Forli, Stefano; Huey, Ruth; Pique, Michael E; Sanner, Michel F; Goodsell, David S; Olson, Arthur J

    2016-05-01

    Computational docking can be used to predict bound conformations and free energies of binding for small-molecule ligands to macromolecular targets. Docking is widely used for the study of biomolecular interactions and mechanisms, and it is applied to structure-based drug design. The methods are fast enough to allow virtual screening of ligand libraries containing tens of thousands of compounds. This protocol covers the docking and virtual screening methods provided by the AutoDock suite of programs, including a basic docking of a drug molecule with an anticancer target, a virtual screen of this target with a small ligand library, docking with selective receptor flexibility, active site prediction and docking with explicit hydration. The entire protocol will require ∼5 h.

  7. A Review on Quantitative Approaches for Dock Door Assignment in Cross-Docking

    Directory of Open Access Journals (Sweden)

    Adibah Shuib

    2012-01-01

    Full Text Available Cross docking is a relatively new technique in supply chain operations. It offers limited storage time to maximize the efficiency of goods transshipment. Efficient operation of a cross docking system requires an appropriate coordination of inbound and outbound flows, accurate planning and dynamic scheduling.  The planning strategies at cross docking terminals, which are receiving growing attention today, are the truck-to-door assignment and destination to door assignment problems. This paper provides a comprehensive literature review of quantitative approaches in dock door assignment problems of cross docking planning. The contributions of this paper are to identify the gap of knowledge in operational levels mainly in dock door assignment and to point out the future research direction in cross docking.

  8. Application of the PM6 semi-empirical method to modeling proteins enhances docking accuracy of AutoDock

    National Research Council Canada - National Science Library

    Bikadi, Zsolt; Hazai, Eszter

    2009-01-01

    .... AutoDockTools software, the interface for preparing input files for one of the most widely used docking programs AutoDock 4, utilizes the Gasteiger partial charge calculation method for both protein...

  9. Random codon re-encoding induces stable reduction of replicative fitness of Chikungunya virus in primate and mosquito cells.

    Directory of Open Access Journals (Sweden)

    Antoine Nougairede

    2013-02-01

    Full Text Available Large-scale codon re-encoding represents a powerful method of attenuating viruses to generate safe and cost-effective vaccines. In contrast to specific approaches of codon re-encoding which modify genome-scale properties, we evaluated the effects of random codon re-encoding on the re-emerging human pathogen Chikungunya virus (CHIKV, and assessed the stability of the resultant viruses during serial in cellulo passage. Using different combinations of three 1.4 kb randomly re-encoded regions located throughout the CHIKV genome six codon re-encoded viruses were obtained. Introducing a large number of slightly deleterious synonymous mutations reduced the replicative fitness of CHIKV in both primate and arthropod cells, demonstrating the impact of synonymous mutations on fitness. Decrease of replicative fitness correlated with the extent of re-encoding, an observation that may assist in the modulation of viral attenuation. The wild-type and two re-encoded viruses were passaged 50 times either in primate or insect cells, or in each cell line alternately. These viruses were analyzed using detailed fitness assays, complete genome sequences and the analysis of intra-population genetic diversity. The response to codon re-encoding and adaptation to culture conditions occurred simultaneously, resulting in significant replicative fitness increases for both re-encoded and wild type viruses. Importantly, however, the most re-encoded virus failed to recover its replicative fitness. Evolution of these viruses in response to codon re-encoding was largely characterized by the emergence of both synonymous and non-synonymous mutations, sometimes located in genomic regions other than those involving re-encoding, and multiple convergent and compensatory mutations. However, there was a striking absence of codon reversion (<0.4%. Finally, multiple mutations were rapidly fixed in primate cells, whereas mosquito cells acted as a brake on evolution. In conclusion, random

  10. PTools: an opensource molecular docking library.

    Science.gov (United States)

    Saladin, Adrien; Fiorucci, Sébastien; Poulain, Pierre; Prévost, Chantal; Zacharias, Martin

    2009-05-01

    Macromolecular docking is a challenging field of bioinformatics. Developing new algorithms is a slow process generally involving routine tasks that should be found in a robust library and not programmed from scratch for every new software application. We present an object-oriented Python/C++ library to help the development of new docking methods. This library contains low-level routines like PDB-format manipulation functions as well as high-level tools for docking and analyzing results. We also illustrate the ease of use of this library with the detailed implementation of a 3-body docking procedure. The PTools library can handle molecules at coarse-grained or atomic resolution and allows users to rapidly develop new software. The library is already in use for protein-protein and protein-DNA docking with the ATTRACT program and for simulation analysis. This library is freely available under the GNU GPL license, together with detailed documentation.

  11. Dock180 expression in epithelial ovarian tumors

    Institute of Scientific and Technical Information of China (English)

    Hui Wang; Huhua Ling; Zhenwei Yao

    2012-01-01

    Objective: The aim of our study was to investigate the expression of guanine nucleotide exchange factor Dock180 in ovarian tumor, and its significance in the initiation and progression of ovarian cancer.Methods: Immunohistochemical staining with SP method was conducted to identify the expression of Dock180 protein in epithelial ovarian tumor in 68 cases.Results: Dock180 present with higher expression in ovarian cancer, as compared with than that in low malignant tumor and benign ovarian tumor (P < 0.01).In ovarian cancer, Dock180 expression was increased with the increased FIGO stage and grade.Conclusion: Dock180 overexpression may play an important role in the development and progression of ovarian cancer and it could be used as a new measurement of malignant biological behavior of ovarian cancer.

  12. Flexible Ligand Docking Using Evolutionary Algorithms

    DEFF Research Database (Denmark)

    Thomsen, Rene

    2003-01-01

    The docking of ligands to proteins can be formulated as a computational problem where the task is to find the most favorable energetic conformation among the large space of possible protein–ligand complexes. Stochastic search methods such as evolutionary algorithms (EAs) can be used to sample large...... search spaces effectively and is one of the commonly used methods for flexible ligand docking. During the last decade, several EAs using different variation operators have been introduced, such as the ones provided with the AutoDock program. In this paper we evaluate the performance of different EA...... settings such as choice of variation operators, population size, and usage of local search. The comparison is performed on a suite of six docking problems previously used to evaluate the performance of search algorithms provided with the AutoDock program package. The results from our investigation confirm...

  13. Developing sporophytes transition from an inducible to a constitutive ecological strategy of desiccation tolerance in the moss Aloina ambigua: effects of desiccation on fitness.

    Science.gov (United States)

    Stark, Lloyd R; Brinda, John C

    2015-03-01

    Two ecological strategies of desiccation tolerance exist in plants, constitutive and inducible. Because of difficulties in culturing sporophytes, very little is known about desiccation tolerance in this generation and how desiccation affects sexual fitness. Cultured sporophytes and vegetative shoots from a single genotype of the moss Aloina ambigua raised in the laboratory were tested for their strategy of desiccation tolerance by desiccating the shoot-sporophyte complex and vegetative shoots at different intensities, and comparing outcomes with those of undried shoot-sporophyte complexes and vegetative shoots. By using a dehardened clonal line, the effects of field, age and genetic variance among plants were removed. The gametophyte and embryonic sporophyte were found to employ a predominantly inducible strategy of desiccation tolerance, while the post-embryonic sporophyte was found to employ a moderately constitutive strategy of desiccation tolerance. Further, desiccation reduced sporophyte fitness, as measured by sporophyte mass, seta length and capsule size. However, the effects of desiccation on sporophyte fitness were reduced if the stress occurred during embryonic development as opposed to postembryonic desiccation. The effects of desiccation on dehardened sporophytes of a bryophyte are shown for the first time. The transition from one desiccation tolerance strategy to the other in a single structure or generation is shown for only the second time in plants and for the first time in bryophytes. Finding degrees of inducible strategies of desiccation tolerance in different life phases prompts the formulation of a continuum hypothesis of ecological desiccation tolerance in mosses, where desiccation tolerance is not an either/or phenomenon, but varies in degree along a gradient of ecological inducibility. © The Author 2015. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For Permissions, please email

  14. Why old tires are still being preferred as dock bumpers in harbours

    CERN Document Server

    Lagos, Miguel

    2012-01-01

    The usage of old tires as dock and tugboat bumpers has been a common practice from long ago, proving to be safe for docking even the largest freighters. The reaction force and stored energy of an axially compressed tire is studied in order to determine the specific features of these variables that make tires so adequate as docking protections. The reaction force is attributed to the elastic deformation of the tread, which is modeled as a not too thin cylindrical shell. Most energy absorption takes place after tread buckling, which bends tread and increases its circumference, inducing strong tensile forces that contribute to stabilize the buckled structure. Results shed light on the mechanical properties that a designed dock bumper should exhibit.

  15. Cucumber mosaic virus satellite RNAs that induce similar symptoms in melon plants show large differences in fitness.

    Science.gov (United States)

    Betancourt, Mónica; Fraile, Aurora; García-Arenal, Fernando

    2011-08-01

    Two groups of Cucumber mosaic virus (CMV) satellite RNAs (satRNAs), necrogenic and non-necrogenic, can be differentiated according to the symptoms they cause in tomato plants, a host in which they also differ in fitness. In most other CMV hosts these CMV-satRNA cause similar symptoms. Here, we analyse whether they differ in traits determining their relative fitness in melon plants, in which the two groups of CMV-satRNAs cause similar symptoms. For this, ten necrogenic and ten non-necrogenic field satRNA genotypes were assayed with Fny-CMV as a helper virus. Neither type of CMV-satRNA modified Fny-CMV symptoms, and both types increased Fny-CMV virulence similarly, as measured by decreases in plant biomass and lifespan. Necrogenic and non-necrogenic satRNAs differed in their ability to multiply in melon tissues; necrogenic satRNAs accumulated to higher levels both in single infection and in competition with non-necrogenic satRNAs. Indeed, multiplication of some non-necrogenic satRNAs was undetectable. Transmission between hosts by aphids was less efficient for necrogenic satRNAs as a consequence of a more severe reduction of CMV accumulation in leaves. The effect of CMV accumulation on aphid transmission was not compensated for by differences in satRNA encapsidation efficiency or transmissibility to CMV progeny. Thus, necrogenic and non-necrogenic satRNAs differ in their relative fitness in melon, and trade-offs are apparent between the within-host and between-host components of satRNA fitness. Hence, CMV-satRNAs could have different evolutionary dynamics in CMV host-plant species in which they do not differ in pathogenicity.

  16. The Drosophila DOCK family protein Sponge is required for development of the air sac primordium.

    Science.gov (United States)

    Morishita, Kazushge; Anh Suong, Dang Ngoc; Yoshida, Hideki; Yamaguchi, Masamitsu

    2017-05-15

    Dedicator of cytokinesis (DOCK) family genes are known as DOCK1-DOCK11 in mammals. DOCK family proteins mainly regulate actin filament polymerization and/or depolymerization and are GEF proteins, which contribute to cellular signaling events by activating small G proteins. Sponge (Spg) is a Drosophila counterpart to mammalian DOCK3/DOCK4, and plays a role in embryonic central nervous system development, R7 photoreceptor cell differentiation, and adult thorax development. In order to conduct further functional analyses on Spg in vivo, we examined its localization in third instar larval wing imaginal discs. Immunostaining with purified anti-Spg IgG revealed that Spg mainly localized in the air sac primordium (ASP) in wing imaginal discs. Spg is therefore predicted to play an important role in the ASP. The specific knockdown of Spg by the breathless-GAL4 driver in tracheal cells induced lethality accompanied with a defect in ASP development and the induction of apoptosis. The monitoring of ERK signaling activity in wing imaginal discs by immunostaining with anti-diphospho-ERK IgG revealed reductions in the ERK signal cascade in Spg knockdown clones. Furthermore, the overexpression of D-raf suppressed defects in survival and the proliferation of cells in the ASP induced by the knockdown of Spg. Collectively, these results indicate that Spg plays a critical role in ASP development and tracheal cell viability that is mediated by the ERK signaling pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Fitness cost

    DEFF Research Database (Denmark)

    Nielsen, Karen L.; Pedersen, Thomas M.; Udekwu, Klas I.

    2012-01-01

    of each isolate was determined in a growth competition assay with a reference isolate. Significant fitness costs of 215 were determined for the MRSA isolates studied. There was a significant negative correlation between number of antibiotic resistances and relative fitness. Multiple regression analysis...... to that seen in Denmark. We propose a significant fitness cost of resistance as the main bacteriological explanation for the disappearance of the multiresistant complex 83A MRSA in Denmark following a reduction in antibiotic usage.......Denmark and several other countries experienced the first epidemic of methicillin-resistant Staphylococcus aureus (MRSA) during the period 196575, which was caused by multiresistant isolates of phage complex 83A. In Denmark these MRSA isolates disappeared almost completely, being replaced by other...

  18. 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.

  19. Laser docking sensor engineering model

    Science.gov (United States)

    Dekome, Kent; Barr, Joseph M.

    NASA JSC has been involved in the development of Laser sensors for the past ten years in order to support future rendezvous and docking missions, both manned and unmanned. Although many candidate technologies have been breadboarded and evaluated, no sensor hardware designed specifically for rendezvous and docking applications has been demonstrated on-orbit. It has become apparent that representative sensors need to be flown and demonstrated as soon as possible, with minimal cost, to provide the capability of the technology in meeting NASA's future AR&C applications. Technology and commercial component reliability have progressed to where it is now feasible to fly hardware as a detailed test objective minimizing the overall cost and development time. This presentation will discuss the ongoing effort to convert an existing in-house developed breadboard to an engineering model configuration suitable for flight. The modifications include improving the ranger resolution and stability with an in-house design, replacing the rack mounted galvanometric scanner drivers with STD-bus cards, replacing the system controlling personal computer with a microcontroller, and repackaging the subsystems as appropriate. The sensor will use the performance parameters defined in previous JSC requirements working groups as design goals and be built to withstand the space environment where fiscally feasible. Testing of the in-house ranger design is expected to be completed in October. The results will be included in the presentation. Preliminary testing of the ranging circuitry indicates a range resolution of 4mm is possible. The sensor will be mounted in the payload bay on a shelf bracket and have command, control, and display capabilities using the payload general support computer via an RS422 data line.

  20. Fitness Club

    CERN Multimedia

    Fitness Club

    2012-01-01

    Get in Shape for Summer with the CERN Fitness Club Saturday 23 June 2012 from 14:30 to 16.30 (doors open at 14.00) Germana’s Fitness Workshop. Build strength and stamina, sculpt and tone your body and get your heart pumping with Germana’s workout mixture of Cardio Attack, Power Pump, Power Step, Cardio Combat and Cross-Training. Where: 216 (Pump room – equipped with changing rooms and showers). What to wear: comfortable clothes and indoor sports shoes + bring a drink! How much: 15 chf Sign up here: https://espace.cern.ch/club-fitness/Lists/Test_Subscription/NewForm.aspx? Join the Party and dance yourself into shape at Marco + Marials Zumba Masterclass. Saturday 30 June 2012 from 15:00 to 16:30 Marco + Mariel’s Zumba Masterclass Where: 216 (Pump room – equipped with changing rooms and showers). What to wear: comfortable clothes and indoor sports shoes + bring a drink! How much: 25 chf Sign up here: https://espace.cern.ch/club-fitness/Lists/Zumba%20...

  1. Fitness Club

    CERN Multimedia

    Fitness Club

    2012-01-01

      The CERN Fitness Club is pleased to announce its new early morning class which will be taking place on: Tuesdays from 24th April 07:30 to 08:15 216 (Pump Hall, close to entrance C) – Facilities include changing rooms and showers. The Classes: The early morning classes will focus on workouts which will help you build not only strength and stamina, but will also improve your balance, and coordination. Our qualified instructor Germana will accompany you throughout the workout  to ensure you stay motivated so you achieve the best results. Sign up and discover the best way to start your working day full of energy! How to subscribe? We invite you along to a FREE trial session, if you enjoy the activity, please sign up via our website: https://espace.cern.ch/club-fitness/Activities/SUBSCRIBE.aspx. * * * * * * * * Saturday 28th April Get in shape for the summer at our fitness workshop and zumba dance party: Fitness workshop with Germana 13:00 to 14:30 - 216 (Pump Hall) Price...

  2. Fitness club

    CERN Multimedia

    Fitness club

    2013-01-01

      Nordic Walking Classes Come join the Nordic walking classes and outings offered by the CERN Fitness Club starting September 2013. Our licensed instructor Christine offers classes for people who’ve never tried Nordic Walking and who would like to learn the technique, and outings for people who have completed the classes and enjoy going out as a group. Course 1: Tuesdays 12:30 - 13:30 24 September, 1 October, 8 October, 15 October Course 2: Tuesdays 12:30 - 13:30 5 November, 12 November, 19 November, 26 November Outings will take place on Thursdays (12:30 to 13:30) from 12 September 2013. We meet at the CERN Club Barracks car park (close to Entrance A) 10 minutes before departure. Prices: 50 CHF for 4 classes, including the 10 CHF Club membership. Payments made directly to instructor. Renting Poles: Poles can be rented from Christine at 5 CHF / hour. Subscription: Please subscribe at: http://cern.ch/club-fitness Looking forward to seeing you among us! Fitness Club FitnessClub@c...

  3. Retraction: Open and closed conformations reveal induced fit movements in butyrate kinase 2 activation. J. Diao, Y. D. Ma, and M. S. Hasson.

    Science.gov (United States)

    2012-06-01

    The following article from Proteins: Structure, Function, and Bioinformatics, "Open and closed conformations reveal induced fit movements in butyrate kinase 2 activation," by Jiasheng Diao, Yunglin D. Ma, and Miriam S. Hasson, published online on 21 October 2010 in Wiley Online Library (onlinelibrary.wiley.com), has been retracted by agreement between the journal Editor in Chief, Bertrand Garcia-Moreno, and Wiley Periodicals. The retraction has been agreed because it was established by internal investigation performed by Purdue University that the authors of this article are not the owners of the data and have no right to publication.

  4. Catalytic Efficiency Is a Function of How Rhodium(I) (5 + 2) Catalysts Accommodate a Conserved Substrate Transition State Geometry: Induced Fit Model for Explaining Transition Metal Catalysis.

    Science.gov (United States)

    Mustard, Thomas J L; Wender, Paul A; Cheong, Paul Ha-Yeon

    2015-03-06

    The origins of differential catalytic reactivities of four Rh(I) catalysts and their derivatives in the (5 + 2) cycloaddition reaction were elucidated using density functional theory. Computed free energy spans are in excellent agreement with known experimental rates. For every catalyst, the substrate geometries in the transition state remained constant (Catalytic efficiency is shown to be a function of how well the catalyst accommodates the substrate transition state geometry and electronics. This shows that the induced fit model for explaining biological catalysis may be relevant to transition metal catalysis. This could serve as a general model for understanding the origins of efficiencies of catalytic reactions.

  5. Advanced Docking System With Magnetic Initial Capture

    Science.gov (United States)

    Lewis, James L.; Carroll, Monty B.; Morales, Ray; Le, Thang

    2004-01-01

    An advanced docking system is undergoing development to enable softer, safer docking than was possible when using prior docking systems. This system is intended for original use in docking of visiting spacecraft and berthing the Crew Return Vehicle at the International Space Station (ISS). The system could also be adapted to a variety of other uses in outer space and on Earth, including mating submersible vehicles, assembling structures, and robotic berthing/handling of payloads and cargo. Heretofore, two large spacecraft have been docked by causing the spacecraft to approach each other at a speed sufficient to activate capture latches - a procedure that results in large docking loads and is made more difficult because of the speed. The basic design and mode of operation of the present advanced docking system would eliminate the need to rely on speed of approach to activate capture latches, thereby making it possible to reduce approach speed and thus docking loads substantially. The system would comprise an active subsystem on one spacecraft and a passive subsystem on another spacecraft with which the active subsystem will be docked. The passive subsystem would include an extensible ring containing magnetic striker plates and guide petals. The active subsystem would include mating guide petals and electromagnets containing limit switches and would be arranged to mate with the magnetic striker plates and guide petals of the passive assembly. The electromagnets would be carried on (but not rigidly attached to) a structural ring that would be instrumented with load sensors. The outputs of the sensors would be sent, along with position information, as feedback to an electronic control subsystem. The system would also include electromechanical actuators that would extend or retract the ring upon command by the control subsystem.

  6. Cognitive fitness.

    Science.gov (United States)

    Gilkey, Roderick; Kilts, Clint

    2007-11-01

    Recent neuroscientific research shows that the health of your brain isn't, as experts once thought, just the product of childhood experiences and genetics; it reflects your adult choices and experiences as well. Professors Gilkey and Kilts of Emory University's medical and business schools explain how you can strengthen your brain's anatomy, neural networks, and cognitive abilities, and prevent functions such as memory from deteriorating as you age. The brain's alertness is the result of what the authors call cognitive fitness -a state of optimized ability to reason, remember, learn, plan, and adapt. Certain attitudes, lifestyle choices, and exercises enhance cognitive fitness. Mental workouts are the key. Brain-imaging studies indicate that acquiring expertise in areas as diverse as playing a cello, juggling, speaking a foreign language, and driving a taxicab expands your neural systems and makes them more communicative. In other words, you can alter the physical makeup of your brain by learning new skills. The more cognitively fit you are, the better equipped you are to make decisions, solve problems, and deal with stress and change. Cognitive fitness will help you be more open to new ideas and alternative perspectives. It will give you the capacity to change your behavior and realize your goals. You can delay senescence for years and even enjoy a second career. Drawing from the rapidly expanding body of neuroscience research as well as from well-established research in psychology and other mental health fields, the authors have identified four steps you can take to become cognitively fit: understand how experience makes the brain grow, work hard at play, search for patterns, and seek novelty and innovation. Together these steps capture some of the key opportunities for maintaining an engaged, creative brain.

  7. Deletion of Dock10 in B Cells Results in Normal Development but a Mild Deficiency upon In Vivo and In Vitro Stimulations

    Directory of Open Access Journals (Sweden)

    Eva Severinson

    2017-05-01

    Full Text Available We sought to identify genes necessary to induce cytoskeletal change in B cells. Using gene expression microarray, we compared B cells stimulated with interleukin-4 (IL-4 and anti-CD40 antibodies that induce B cell spreading, cell motility, tight aggregates, and extensive microvilli with B cells stimulated with lipopolysaccharide that lack these cytoskeletal changes. We identified 84 genes with 10-fold or greater expression in anti-CD40 + IL-4 stimulated B cells, one of these encoded the guanine nucleotide exchange factor (GEF dedicator of cytokinesis 10 (Dock10. IL-4 selectively induced Dock10 expression in B cells. Using lacZ expression to monitor Dock10 promoter activity, we found that Dock10 was expressed at all stages during B cell development. However, specific deletion of Dock10 in B cells was associated with a mild phenotype with normal B cell development and normal B cell spreading, polarization, motility, chemotaxis, aggregation, and Ig class switching. Dock10-deficient B cells showed lower proliferation in response to anti-CD40 and IL-4 stimulation. Moreover, the IgG response to soluble antigen in vivo was lower when Dock10 was specifically deleted in B cells. Together, we found that most B cell responses were intact in the absence of Dock10. However, specific deletion of Dock10 in B cells was associated with a mild reduction in B cell activation in vitro and in vivo.

  8. Development of a Robotics-based Satellites Docking Simulator

    NARCIS (Netherlands)

    Zebenay, M.

    2014-01-01

    The European Proximity Operation Simulator (EPOS) is a hardware-in-the-loop (HIL) system aiming, among other objectives, at emulating on-orbit docking of spacecraft for verification and validation of the docking phase. This HIL docking simulator set-up essentially consists of docking interfaces, sim

  9. Docking and scoring of metallo-beta-lactamases inhibitors

    DEFF Research Database (Denmark)

    Olsen, Lars; Pettersson, Ingrid; Hemmingsen, Lars

    2004-01-01

    The performance of the AutoDock, GOLD and FlexX docking programs was evaluated for docking of dicarboxylic acid inhibitors into metallo-beta-lactamases (MBLs). GOLD provided the best overall performance, with RMSDs between experimental and docked structures of 1.8-2.6 A and a good correlation...

  10. Probing S-state advancements and recombination pathways in photosystem II with a global fit program for flash-induced oxygen evolution pattern.

    Science.gov (United States)

    Pham, Long Vo; Messinger, Johannes

    2016-06-01

    The oxygen-evolving complex (OEC) in photosystem II catalyzes the oxidation of water to molecular oxygen. Four decades ago, measurements of flash-induced oxygen evolution have shown that the OEC steps through oxidation states S(0), S(1), S(2), S(3) and S(4) before O(2) is released and the S(0) state is reformed. The light-induced transitions between these states involve misses and double hits. While it is widely accepted that the miss parameter is S state dependent and may be further modulated by the oxidation state of the acceptor side, the traditional way of analyzing each flash-induced oxygen evolution pattern (FIOP) individually did not allow using enough free parameters to thoroughly test this proposal. Furthermore, this approach does not allow assessing whether the presently known recombination processes in photosystem II fully explain all measured oxygen yields during Si state lifetime measurements. Here we present a global fit program that simultaneously fits all flash-induced oxygen yields of a standard FIOP (2 Hz flash frequency) and of 11-18 FIOPs each obtained while probing the S(0), S(2) and S(3) state lifetimes in spinach thylakoids at neutral pH. This comprehensive data treatment demonstrates the presence of a very slow phase of S(2) decay, in addition to the commonly discussed fast and slow reduction of S(2) by YD and QB(-), respectively. Our data support previous suggestions that the S(0)→S(1) and S(1)→S(2) transitions involve low or no misses, while high misses occur in the S(2)→S(3) or S(3)→S(0) transitions.

  11. Full structure building and docking of NifS from extremophile Acidithiobacillus ferrooxidans

    Institute of Scientific and Technical Information of China (English)

    LIU Yuan-dong; QIU Guan-zhou; WANG Hai-dong; JIANG Ying; ZHANG Cheng-gui; XIA Le-xia

    2008-01-01

    The gene iscS-2 from extremophile Acidithiobacillus ferrooxidans may play a crucial role in nitrogenase maturation. To investigate the protein encoded by this gene, a reliable integral three-dimensional molecular structure was built. The obtained structure was further used to search binding sites, carry out the flexible docking with cofactor pyridoxal 5′-phosphate(PLP) and substrate cysteine, and identify its key residues. The docking results of PLP reveal that the residues of Lys203, His100, Thr73, Ser200, His202, Asp177 and Gln180 have large interaction energies and/or hydrogen bonds fixation with PLP. The docking results of cysteine show that the amino group in cysteine is very near His100, Lys203 and PLP, and the interaction energies for cysteine with them are very big. These identified residues are in line with the experimental facts of NifS from other sources. Moreover, the four residues of Asn152, Val179, Ala102 and Met148 in the PLP docking and the two residues of Lys208 and Ala102 in the cysteine docking also have large interaction energies, which are fitly conserved in NifS from all kinds of sources but have not been identified before. According to these results, this gene encodes NifS protein, and the substrate cysteine can be effectively recruited into the active site. Furthermore, all of the above detected key residues are directly responsible for the binding and/or catalysis of PLP and cysteine.

  12. Fitness Club

    CERN Multimedia

    Fitness Club

    2012-01-01

    Nordic Walking Classes Sessions of four classes of one hour each are held on Tuesdays. RDV barracks parking at Entrance A, 10 minutes before class time. Session 1 =  11.09 / 18.09 / 25.09 / 02.10, 18:15 - 19:15 Session 2 = 25.09 / 02.10 / 09.10 / 16.10, 12:30 - 13:30 Session 3 = 23.10 / 30.10 / 06.11 / 13.11, 12:30 - 13:30 Session 4 = 20.11 / 27.11 / 04.12 / 11.12, 12:30 - 13:30 Prices 40 CHF per session + 10 CHF club membership 5 CHF/hour pole rental Check out our schedule and enroll at http://cern.ch/club-fitness   Hope to see you among us!  fitness.club@cern.ch In spring 2012 there was a long-awaited progress in CERN Fitness club. We have officially opened a Powerlifting @ CERN, and the number of members of the new section has been increasing since then reaching 70+ people in less than 4 months. Powerlifting is a strength sport, which is simple as 1-2-3 and efficient. The "1-2-3" are the three basic lifts (bench press...

  13. Pseudomonas fluorescens induces strain-dependent and strain-independent host plant responses in defense networks, primary metabolism, photosynthesis, and fitness.

    Science.gov (United States)

    Weston, David J; Pelletier, Dale A; Morrell-Falvey, Jennifer L; Tschaplinski, Timothy J; Jawdy, Sara S; Lu, Tse-Yuan; Allen, Sara M; Melton, Sarah J; Martin, Madhavi Z; Schadt, Christopher W; Karve, Abhijit A; Chen, Jin-Gui; Yang, Xiaohan; Doktycz, Mitchel J; Tuskan, Gerald A

    2012-06-01

    Colonization of plants by nonpathogenic Pseudomonas fluorescens strains can confer enhanced defense capacity against a broad spectrum of pathogens. Few studies, however, have linked defense pathway regulation to primary metabolism and physiology. In this study, physiological data, metabolites, and transcript profiles are integrated to elucidate how molecular networks initiated at the root-microbe interface influence shoot metabolism and whole-plant performance. Experiments with Arabidopsis thaliana were performed using the newly identified P. fluorescens GM30 or P. fluorescens Pf-5 strains. Co-expression networks indicated that Pf-5 and GM30 induced a subnetwork specific to roots enriched for genes participating in RNA regulation, protein degradation, and hormonal metabolism. In contrast, only GM30 induced a subnetwork enriched for calcium signaling, sugar and nutrient signaling, and auxin metabolism, suggesting strain dependence in network architecture. In addition, one subnetwork present in shoots was enriched for genes in secondary metabolism, photosynthetic light reactions, and hormone metabolism. Metabolite analysis indicated that this network initiated changes in carbohydrate and amino acid metabolism. Consistent with this, we observed strain-specific responses in tryptophan and phenylalanine abundance. Both strains reduced host plant carbon gain and fitness, yet provided a clear fitness benefit when plants were challenged with the pathogen P. syringae DC3000.

  14. AutoDockFR: Advances in Protein-Ligand Docking with Explicitly Specified Binding Site Flexibility.

    Directory of Open Access Journals (Sweden)

    Pradeep Anand Ravindranath

    2015-12-01

    Full Text Available Automated docking of drug-like molecules into receptors is an essential tool in structure-based drug design. While modeling receptor flexibility is important for correctly predicting ligand binding, it still remains challenging. This work focuses on an approach in which receptor flexibility is modeled by explicitly specifying a set of receptor side-chains a-priori. The challenges of this approach include the: 1 exponential growth of the search space, demanding more efficient search methods; and 2 increased number of false positives, calling for scoring functions tailored for flexible receptor docking. We present AutoDockFR-AutoDock for Flexible Receptors (ADFR, a new docking engine based on the AutoDock4 scoring function, which addresses the aforementioned challenges with a new Genetic Algorithm (GA and customized scoring function. We validate ADFR using the Astex Diverse Set, demonstrating an increase in efficiency and reliability of its GA over the one implemented in AutoDock4. We demonstrate greatly increased success rates when cross-docking ligands into apo receptors that require side-chain conformational changes for ligand binding. These cross-docking experiments are based on two datasets: 1 SEQ17 -a receptor diversity set containing 17 pairs of apo-holo structures; and 2 CDK2 -a ligand diversity set composed of one CDK2 apo structure and 52 known bound inhibitors. We show that, when cross-docking ligands into the apo conformation of the receptors with up to 14 flexible side-chains, ADFR reports more correctly cross-docked ligands than AutoDock Vina on both datasets with solutions found for 70.6% vs. 35.3% systems on SEQ17, and 76.9% vs. 61.5% on CDK2. ADFR also outperforms AutoDock Vina in number of top ranking solutions on both datasets. Furthermore, we show that correctly docked CDK2 complexes re-create on average 79.8% of all pairwise atomic interactions between the ligand and moving receptor atoms in the holo complexes. Finally, we

  15. AutoDockFR: Advances in Protein-Ligand Docking with Explicitly Specified Binding Site Flexibility.

    Science.gov (United States)

    Ravindranath, Pradeep Anand; Forli, Stefano; Goodsell, David S; Olson, Arthur J; Sanner, Michel F

    2015-12-01

    Automated docking of drug-like molecules into receptors is an essential tool in structure-based drug design. While modeling receptor flexibility is important for correctly predicting ligand binding, it still remains challenging. This work focuses on an approach in which receptor flexibility is modeled by explicitly specifying a set of receptor side-chains a-priori. The challenges of this approach include the: 1) exponential growth of the search space, demanding more efficient search methods; and 2) increased number of false positives, calling for scoring functions tailored for flexible receptor docking. We present AutoDockFR-AutoDock for Flexible Receptors (ADFR), a new docking engine based on the AutoDock4 scoring function, which addresses the aforementioned challenges with a new Genetic Algorithm (GA) and customized scoring function. We validate ADFR using the Astex Diverse Set, demonstrating an increase in efficiency and reliability of its GA over the one implemented in AutoDock4. We demonstrate greatly increased success rates when cross-docking ligands into apo receptors that require side-chain conformational changes for ligand binding. These cross-docking experiments are based on two datasets: 1) SEQ17 -a receptor diversity set containing 17 pairs of apo-holo structures; and 2) CDK2 -a ligand diversity set composed of one CDK2 apo structure and 52 known bound inhibitors. We show that, when cross-docking ligands into the apo conformation of the receptors with up to 14 flexible side-chains, ADFR reports more correctly cross-docked ligands than AutoDock Vina on both datasets with solutions found for 70.6% vs. 35.3% systems on SEQ17, and 76.9% vs. 61.5% on CDK2. ADFR also outperforms AutoDock Vina in number of top ranking solutions on both datasets. Furthermore, we show that correctly docked CDK2 complexes re-create on average 79.8% of all pairwise atomic interactions between the ligand and moving receptor atoms in the holo complexes. Finally, we show that down

  16. Fully automated flexible docking of ligands into flexible synthetic receptors using forward and inverse docking strategies.

    Science.gov (United States)

    Kämper, Andreas; Apostolakis, Joannis; Rarey, Matthias; Marian, Christel M; Lengauer, Thomas

    2006-01-01

    The prediction of the structure of host-guest complexes is one of the most challenging problems in supramolecular chemistry. Usual procedures for docking of ligands into receptors do not take full conformational freedom of the host molecule into account. We describe and apply a new docking approach which performs a conformational sampling of the host and then sequentially docks the ligand into all receptor conformers using the incremental construction technique of the FlexX software platform. The applicability of this approach is validated on a set of host-guest complexes with known crystal structure. Moreover, we demonstrate that due to the interchangeability of the roles of host and guest, the docking process can be inverted. In this inverse docking mode, the receptor molecule is docked around its ligand. For all investigated test cases, the predicted structures are in good agreement with the experiment for both normal (forward) and inverse docking. Since the ligand is often smaller than the receptor and, thus, its conformational space is more restricted, the inverse docking approach leads in most cases to considerable speed-up. By having the choice between two alternative docking directions, the application range of the method is significantly extended. Finally, an important result of this study is the suitability of the simple energy function used here for structure prediction of complexes in organic media.

  17. 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

    In pig production, piglets are tail docked at birth in order to prevent tail biting later in life. In order to examine the effects of tail docking and docking length on the formation of neuromas, we used 65 pigs and the following four treatments: intact tails (n=18); leaving 75% (n=17); leaving 50......% (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...

  18. GPU.proton.DOCK: Genuine Protein Ultrafast proton equilibria consistent DOCKing.

    Science.gov (United States)

    Kantardjiev, Alexander A

    2011-07-01

    GPU.proton.DOCK (Genuine Protein Ultrafast proton equilibria consistent DOCKing) is a state of the art service for in silico prediction of protein-protein interactions via rigorous and ultrafast docking code. It is unique in providing stringent account of electrostatic interactions self-consistency and proton equilibria mutual effects of docking partners. GPU.proton.DOCK is the first server offering such a crucial supplement to protein docking algorithms--a step toward more reliable and high accuracy docking results. The code (especially the Fast Fourier Transform bottleneck and electrostatic fields computation) is parallelized to run on a GPU supercomputer. The high performance will be of use for large-scale structural bioinformatics and systems biology projects, thus bridging physics of the interactions with analysis of molecular networks. We propose workflows for exploring in silico charge mutagenesis effects. Special emphasis is given to the interface-intuitive and user-friendly. The input is comprised of the atomic coordinate files in PDB format. The advanced user is provided with a special input section for addition of non-polypeptide charges, extra ionogenic groups with intrinsic pK(a) values or fixed ions. The output is comprised of docked complexes in PDB format as well as interactive visualization in a molecular viewer. GPU.proton.DOCK server can be accessed at http://gpudock.orgchm.bas.bg/.

  19. PSI-DOCK: towards highly efficient and accurate flexible ligand docking.

    Science.gov (United States)

    Pei, Jianfeng; Wang, Qi; Liu, Zhenming; Li, Qingliang; Yang, Kun; Lai, Luhua

    2006-03-01

    We have developed a new docking method, Pose-Sensitive Inclined (PSI)-DOCK, for flexible ligand docking. An improved SCORE function has been developed and used in PSI-DOCK for binding free energy evaluation. The improved SCORE function was able to reproduce the absolute binding free energies of a training set of 200 protein-ligand complexes with a correlation coefficient of 0.788 and a standard error of 8.13 kJ/mol. For ligand binding pose exploration, a unique searching strategy was designed in PSI-DOCK. In the first step, a tabu-enhanced genetic algorithm with a rapid shape-complementary scoring function is used to roughly explore and store potential binding poses of the ligand. Then, these predicted binding poses are optimized and compete against each other by using a genetic algorithm with the accurate SCORE function to determine the binding pose with the lowest docking energy. The PSI-DOCK 1.0 program is highly efficient in identifying the experimental binding pose. For a test dataset of 194 complexes, PSI-DOCK 1.0 achieved a 67% success rate (RMSD DOCK can also predict the docking binding free energy with high accuracy. For a test set of 64 complexes, the correlation between the experimentally observed binding free energies and the docking binding free energies for 64 complexes is r = 0.777 with a standard deviation of 7.96 kJ/mol. Moreover, compared with other docking methods, PSI-DOCK 1.0 is extremely easy to use and requires minimum docking preparations. There is no requirement for the users to add hydrogen atoms to proteins because all protein hydrogen atoms and the flexibility of the terminal protein atoms are intrinsically taken into account in PSI-DOCK. There is also no requirement for the users to calculate partial atomic charges because PSI-DOCK does not calculate an electrostatic energy term. These features are not only convenient for the users but also help to avoid the influence of different preparation methods. 2006 Wiley-Liss, Inc.

  20. Evaluation of OMV ranging and docking systems

    Science.gov (United States)

    McDonald, M. W.

    1985-01-01

    The Orbital Maneuvering Vehicle (OMV) will serve as a shuttle-based or permanent space station-based vehicle designed to rendezvous and soft dock with various other free-flying space vehicles for purposes of inspection, support, and retrieval. This study is concerned primarily with the eventual need for the OMV to rendezvous and dock softly with the Edwin P. Hubble Space Telescope (ST). Utilizing the available capabilities of the large microwave anechoic chamber facility at Marshall Space Flight Center for simulating docking target vehicle motions in a free-space environment, a program is being devised for benchmark testing of rendezvous and docking sensor systems proposed for use on the OMV. A testing regimen suitable for evaluating the accuracy and tracking agility in sensing range, range rate, and angle information at close ranges (0 R 30m) has been developed.

  1. Next generation of dock safety equipment.

    Science.gov (United States)

    Swietlik, Walt

    2013-09-01

    OSHA and forklift manufacturers have made extensive efforts to improve the safety of forklift operation in and around industrial facilities and warehouses. However, the use of next-generation vehicle restraint and light communications technology will go much farther toward protecting forklift operators and pedestrians, reducing accidents, and improving productivity at the loading dock. While these new technologies mark a significant advance in loading dock safety, they cannot replace forklift and loading dock safety policies. Employers must continue to focus on forklift safety training and consider the use of multiple safety devices, such as strategically placed signs, painted aisles, and guarded walkways. The best practice is to seek the advice of safety consultants and qualified loading dock equipment representatives.

  2. Dockomatic - automated ligand creation and docking

    OpenAIRE

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

    2010-01-01

    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 frie...

  3. Multiple receptor conformation docking, dock pose clustering and 3D QSAR studies on human poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors.

    Science.gov (United States)

    Fatima, Sabiha; Jatavath, Mohan Babu; Bathini, Raju; Sivan, Sree Kanth; Manga, Vijjulatha

    2014-10-01

    Poly(ADP-ribose) polymerase-1 (PARP-1) functions as a DNA damage sensor and signaling molecule. It plays a vital role in the repair of DNA strand breaks induced by radiation and chemotherapeutic drugs; inhibitors of this enzyme have the potential to improve cancer chemotherapy or radiotherapy. Three-dimensional quantitative structure activity relationship (3D QSAR) models were developed using comparative molecular field analysis, comparative molecular similarity indices analysis and docking studies. A set of 88 molecules were docked into the active site of six X-ray crystal structures of poly(ADP-ribose)polymerase-1 (PARP-1), by a procedure called multiple receptor conformation docking (MRCD), in order to improve the 3D QSAR models through the analysis of binding conformations. The docked poses were clustered to obtain the best receptor binding conformation. These dock poses from clustering were used for 3D QSAR analysis. Based on MRCD and QSAR information, some key features have been identified that explain the observed variance in the activity. Two receptor-based QSAR models were generated; these models showed good internal and external statistical reliability that is evident from the [Formula: see text], [Formula: see text] and [Formula: see text]. The identified key features enabled us to design new PARP-1 inhibitors.

  4. Triangulation methods for automated docking

    Science.gov (United States)

    Bales, John W.

    1996-01-01

    An automated docking system must have a reliable method for determining range and orientation of the passive (target) vehicle with respect to the active vehicle. This method must also provide accurate information on the rates of change of range to and orientation of the passive vehicle. The method must be accurate within required tolerances and capable of operating in real time. The method being developed at Marshall Space Flight Center employs a single TV camera, a laser illumination system and a target consisting, in its minimal configuration, of three retro-reflectors. Two of the retro-reflectors are mounted flush to the same surface, with the third retro-reflector mounted to a post fixed midway between the other two and jutting at a right angle from the surface. For redundancy, two additional retroreflectors are mounted on the surface on a line at right angles to the line containing the first two retro-reflectors, and equally spaced on either side of the post. The target vehicle will contain a large target for initial acquisition and several smaller targets for close range.

  5. 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.

  6. 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.

  7. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading.

    Science.gov (United States)

    Trott, Oleg; Olson, Arthur J

    2010-01-30

    AutoDock Vina, a new program for molecular docking and virtual screening, is presented. AutoDock Vina achieves an approximately two orders of magnitude speed-up compared with the molecular docking software previously developed in our lab (AutoDock 4), while also significantly improving the accuracy of the binding mode predictions, judging by our tests on the training set used in AutoDock 4 development. Further speed-up is achieved from parallelism, by using multithreading on multicore machines. AutoDock Vina automatically calculates the grid maps and clusters the results in a way transparent to the user. Copyright 2009 Wiley Periodicals, Inc.

  8. Milk Yield of Holstein Cows Induced into Lactation Twice Consecutively and Lactation Curve Models Fitted to Artiifcial Lactations

    Institute of Scientific and Technical Information of China (English)

    Jesus Mellado; Edgar Sepulveda; Jose E Garcia; Alvaro Rodriguez; Maria A De Santiago; Francisco G Veliz; Miguel Mellado

    2014-01-01

    Nineteen multiparous barren Holstein cows were subjected to an induction of lactation protocol for 21 d administering estradiol cypionate (2 mg kg-1 of body weight (BW) d-1, on day 1 to 14), progesterone (0.10 mg kg-1 of BW, on day 1 to 7), lfumethasone (0.03 mg kg-1 of BW, on day 18 to 20) and recombinant bovine somatotropin (rbST;500 mg per cow, on day 1, 6, 16 and 21). At the end of lactation and with a minimum of a 2-mon dry period, the same cows were again hormonally induced into lactation. Cows in both lactations were not artiifcially inseminated, they were milked 3 times daily and received rbST throughout lactation. Mean accumulated milk yield at 305 d in milk (DIM) did not differ between the ifrst and second induced lactations ((9 710 ±1 728) vs. (9 309±2 150) kg;mean±SD). Total milk yield ((12 707±3 406) vs. (12 306±4 218) kg;mean±SD) and lactation length ((405±100) vs. (410±91) d;mean±SD) were not different between the ifrst and second induced lactations. In a second study, 15 empirical models including exponential, power law, yield-density, sigmoidal and miscellaneous models were compared for their suitability by modeling 12-mon (n=334), 18-mon (n=164) and 29-mon (n=22) lactation cycles of Holsteins cows induced into lactation and treated with rbST throughout the lactation. Hoerl (Y=ab1/xxc), Wood (Y=axb exp(cx)) and Dhanoa (Y=ax(bc)exp(cx)) models were equally suitable to describe 12-mon lactations. An exponential model with ifve parameters (Y=exp(a+bx+cd2+e/x)) showed the best ift for milk yield for 18-mon lactations. The rational model (Y=a+bx/1+cx+dx2) was found to produce the closest ift for 29-mon lactations. It was concluded that, with the protocol used in the present study, multiparous cows respond favorably to a second cycle of induced lactation, with milk yield similar to that experienced during the ifrst cycle. Thus, dairy producers might be able to lengthen the productive life of infertile high producing cows with a renewal of

  9. Fitness club

    CERN Multimedia

    Fitness club

    2013-01-01

    Nordic Walking Classes New session of 4 classes of 1 hour each will be held on Tuesdays in May 2013. Meet at the CERN barracks parking at Entrance A, 10 minutes before class time. Dates and time: 07.05, 14.05, 21.05 and 28.05, fom  12 h 30 to 13 h 30 Prices: 40 CHF per session + 10 CHF club membership – 5 CHF / hour pole rental Check out our schedule and enroll at http://cern.ch/club-fitness Hope to see you among us! 

  10. "Soft docking": matching of molecular surface cubes.

    Science.gov (United States)

    Jiang, F; Kim, S H

    1991-05-05

    Molecular recognition is achieved through the complementarity of molecular surface structures and energetics with, most commonly, associated minor conformational changes. This complementarity can take many forms: charge-charge interaction, hydrogen bonding, van der Waals' interaction, and the size and shape of surfaces. We describe a method that exploits these features to predict the sites of interactions between two cognate molecules given their three-dimensional structures. We have developed a "cube representation" of molecular surface and volume which enables us not only to design a simple algorithm for a six-dimensional search but also to allow implicitly the effects of the conformational changes caused by complex formation. The present molecular docking procedure may be divided into two stages. The first is the selection of a population of complexes by geometric "soft docking", in which surface structures of two interacting molecules are matched with each other, allowing minor conformational changes implicitly, on the basis of complementarity in size and shape, close packing, and the absence of steric hindrance. The second is a screening process to identify a subpopulation with many favorable energetic interactions between the buried surface areas. Once the size of the subpopulation is small, one may further screen to find the correct complex based on other criteria or constraints obtained from biochemical, genetic, and theoretical studies, including visual inspection. We have tested the present method in two ways. First is a control test in which we docked the components of a molecular complex of known crystal structure available in the Protein Data Bank (PDB). Two molecular complexes were used: (1) a ternary complex of dihydrofolate reductase, NADPH and methotrexate (3DFR in PDB) and (2) a binary complex of trypsin and trypsin inhibitor (2PTC in PDB). The components of each complex were taken apart at an arbitrary relative orientation and then docked

  11. Structural evidence for induced fit and a mechanism for sugar/H+ symport in LacY

    DEFF Research Database (Denmark)

    Mirza, Osman Asghar; Guan, Lan; Verner, Gill

    2006-01-01

    Cation-coupled active transport is an essential cellular process found ubiquitously in all living organisms. Here, we present two novel ligand-free X-ray structures of the lactose permease (LacY) of Escherichia coli determined at acidic and neutral pH, and propose a model for the mechanism...... of coupling between lactose and H+ translocation. No sugar-binding site is observed in the absence of ligand, and deprotonation of the key residue Glu269 is associated with ligand binding. Thus, substrate induces formation of the sugar-binding site, as well as the initial step in H+ transduction....

  12. SwissDock, a protein-small molecule docking web service based on EADock DSS.

    Science.gov (United States)

    Grosdidier, Aurélien; Zoete, Vincent; Michielin, Olivier

    2011-07-01

    Most life science processes involve, at the atomic scale, recognition between two molecules. The prediction of such interactions at the molecular level, by so-called docking software, is a non-trivial task. Docking programs have a wide range of applications ranging from protein engineering to drug design. This article presents SwissDock, a web server dedicated to the docking of small molecules on target proteins. It is based on the EADock DSS engine, combined with setup scripts for curating common problems and for preparing both the target protein and the ligand input files. An efficient Ajax/HTML interface was designed and implemented so that scientists can easily submit dockings and retrieve the predicted complexes. For automated docking tasks, a programmatic SOAP interface has been set up and template programs can be downloaded in Perl, Python and PHP. The web site also provides an access to a database of manually curated complexes, based on the Ligand Protein Database. A wiki and a forum are available to the community to promote interactions between users. The SwissDock web site is available online at http://www.swissdock.ch. We believe it constitutes a step toward generalizing the use of docking tools beyond the traditional molecular modeling community.

  13. Critical assessment of the automated AutoDock as a new docking tool for virtual screening.

    Science.gov (United States)

    Park, Hwangseo; Lee, Jinuk; Lee, Sangyoub

    2006-11-15

    A major problem in virtual screening concerns the accuracy of the binding free energy between a target protein and a putative ligand. Here we report an example supporting the outperformance of the AutoDock scoring function in virtual screening in comparison to the other popular docking programs. The original AutoDock program is in itself inefficient to be used in virtual screening because the grids of interaction energy have to be calculated for each putative ligand in chemical database. However, the automation of the AutoDock program with the potential grids defined in common for all putative ligands leads to more than twofold increase in the speed of virtual database screening. The utility of the automated AutoDock in virtual screening is further demonstrated by identifying the actual inhibitors of various target enzymes in chemical databases with accuracy higher than the other docking tools including DOCK and FlexX. These results exemplify the usefulness of the automated AutoDock as a new promising tool in structure-based virtual screening. (c) 2006 Wiley-Liss, Inc.

  14. Status of GPCR modeling and docking as reflected by community-wide GPCR Dock 2010 assessment.

    NARCIS (Netherlands)

    Kufareva, I.; Rueda, M.; Katritch, V.; Stevens, R.C.; Abagyan, R.; Vroling, B.; Sanders, M.P.A.

    2011-01-01

    The community-wide GPCR Dock assessment is conducted to evaluate the status of molecular modeling and ligand docking for human G protein-coupled receptors. The present round of the assessment was based on the recent structures of dopamine D3 and CXCR4 chemokine receptors bound to small molecule

  15. Dock/Nck facilitates PTP61F/PTP1B regulation of insulin signalling.

    Science.gov (United States)

    Wu, Chia-Lun; Buszard, Bree; Teng, Chun-Hung; Chen, Wei-Lin; Warr, Coral G; Tiganis, Tony; Meng, Tzu-Ching

    2011-10-01

    PTP1B (protein tyrosine phosphatase 1B) is a negative regulator of IR (insulin receptor) activation and glucose homoeostasis, but the precise molecular mechanisms governing PTP1B substrate selectivity and the regulation of insulin signalling remain unclear. In the present study we have taken advantage of Drosophila as a model organism to establish the role of the SH3 (Src homology 3)/SH2 adaptor protein Dock (Dreadlocks) and its mammalian counterpart Nck in IR regulation by PTPs. We demonstrate that the PTP1B orthologue PTP61F dephosphorylates the Drosophila IR in S2 cells in vitro and attenuates IR-induced eye overgrowth in vivo. Our studies indicate that Dock forms a stable complex with PTP61F and that Dock/PTP61F associate with the IR in response to insulin. We report that Dock is required for effective IR dephosphorylation and inactivation by PTP61F in vitro and in vivo. Furthermore, we demonstrate that Nck interacts with PTP1B and that the Nck/PTP1B complex inducibly associates with the IR for the attenuation of IR activation in mammalian cells. Our studies reveal for the first time that the adaptor protein Dock/Nck attenuates insulin signalling by recruiting PTP61F/PTP1B to its substrate, the IR.

  16. Crusader Automated Docking System Phase 3 report

    Energy Technology Data Exchange (ETDEWEB)

    Jatko, W.B.; Goddard, J.S.; Ferrell, R.K.; Gleason, S.S.; Hicks, J.S.; Varma, V.K.

    1996-03-01

    The US Army is developing the next generation of battlefield artillery vehicles, including an advanced, self-propelled howitzer and a companion resupply vehicle. The resupply vehicle is intended to rendezvous with the howitzer near the battlefront and to upload ammunition to the howitzer. The Army has recommended that the vehicles incorporate robotics to increase safety, by allowing the crew to remain inside their vehicles during resupply operations. Oak Ridge National Laboratory has developed an autonomous docking system for a 6-D.F. robotic, ammunition transfer arm. The docking system augments the operator`s abilities by determining the position and orientation (pose) of a docking port. The pose is the location of the x, y, and z reference axes in 3-D space; and the orientation is the rotations--roll, pitch, and yaw--about those axes. Bye precisely determining the pose of the docking port, the robot can be instructed to move to the docking position without operator intervention. The system uses a video camera and frame grabber to digitize images of the special docking port. Custom algorithms were developed to recognize the port in the camera image, to determine the pose from its image features, and to distribute the results to the robot control computer. The system is loosely coupled to the robot and can be easily adapted to different mechanical configurations. The system has successfully demonstrated autonomous docking on a 24-in. tabletop robot and a 12-ft ammunition resupply robot. The update rate, measurement accuracy, continuous operation, and accuracy with obstructed view have been determined experimentally.

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

    Directory of Open Access Journals (Sweden)

    Rezaul Chowdhury

    Full Text Available MOTIVATION: 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. 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 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. 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

  18. Protein-protein docking with F(2)Dock 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

    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

  19. 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

  20. Focal fits during chlorambucil therapy

    Science.gov (United States)

    Naysmith, A.; Robson, R. H.

    1979-01-01

    An elderly man receiving chlorambucil for chronic lymphatic leukaemia developed focal fits. The onset and frequency were dose related. There was no evidence of metabolic disturbance or of meningeal leukaemia. Although reported in children and well recognized in animals, chlorambucil-induced fits in an adult have not been previously recorded. PMID:118440

  1. 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...... and an adaptive large neighborhood search heuristic is proposed to compute near-optimal solutions of real size instances. Computational experiments show that the proposed heuristic algorithm can obtain high-quality solutions within short computation times. We apply the model to cross-dock scheduling and design...... problems of four warehouses of a large retailer and show that substantially smaller cross-docks can be used by using dock-doors flexibly and properly scheduling the trucks....

  2. Udock, the interactive docking entertainment system.

    Science.gov (United States)

    Levieux, Guillaume; Tiger, Guillaume; Mader, Stéphanie; Zagury, Jean-François; Natkin, Stéphane; Montes, Matthieu

    2014-01-01

    Protein-protein interactions play a crucial role in biological processes. Protein docking calculations' goal is to predict, given two proteins of known structures, the associate conformation of the corresponding complex. Here, we present a new interactive protein docking system, Udock, that makes use of users' cognitive capabilities added up. In Udock, the users tackle simplified representations of protein structures and explore protein-protein interfaces' conformational space using a gamified interactive docking system with on the fly scoring. We assumed that if given appropriate tools, a naïve user's cognitive capabilities could provide relevant data for (1) the prediction of correct interfaces in binary protein complexes and (2) the identification of the experimental partner in interaction among a set of decoys. To explore this approach experimentally, we conducted a preliminary two week long playtest where the registered users could perform a cross-docking on a dataset comprising 4 binary protein complexes. The users explored almost all the surface of the proteins that were available in the dataset but favored certain regions that seemed more attractive as potential docking spots. These favored regions were located inside or nearby the experimental binding interface for 5 out of the 8 proteins in the dataset. For most of them, the best scores were obtained with the experimental partner. The alpha version of Udock is freely accessible at http://udock.fr.

  3. PTools: an opensource molecular docking library

    Directory of Open Access Journals (Sweden)

    Poulain Pierre

    2009-05-01

    Full Text Available Abstract Background Macromolecular docking is a challenging field of bioinformatics. Developing new algorithms is a slow process generally involving routine tasks that should be found in a robust library and not programmed from scratch for every new software application. Results We present an object-oriented Python/C++ library to help the development of new docking methods. This library contains low-level routines like PDB-format manipulation functions as well as high-level tools for docking and analyzing results. We also illustrate the ease of use of this library with the detailed implementation of a 3-body docking procedure. Conclusion The PTools library can handle molecules at coarse-grained or atomic resolution and allows users to rapidly develop new software. The library is already in use for protein-protein and protein-DNA docking with the ATTRACT program and for simulation analysis. This library is freely available under the GNU GPL license, together with detailed documentation.

  4. Resistance of a rodent malaria parasite to a thymidylate synthase inhibitor induces an apoptotic parasite death and imposes a huge cost of fitness.

    Directory of Open Access Journals (Sweden)

    Francis W Muregi

    Full Text Available BACKGROUND: The greatest impediment to effective malaria control is drug resistance in Plasmodium falciparum, and thus understanding how resistance impacts on the parasite's fitness and pathogenicity may aid in malaria control strategy. METHODOLOGY/PRINCIPAL FINDINGS: To generate resistance, P. berghei NK65 was subjected to 5-fluoroorotate (FOA, an inhibitor of thymidylate synthase, TS pressure in mice. After 15 generations of drug pressure, the 2% DT (the delay time for proliferation of parasites to 2% parasitaemia, relative to untreated wild-type controls reduced from 8 days to 4, equalling the controls. Drug sensitivity studies confirmed that FOA-resistance was stable. During serial passaging in the absence of drug, resistant parasite maintained low growth rates (parasitaemia, 15.5%±2.9, 7 dpi relative to the wild-type (45.6%±8.4, translating into resistance cost of fitness of 66.0%. The resistant parasite showed an apoptosis-like death, as confirmed by light and transmission electron microscopy and corroborated by oligonucleosomal DNA fragmentation. CONCLUSIONS/SIGNIFICANCE: The resistant parasite was less fit than the wild-type, which implies that in the absence of drug pressure in the field, the wild-type alleles may expand and allow drugs withdrawn due to resistance to be reintroduced. FOA resistance led to depleted dTTP pools, causing thymineless parasite death via apoptosis. This supports the tenet that unicellular eukaryotes, like metazoans, also undergo apoptosis. This is the first report where resistance to a chemical stimulus and not the stimulus itself is shown to induce apoptosis in a unicellular parasite. This finding is relevant in cancer therapy, since thymineless cell death induced by resistance to TS-inhibitors can further be optimized via inhibition of pyrimidine salvage enzymes, thus providing a synergistic impact. We conclude that since apoptosis is a process that can be pharmacologically modulated, the parasite

  5. Tyramine biosynthesis is transcriptionally induced at low pH and improves the fitness of Enterococcus faecalis in acidic environments.

    Science.gov (United States)

    Perez, Marta; Calles-Enríquez, Marina; Nes, Ingolf; Martin, Maria Cruz; Fernandez, Maria; Ladero, Victor; Alvarez, Miguel A

    2015-04-01

    Enterococcus faecalis is a commensal bacterium of the human gut that requires the ability to pass through the stomach and therefore cope with low pH. E. faecalis has also been identified as one of the major tyramine producers in fermented food products, where they also encounter acidic environments. In the present work, we have constructed a non-tyramine-producing mutant to study the role of the tyramine biosynthetic pathway, which converts tyrosine to tyramine via amino acid decarboxylation. Wild-type strain showed higher survival in a system that mimics gastrointestinal stress, indicating that the tyramine biosynthetic pathway has a role in acid resistance. Transcriptional analyses of the E. faecalis V583 tyrosine decarboxylase cluster showed that an acidic pH, together with substrate availability, induces its expression and therefore the production of tyramine. The protective role of the tyramine pathway under acidic conditions appears to be exerted through the maintenance of the cytosolic pH. Tyramine production should be considered important in the adaptability of E. faecalis to acidic environments, such as fermented dairy foods, and to survive passage through the human gastrointestinal tract.

  6. The binding of cytochrome c to neuroglobin: A docking and surface plasmon resonance study

    DEFF Research Database (Denmark)

    Bønding, Signe Helbo; Henty, K.; Dingley, A.J.

    2008-01-01

    It has recently been proposed that the role of neuroglobin in the protection of neurons from ischaemia induced cell death requires the formation of a transient complex with cytochrome c. No such complex has yet been isolated. Here, we present the results of soft docking calculations, which indicate...

  7. 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.

  8. Quantum.Ligand.Dock: protein-ligand docking with quantum entanglement refinement on a GPU system.

    Science.gov (United States)

    Kantardjiev, Alexander A

    2012-07-01

    Quantum.Ligand.Dock (protein-ligand docking with graphic processing unit (GPU) quantum entanglement refinement on a GPU system) is an original modern method for in silico prediction of protein-ligand interactions via high-performance docking code. The main flavour of our approach is a combination of fast search with a special account for overlooked physical interactions. On the one hand, we take care of self-consistency and proton equilibria mutual effects of docking partners. On the other hand, Quantum.Ligand.Dock is the the only docking server offering such a subtle supplement to protein docking algorithms as quantum entanglement contributions. The motivation for development and proposition of the method to the community hinges upon two arguments-the fundamental importance of quantum entanglement contribution in molecular interaction and the realistic possibility to implement it by the availability of supercomputing power. The implementation of sophisticated quantum methods is made possible by parallelization at several bottlenecks on a GPU supercomputer. The high-performance implementation will be of use for large-scale virtual screening projects, structural bioinformatics, systems biology and fundamental research in understanding protein-ligand recognition. The design of the interface is focused on feasibility and ease of use. Protein and ligand molecule structures are supposed to be submitted as atomic coordinate files in PDB format. A customization section is offered for addition of user-specified charges, extra ionogenic groups with intrinsic pK(a) values or fixed ions. Final predicted complexes are ranked according to obtained scores and provided in PDB format as well as interactive visualization in a molecular viewer. Quantum.Ligand.Dock server can be accessed at http://87.116.85.141/LigandDock.html.

  9. Efficacy of WBV as a modality for inducing changes in body composition, aerobic fitness, and muscular strength: a pilot study

    Directory of Open Access Journals (Sweden)

    Tapp LR

    2013-12-01

    Full Text Available Lauren R Tapp,1,3 Joseph F Signorile1,2,41Departments of Kinesiology and Sport Sciences, Coral Gables, 2Center on Aging, University of Miami Miller School of Medicine, Miami, FL, 3Department of Kinesiology, Temple University, Philadelphia, PA, 4Geriatric Research, Education, and Clinical Center, Bruce W Carter Department of Veterans Affairs Medical Center, Miami, FL, USAAbstract: The purpose of this pilot study was to evaluate the effectiveness of whole body vibration (WBV training as a modality for inducing changes in body composition, cardiovascular condition, and muscular strength in sedentary postmenopausal women. WBV training was compared with other training regimens, ie, aerobic training and circuit resistance training, commonly used to promote weight loss, cardiovascular conditioning, and muscular strength. Postmenopausal women (aged 48–60 years were randomly assigned to WBV training, circuit resistance training, or aerobic training. Participants trained three times per week for 8 weeks. The training regimens were progressive in nature, with increases in training intensity and duration occurring throughout the 8-week period. Body composition was assessed using dual-energy X-ray absorptiometry analyses. A modified Bruce treadmill protocol was used to assess aerobic capacity (VO2peak and time to peak exhaustion. Upper and lower body strengths were determined by one repetition maximum (1-RM chest and leg presses, respectively. Variables were analyzed using separate 3 (exercise mode × 2 (time repeated-measures analysis of variance with effect sizes due to the small sample size. No significant main effects or interactions were seen for any body composition variable; however, moderate to large effect sizes (η2=0.243 and η2=0.257 were detected regarding interactions for percent body fat and lean body mass favoring aerobic training and circuit resistance training. For VO2peak, no significant main effects or interactions were detected (time

  10. 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.

  11. INSILICO MODELING AND DOCKING STUDIES OF NEW DELHI METALLO BETA LACTAMASE-1 (SUPER BUG

    Directory of Open Access Journals (Sweden)

    DR. JAYASREE GANUGAPATI,

    2011-03-01

    Full Text Available New Delhi Metallo Beta Lactamase-1 (NDM-1 is a novel beta -lactamase enzyme that is ubiquitously found in Escherichia coli. This enzyme belongs to a B1 subclass of Metallo Beta Lactamases and is known to induce resistance to standard intravenous antibiotics. The tertiary structure of NDM-1 was predicted using Modeller9v7, based on the structural homology of the x-ray crystallographic structures of VIM-2 & VIM- 4 (Verona imipenemase-2 & -4 proteins from Pseudomonas aeruginosa. Further refinement of the structure was done using the loop modeling. Docking Analysis of NDM-1 with flavonoids was then performed using, GOLD, Auto Dock and Argus Lab. The analysis of the results of all three docking softwares suggested that Quercetin may be a potential inhibitor of NDM-1. Further analysis in the wet labmay provide us more information regarding inhibiting of NDM-1.

  12. A New Scoring Function for Molecular Docking Based on AutoDock and AutoDock Vina.

    Science.gov (United States)

    Tanchuk, Vsevolod Yu; Tanin, Volodymyr O; Vovk, Andriy I; Poda, Gennady

    2015-01-01

    Molecular docking of small molecules in the protein binding sites is the most widely used computational technique in modern structure-based drug discovery. Although accurate prediction of binding modes of small molecules can be achieved in most cases, estimation of their binding affinities remains mediocre at best. As an attempt to improve the correlation between the inhibitory constants, pKi, and scoring, we created a new, hybrid scoring function. The new function is a linear combination of the terms of the scoring functions of AutoDock and AutoDock Vina. It was trained on 2,412 protein-ligand complexes from the PDBbind database (www.pdbbind.org.cn, version 2012) and validated on a set of 313 complexes released in the 2013 version as a test set. The new function was included in a modified version of AutoDock. The hybrid scoring function showed a statistically significant improvement in both training and test sets in terms of correlation with and root mean square and mean absolute errors in prediction of pKi values. It was also tested on the CSAR 2014 Benchmark Exercise dataset (team T) and produced reasonably good results.

  13. AutoDock4Zn: An Improved AutoDock Force Field for Small-Molecule Docking to Zinc Metalloproteins

    Science.gov (United States)

    2015-01-01

    Zinc is present in a wide variety of proteins and is important in the metabolism of most organisms. Zinc metalloenzymes are therapeutically relevant targets in diseases such as cancer, heart disease, bacterial infection, and Alzheimer’s disease. In most cases a drug molecule targeting such enzymes establishes an interaction that coordinates with the zinc ion. Thus, accurate prediction of the interaction of ligands with zinc is an important aspect of computational docking and virtual screening against zinc containing proteins. We have extended the AutoDock force field to include a specialized potential describing the interactions of zinc-coordinating ligands. This potential describes both the energetic and geometric components of the interaction. The new force field, named AutoDock4Zn, was calibrated on a data set of 292 crystal complexes containing zinc. Redocking experiments show that the force field provides significant improvement in performance in both free energy of binding estimation as well as in root-mean-square deviation from the crystal structure pose. The new force field has been implemented in AutoDock without modification to the source code. PMID:24931227

  14. AutoDock4(Zn): an improved AutoDock force field for small-molecule docking to zinc metalloproteins.

    Science.gov (United States)

    Santos-Martins, Diogo; Forli, Stefano; Ramos, Maria João; Olson, Arthur J

    2014-08-25

    Zinc is present in a wide variety of proteins and is important in the metabolism of most organisms. Zinc metalloenzymes are therapeutically relevant targets in diseases such as cancer, heart disease, bacterial infection, and Alzheimer's disease. In most cases a drug molecule targeting such enzymes establishes an interaction that coordinates with the zinc ion. Thus, accurate prediction of the interaction of ligands with zinc is an important aspect of computational docking and virtual screening against zinc containing proteins. We have extended the AutoDock force field to include a specialized potential describing the interactions of zinc-coordinating ligands. This potential describes both the energetic and geometric components of the interaction. The new force field, named AutoDock4Zn, was calibrated on a data set of 292 crystal complexes containing zinc. Redocking experiments show that the force field provides significant improvement in performance in both free energy of binding estimation as well as in root-mean-square deviation from the crystal structure pose. The new force field has been implemented in AutoDock without modification to the source code.

  15. Dock-family exchange factors in cell migration and disease.

    Science.gov (United States)

    Gadea, Gilles; Blangy, Anne

    2014-10-01

    Dock family proteins are evolutionary conserved exchange factors for the Rho GTPases Rac and Cdc42. There are 11 Dock proteins in mammals, named Dock1 (or Dock180) to Dock11 that play different cellular functions. In particular, Dock proteins regulate actin cytoskeleton, cell adhesion and migration. Not surprisingly, members of the Dock family have been involved in various pathologies, including cancer and defects in the central nervous and immune systems. This review proposes an update of the recent findings regarding the function of Dock proteins, focusing on their role in the control of cell migration and invasion and the consequences in human diseases. Copyright © 2014 Elsevier GmbH. All rights reserved.

  16. Molecular docking of bacosides with tryptophan hydroxylase: a model to understand the bacosides mechanism.

    Science.gov (United States)

    Rajathei, David Mary; Preethi, Jayakumar; Singh, Hemant K; Rajan, Koilmani Emmanuvel

    2014-08-01

    Tryptophan hydroxylase (TPH) catalyses l-tryptophan into 5-hydroxy-l-tryptophan, which is the first and rate-limiting step of serotonin (5-HT) biosynthesis. Earlier, we found that TPH2 up-regulated in the hippocampus of postnatal rats after the oral treatment of Bacopa monniera leaf extract containing the active compound bacosides. However, the knowledge about the interactions between bacosides with TPH is limited. In this study, we take advantage of in silico approach to understand the interaction of bacoside-TPH complex using three different docking algorithms such as HexDock, PatchDock and AutoDock. All these three algorithms showed that bacoside A and A3 well fit into the cavity consists of active sites. Further, our analysis revealed that major active compounds bacoside A3 and A interact with different residues of TPH through hydrogen bond. Interestingly, Tyr235, Thr265 and Glu317 are the key residues among them, but none of them are either at tryptophan or BH4 binding region. However, its note worthy to mention that Tyr 235 is a catalytic sensitive residue, Thr265 is present in the flexible loop region and Glu317 is known to interacts with Fe. Interactions with these residues may critically regulate TPH function and thus serotonin synthesis. Our study suggested that the interaction of bacosides (A3/A) with TPH might up-regulate its activity to elevate the biosynthesis of 5-HT, thereby enhances learning and memory formation.

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

    NARCIS (Netherlands)

    de Vries, S.J.; van Dijk, M.; Bonvin, A.M.J.J.

    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

  18. Flexible Ligand Docking Using Evolutionary Algorithms

    DEFF Research Database (Denmark)

    Thomsen, Rene

    2003-01-01

    The docking of ligands to proteins can be formulated as a computational problem where the task is to find the most favorable energetic conformation among the large space of possible protein–ligand complexes. Stochastic search methods such as evolutionary algorithms (EAs) can be used to sample large...

  19. 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...

  20. Flexible Ligand Docking Using Differential Evolution

    DEFF Research Database (Denmark)

    Thomsen, René

    2003-01-01

    the most favorable energetic conformation among the large space of possible protein-ligand complexes. Stochastic search methods, such as evolutionary algorithms (EAs), can be used to sample large search spaces effectively and is one of the preferred methods for flexible ligand docking. The differential...

  1. Vision-guided heterogeneous mobile robot docking

    Science.gov (United States)

    Spofford, John R.; Blitch, John; Klarquist, William N.; Murphy, Robin R.

    1999-08-01

    Teams of heterogeneous mobile robots are a key aspect of future unmanned system for operations in complex and dynamic urban environments, such as that envisioned by DARPA's Tactical Mobile Robotics program. One examples of an interaction among such team members is the docking of small robot of limited sensory and processing capability with a larger, more capable robot. Applications for such docking include the transfer of power, data, and materia, as well as physically combined maneuver or manipulation. A two-robot system is considered in this paper. The smaller 'throwable' robot contains a video camera capable of imaging the larger 'packable' robot and transmitting the imagery. The packable robot can both sense the throwable robot through an onboard camera, as well as sense itself through the throwable robot's transmitted video, and is capable of processing imagery from either source. This paper describes recent results in the development of control and sensing strategies for automatic mid-range docking of these two robots. Decisions addressed include the selection of which robot's image sensor to use and which robot to maneuver. Initial experimental results are presented for docking using sensor data from each robot.

  2. Pharmacophore-based similarity scoring for DOCK.

    Science.gov (United States)

    Jiang, Lingling; Rizzo, Robert C

    2015-01-22

    Pharmacophore modeling incorporates geometric and chemical features of known inhibitors and/or targeted binding sites to rationally identify and design new drug leads. In this study, we have encoded a three-dimensional pharmacophore matching similarity (FMS) scoring function into the structure-based design program DOCK. Validation and characterization of the method are presented through pose reproduction, crossdocking, and enrichment studies. When used alone, FMS scoring dramatically improves pose reproduction success to 93.5% (∼20% increase) and reduces sampling failures to 3.7% (∼6% drop) compared to the standard energy score (SGE) across 1043 protein-ligand complexes. The combined FMS+SGE function further improves success to 98.3%. Crossdocking experiments using FMS and FMS+SGE scoring, for six diverse protein families, similarly showed improvements in success, provided proper pharmacophore references are employed. For enrichment, incorporating pharmacophores during sampling and scoring, in most cases, also yield improved outcomes when docking and rank-ordering libraries of known actives and decoys to 15 systems. Retrospective analyses of virtual screenings to three clinical drug targets (EGFR, IGF-1R, and HIVgp41) using X-ray structures of known inhibitors as pharmacophore references are also reported, including a customized FMS scoring protocol to bias on selected regions in the reference. Overall, the results and fundamental insights gained from this study should benefit the docking community in general, particularly researchers using the new FMS method to guide computational drug discovery with DOCK.

  3. Side docking of the da Vinci robotic system for radical prostatectomy: advantages over traditional docking.

    Science.gov (United States)

    Cestari, Andrea; Ferrari, Matteo; Zanoni, Matteo; Sangalli, Mattia; Ghezzi, Massimo; Fabbri, Fabio; Sozzi, Francesco; Rigatti, Patrizio

    2015-09-01

    The standard low lithotomic position, used during robot-assisted radical prostatectomy (RARP), with prolonged positioning in stirrups together with steep Trendelenburg may expose the patient to neurapraxia phenomena of the lower limbs and can rarely be used in patients with problems of hip abduction. To overcome these hurdles, we evaluated the clinical benefits of "side docking" (SD) of the da Vinci(®) robotic system in comparison to "traditional docking" (TD). A cohort of 120 patients submitted to RARP were prospectively randomized into two groups by docking approach: SD with the patient supine with lower limbs slightly abducted on the operating table, and TD docking time, intraoperative number of collisions between the robotic arms and postoperative neurological problems in the lower limbs were noted. Descriptive statistics was used to analyze outcomes. Docking time was shorter for the SD group [SD: median 13 min (range 10-18); TD: median 21 min (range 15-34)]. None in the SD group and six of 60 patients (10%) in the TD group suffered from temporary (<30 days) unilateral neurological deficits of the lower limbs. In both groups no collisions between the robotic arms occurred. The SD approach is technically feasible. It does not cause collisions between the robotic arms, and is a reliable method for reducing the setup time of RARP. The supine position of the patient may prevent neurological complications of the lower limbs. Based on these results, SD has become the standard docking technique used by our department.

  4. Modified AutoDock for accurate docking of protein kinase inhibitors.

    Science.gov (United States)

    Buzko, Oleksandr V; Bishop, Anthony C; Shokat, Kevan M

    2002-02-01

    Protein kinases are an important class of enzymes controlling virtually all cellular signaling pathways. Consequently, selective inhibitors of protein kinases have attracted significant interest as potential new drugs for many diseases. Computational methods, including molecular docking, have increasingly been used in the inhibitor design process [1]. We have considered several docking packages in order to strengthen our kinase inhibitor work with computational capabilities. In our experience, AutoDock offered a reasonable combination of accuracy and speed, as opposed to methods that specialize either in fast database searches or detailed and computationally intensive calculations. However, AutoDock did not perform well in cases where extensive hydrophobic contacts were involved, such as docking of SB203580 to its target protein kinase p38. Another shortcoming was a hydrogen bonding energy function, which underestimated the attraction component and, thus, did not allow for sufficiently accurate modeling of the key hydrogen bonds in the kinase-inhibitor complexes. We have modified the parameter set used to model hydrogen bonds, which increased the accuracy of AutoDock and appeared to be generally applicable to many kinase-inhibitor pairs without customization. Binding to largely hydrophobic sites, such as the active site of p38, was significantly improved by introducing a correction factor selectively affecting only carbon and hydrogen energy grids, thus, providing an effective, although approximate, treatment of solvation.

  5. VORFFIP-Driven Dock: V-D2OCK, a Fast and Accurate Protein Docking Strategy

    Science.gov (United States)

    Segura, Joan; Marín-López, Manuel Alejandro; Jones, Pamela F.; Oliva, Baldo; Fernandez-Fuentes, Narcis

    2015-01-01

    The experimental determination of the structure of protein complexes cannot keep pace with the generation of interactomic data, hence resulting in an ever-expanding gap. As the structural details of protein complexes are central to a full understanding of the function and dynamics of the cell machinery, alternative strategies are needed to circumvent the bottleneck in structure determination. Computational protein docking is a valid and valuable approach to model the structure of protein complexes. In this work, we describe a novel computational strategy to predict the structure of protein complexes based on data-driven docking: VORFFIP-driven dock (V-D2OCK). This new approach makes use of our newly described method to predict functional sites in protein structures, VORFFIP, to define the region to be sampled during docking and structural clustering to reduce the number of models to be examined by users. V-D2OCK has been benchmarked using a validated and diverse set of protein complexes and compared to a state-of-art docking method. The speed and accuracy compared to contemporary tools justifies the potential use of VD2OCK for high-throughput, genome-wide, protein docking. Finally, we have developed a web interface that allows users to browser and visualize V-D2OCK predictions from the convenience of their web-browsers. PMID:25763838

  6. VORFFIP-driven dock: V-D2OCK, a fast and accurate protein docking strategy.

    Directory of Open Access Journals (Sweden)

    Joan Segura

    Full Text Available The experimental determination of the structure of protein complexes cannot keep pace with the generation of interactomic data, hence resulting in an ever-expanding gap. As the structural details of protein complexes are central to a full understanding of the function and dynamics of the cell machinery, alternative strategies are needed to circumvent the bottleneck in structure determination. Computational protein docking is a valid and valuable approach to model the structure of protein complexes. In this work, we describe a novel computational strategy to predict the structure of protein complexes based on data-driven docking: VORFFIP-driven dock (V-D2OCK. This new approach makes use of our newly described method to predict functional sites in protein structures, VORFFIP, to define the region to be sampled during docking and structural clustering to reduce the number of models to be examined by users. V-D2OCK has been benchmarked using a validated and diverse set of protein complexes and compared to a state-of-art docking method. The speed and accuracy compared to contemporary tools justifies the potential use of VD2OCK for high-throughput, genome-wide, protein docking. Finally, we have developed a web interface that allows users to browser and visualize V-D2OCK predictions from the convenience of their web-browsers.

  7. VORFFIP-driven dock: V-D2OCK, a fast and accurate protein docking strategy.

    Science.gov (United States)

    Segura, Joan; Marín-López, Manuel Alejandro; Jones, Pamela F; Oliva, Baldo; Fernandez-Fuentes, Narcis

    2015-01-01

    The experimental determination of the structure of protein complexes cannot keep pace with the generation of interactomic data, hence resulting in an ever-expanding gap. As the structural details of protein complexes are central to a full understanding of the function and dynamics of the cell machinery, alternative strategies are needed to circumvent the bottleneck in structure determination. Computational protein docking is a valid and valuable approach to model the structure of protein complexes. In this work, we describe a novel computational strategy to predict the structure of protein complexes based on data-driven docking: VORFFIP-driven dock (V-D2OCK). This new approach makes use of our newly described method to predict functional sites in protein structures, VORFFIP, to define the region to be sampled during docking and structural clustering to reduce the number of models to be examined by users. V-D2OCK has been benchmarked using a validated and diverse set of protein complexes and compared to a state-of-art docking method. The speed and accuracy compared to contemporary tools justifies the potential use of VD2OCK for high-throughput, genome-wide, protein docking. Finally, we have developed a web interface that allows users to browser and visualize V-D2OCK predictions from the convenience of their web-browsers.

  8. Dock protein family in brain development and neurological disease.

    Science.gov (United States)

    Shi, Lei

    2013-11-01

    The family of dedicator of cytokinesis (Dock), a protein family that belongs to the atypical Rho guanine nucleotide exchange factors (GEFs) for Rac and/or Cdc42 GTPases, plays pivotal roles in various processes of brain development. To date, 11 members of Docks have been identified in the mammalian system. Emerging evidence has suggested that members of the Dock family are associated with several neurodegenerative and neuropsychiatric diseases, including Alzheimer disease and autism spectrum disorders. This review summarizes recent advances on the understanding of the roles of the Dock protein family in normal and diseased processes in the nervous system. Furthermore, interacting proteins and the molecular regulation of Docks are discussed.

  9. A comparison between single- and multi-objective optimization to fit spectral induced polarization data from laboratory measurements on alluvial sediments

    Science.gov (United States)

    Inzoli, S.; Giudici, M.

    2015-11-01

    Spectral induced polarization measurements on unconsolidated and saturated alluvial samples, sand-clay mixtures and well sorted sandy samples, are modelled with the generalized Cole-Cole phenomenological model and two simplified models: the standard Cole-Cole and the Cole-Davidson model. The goodness of fit is evaluated, as a first step, through the root mean square error, weighted on the data errors of the real and the imaginary component. At a later stage a multi-objective optimization is proposed, based on two different indicators for the resistivity amplitude and phase misfit. The analysis of the misfits variations among all the tested parameters associations is conducted to identify the Pareto set of optimal solutions. Both procedures lead to model parameter estimates comparable with literature values. However, the multi-objective approach provides information about the uncertainty of the parameter estimates and highlights the presence of more than one characteristic value for the relaxation time and the frequency exponent in many samples, thus suggesting the possible occurrence of different polarization processes in the investigated frequency range.

  10. Drosophila DOCK family protein sponge regulates the JNK pathway during thorax development.

    Science.gov (United States)

    Morishita, Kazushige; Ozasa, Fumito; Eguchi, Koichi; Yoshioka, Yasuhide; Yoshida, Hideki; Hiai, Hiroshi; Yamaguchi, Masamitsu

    2014-01-01

    The dedicator of cytokinesis (DOCK) family proteins that are conserved in a wide variety of species are known as DOCK1-DOCK11 in mammals. The Sponge (Spg) is a Drosophila counterpart to the mammalian DOCK3. Specific knockdown of spg by pannir-GAL4 or apterous-GAL4 driver in wing discs induced split thorax phenotype in adults. Reduction of the Drosophila c-Jun N-terminal kinase (JNK), basket (bsk) gene dose enhanced the spg knockdown-induced phenotype. Conversely, overexpression of bsk suppressed the split thorax phenotype. Monitoring JNK activity in the wing imaginal discs by immunostaining with anti-phosphorylated JNK (anti-pJNK) antibody together with examination of lacZ expression in a puckered-lacZ enhancer trap line revealed the strong reduction of the JNK activity in the spg knockdown clones. This was further confirmed by Western immunoblot analysis of extracts from wing discs of spg knockdown fly with anti-pJNK antibody. Furthermore, the Duolink in situ Proximity Ligation Assay method detected interaction signals between Spg and Rac1 in the wing discs. Taken together, these results indicate Spg positively regulates JNK pathway that is required for thorax development and the regulation is mediated by interaction with Rac1.

  11. [Study on anti-hyperlipidemia mechanism of high frequency herb pairs by molecular docking method].

    Science.gov (United States)

    Jiang, Lu-di; He, Yu-su; Chen, Xi; Tao, Ou; Li, Gong-Yu; Zhang, Yan-ling

    2015-06-01

    Traditional Chinese medicine (TCM) has definitely clinical effect in treating hyperlipidemia, but the action mechanism still need to be explored. Based on consulting Chinese Pharmacopoeia (2010), all the lipid-lowering Chinese patent medicines were analyzed by associated rules data mining method to explore high frequency herb pairs. The top three couplet medicines with high support degree were Puerariae Lobatae Radix-Crataegi Fructus, Salviae Miltiorrhizae Radix et Rhizoma-Crataegi Fructus, and Polygoni Multiflori Radix-Crataegi Fructus. The 20 main ingredients were selected from the herb pairs and docked with 3 key hyperlipidemia targets, namely 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), peroxisome proliferator activated receptor-α (PPAR-α ) and niemann-pick C1 like 1 (NPC1L1) to further discuss the molecular mechanism of the high frequency herb pairs, by using the docking program, LibDock. To construct evaluation rules for the ingredients of herb pairs, the root-mean-square deviation (RMSD) value between computed and initial complexes was first calculated to validate the fitness of LibDock models. Then, the key residues were also confirmed by analyzing the interactions of those 3 proteins and corresponding marketed drugs. The docking results showed that hyperin, puerarin, salvianolic acid A and polydatin can interact with two targets, and the other five compounds may be potent for at least one of the three targets. In this study, the multi-target effect of high frequency herb pairs for lipid-lowering was discussed on the molecular level, which can help further researching new multi-target anti-hyperlipidemia drug.

  12. Satellite Docking Simulator with Generic Contact Dynamics Capabilities

    Science.gov (United States)

    Ma, O.; Crabtree, D.; Carr, R.; Gonthier, Y.; Martin, E.; Piedboeuf, J.-C.

    2002-01-01

    Satellite docking (and capture) systems are critical for the servicing or salvage of satellites. Satellite servicing has comparatively recently become a realistic and promising space operation/mission. Satellite servicing includes several of the following operations: rendezvous; docking (capturing); inspection; towing (transporting); refueling; refurbishing (replacement of faulty or "used-up" modules/boxes); and un-docking (releasing). Because spacecraft servicing has been, until recently non-feasible or non-economical, spacecraft servicing technology has been neglected. Accordingly, spacecraft designs have featured self- contained systems without consideration for operational servicing. Consistent with this view, most spacecrafts were designed and built without docking interfaces. If, through some mishap, a spacecraft was rendered non-operational, it was simply considered expendable. Several feasibility studies are in progress on salvaging stranded satellites (which, in fact had led to this project). The task of the designer of the docking system for a salvaging task is difficult. He/she has to work with whatever it is on orbit, and this excludes any special docking interfaces, which might have made his/her task easier. As satellite servicing becomes an accepted design requirement, many future satellites will be equipped with appropriate docking interfaces. The designer of docking systems will be faced with slightly different challenges: reliable, cost-effective, docking (and re-supply) systems. Thus, the role of designers of docking systems will increase from one of a kind, ad-hoc interfaces intended for salvaging operations, to docking systems for satellites and "caretaker" spacecraft which are meant for servicing and are produced in larger numbers. As in any space system (for which full and representative ground hardware test-beds are very expensive and often impossible to develop), simulations are mandatory for the development of systems and operations for

  13. Autonomous Rendezvous and Docking Conference, volume 1

    Science.gov (United States)

    1990-01-01

    This document consists of the presentation submitted at the Autonomous Rendezvous and Docking (ARD) Conference. It contains three volumes: ARD hardware technology; ARD software technology; and ARD operations. The purpose of this conference is to identify the technologies required for an on orbit demonstration of the ARD, assess the maturity of these technologies, and provide the necessary insight for a quality assessment of the programmatic management, technical, schedule, and cost risks.

  14. Autonomous Rendezvous and Docking Conference, volume 3

    Science.gov (United States)

    1990-01-01

    This document consists of the presentation submitted at the Autonomous Rendezvous and Docking (ARD) Conference. The document contains three volumes: ARD hardware technology; ARD software technology; and ARD operations. The purpose of this conference is to identify the technologies required for an on orbit demonstration of ARD, assess the maturity of these technologies, and provide the necessary insight for a quality assessment of programmatic management, technical, schedule, and cost risks.

  15. Differential regulation of protein tyrosine kinase signalling by Dock and the PTP61F variants.

    Science.gov (United States)

    Willoughby, Lee F; Manent, Jan; Allan, Kirsten; Lee, Han; Portela, Marta; Wiede, Florian; Warr, Coral; Meng, Tzu-Ching; Tiganis, Tony; Richardson, Helena E

    2017-07-01

    Tyrosine phosphorylation-dependent signalling is coordinated by the opposing actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). There is a growing list of adaptor proteins that interact with PTPs and facilitate the dephosphorylation of substrates. The extent to which any given adaptor confers selectivity for any given substrate in vivo remains unclear. Here we have taken advantage of Drosophila melanogaster as a model organism to explore the influence of the SH3/SH2 adaptor protein Dock on the abilities of the membrane (PTP61Fm)- and nuclear (PTP61Fn)-targeted variants of PTP61F (the Drosophila othologue of the mammalian enzymes PTP1B and TCPTP respectively) to repress PTK signalling pathways in vivo. PTP61Fn effectively repressed the eye overgrowth associated with activation of the epidermal growth factor receptor (EGFR), PTK, or the expression of the platelet-derived growth factor/vascular endothelial growth factor receptor (PVR) or insulin receptor (InR) PTKs. PTP61Fn repressed EGFR and PVR-induced mitogen-activated protein kinase signalling and attenuated PVR-induced STAT92E signalling. By contrast, PTP61Fm effectively repressed EGFR- and PVR-, but not InR-induced tissue overgrowth. Importantly, coexpression of Dock with PTP61F allowed for the efficient repression of the InR-induced eye overgrowth, but did not enhance the PTP61Fm-mediated inhibition of EGFR and PVR-induced signalling. Instead, Dock expression increased, and PTP61Fm coexpression further exacerbated the PVR-induced eye overgrowth. These results demonstrate that Dock selectively enhances the PTP61Fm-mediated attenuation of InR signalling and underscores the specificity of PTPs and the importance of adaptor proteins in regulating PTP function in vivo. © 2017 Federation of European Biochemical Societies.

  16. Combined Immunodeficiency Associated with DOCK8 Mutations

    Science.gov (United States)

    Zhang, Qian; Davis, Jeremiah C.; Lamborn, Ian T.; Freeman, Alexandra F.; Jing, Huie; Favreau, Amanda J.; Matthews, Helen F.; Davis, Joie; Turner, Maria L.; Uzel, Gulbu; Holland, Steven M.; Su, Helen C.

    2010-01-01

    BACKGROUND Recurrent sinopulmonary and cutaneous viral infections with elevated serum levels of IgE are features of some variants of combined immunodeficiency. The genetic causes of these variants are unknown. METHODS We collected longitudinal clinical data on 11 patients from eight families who had recurrent sinopulmonary and cutaneous viral infections. We performed comparative genomic hybridization arrays and targeted gene sequencing. Variants with predicted loss-of-expression mutations were confirmed by means of a quantitative reverse-transcriptase –polymerase-chain-reaction assay and immunoblotting. We evaluated the number and function of lymphocytes with the use of in vitro assays and flow cytometry. RESULTS Patients had recurrent otitis media, sinusitis, and pneumonias; recurrent Staphylococcus aureus skin infections with otitis externa; recurrent, severe herpes simplex virus or herpes zoster infections; extensive and persistent infections with molluscum contagiosum; and human papillomavirus infections. Most patients had severe atopy with anaphylaxis; several had squamous-cell carcinomas, and one had T-cell lymphoma –leukemia. Elevated serum IgE levels, hypereosinophilia, low numbers of T cells and B cells, low serum IgM levels, and variable IgG antibody responses were common. Expansion in vitro of activated CD8 T cells was impaired. Novel homozygous or compound heterozygous deletions and point mutations in the gene encoding the dedicator of cytokinesis 8 protein (DOCK8) led to the absence of DOCK8 protein in lymphocytes. CONCLUSIONS Autosomal recessive DOCK8 deficiency is associated with a novel variant of combined immunodeficiency. PMID:19776401

  17. Fit for purpose: Australia's National Fitness Campaign.

    Science.gov (United States)

    Collins, Julie A; Lekkas, Peter

    2011-12-19

    During a time of war, the federal government passed the National Fitness Act 1941 to improve the fitness of the youth of Australia and better prepare them for roles in the armed services and industry. Implementation of the National Fitness Act made federal funds available at a local level through state-based national fitness councils, which coordinated promotional campaigns, programs, education and infrastructure for physical fitness, with volunteers undertaking most of the work. Specifically focused on children and youth, national fitness councils supported the provision of children's playgrounds, youth clubs and school camping programs, as well as the development of physical education in schools and its teaching and research in universities. By the time the Act was repealed in 1994, fitness had become associated with leisure and recreation rather than being seen as equipping people for everyday life and work. The emergence of the Australian National Preventive Health Agency Act 2010 offers the opportunity to reflect on synergies with its historic precedent.

  18. Application of the PM6 semi-empirical method to modeling proteins enhances docking accuracy of AutoDock.

    Science.gov (United States)

    Bikadi, Zsolt; Hazai, Eszter

    2009-09-11

    Molecular docking methods are commonly used for predicting binding modes and energies of ligands to proteins. For accurate complex geometry and binding energy estimation, an appropriate method for calculating partial charges is essential. AutoDockTools software, the interface for preparing input files for one of the most widely used docking programs AutoDock 4, utilizes the Gasteiger partial charge calculation method for both protein and ligand charge calculation. However, it has already been shown that more accurate partial charge calculation - and as a consequence, more accurate docking- can be achieved by using quantum chemical methods. For docking calculations quantum chemical partial charge calculation as a routine was only used for ligands so far. The newly developed Mozyme function of MOPAC2009 allows fast partial charge calculation of proteins by quantum mechanical semi-empirical methods. Thus, in the current study, the effect of semi-empirical quantum-mechanical partial charge calculation on docking accuracy could be investigated. The docking accuracy of AutoDock 4 using the original AutoDock scoring function was investigated on a set of 53 protein ligand complexes using Gasteiger and PM6 partial charge calculation methods. This has enabled us to compare the effect of the partial charge calculation method on docking accuracy utilizing AutoDock 4 software. Our results showed that the docking accuracy in regard to complex geometry (docking result defined as accurate when the RMSD of the first rank docking result complex is within 2 A of the experimentally determined X-ray structure) significantly increased when partial charges of the ligands and proteins were calculated with the semi-empirical PM6 method. Out of the 53 complexes analyzed in the course of our study, the geometry of 42 complexes were accurately calculated using PM6 partial charges, while the use of Gasteiger charges resulted in only 28 accurate geometries. The binding affinity estimation was

  19. InterEvDock: a docking server to predict the structure of protein-protein interactions using evolutionary information.

    Science.gov (United States)

    Yu, Jinchao; Vavrusa, Marek; Andreani, Jessica; Rey, Julien; Tufféry, Pierre; Guerois, Raphaël

    2016-07-01

    The structural modeling of protein-protein interactions is key in understanding how cell machineries cross-talk with each other. Molecular docking simulations provide efficient means to explore how two unbound protein structures interact. InterEvDock is a server for protein docking based on a free rigid-body docking strategy. A systematic rigid-body docking search is performed using the FRODOCK program and the resulting models are re-scored with InterEvScore and SOAP-PP statistical potentials. The InterEvScore potential was specifically designed to integrate co-evolutionary information in the docking process. InterEvDock server is thus particularly well suited in case homologous sequences are available for both binding partners. The server returns 10 structures of the most likely consensus models together with 10 predicted residues most likely involved in the interface. In 91% of all complexes tested in the benchmark, at least one residue out of the 10 predicted is involved in the interface, providing useful guidelines for mutagenesis. InterEvDock is able to identify a correct model among the top10 models for 49% of the rigid-body cases with evolutionary information, making it a unique and efficient tool to explore structural interactomes under an evolutionary perspective. The InterEvDock web interface is available at http://bioserv.rpbs.univ-paris-diderot.fr/services/InterEvDock/.

  20. Modeling of protein-peptide interactions using the CABS-dock web server for binding site search and flexible docking.

    Science.gov (United States)

    Blaszczyk, Maciej; Kurcinski, Mateusz; Kouza, Maksim; Wieteska, Lukasz; Debinski, Aleksander; Kolinski, Andrzej; Kmiecik, Sebastian

    2016-01-15

    Protein-peptide interactions play essential functional roles in living organisms and their structural characterization is a hot subject of current experimental and theoretical research. Computational modeling of the structure of protein-peptide interactions is usually divided into two stages: prediction of the binding site at a protein receptor surface, and then docking (and modeling) the peptide structure into the known binding site. This paper presents a comprehensive CABS-dock method for the simultaneous search of binding sites and flexible protein-peptide docking, available as a user's friendly web server. We present example CABS-dock results obtained in the default CABS-dock mode and using its advanced options that enable the user to increase the range of flexibility for chosen receptor fragments or to exclude user-selected binding modes from docking search. Furthermore, we demonstrate a strategy to improve CABS-dock performance by assessing the quality of models with classical molecular dynamics. Finally, we discuss the promising extensions and applications of the CABS-dock method and provide a tutorial appendix for the convenient analysis and visualization of CABS-dock results. The CABS-dock web server is freely available at http://biocomp.chem.uw.edu.pl/CABSdock/. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  1. Protein Alpha Shape (PAS) Dock: A new gaussian-based score function suitable for docking in homology modelled protein structures

    Science.gov (United States)

    Tøndel, Kristin; Anderssen, Endre; Drabløs, Finn

    2006-03-01

    Protein Alpha Shape (PAS) Dock is a new empirical score function suitable for virtual library screening using homology modelled protein structures. Here, the score function is used in combination with the geometry search method Tabu search. A description of the protein binding site is generated using gaussian property fields like in Protein Alpha Shape Similarity Analysis (PASSA). Gaussian property fields are also used to describe the ligand properties. The overlap between the receptor and ligand hydrophilicity and lipophilicity fields is maximised, while minimising steric clashes. Gaussian functions introduce a smoothing of the property fields. This makes the score function robust against small structural variations, and therefore suitable for use with homology models. This also makes it less critical to include protein flexibility in the docking calculations. We use a fast and simplified version of the score function in the geometry search, while a more detailed version is used for the final prediction of the binding free energies. This use of a two-level scoring makes PAS-Dock computationally efficient, and well suited for virtual screening. The PAS-Dock score function is trained on 218 X-ray structures of protein- ligand complexes with experimental binding affinities. The performance of PAS-Dock is compared to two other docking methods, AutoDock and MOE-Dock, with respect to both accuracy and computational efficiency. According to this study, PAS-Dock is more computationally efficient than both AutoDock and MOE-Dock, and gives a better prediction of the free energies of binding. PAS-Dock is also more robust against structural variations than AutoDock.

  2. Discovery of Novel Inhibitors for Nek6 Protein through Homology Model Assisted Structure Based Virtual Screening and Molecular Docking Approaches

    Directory of Open Access Journals (Sweden)

    P. Srinivasan

    2014-01-01

    Full Text Available Nek6 is a member of the NIMA (never in mitosis, gene A-related serine/threonine kinase family that plays an important role in the initiation of mitotic cell cycle progression. This work is an attempt to emphasize the structural and functional relationship of Nek6 protein based on homology modeling and binding pocket analysis. The three-dimensional structure of Nek6 was constructed by molecular modeling studies and the best model was further assessed by PROCHECK, ProSA, and ERRAT plot in order to analyze the quality and consistency of generated model. The overall quality of computed model showed 87.4% amino acid residues under the favored region. A 3 ns molecular dynamics simulation confirmed that the structure was reliable and stable. Two lead compounds (Binding database ID: 15666, 18602 were retrieved through structure-based virtual screening and induced fit docking approaches as novel Nek6 inhibitors. Hence, we concluded that the potential compounds may act as new leads for Nek6 inhibitors designing.

  3. 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.

  4. 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 ...

  5. FitEM2EM--tools for low resolution study of macromolecular assembly and dynamics.

    Directory of Open Access Journals (Sweden)

    Ziv Frankenstein

    Full Text Available Studies of the structure and dynamics of macromolecular assemblies often involve comparison of low resolution models obtained using different techniques such as electron microscopy or atomic force microscopy. We present new computational tools for comparing (matching and docking of low resolution structures, based on shape complementarity. The matched or docked objects are represented by three dimensional grids where the value of each grid point depends on its position with regard to the interior, surface or exterior of the object. The grids are correlated using fast Fourier transformations producing either matches of related objects or docking models depending on the details of the grid representations. The procedures incorporate thickening and smoothing of the surfaces of the objects which effectively compensates for differences in the resolution of the matched/docked objects, circumventing the need for resolution modification. The presented matching tool FitEM2EMin successfully fitted electron microscopy structures obtained at different resolutions, different conformers of the same structure and partial structures, ranking correct matches at the top in every case. The differences between the grid representations of the matched objects can be used to study conformation differences or to characterize the size and shape of substructures. The presented low-to-low docking tool FitEM2EMout ranked the expected models at the top.

  6. Synthesis and docking studies of novel antitumor benzimidazoles.

    Science.gov (United States)

    Omar, Mohamed A; Shaker, Yasser M; Galal, Shadia A; Ali, Mamdouh M; Kerwin, Sean M; Li, Jing; Tokuda, Harukuni; Ramadan, Raghda A; El Diwani, Hoda I

    2012-12-15

    In this work, the benzimidazole-pyrrole conjugates 6a-h and benzimidazole-tetracycles conjugates 12-14 were prepared. The cytotoxicity of the compounds 3, 4a-h, 6a-h, 8, 10 and 12-14 was tested against lung cancer cell line A549. Compound 6b exhibited higher activity than the bis-benzoxazole natural product (UK-1), the standard. The tested 4g,h, 6a-h, 10 and 12-14 exhibited remarkable cytotoxicity activity against breast cancer cell line MCF-7 with higher activity than tamoxifen. Furthermore, compound 4h was found to be also more potent than doxurubicin. The antitumor promotion activity of synthesized compounds 4g,h, 6a-h, 10 and 12-14 has been estimated by studying their possible inhibitory effects on EBV-EA activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). Among the studied compounds, the inhibitory activities of compounds 8, 13 and 14 demonstrated strong inhibitory effects on the Epstein-Barr virus early antigen (EBV-EA) activation without showing any cytotoxicity on the Raji cells and their effects being stronger than that of a representative control, oleanolic acid. Moreover, the molecular docking of the new compounds into plasminogen activator (uPA) receptor has been in correlation with the antitumor activity. All synthesized compounds 3, 4a-h, 6a-h, 8, 10 and 12-14 were docked into same groove of the binding site of the native co-crystalized (4-iodobenzo[b]thiophene-2-carboxamidine) ligand (PDB code:1c5x) for activity explaination. Compounds 4h, 6b and 13, giving the best docking results, were further studied to estimate their effect on the level of uPA using AssayMax human urokinase (uPA) ELISA kit. In case of A549 cell line, compound 6 exhibited similar activity to MMC, and for MCF-7 cell line, compound 4h exhibited similar activity to doxorubicin, in inhibiting the expression of uPA.

  7. A Review: Mathematical Modles for Cross Docking Planning

    Directory of Open Access Journals (Sweden)

    Dwi Agustina

    2010-09-01

    Full Text Available This paper provides a comprehensive literature review of mathematical models in cross docking planning. From the reviews, the models are classified in three different levels regarding its decisions level which are operational, tactical, and strategic level. The researches in operational level are mainly related to develop model in scheduling, dock door assignment, transhipment problem, vehicle routing, and product allocation. For tactical and strategic level, the researches are mainly proposing model to design the layout and the network of cross docking respectively. The contribution of this paper is to realize the gaps of knowledge in strategic, tactical and operational levels and point out the future research directions in cross docking.

  8. ProFit: Bayesian galaxy fitting tool

    Science.gov (United States)

    Robotham, A. S. G.; Taranu, D.; Tobar, R.

    2016-12-01

    ProFit is a Bayesian galaxy fitting tool that uses the fast C++ image generation library libprofit (ascl:1612.003) and a flexible R interface to a large number of likelihood samplers. It offers a fully featured Bayesian interface to galaxy model fitting (also called profiling), using mostly the same standard inputs as other popular codes (e.g. GALFIT ascl:1104.010), but it is also able to use complex priors and a number of likelihoods.

  9. Docking small peptides remains a great challenge: an assessment using AutoDock Vina.

    Science.gov (United States)

    Rentzsch, Robert; Renard, Bernhard Y

    2015-11-01

    There is a growing interest in the mechanisms and the prediction of how flexible peptides bind proteins, often in a highly selective and conserved manner. While both existing small-molecule docking methods and custom protocols can be used, even short peptides make difficult targets owing to their high torsional flexibility. Any benchmarking should therefore start with those. We compiled a meta-data set of 47 complexes with peptides up to five residues, based on 11 related studies from the past decade. Although their highly varying strategies and constraints preclude direct, quantitative comparisons, we still provide a comprehensive overview of the reported results, using a simple yet stringent measure: the quality of the top-scoring peptide pose. Using the entire data set, this is augmented by our own benchmark of AutoDock Vina, a freely available, fast and widely used docking tool. It particularly addresses non-expert users and was therefore implemented in a highly integrated manner. Guidelines addressing important issues such as the amount of sampling required for result reproducibility are so far lacking. Using peptide docking as an example, this is the first study to address these issues in detail. Finally, to encourage further, standardized benchmarking efforts, the compiled data set is made available in an accessible, transparent and extendable manner. © The Author 2015. Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  10. Autonomous Rendezvous and Docking Conference, volume 2

    Science.gov (United States)

    1990-01-01

    Autonomous Rendezvous and Docking (ARD) will be a requirement for future space programs. Clear examples include satellite servicing, repair, recovery, and reboost in the near term, and the longer range lunar and planetary exploration programs. ARD will permit more aggressive unmanned space activities, while providing a valuable operational capability for manned missions. The purpose of the conference is to identify the technologies required for an on-orbit demonstration of ARD, assess the maturity of those technologies, and provide the necessary insight for a quality assessment of programmatic management, technical, schedule, and cost risks.

  11. Rendezvous and docking with remote piloted vehicles

    Science.gov (United States)

    Micheal, J. D.

    The man-in-the-loop control system requirements for the Orbital Maneuvering Vehicle (OMV) are examined. Since many similarities exist between the Teleoperator Retrieval System (TRS) and the unfolding OMV concept, a review of the TRS control system baseline along with selected design trades which led to that baseline are discussed. TRS program issues relevant to the man-in-the-loop control system design include thruster size, communication delays and TV bandwidth compression, range/range rate radar, tumbling targets, shimmed docking interface, and control system definition. A TRS vs. OMV simulation comparative study is summarized, and the major issues currently facing the control system designer on OMV are discussed.

  12. A Pretty Good Fit

    Science.gov (United States)

    Erickson, Tim

    2008-01-01

    We often look for a best-fit function to a set of data. This article describes how a "pretty good" fit might be better than a "best" fit when it comes to promoting conceptual understanding of functions. In a pretty good fit, students design the function themselves rather than choosing it from a menu; they use appropriate variable names; and they…

  13. Unge, sundhed og fitness

    DEFF Research Database (Denmark)

    Jensen, Jens-Ole

    2003-01-01

    Artiklen redegør for udbredelsen af fitness blandt unge og diskuterer, hvor det er blevet så populært at dyrke fitness.......Artiklen redegør for udbredelsen af fitness blandt unge og diskuterer, hvor det er blevet så populært at dyrke fitness....

  14. AutoDock and AutoDockTools for Protein-Ligand Docking: Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1(BACE1) as a Case Study.

    Science.gov (United States)

    El-Hachem, Nehme; Haibe-Kains, Benjamin; Khalil, Athar; Kobeissy, Firas H; Nemer, Georges

    2017-01-01

    Computational docking and scoring techniques have revolutionized structural bioinformatics by providing unprecedented insights on key aspects of ligand-receptor interaction. Docking is used for optimizing known drugs and for identifying novel binders by predicting their binding mode and affinity. AutoDock and AutoDockTools are free of charge techniques that have been extensively cited in the literature as essential tools in structure-based drug design. Moreover, these methods are fast enough to permit virtual screening of ligand libraries containing tens of thousands of compounds. However using Autodock requires some knowledge in programming which creates a limitation for biologists and makes them prone for commercial applications. Here, we selected a relevant target involved in the progression of Alzheimer disease and provided a fully reproducible docking protocol. This example will show how docking techniques would be an important asset to identify new BACE1 inhibitors. The following friendly user tutorial targets both undergraduate and graduate students, allowing them to understand docking as a computational tool for structure-based drug design.

  15. Molecular Docking and Anticonvulsant Activity of Newly Synthesized Quinazoline Derivatives

    Directory of Open Access Journals (Sweden)

    Hatem A. Abuelizz

    2017-06-01

    Full Text Available A new series of quinazoline-4(3H-ones are evaluated for anticonvulsant activity. After intraperitoneal (ip injection to albino mice at a dose of 100 mg/kg body weight, synthesized quinazolin-4(3H-ones (1–24 were examined in the maximal electroshock (MES induced seizures and subcutaneous pentylenetetrazole (scPTZ induced seizure models in mice. The Rotarod method was applied to determine the neurotoxicity. Most of the compounds displayed anticonvulsant activity in the scPTZ screen at a dose range of 0.204–0.376 mmol/mL. Out of twenty-four, compounds 8, 13 and 19 proved to be the most active with a remarkable protection (100% against PTZ induced convulsions and four times more potent activity than ethosuximide. The structure-activity relationship concluded valuable pharmacophoric information, which was confirmed by the molecular docking studies using the target enzyme human carbon anhydrase II (HCA II. The studied quinazoline analogues suggested that the butyl substitution at position 3 has a significant effect on preventing the spread of seizure discharge and on raising the seizure threshold. However, benzyl substitution at position 3 has shown a strong anticonvulsant activity but with less seizure prevention compared to the butyl substitution.

  16. CABS-dock web server for the flexible docking of peptides to proteins without prior knowledge of the binding site.

    Science.gov (United States)

    Kurcinski, Mateusz; Jamroz, Michal; Blaszczyk, Maciej; Kolinski, Andrzej; Kmiecik, Sebastian

    2015-07-01

    Protein-peptide interactions play a key role in cell functions. Their structural characterization, though challenging, is important for the discovery of new drugs. The CABS-dock web server provides an interface for modeling protein-peptide interactions using a highly efficient protocol for the flexible docking of peptides to proteins. While other docking algorithms require pre-defined localization of the binding site, CABS-dock does not require such knowledge. Given a protein receptor structure and a peptide sequence (and starting from random conformations and positions of the peptide), CABS-dock performs simulation search for the binding site allowing for full flexibility of the peptide and small fluctuations of the receptor backbone. This protocol was extensively tested over the largest dataset of non-redundant protein-peptide interactions available to date (including bound and unbound docking cases). For over 80% of bound and unbound dataset cases, we obtained models with high or medium accuracy (sufficient for practical applications). Additionally, as optional features, CABS-dock can exclude user-selected binding modes from docking search or to increase the level of flexibility for chosen receptor fragments. CABS-dock is freely available as a web server at http://biocomp.chem.uw.edu.pl/CABSdock. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  17. Fitness World - Fremtidig overlevelse

    OpenAIRE

    Rice, Kasper; Klink, Nikolaj; Nielsen, Mie; Carlson, Andre; Boy, Mikkel; Hansen, Alexander

    2015-01-01

    Our project is a case study with Fitness World as a baseline. Our project will enhance Fitness Worlds penetration on their current position on the market. Our empiricism includes both qualitative and quantitative methodical approaches by the use of an expert interview and a questionnaire survey. These methods contribute and generate general knowledge about the fitness culture in Denmark and the customers in the fitness industry. We have stated a possible strategic opportunity for Fitness Worl...

  18. A phosphoserine-regulated docking site in the protein kinase RSK2 that recruits and activates PDK1

    DEFF Research Database (Denmark)

    Frödin, M; Jensen, Claus Antonio Juel; Merienne, K

    2000-01-01

    -phosphoinositide-dependent protein kinase-1 (PDK1) through phosphorylation of Ser227, and phosphorylates the substrates of RSK. Here, we identify Ser386 in the hydrophobic motif of RSK2 as a phosphorylation-dependent docking site and activator of PDK1. Treatment of cells with growth factor induced recruitment...

  19. rDock: a fast, versatile and open source program for docking ligands to proteins and nucleic acids.

    Directory of Open Access Journals (Sweden)

    Sergio Ruiz-Carmona

    2014-04-01

    Full Text Available Identification of chemical compounds with specific biological activities is an important step in both chemical biology and drug discovery. When the structure of the intended target is available, one approach is to use molecular docking programs to assess the chemical complementarity of small molecules with the target; such calculations provide a qualitative measure of affinity that can be used in virtual screening (VS to rank order a list of compounds according to their potential to be active. rDock is a molecular docking program developed at Vernalis for high-throughput VS (HTVS applications. Evolved from RiboDock, the program can be used against proteins and nucleic acids, is designed to be computationally very efficient and allows the user to incorporate additional constraints and information as a bias to guide docking. This article provides an overview of the program structure and features and compares rDock to two reference programs, AutoDock Vina (open source and Schrödinger's Glide (commercial. In terms of computational speed for VS, rDock is faster than Vina and comparable to Glide. For binding mode prediction, rDock and Vina are superior to Glide. The VS performance of rDock is significantly better than Vina, but inferior to Glide for most systems unless pharmacophore constraints are used; in that case rDock and Glide are of equal performance. The program is released under the Lesser General Public License and is freely available for download, together with the manuals, example files and the complete test sets, at http://rdock.sourceforge.net/

  20. Evaluation of molecular docking using polynomial empirical scoring functions.

    Science.gov (United States)

    Dias, Raquel; Timmers, Luis Fernando Saraiva Macedo; Caceres, Rafael Andrade; de Azevedo, Walter Filgueira

    2008-12-01

    Molecular docking simulations are of pivotal importance for analysis of protein-ligand interactions and also an essential resource for virtual-screening initiatives. In molecular docking simulations several possible docked structures are generated, which create an ensemble of structures representing binary complexes. Therefore, it is crucial to find the best solution for the simulation. One approach to this problem is to employ empirical scoring function to identify the best docked structure. It is expected that scoring functions show a descriptive funnel-shaped energy surface without many false minima to impair the efficiency of conformational sampling. We employed this methodology against a test set with 300 docked structures. Docking simulations of these ligands against enzyme binding pocket indicated a funnel-shaped behavior of the complexation for this system. This review compares a set of recently proposed polynomial empirical scoring functions, implemented in a program called POLSCORE, with two popular scoring function programs (XSCORE and DrugScore). Overall comparison indicated that POLSCORE works better to predict the correct docked position, for the ensemble of docked structures analyzed in the present work.

  1. Numerical errors and chaotic behavior in docking simulations.

    Science.gov (United States)

    Feher, Miklos; Williams, Christopher I

    2012-03-26

    This work examines the sensitivity of docking programs to tiny changes in ligand input files. The results show that nearly identical ligand input structures can produce dramatically different top-scoring docked poses. Even changing the atom order in a ligand input file can produce significantly different poses and scores. In well-behaved cases the docking variations are small and follow a normal distribution around a central pose and score, but in many cases the variations are large and reflect wildly different top scores and binding modes. The docking variations are characterized by statistical methods, and the sensitivity of high-throughput and more precise docking methods are compared. The results demonstrate that part of docking variation is due to numerical sensitivity and potentially chaotic effects in current docking algorithms and not solely due to incomplete ligand conformation and pose searching. These results have major implications for the way docking is currently used for pose prediction, ranking, and virtual screening. © 2012 American Chemical Society

  2. A hierarchical method for molecular docking using cloud computing.

    Science.gov (United States)

    Kang, Ling; Guo, Quan; Wang, Xicheng

    2012-11-01

    Discovering small molecules that interact with protein targets will be a key part of future drug discovery efforts. Molecular docking of drug-like molecules is likely to be valuable in this field; however, the great number of such molecules makes the potential size of this task enormous. In this paper, a method to screen small molecular databases using cloud computing is proposed. This method is called the hierarchical method for molecular docking and can be completed in a relatively short period of time. In this method, the optimization of molecular docking is divided into two subproblems based on the different effects on the protein-ligand interaction energy. An adaptive genetic algorithm is developed to solve the optimization problem and a new docking program (FlexGAsDock) based on the hierarchical docking method has been developed. The implementation of docking on a cloud computing platform is then discussed. The docking results show that this method can be conveniently used for the efficient molecular design of drugs.

  3. Protein-Ligand Docking Based on Beta-Shape

    Science.gov (United States)

    Kim, Chong-Min; Won, Chung-In; Kim, Jae-Kwan; Ryu, Joonghyun; Bhak, Jong; Kim, Deok-Soo

    Protein-ligand docking is to predict the location and orientation of a ligand with respect to a protein within its binding site, and has been known to be essential for the development of new drugs. The protein-ligand docking problem is usually formulated as an energy minimization problem to identify the docked conformation of the ligand. A ligand usually docks around a depressed region, called a pocket, on the surface of a protein. Presented in this paper is a docking method, called BetaDock, based on the newly developed geometric construct called the β-shape and the β-complex. To cope with the computational intractability, the global minimum of the potential energy function is searched using the genetic algorithm. The proposed algorithm first locates initial chromosomes at some locations within the pocket recognized according to the local shape of the β-shape. Then, the algorithm proceeds generations by taking advantage of powerful properties of the β-shape to achieve an extremely fast and good solution. We claim that the proposed method is much faster than other popular docking softwares including AutoDock.

  4. Layout and control policies for cross docking operations

    NARCIS (Netherlands)

    Vis, Iris F. A.; Roodbergen, Kees Jan

    2011-01-01

    Many supply chains strive to shorten the time between a customer's order and the actual delivery of the ordered goods. Cross docking is one of the options to reduce these response times. Cross docking facilities are dynamic environments where products arrive and leave the same day. To deal with thes

  5. Layout and control policies for cross docking operations

    NARCIS (Netherlands)

    Vis, Iris F. A.; Roodbergen, Kees Jan

    2011-01-01

    Many supply chains strive to shorten the time between a customer's order and the actual delivery of the ordered goods. Cross docking is one of the options to reduce these response times. Cross docking facilities are dynamic environments where products arrive and leave the same day. To deal with thes

  6. Layout and control policies for cross docking operations

    NARCIS (Netherlands)

    Vis, Iris F. A.; Roodbergen, Kees Jan

    2011-01-01

    Many supply chains strive to shorten the time between a customer's order and the actual delivery of the ordered goods. Cross docking is one of the options to reduce these response times. Cross docking facilities are dynamic environments where products arrive and leave the same day. To deal with

  7. Dock GEFs and their therapeutic potential: neuroprotection and axon regeneration.

    Science.gov (United States)

    Namekata, Kazuhiko; Kimura, Atsuko; Kawamura, Kazuto; Harada, Chikako; Harada, Takayuki

    2014-11-01

    The dedicator of cytokinesis (Dock) family is composed of atypical guanine exchange factors (GEFs) that activate the Rho GTPases Rac1 and Cdc42. Rho GTPases are best documented for their roles in actin polymerization and they regulate important cellular functions, including morphogenesis, migration, neuronal development, and cell division and adhesion. To date, 11 Dock family members have been identified and their roles have been reported in diverse contexts. There has been increasing interest in elucidating the roles of Dock proteins in recent years and studies have revealed that they are potential therapeutic targets for various diseases, including glaucoma, Alzheimer's disease, cancer, attention deficit hyperactivity disorder and combined immunodeficiency. Among the Dock proteins, Dock3 is predominantly expressed in the central nervous system and recent studies have revealed that Dock3 plays a role in protecting retinal ganglion cells from neurotoxicity and oxidative stress as well as in promoting optic nerve regeneration. In this review, we discuss the current understanding of the 11 Dock GEFs and their therapeutic potential, with a particular focus on Dock3 as a novel target for the treatment of glaucoma and other neurodegenerative diseases. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. The Impact of BIB-Spiralling Induced Missing Data Patterns on Goodness-of-Fit Tests in Factor Analysis. Occasional Paper OP93-1.

    Science.gov (United States)

    Kaplan, David

    The impact of the use of data arising from balanced incomplete block (BIB) spiralled designs on the chi-square goodness-of-fit test in factor analysis is considered. Data from BIB designs posses a unique pattern of missing data that can be characterized as missing completely at random (MCAR). Standard approaches to factor analyzing such data rest…

  9. MUNI-FITS-Utils

    Science.gov (United States)

    Chrastina, M.; Zejda, M.; Mikulášek, Z.

    2010-12-01

    The FITS standard allows arbitrary use of name-space for keywords, except some reserved keywords. Result of this freedom is that several keywords have the same meaning. Similar problem is that values of keywords have different physical units. These facts complicate automated data processing and also creation of FITS file archives with simple structure. MUNI-FITS-Utils is a package of Python scripts which have been developed in PyFITS, a Python FITS Module. Scripts are user-friendly and allow manipulating FITS headers to get uniform shape. Further functions will be added soon.

  10. FIT3D: Fitting optical spectra

    Science.gov (United States)

    Sánchez, S. F.; Pérez, E.; Sánchez-Blázquez, P.; González, J. J.; Rosales-Ortega, F. F.; Cano-Díaz, M.; López-Cobá, C.; Marino, R. A.; Gil de Paz, A.; Mollá, M.; López-Sánchez, A. R.; Ascasibar, Y.; Barrera-Ballesteros, J.

    2016-09-01

    FIT3D fits optical spectra to deblend the underlying stellar population and the ionized gas, and extract physical information from each component. FIT3D is focused on the analysis of Integral Field Spectroscopy data, but is not restricted to it, and is the basis of Pipe3D, a pipeline used in the analysis of datasets like CALIFA, MaNGA, and SAMI. It can run iteratively or in an automatic way to derive the parameters of a large set of spectra.

  11. BDT: an easy-to-use front-end application for automation of massive docking tasks and complex docking strategies with AutoDock.

    Science.gov (United States)

    Vaqué, Montserrat; Arola, Anna; Aliagas, Carles; Pujadas, Gerard

    2006-07-15

    AutoGrid/AutoDock is one of the most popular software packages for docking, but its automation is not trivial for tasks such as (1) the virtual screening of a library of ligands against a set of possible receptors; (2) the use of receptor flexibility and (3) making a blind-docking experiment with the whole receptor surface. This is an obstacle for research teams in the fields of Chemistry and the Life Sciences who are interested in conducting this kind of experiment but do not have enough programming skills. To overcome these limitations, we have designed BDT, an easy-to-use graphic interface for AutoGrid/AutoDock. BDT is available for free, upon request, for non-commercial research.

  12. PERANCANGAN FLOATING DOCK UNTUK DAERAH PERAIRAN PELABUHAN KOTA TEGAL

    Directory of Open Access Journals (Sweden)

    Kiryanto Kiryanto

    2013-06-01

    Full Text Available Floating dock merupakan bangunan air sebagai tempat reparasi kapal yang dinilai cukup efisien dalam pembangunannya karena tidak membutuhkan dana yang terlalu mahal. Di sektor indusrti perkapalan kota tegal sudah memiliki galangan dan dock reparasi kapal yang cukup berkembang.  Ide perancangan floating dock ini dirancang sebagai alternatif baru pelayanan reparasi kapal. Perancangan floating dock ini juga memperhatikan dengan detail kapasitas kapal – kapal yang pernah melakukan repararasi di sekitar galangan di Kota Tegal agar ditemukan ukuran utama floating dock yang tepat. Dari Kapasitas kapal yang ada dan berdasarkan metode perbandingan ukuran beberapa floating dock, maka ditemukan ukuran utama yang tepat untuk menampung kebutuhan pelayanan reparasi kapal yaitu LOA = 136,37 m, Lpt = 114.80 m, Bmax = 36,40 m, Bmd: 30,80 m, Tmin = 0,86 m, Tmax = 1,58 m, Hpt = 2,10 m, HOA = 9,60 m. Berdasarkan perhitungan ditemukan juga Ton Lifting Capacity (TLC sebesar 3000 ton. Perancangan menggunakan software perkapalan yaitu dengan menggunakan AutoCad, Delftship, Maxsurf dan Hidromax. Dengan analisa stabilitas menggunakan software Hidromax diketahui bahwa floating dock ini mampu memiliki stabilitas yang baik dengan 4 kondisi yang semua memenuhi criteria  International Maritime Organisation (IMO. Perancangan floating dock ini juga menghitung analisa ekonomis dan investasi. Dari rekapitulasi dana investasi pembangunan floating dock yaitu sebesar Rp.136.622.888.000,00 dengan nilai kembali atau break even point selama 10 tahun dengan modal sendiri, 14 tahun dengan 50% modal sendiri dan 50 % pinjaman bank, dan break event point 18 tahun untuk dana pembangunan floating dock yang berasal dari 100 % pinjaman bank

  13. AutoDock-GIST: Incorporating Thermodynamics of Active-Site Water into Scoring Function for Accurate Protein-Ligand Docking.

    Science.gov (United States)

    Uehara, Shota; Tanaka, Shigenori

    2016-11-23

    Water plays a significant role in the binding process between protein and ligand. However, the thermodynamics of water molecules are often underestimated, or even ignored, in protein-ligand docking. Usually, the free energies of active-site water molecules are substantially different from those of waters in the bulk region. The binding of a ligand to a protein causes a displacement of these waters from an active site to bulk, and this displacement process substantially contributes to the free energy change of protein-ligand binding. The free energy of active-site water molecules can be calculated by grid inhomogeneous solvation theory (GIST), using molecular dynamics (MD) and the trajectory of a target protein and water molecules. Here, we show a case study of the combination of GIST and a docking program and discuss the effectiveness of the displacing gain of unfavorable water in protein-ligand docking. We combined the GIST-based desolvation function with the scoring function of AutoDock4, which is called AutoDock-GIST. The proposed scoring function was assessed employing 51 ligands of coagulation factor Xa (FXa), and results showed that both scoring accuracy and docking success rate were improved. We also evaluated virtual screening performance of AutoDock-GIST using FXa ligands in the directory of useful decoys-enhanced (DUD-E), thus finding that the displacing gain of unfavorable water is effective for a successful docking campaign.

  14. AutoDock VinaXB: implementation of XBSF, new empirical halogen bond scoring function, into AutoDock Vina.

    Science.gov (United States)

    Koebel, Mathew R; Schmadeke, Grant; Posner, Richard G; Sirimulla, Suman

    2016-01-01

    Halogen bonding has recently come to play as a target for lead optimization in rational drug design. However, most docking program don't account for halogen bonding in their scoring functions and are not able to utilize this new approach. In this study a new and improved halogen bonding scoring function (XBSF) is presented along with its implementation in the AutoDock Vina molecular docking software. This new improved program is termed as AutoDock VinaXB, where XB stands for the halogen bonding parameters that were added. XBSF scoring function is derived based on the X···A distance and C-X···A angle of interacting atoms. The distance term was further corrected to account for the polar flattening effect of halogens. A total of 106 protein-halogenated ligand complexes were tested and compared in terms of binding affinity and docking poses using Vina and VinaXB. VinaXB performed superior to Vina in the majority of instances. VinaXB was closer to native pose both above and below 2 Å deviation categories almost twice as frequently as Vina. Implementation of XBSF into AutoDock Vina has been shown to improve the accuracy of the docking result with regards to halogenated ligands. AutoDock VinaXB addresses the issues of halogen bonds that were previously being scored unfavorably due to repulsion factors, thus effectively lowering the output RMSD values.

  15. Carborane clusters in computational drug design: a comparative docking evaluation using AutoDock, FlexX, Glide, and Surflex.

    Science.gov (United States)

    Tiwari, Rohit; Mahasenan, Kiran; Pavlovicz, Ryan; Li, Chenglong; Tjarks, Werner

    2009-06-01

    Compounds containing boron atoms play increasingly important roles in the therapy and diagnosis of various diseases, particularly cancer. However, computational drug design of boron-containing therapeutics and diagnostics is hampered by the fact that many software packages used for this purpose lack parameters for all or part of the various types of boron atoms. In the present paper, we describe simple and efficient strategies to overcome this problem, which are based on the replacement of boron atom types with carbon atom types. The developed methods were validated by docking closo- and nido-carboranyl antifolates into the active site of a human dihydrofolate reductase (hDHFR) using AutoDock, Glide, FlexX, and Surflex and comparing the obtained docking poses with the poses of their counterparts in the original hDHFR-carboranyl antifolate crystal structures. Under optimized conditions, AutoDock and Glide were equally good in docking of the closo-carboranyl antifolates followed by Surflex and FlexX, whereas Autodock, Glide, and Surflex proved to be comparably efficient in the docking of nido-carboranyl antifolates followed by FlexX. Differences in geometries and partial atom charges in the structures of the carboranyl antifolates resulting from different data sources and/or optimization methods did not impact the docking performances of AutoDock or Glide significantly. Binding energies predicted by all four programs were in accordance with experimental data.

  16. Family Activities for Fitness

    Science.gov (United States)

    Grosse, Susan J.

    2009-01-01

    This article discusses how families can increase family togetherness and improve physical fitness. The author provides easy ways to implement family friendly activities for improving and maintaining physical health. These activities include: walking, backyard games, and fitness challenges.

  17. Nonlinear fitness landscape of a molecular pathway.

    Directory of Open Access Journals (Sweden)

    Lilia Perfeito

    2011-07-01

    Full Text Available Genes are regulated because their expression involves a fitness cost to the organism. The production of proteins by transcription and translation is a well-known cost factor, but the enzymatic activity of the proteins produced can also reduce fitness, depending on the internal state and the environment of the cell. Here, we map the fitness costs of a key metabolic network, the lactose utilization pathway in Escherichia coli. We measure the growth of several regulatory lac operon mutants in different environments inducing expression of the lac genes. We find a strikingly nonlinear fitness landscape, which depends on the production rate and on the activity rate of the lac proteins. A simple fitness model of the lac pathway, based on elementary biophysical processes, predicts the growth rate of all observed strains. The nonlinearity of fitness is explained by a feedback loop: production and activity of the lac proteins reduce growth, but growth also affects the density of these molecules. This nonlinearity has important consequences for molecular function and evolution. It generates a cliff in the fitness landscape, beyond which populations cannot maintain growth. In viable populations, there is an expression barrier of the lac genes, which cannot be exceeded in any stationary growth process. Furthermore, the nonlinearity determines how the fitness of operon mutants depends on the inducer environment. We argue that fitness nonlinearities, expression barriers, and gene-environment interactions are generic features of fitness landscapes for metabolic pathways, and we discuss their implications for the evolution of regulation.

  18. Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections.

    Science.gov (United States)

    Dobbs, Kerry; Domínguez Conde, Cecilia; Zhang, Shen-Ying; Parolini, Silvia; Audry, Magali; Chou, Janet; Haapaniemi, Emma; Keles, Sevgi; Bilic, Ivan; Okada, Satoshi; Massaad, Michel J; Rounioja, Samuli; Alwahadneh, Adel M; Serwas, Nina K; Capuder, Kelly; Çiftçi, Ergin; Felgentreff, Kerstin; Ohsumi, Toshiro K; Pedergnana, Vincent; Boisson, Bertrand; Haskoloğlu, Şule; Ensari, Arzu; Schuster, Michael; Moretta, Alessandro; Itan, Yuval; Patrizi, Ornella; Rozenberg, Flore; Lebon, Pierre; Saarela, Janna; Knip, Mikael; Petrovski, Slavé; Goldstein, David B; Parrott, Roberta E; Savas, Berna; Schambach, Axel; Tabellini, Giovanna; Bock, Christoph; Chatila, Talal A; Comeau, Anne Marie; Geha, Raif S; Abel, Laurent; Buckley, Rebecca H; İkincioğulları, Aydan; Al-Herz, Waleed; Helminen, Merja; Doğu, Figen; Casanova, Jean-Laurent; Boztuğ, Kaan; Notarangelo, Luigi D

    2015-06-18

    Background Combined immunodeficiencies are marked by inborn errors of T-cell immunity in which the T cells that are present are quantitatively or functionally deficient. Impaired humoral immunity is also common. Patients have severe infections, autoimmunity, or both. The specific molecular, cellular, and clinical features of many types of combined immunodeficiencies remain unknown. Methods We performed genetic and cellular immunologic studies involving five unrelated children with early-onset invasive bacterial and viral infections, lymphopenia, and defective T-cell, B-cell, and natural killer (NK)-cell responses. Two patients died early in childhood; after allogeneic hematopoietic stem-cell transplantation, the other three had normalization of T-cell function and clinical improvement. Results We identified biallelic mutations in the dedicator of cytokinesis 2 gene (DOCK2) in these five patients. RAC1 activation was impaired in the T cells. Chemokine-induced migration and actin polymerization were defective in the T cells, B cells, and NK cells. NK-cell degranulation was also affected. Interferon-α and interferon-λ production by peripheral-blood mononuclear cells was diminished after viral infection. Moreover, in DOCK2-deficient fibroblasts, viral replication was increased and virus-induced cell death was enhanced; these conditions were normalized by treatment with interferon alfa-2b or after expression of wild-type DOCK2. Conclusions Autosomal recessive DOCK2 deficiency is a new mendelian disorder with pleiotropic defects of hematopoietic and nonhematopoietic immunity. Children with clinical features of combined immunodeficiencies, especially with early-onset, invasive infections, may have this condition. (Supported by the National Institutes of Health and others.).

  19. FIPSDock: a new molecular docking technique driven by fully informed swarm optimization algorithm.

    Science.gov (United States)

    Liu, Yu; Zhao, Lei; Li, Wentao; Zhao, Dongyu; Song, Miao; Yang, Yongliang

    2013-01-05

    The accurate prediction of protein-ligand binding is of great importance for rational drug design. We present herein a novel docking algorithm called as FIPSDock, which implements a variant of the Fully Informed Particle Swarm (FIPS) optimization method and adopts the newly developed energy function of AutoDock 4.20 suite for solving flexible protein-ligand docking problems. The search ability and docking accuracy of FIPSDock were first evaluated by multiple cognate docking experiments. In a benchmarking test for 77 protein/ligand complex structures derived from GOLD benchmark set, FIPSDock has obtained a successful predicting rate of 93.5% and outperformed a few docking programs including particle swarm optimization (PSO)@AutoDock, SODOCK, AutoDock, DOCK, Glide, GOLD, FlexX, Surflex, and MolDock. More importantly, FIPSDock was evaluated against PSO@AutoDock, SODOCK, and AutoDock 4.20 suite by cross-docking experiments of 74 protein-ligand complexes among eight protein targets (CDK2, ESR1, F2, MAPK14, MMP8, MMP13, PDE4B, and PDE5A) derived from Sutherland-crossdock-set. Remarkably, FIPSDock is superior to PSO@AutoDock, SODOCK, and AutoDock in seven out of eight cross-docking experiments. The results reveal that FIPS algorithm might be more suitable than the conventional genetic algorithm-based algorithms in dealing with highly flexible docking problems. Copyright © 2012 Wiley Periodicals, Inc.

  20. Orion Handling Qualities During ISS Proximity Operations and Docking

    Science.gov (United States)

    Stephens, John-Paul; Vos, Gordon A.; Bilimoria, Karl D.; Mueller, Eric R.; Brazzel, Jack; Spehar, Pete

    2011-01-01

    NASA's Orion spacecraft is designed to autonomously rendezvous and dock with many vehicles including the International Space Station. However, the crew is able to assume manual control of the vehicle s attitude and flight path. In these instances, Orion must meet handling qualities requirements established by NASA. Two handling qualities assessments were conducted at the Johnson Space Center to evaluate preliminary designs of the vehicle using a six degree of freedom, high-fidelity guidance, navigation, and control simulation. The first assessed Orion s handling qualities during the last 20 ft before docking, and included both steady and oscillatory motions of the docking target. The second focused on manual acquisition of the docking axis during the proximity operations phase and subsequent station-keeping. Cooper-Harper handling qualities ratings, workload ratings and comments were provided by 10 evaluation pilots for the docking study and 5 evaluation pilots for the proximity operations study. For the docking task, both cases received 90% Level 1 (satisfactory) handling qualities ratings, exceeding NASA s requirement. All ratings for the ProxOps task were Level 1. These evaluations indicate that Orion is on course to meet NASA's handling quality requirements for ProxOps and docking.

  1. Combining docking with pharmacophore filtering for improved virtual screening

    Directory of Open Access Journals (Sweden)

    Peach Megan L

    2009-05-01

    Full Text Available Abstract Background Virtual screening is used to distinguish potential leads from inactive compounds in a database of chemical samples. One method for accomplishing this is by docking compounds into the structure of a receptor binding site in order to rank-order compounds by the quality of the interactions they form with the receptor. It is generally established that docking can be reasonably successful at generating good poses of a ligand in an active site. However, the scoring functions that are used with docking are typically not successful at correctly ranking ligands according to binding affinity or even distinguishing correct poses of a given ligand from incorrect ones. Results We have developed a simple method for reducing the number of false positives in a virtual screen, meaning ligands which are scored highly by the docking program but do not bind well in reality. This method uses a docking program for pose generation without regard to scoring, followed by filtering with receptor-based pharmacophore searches. We applied it to three test-case targets: neuraminidase A, cyclin-dependent kinase 2, and the C1 domain of protein kinase C. Conclusion The pharmacophore filtering method can perform better than more traditional docking + scoring methods, and allows the advantages of both docking-based and pharmacophore-based approaches to virtual screening to be fully realized.

  2. Quasispecies on Fitness Landscapes.

    Science.gov (United States)

    Schuster, Peter

    2016-01-01

    Selection-mutation dynamics is studied as adaptation and neutral drift on abstract fitness landscapes. Various models of fitness landscapes are introduced and analyzed with respect to the stationary mutant distributions adopted by populations upon them. The concept of quasispecies is introduced, and the error threshold phenomenon is analyzed. Complex fitness landscapes with large scatter of fitness values are shown to sustain error thresholds. The phenomenological theory of the quasispecies introduced in 1971 by Eigen is compared to approximation-free numerical computations. The concept of strong quasispecies understood as mutant distributions, which are especially stable against changes in mutations rates, is presented. The role of fitness neutral genotypes in quasispecies is discussed.

  3. Investigation of MM-PBSA rescoring of docking poses.

    Science.gov (United States)

    Thompson, David C; Humblet, Christine; Joseph-McCarthy, Diane

    2008-05-01

    Target-based virtual screening is increasingly used to generate leads for targets for which high quality three-dimensional (3D) structures are available. To allow large molecular databases to be screened rapidly, a tiered scoring scheme is often employed whereby a simple scoring function is used as a fast filter of the entire database and a more rigorous and time-consuming scoring function is used to rescore the top hits to produce the final list of ranked compounds. Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) approaches are currently thought to be quite effective at incorporating implicit solvation into the estimation of ligand binding free energies. In this paper, the ability of a high-throughput MM-PBSA rescoring function to discriminate between correct and incorrect docking poses is investigated in detail. Various initial scoring functions are used to generate docked poses for a subset of the CCDC/Astex test set and to dock one set of actives/inactives from the DUD data set. The effectiveness of each of these initial scoring functions is discussed. Overall, the ability of the MM-PBSA rescoring function to (i) regenerate the set of X-ray complexes when docking the bound conformation of the ligand, (ii) regenerate the X-ray complexes when docking conformationally expanded databases for each ligand which include "conformation decoys" of the ligand, and (iii) enrich known actives in a virtual screen for the mineralocorticoid receptor in the presence of "ligand decoys" is assessed. While a pharmacophore-based molecular docking approach, PhDock, is used to carry out the docking, the results are expected to be general to use with any docking method.

  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. Game Theoretic Approach to Post-Docked Satellite Control

    Science.gov (United States)

    Hiramatsu, Takashi; Fitz-Coy, Norman G.

    2007-01-01

    This paper studies the interaction between two satellites after docking. In order to maintain the docked state with uncertainty in the motion of the target vehicle, a game theoretic controller with Stackelberg strategy to minimize the interaction between the satellites is considered. The small perturbation approximation leads to LQ differential game scheme, which is validated to address the docking interactions between a service vehicle and a target vehicle. The open-loop solution are compared with Nash strategy, and it is shown that less control efforts are obtained with Stackelberg strategy.

  6. Orbital Maneuvering Vehicle (OMV) three-point docking latch

    Science.gov (United States)

    Myers, W. Neill; Forbes, John C.; Barnes, Wayne L.

    1990-01-01

    The primary purpose of the OMV is to dock with orbiting payloads and then either transfer them to a different orbit or return them to the Space Shuttle for servicing. Some such missions will involve docking with payloads equipped with a Flight Support System (FSS) type of interface; an example is the Hubble Space Telescope (HST). The design and development of a mechanism to be used for testing this docking concept on the NASA-Marshall test beds is described. The test results to date are also presented.

  7. Linear Actuator System for the NASA Docking System

    Science.gov (United States)

    Dick, Brandon; Oesch, Chris

    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, which implements the Soft Impact Mating and Attenuation Concept (SIMAC). 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.

  8. LPD 17 San Antonio Class Amphibious Transport Dock (LPD 17)

    Science.gov (United States)

    2015-12-01

    Selected Acquisition Report (SAR) RCS: DD-A&T(Q&A)823-542 LPD 17 San Antonio Class Amphibious Transport Dock (LPD 17) As of FY 2017 President’s...LPD 17 December 2015 SAR March 8, 2016 11:18:10 UNCLASSIFIED 4 CAPT Darren Plath LPD 17 Amphibious Transport Dock Ship Program Office (PMS317) PEO...Information Program Name LPD 17 San Antonio Class Amphibious Transport Dock (LPD 17) DoD Component Navy Responsible Office References SAR Baseline

  9. [Reference Intervals of Standard Test Items in Ningen Dock Examination].

    Science.gov (United States)

    Yamakado, Minoru

    2016-03-01

    Reference intervals (RIs) were derived from records of 1,499,288 individuals who underwent ningen dock examination in 188 institutes which belong to Japan Society of Ningen Dock in 2012. Targets were 27 basic laboratory tests, including the body mass index (BMI) and systolic and diastolic blood pressures (SBP, DBP). Individuals fulfilling strict criteria were chosen: SBP dock results will enable the appropriate interpretation of test results in health screening, and promote the effective application of CDLs for therapeutic intervention, taking into account the sex, age, and other health attributes.

  10. Selective flexibility of side-chain residues improves VEGFR-2 docking score using AutoDock Vina.

    Science.gov (United States)

    Abreu, Rui M V; Froufe, Hugo J C; Queiroz, Maria-João R P; Ferreira, Isabel C F R

    2012-04-01

    Selective side-chain residue flexibility is an option available on AutoDock Vina docking software. This approach is promising as it attempts to provide a more realistic ligand-protein interaction environment without an unmanageable increase in computer processing time. However, studies validating this approach are still scarce. VEGFR-2 (vascular endothelial growth factor receptor 2), a known protein target for anti-angiogenic agents, was used in this study. Four residues located in the VEGFR-2 kinase site were selected and made flexible: Lys868, Glu885, Cys919, and Asp1046. The docking scores for all possible combinations of flexible residues were compared to the docking scores using a rigid conformation. The best overall docking scores were obtained using the Glu885 flexible conformation, with Pearson and Spearman rank correlation values of 0.568 and 0.543, respectively, and a 51% increase in processing time. Using different VEGFR-2 crystal structures, a similar trend was observed with the Glu885 flexible conformation presenting best scores. This study demonstrates that careful use of selective side-chain residue flexibility can improve AutoDock Vina docking score accuracy, without a significant increase in processing time. This methodology can be a valuable tool in drug design projects using VEGFR-2 but will also probably be useful if applied to other protein targets. © 2011 John Wiley & Sons A/S.

  11. DockBench as docking selector tool: the lesson learned from D3R Grand Challenge 2015

    Science.gov (United States)

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

    2016-09-01

    Structure-based drug design (SBDD) has matured within the last two decades as a valuable tool for the optimization of low molecular weight lead compounds to highly potent drugs. The key step in SBDD requires knowledge of the three-dimensional structure of the target-ligand complex, which is usually determined by X-ray crystallography. In the absence of structural information for the complex, SBDD relies on the generation of plausible molecular docking models. However, molecular docking protocols suffer from inaccuracies in the description of the interaction energies between the ligand and the target molecule, and often fail in the prediction of the correct binding mode. In this context, the appropriate selection of the most accurate docking protocol is absolutely relevant for the final molecular docking result, even if addressing this point is absolutely not a trivial task. D3R Grand Challenge 2015 has represented a precious opportunity to test the performance of DockBench, an integrate informatics platform to automatically compare RMDS-based molecular docking performances of different docking/scoring methods. The overall performance resulted in the blind prediction are encouraging in particular for the pose prediction task, in which several complex were predicted with a sufficient accuracy for medicinal chemistry purposes.

  12. The human olfactory receptor 17-40: requisites for fitting into the binding pocket.

    Science.gov (United States)

    Anselmi, Cecilia; Buonocore, Anna; Centini, Marisanna; Facino, Roberto Maffei; Hatt, Hanns

    2011-06-01

    To gain structural insight on the interactions between odorants and the human olfactory receptor, we did homology modelling of the receptor structure, followed by molecular docking simulation with ligands. Molecular dynamics simulation on the structures resulting from docking served to estimate the binding free energy of the various odorant families. A correlation with the odorous properties of the ligands is proposed. We also investigated which residues were involved in the binding of a set of properly synthesised ligands and which were required for fitting inside the binding pocket. Olfactive stimulation of the olfactory receptor with odorous molecules was also investigated, using calcium imaging or electrophysiological recordings.

  13. Spectroscopic and molecular docking studies on the interaction of troxerutin with DNA.

    Science.gov (United States)

    Subastri, A; Ramamurthy, C H; Suyavaran, A; Mareeswaran, R; Lokeswara Rao, P; Harikrishna, M; Suresh Kumar, M; Sujatha, V; Thirunavukkarasu, C

    2015-01-01

    Troxerutin (TXER) is a derivative of naturally occurring bioflavonoid rutin. It possesses different biological activities in rising clinical world. The biological activity possessed by most of the drugs mainly targets on macromolecules. Hence, in the current study we have examined the interaction mechanism of TXER with calf thymus DNA (CT-DNA) by using various spectroscopic methods, isothermal titration calorimetry (ITC) and molecular docking studies. Further, DNA cleavage study was carried out to find the DNA protection activity of TXER. UV-absorption and emission spectroscopy showed low binding constant values via groove binding. Circular dichroism study indicates that TXER does not modify native B-form of DNA, and it retains the native B-conformation. Furthermore, no effective positive potential peak shift was observed in TXER-DNA complex during electrochemical analysis by which it represents an interaction of TXER with DNA through groove binding. Molecular docking study showed thymine guanine based interaction with docking score -7.09 kcal/mol. This result was compared to experimental ITC value. The DNA cleavage study illustrates that TXER does not cause any DNA damage as well as TXER showed DNA protection against hydroxyl radical induced DNA damage. From this study, we conclude that TXER interacts with DNA by fashion of groove binding.

  14. Economic Impacts From Spending by Private Dock Owners at Hartwell Lake

    Science.gov (United States)

    2008-03-01

    cost is variable. The lakes and market segments studied were: • Table Rock Lake, community dock • Rough River Lake, community dock • Pomme de... Terre Lake, community dock • Harry S. Truman Dam and Reservoir, marina • Raystown Lake, marina • Hartwell Lake, private dock • Lake Barkley, private

  15. Markov models of the apo-MDM2 lid region reveal diffuse yet two-state binding dynamics and receptor poses for computational docking

    Science.gov (United States)

    Mukherjee, Sudipto; Pantelopulos, George A.; Voelz, Vincent A.

    2016-08-01

    MDM2 is a negative regulator of p53 activity and an important target for cancer therapeutics. The N-terminal lid region of MDM2 modulates interactions with p53 via competition for its binding cleft, exchanging slowly between docked and undocked conformations in the absence of p53. To better understand these dynamics, we constructed Markov State Models (MSMs) from large collections of unbiased simulation trajectories of apo-MDM2, and find strong evidence for diffuse, yet two-state folding and binding of the N-terminal region to the p53 receptor site. The MSM also identifies holo-like receptor conformations highly suitable for computational docking, despite initiating trajectories from closed-cleft receptor structures unsuitable for docking. Fixed-anchor docking studies using a test set of high-affinity small molecules and peptides show simulated receptor ensembles achieve docking successes comparable to cross-docking studies using crystal structures of receptors bound by alternative ligands. For p53, the best-scoring receptor structures have the N-terminal region lid region bound in a helical conformation mimicking the bound structure of p53, suggesting lid region association induces receptor conformations suitable for binding. These results suggest that MD + MSM approaches can sample binding-competent receptor conformations suitable for computational peptidomimetic design, and that inclusion of disordered regions may be essential to capturing the correct receptor dynamics.

  16. Identification of IFN-alpha Induced Envelope Mutations of Hepatitis C Virus In Vitro Associated with Increased Viral Fitness and Interferon Resistance

    DEFF Research Database (Denmark)

    Serre, Stéphanie B N; Krarup, Henrik B; Bukh, Jens

    2013-01-01

    with acquisition of putative escape mutations in HCV structural and nonstructural proteins. Reverse genetic studies showed that primarily amino acid changes I348T in 1a(H77) E1 and F345V/V414A in 3a(S52) E1/E2 increased viral fitness. Single-cycle assays revealed that I348T and F345V/V414A enhanced viral entry...... is limited. Experimental studies were hampered by lack of HCV culture systems. Using genotype (strain) 1a(H77) and 3a(S52) Core-NS2 JFH1-based recombinants, we aimed at identifying viral correlates of IFN-α resistance in vitro. Long-term culture with IFN-α2b in Huh7.5 cells resulted in viral spread...... and release, respectively. In assays allowing viral spread, these mutations conferred a level of IFN-α resistance exceeding the observed fitness effect. The identified mutations acted in a subtype-specific manner but were not found in genotype 1a and 3a patients, who failed IFN-α therapy. Studies with HCV...

  17. Development of a Current Fit Function for NbTi to be Used for Calculation of Persistent Current Induced Field Errors in the LHC Main Dipoles

    CERN Document Server

    Schwerg, N

    2006-01-01

    A new fit function for the critical current density of superconducting NbTi cables for the LHC main dipoles is presented. Existing fit functions usually show a good matching of the very low field range, but produce a current density which is significantly too small for the intermediate and high field range. Consequently the multipole range measured at cold is only partially reproduced and loops from current cycling do not match. The presented function is used as input for the field quality calculation of a complete magnet cross-section including arbitrary current cycling and all hysteresis effects. This way allows to trace a so-called finger-print of the cable combination used in the LHC main bending magnets. The finger-print pattern is a consequence of the differences of the measured superconductor magnetization of cables from different manufacturers. The simulation results have been compared with measurements at cold obtained from LHC main dipoles and a very good agreement for low and intermediate field val...

  18. Dock6, a Dock-C subfamily guanine nucleotide exchanger, has the dual specificity for Rac1 and Cdc42 and regulates neurite outgrowth.

    Science.gov (United States)

    Miyamoto, Yuki; Yamauchi, Junji; Sanbe, Atsushi; Tanoue, Akito

    2007-02-15

    Small GTPases of the Rho family, Rho, Rac, and Cdc42, are critical regulators of the changes in the actin cytoskeleton. Rho GTPases are typically activated by Dbl-homology (DH)-domain-containing guanine nucleotide exchange factors (GEFs). Recent genetic and biochemical studies revealed a new type of GEF for the Rho GTPases. This family is composed of 11 genes, designated as Dock1 to Dock11, and is structurally divided into four classes Dock-A, -B, -C, and -D. Dock-A and -B subfamilies are typically GEFs specific for Rac1, while the Dock-D subfamily is specific for Cdc42. Here we show that Dock6, a member of the Dock-C subfamily, exchanges GDP for GTP for Rac1 and Cdc42 in vitro and in vivo. Furthermore, we find that, in mouse N1E-115 neuroblastoma cells, expression of Dock6 is increased following differentiation. Transfection of the catalytic Dock Homology Region-2 (DHR-2) domain of Dock6 promotes neurite outgrowth mediated by Rac1 and Cdc42. Conversely, knockdown of endogenous Dock6 by small interference RNA reduces activation of Rac1 and Cdc42 and neurite outgrowth. Taken together, these results suggest that Dock6 differs from all of the identified Dock180-related proteins, in that it is the GEF specific for both Rac1 and Cdc42 and may be one of physiological regulators of neurite outgrowth.

  19. Getting CSR communication fit

    DEFF Research Database (Denmark)

    Schmeltz, Line

    2017-01-01

    Companies experience increasing legal and societal pressure to communicate about their corporate social responsibility (CSR) engagements from a number of different publics. One very important group is that of young consumers who are predicted to be the most important and influential consumer group...... in the near future. From a value- theoretical base, this article empirically explores the role and applicability of ‘fit’ in strategic CSR communication targeted at young consumers. Point of departure is taken in the well-known strategic fit (a logical link between a company’s CSR commitment and its core...... values) and is further developed by introducing two additional fits, the CSR- Consumer fit and the CSR-Consumer-Company fit (Triple Fit). Through a sequential design, the three fits are empirically tested and their potential for meeting young consumers’ expectations for corporate CSR messaging...

  20. 300,000-tonnage Crude Oil Dock Put into Operation

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    @@ Aproject of Jointly establishing 300,000-tonnage crude oil dock of Tianjin Port has been put into operations, thanks to its outut grid successfully connected with oil pipeline of Sinopec Tanggu reservior.

  1. 18 CFR 1304.204 - Docks, piers, and boathouses.

    Science.gov (United States)

    2010-04-01

    ... required to submit accurate drawings with dimensions of all proposed facilities. (a) Docks, piers... the four walls are constructed of wire or screen mesh from floor to ceiling, and the wire or screen...

  2. Yada: a novel tool for molecular docking calculations

    Science.gov (United States)

    Piotto, S.; Di Biasi, L.; Fino, R.; Parisi, R.; Sessa, L.; Concilio, S.

    2016-09-01

    Molecular docking is a computational method employed to estimate the binding between a small ligand (the drug candidate) and a protein receptor that has become a standard part of workflow in drug discovery. Generally, when the binding site is known and a molecule is similar to known ligands, the most popular docking methods are rather accurate in the prediction of the geometry. Unfortunately, when the binding site is unknown, the blind docking analysis requires large computational resources and the results are often not accurate. Here we present Yada, a new tool for molecular docking that is capable to distribute efficiently calculations onto general purposes computer grid and that combines biological and structural information of the receptor. Yada is available for Windows and Linux and it is free to download at >www.yada.unisa.it.

  3. Discovery of potential cyclooxygenase inhibitors using in silico docking studies

    Directory of Open Access Journals (Sweden)

    Arumugam Madeswaran

    2012-03-01

    Full Text Available This study deals with the evaluation of the cyclooxygenase inhibitory activity of flavonoids (tangeritin, morin, rhamnetin, theaflavin, pachypodol, eriodictyol, homoeriodictyol, aromadedrin, okanin using in silico docking studies. In silico docking studies were carried out using AutoDock 4.2. Three important parameters like binding energy, inhibition constant and intermolecular energy were determined. The results showed that all the selected flavonoids showed binding energy ranging between -8.77 kcalmol-1 to -6.10 kcalmol-1 when compared with that of the standard (-8.30 kcalmol-1. Intermolecular energy (-10.56 kcalmol-1 to -7.89 kcalmol-1 and inhibition constant (373.91 nM to 34.03 µM of the ligands also coincide with the binding energy. All the selected flavonoids contributed cyclooxygenase inhibitory activity because of its structural parameters. These molecular docking analyses could lead to the further development of potent cyclooxygenase inhibitors.

  4. Virtual Screening with AutoDock: Theory and Practice.

    Science.gov (United States)

    Cosconati, Sandro; Forli, Stefano; Perryman, Alex L; Harris, Rodney; Goodsell, David S; Olson, Arthur J

    2010-06-01

    IMPORTANCE TO THE FIELD: Virtual screening is a computer-based technique for identifying promising compounds to bind to a target molecule of known structure. Given the rapidly increasing number of protein and nucleic acid structures, virtual screening continues to grow as an effective method for the discovery of new inhibitors and drug molecules. AREAS COVERED IN THIS REVIEW: We describe virtual screening methods that are available in the AutoDock suite of programs, and several of our successes in using AutoDock virtual screening in pharmaceutical lead discovery. WHAT THE READER WILL GAIN: A general overview of the challenges of virtual screening is presented, along with the tools available in the AutoDock suite of programs for addressing these challenges. TAKE HOME MESSAGE: Virtual screening is an effective tool for the discovery of compounds for use as leads in drug discovery, and the free, open source program AutoDock is an effective tool for virtual screening.

  5. JADOPPT: java based AutoDock preparing and processing tool.

    Science.gov (United States)

    García-Pérez, Carlos; Peláez, Rafael; Therón, Roberto; Luis López-Pérez, José

    2017-02-15

    AutoDock is a very popular software package for docking and virtual screening. However, currently it is hard work to visualize more than one result from the virtual screening at a time. To overcome this limitation we have designed JADOPPT, a tool for automatically preparing and processing multiple ligand-protein docked poses obtained from AutoDock. It allows the simultaneous visual assessment and comparison of multiple poses through clustering methods. Moreover, it permits the representation of reference ligands with known binding modes, binding site residues, highly scoring regions for the ligand, and the calculated binding energy of the best ranked results. JADOPPT, supplementary material (Case Studies 1 and 2) and video tutorials are available at http://visualanalytics.land/cgarcia/JADOPPT.html. carlosgarcia@usal.es or pelaez@usal.es. Supplementary data are available at Bioinformatics online.

  6. AggieSat: Autonomous Rendezvous and Docking Technology Demonstrator Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Current autonomous rendezvous and docking (AR&D) capability in low Earth orbit (LEO) is constrained by sensor and effector mass, power, and accuracy limits. To...

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

    African Journals Online (AJOL)

    ... mutated at amino acid position 43 to a biphenylalanine (biPhe-43) residue. ... to verify the docking results based on the Gibbs free binding energies. ... should involve an extended but conformational flexible aromatic group, i.e. a biphenyl.

  8. Docking analysis of verteporfin with YAP WW domain.

    Science.gov (United States)

    Kandoussi, Ilham; Lakhlili, Wiame; Taoufik, Jamal; Ibrahimi, Azeddine

    2017-01-01

    The YAP oncogene is a known cancer target. Therefore, it is of interest to understand the molecular docking interaction of verteporfin (a derivative of benzo-porphyrin) with the WW domain of YAP (clinically used for photo-dynamic therapy in macular degeneration) as a potential WW domain-ligand modulator by inhibition. A homology protein SWISS MODEL of the human YAP protein was constructed to dock (using AutoDock vina) with the PubChem verteporfin structure for interaction analysis. The docking result shows the possibilities of verteporfin interaction with the oncogenic transcription cofactor YAP having WW1 and WW2 domains. Thus, the ability of verteporfin to bind with the YAP WW domain having modulator activity is implied in this analysis.

  9. Docking and scoring of metallo-beta-lactamases inhibitors

    DEFF Research Database (Denmark)

    Olsen, Lars; Pettersson, Ingrid; Hemmingsen, Lars

    2004-01-01

    The performance of the AutoDock, GOLD and FlexX docking programs was evaluated for docking of dicarboxylic acid inhibitors into metallo-beta-lactamases (MBLs). GOLD provided the best overall performance, with RMSDs between experimental and docked structures of 1.8-2.6 A and a good correlation...... between the experimentally determined MBL-inhibitor affinities and the GOLD scores. GOLD was selected for a test including a broad spectrum of inhibitors for which experimental MBL-inhibitor binding affinities are available. This study revealed that (1) for most compound classes (dicarboxylic acids...... and descriptors associated with binding of the IMP-1 inhibitors to the enzyme. The external Q2 for the test set is 0.73. This final model for prediction of IMP-1 MBL-inhibitor affinity handled all known classes of MBL-inhibitors, except small sulphur compounds....

  10. Virtual Screening with AutoDock: Theory and Practice

    Science.gov (United States)

    Cosconati, Sandro; Forli, Stefano; Perryman, Alex L.; Harris, Rodney; Goodsell, David S.; Olson, Arthur J.

    2011-01-01

    Importance to the field Virtual screening is a computer-based technique for identifying promising compounds to bind to a target molecule of known structure. Given the rapidly increasing number of protein and nucleic acid structures, virtual screening continues to grow as an effective method for the discovery of new inhibitors and drug molecules. Areas covered in this review We describe virtual screening methods that are available in the AutoDock suite of programs, and several of our successes in using AutoDock virtual screening in pharmaceutical lead discovery. What the reader will gain A general overview of the challenges of virtual screening is presented, along with the tools available in the AutoDock suite of programs for addressing these challenges. Take home message Virtual screening is an effective tool for the discovery of compounds for use as leads in drug discovery, and the free, open source program AutoDock is an effective tool for virtual screening. PMID:21532931

  11. Molecular docking and in silico ADMET studies of silibinin and ...

    African Journals Online (AJOL)

    promising clinical trials and validation. ... various experimental trials. The compounds are ... tumorigenic and reproductive risks (Table 1). Docking studies .... Table 2: Comparison of drug-likeness properties of silibinin and glycyrrhetic acid.

  12. Fault-Tolerant Relative Navigation System (RNS) for Docking Project

    Data.gov (United States)

    National Aeronautics and Space Administration — A method is propsed to develop a sensor fusion process for blending GPS/IMU/EO data for fault tolerant rendezvous and docking of spacecraft. The methodology takes...

  13. Optimal Rendezvous and Docking Simulator for Elliptical Orbits Project

    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...

  14. Improving NEC Fit

    Science.gov (United States)

    2015-09-01

    Fill cannot. NEC Fit NEC Fit measures more than the crew’s total skill sets. It also accounts for how these sailors are used by crediting an NEC...Abstract Navy enlisted classifications (NECs) denote special skills beyond those associated with a rating. They are used in defining manpower...requirements and in managing personnel by tracking sailors who have acquired these skills . NEC Fit is one of two primary metrics that Navy leadership

  15. Scheduling inbound and outbound trucks at cross docking terminals

    OpenAIRE

    Nils Boysen; Malte Fliedner; Armin Scholl

    2007-01-01

    At cross docking terminals, shipments from inbound trucks are unloaded, sorted and moved to dispatch points where they are directly loaded onto outbound trucks for an immediate delivery elsewhere in the distribution system. This warehouse management concept aims at realizing economies in transportation cost by consolidating divergent shipments to full truckloads without requiring excessive inventory at the cross dock. The efficient operation of such a system requires an appropriate coordinati...

  16. 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.

  17. Demonstration of automated proximity and docking technologies

    Science.gov (United States)

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

    1991-01-01

    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.

  18. Nucleotide Docking: Prediction of Reactant State Complexes for Ribonuclease Enzymes

    Energy Technology Data Exchange (ETDEWEB)

    Elsasser, Brigitta M.; Fels, Gregor

    2010-12-01

    Ribonuclease enzymes (RNases) play key roles in the maturation and metabolism of all RNA molecules. Computational simulations of the processes involved can help to elucidate the underlying enzymatic mechanism and is often employed in a synergistic approach together with biochemical experiments. Theoretical calculations require atomistic details regarding the starting geometries of the molecules involved, which, in the absence of crystallographic data, can only be achieved from computational docking studies. Fortunately, docking algorithms have improved tremendously in recent years, so that reliable structures of enzyme-ligand complexes can now be successfully obtained from computation. However, most docking programs are not particularly optimized for nucleotide docking. In order to assist our studies on the cleavage of RNA by the two most important ribonuclease enzymes, RNase A and RNase H, we evaluated four docking tools - MOE2009, Glide 5.5, QXP-Flo+0802, and Autodock 4.0 - for their ability to simulate complexes between these enzymes and RNA oligomers. To validate our results, we analyzed the docking results with respect to the known key interactions between the protein and the nucleotide. In addition, we compared the predicted complexes with X-ray structures of the mutated enzyme as well as with structures obtained from previous calculations. In this manner, we were able to prepare the desired reaction state complex so that it could be used as the starting structure for further DFT/B3LYP QM/MM reaction mechanism studies.

  19. 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

    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...... 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...... of the tail length, tail docking led to signs of procedural pain, which could be reduced by administration of Lidocain. Preemptive use of Meloxicam did not affect the signs of procedural pain. The results show that tail docking led to behavioural changes throughout the 5 h observation period indicating...

  20. Homology modeling and docking studies of IscS from extremophile Acidithiobacillus ferrooxidans

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The gene iscS-3 from Acidithiobacillus ferrooxidans may play a central role in the delivery of sulfur to a variety of metabolic pathways in this organism. For insight into the sulfur metabolic mechanism of the bacteria, an integral three-dimensional (3D) molecular structure of the protein encoded by this gene was built by homology modeling techniques, refined by molecular dynamics simulations, assessed by PROFILE-3D and PROSTAT programs and further used to search bind sites, carry out flexible docking with cofactor pyridoxal 5'-phosphate(PLP) and substrate cysteine and hereby detect its key residues. Through these procedures, the detail conformations of PLP-IscS(P-I) and cysteine-PLP-IscS(C-P-I) complexes were obtained. In P-I complex, the residues of Lys208, His106, Thr78, Ser205, His207, Asp182 and Gln185 have large interaction energies and/or hydrogen bonds fixation with PLP. In C-P-I complex, the amino group in cysteine is very near His106, Lys208 and PLP, the interaction energies for cysteine with them are very high. The above results are well consistent with those experimental facts of the homologues from other sources. Interestingly, the four residues of Glu105, Glu79, Ser203 and His180 in P-I docking and the residue of Lys213 in C-P-I docking also have great interaction energies, which are fitly conservation in IscSs from all kinds of sources but have not been identified before. From these results, this gene can be confirmed at 3D level to encode the iron-sulfur cluster assembly protein lscS and subsequently play a sulfur traffic role. Furthermore, the substrate cysteine can be presumed to be effectively recruited into the active site. Finally, the above detected key residues can be conjectured to be directly responsible for the bind and/or catalysis of PLP and cysteine.

  1. The universal Higgs fit

    DEFF Research Database (Denmark)

    Giardino, P. P.; Kannike, K.; Masina, I.

    2014-01-01

    Higgs models, models with extra Higgs doublets, supersymmetry, extra particles in the loops, anomalous top couplings, and invisible Higgs decays into Dark Matter. Best fit regions lie around the Standard Model predictions and are well approximated by our 'universal' fit. Latest data exclude the dilaton...

  2. Fit 2-B FATHERS.

    Science.gov (United States)

    Maiorano, Joseph J.

    2001-01-01

    Fit 2-B FATHERS is a parenting-skills education program for incarcerated adult males. The goals of this program are for participants to have reduced recidivism rates and a reduced risk of their children acquiring criminal records. These goals are accomplished by helping participants become physically, practically, and socially fit for the demands…

  3. Best Fit for 'Bounce'

    Science.gov (United States)

    2004-01-01

    The mineralogy of 'Bounce' rock was determined by fitting spectra from a library of laboratory minerals to the spectrum of Bounce taken by the Mars Exploration Rover Opportunity's miniature thermal emission spectrometer. The minerals that give the best fit include pyroxene, plagioclase and olivine -- minerals commonly found in basaltic volcanic rocks -- and typical martian dust produced by the rover's rock abrasion tool.

  4. Fitness Test and Tips

    Institute of Scientific and Technical Information of China (English)

    Karen; Clark

    2005-01-01

    Summer is a time to exercise and keep fit.Ask yourself these quick questions and check your score below.How fit are you? 1.What is your pulse[脉搏]?Find your pulse in your wrist[手腕], count the number of beats[跳动] in one minute,Now

  5. The Quality Fit.

    Science.gov (United States)

    Vertiz, Virginia C.; Downey, Carolyn J.

    This paper proposes a two-pronged approach for examining an educational program's "quality of fit." The American Association of School Administrators' (AASA's) Curriculum Management Audit for quality indicators is reviewed, using the Downey Quality Fit Framework and Deming's 4 areas of profound knowledge and 14 points. The purpose is to…

  6. Distributed automated docking of flexible ligands to proteins: parallel applications of AutoDock 2.4.

    Science.gov (United States)

    Morris, G M; Goodsell, D S; Huey, R; Olson, A J

    1996-08-01

    AutoDock 2.4 predicts the bound conformations of a small, flexible ligand to a nonflexible macromolecular target of known structure. The technique combines simulated annealing for conformation searching with a rapid grid-based method of energy evaluation based on the AMBER force field. AutoDock has been optimized in performance without sacrificing accuracy; it incorporates many enhancements and additions, including an intuitive interface. We have developed a set of tools for launching and analyzing many independent docking jobs in parallel on a heterogeneous network of UNIX-based workstations. This paper describes the current release, and the results of a suite of diverse test systems. We also present the results of a systematic investigation into the effects of varying simulated-annealing parameters on molecular docking. We show that even for ligands with a large number of degrees of freedom, root-mean-square deviations of less than 1 A from the crystallographic conformation are obtained for the lowest-energy dockings, although fewer dockings find the crystallographic conformation when there are more degrees of freedom.

  7. 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

  8. Status of GPCR modeling and docking as reflected by community-wide GPCR Dock 2010 assessment.

    Science.gov (United States)

    Kufareva, Irina; Rueda, Manuel; Katritch, Vsevolod; Stevens, Raymond C; Abagyan, Ruben

    2011-08-10

    The community-wide GPCR Dock assessment is conducted to evaluate the status of molecular modeling and ligand docking for human G protein-coupled receptors. The present round of the assessment was based on the recent structures of dopamine D3 and CXCR4 chemokine receptors bound to small molecule antagonists and CXCR4 with a synthetic cyclopeptide. Thirty-five groups submitted their receptor-ligand complex structure predictions prior to the release of the crystallographic coordinates. With closely related homology modeling templates, as for dopamine D3 receptor, and with incorporation of biochemical and QSAR data, modern computational techniques predicted complex details with accuracy approaching experimental. In contrast, CXCR4 complexes that had less-characterized interactions and only distant homology to the known GPCR structures still remained very challenging. The assessment results provide guidance for modeling and crystallographic communities in method development and target selection for further expansion of the structural coverage of the GPCR universe. Copyright © 2011 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

    Castro-Alvarez, Alejandro; Costa, Anna M; Vilarrasa, Jaume

    2017-01-17

    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.

  10. 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.

  11. Induced fit on heme binding to the Pseudomonas aeruginosa cytoplasmic protein (PhuS) drives interaction with heme oxygenase (HemO)

    OpenAIRE

    2012-01-01

    Iron, an essential nutrient with limited bioavailability, requires specialized cellular mechanisms for uptake. Although iron uptake into the cytoplasm in the form of heme has been well characterized in many bacteria, the subsequent trafficking is poorly understood. The cytoplasmic heme-binding proteins belong to a structurally related family thought to have evolved as “induced fit” ligand-binding macromolecules. One member, Pseudomonas aeruginosa cytoplasmic protein (PhuS), has previously bee...

  12. Improved video guidance sensor for automated docking

    Science.gov (United States)

    Howard, Richard T.; Book, Michael L.

    1995-06-01

    The Video Guidance Sensor (VGS) has been developed by NASA's Marshall Space Flight Center (MSFC) to provide the capability for a spacecraft to find and track a target vehicle and determine the relative positions and attitudes between the sensor and the target. The sensor uses laser diodes to illuminate the target, a CCD-based camera to sense the target, and a frame-grabber and processor to convert the video information into relative range, azimuth, elevation, roll, pitch, and yaw. The sensor was first built in 1988 and used in successful automated docking experiments using the air-bearing spacecraft simulator in MSFC's Flight Robotics Laboratory. Since then, many changes and improvements have been made, based on the results of testing. In addition to the use of this system for space vehicles, it has been adapted for commercial application. The current design is being built as a prototype to prepare for flight testing on the Space Shuttle. Some of the changes from the original system were designed to improve the noise rejection of the system. Other changes were made to improve the overall range of operation of the system, and still other changes improved the bandwidth of the system. The current VGS is designed to operate from 110 meters down to 0.5 meters and output the relative position and attitude data at 5 Hz. The system will be able to operate under any orbital lighting conditions from full solar illumination to complete darkness. The VGS is also designed to be used with more than one target and sensor to allow for redundant configurations. This new prototype should be completed and undergoing open- and closed-loop testing after March 1995.

  13. Synthesis, crystal structure, superoxide scavenging activity, anticancer and docking studies of novel adamantyl nitroxide derivatives

    Science.gov (United States)

    Zhu, Xiao-he; Sun, Jin; Wang, Shan; Bu, Wei; Yao, Min-na; Gao, Kai; Song, Ying; Zhao, Jin-yi; Lu, Cheng-tao; Zhang, En-hu; Yang, Zhi-fu; Wen, Ai-dong

    2016-03-01

    A novel adamantyl nitroxide derivatives has been synthesized and characterized by IR, ESI-MS and elemental analysis. Quantum chemical calculations have also been performed to calculate the molecular geometry using density functional theory (B3LYP) with the 6-31G (d,p) basis set. The calculated results showed that the optimized geometry can well reproduce the crystal structure. The antioxidant and antiproliferative activity were evaluated by superoxide (NBT) and MTT assay. The adamantyl nitroxide derivatives exhibited stronger scavenging ability towards O2· - radicals when compared to Vitamin C, and demonstrated a remarked anticancer activity against all the tested cell lines, especially Bel-7404 cells with IC50 of 43.3 μM, compared to the positive control Sorafenib (IC50 = 92.0 μM). The results of molecular docking within EGFR using AutoDock confirmed that the titled compound favorably fitted into the ATP binding site of EGFR and would be a potential anticancer agent.

  14. 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.

  15. Limitations of inclusive fitness.

    Science.gov (United States)

    Allen, Benjamin; Nowak, Martin A; Wilson, Edward O

    2013-12-10

    Until recently, inclusive fitness has been widely accepted as a general method to explain the evolution of social behavior. Affirming and expanding earlier criticism, we demonstrate that inclusive fitness is instead a limited concept, which exists only for a small subset of evolutionary processes. Inclusive fitness assumes that personal fitness is the sum of additive components caused by individual actions. This assumption does not hold for the majority of evolutionary processes or scenarios. To sidestep this limitation, inclusive fitness theorists have proposed a method using linear regression. On the basis of this method, it is claimed that inclusive fitness theory (i) predicts the direction of allele frequency changes, (ii) reveals the reasons for these changes, (iii) is as general as natural selection, and (iv) provides a universal design principle for evolution. In this paper we evaluate these claims, and show that all of them are unfounded. If the objective is to analyze whether mutations that modify social behavior are favored or opposed by natural selection, then no aspect of inclusive fitness theory is needed.

  16. Multi-Sensor Testing for Automated Rendezvous and Docking Sensor Testing at the Flight Robotics Lab

    Science.gov (United States)

    Brewster, Linda L.; Howard, Richard T.; Johnston, A. S.; Carrington, Connie; Mitchell, Jennifer D.; Cryan, Scott P.

    2008-01-01

    ) using the FRL's 6-DOF gantry system, called the Dynamic Overhead Target System (DOTS). The target vehicle for "docking" in the laboratory was a mockup that was representative of the proposed CEV docking system, with added retroreflectors for the AVGS.' The multi-sensor test configuration used 35 open-loop test trajectories covering three major objectives: (l) sensor characterization trajectories designed to test a wide range of performance parameters; (2) CEV-specific trajectories designed to test performance during CEV-like approach and departure profiles; and (3) sensor characterization tests designed for evaluating sensor performance under more extreme conditions as might be induced during a spacecraft failure or during contingency situations. This paper describes the test development, test facility, test preparations, test execution, and test results of the multisensor series oftrajectories

  17. Multi-Sensor Testing for Automated Rendezvous and Docking Sensor Testing at the Flight Robotics Lab

    Science.gov (United States)

    Brewster, Linda L.; Howard, Richard T.; Johnston, A. S.; Carrington, Connie; Mitchell, Jennifer D.; Cryan, Scott P.

    2008-01-01

    ) using the FRL's 6-DOF gantry system, called the Dynamic Overhead Target System (DOTS). The target vehicle for "docking" in the laboratory was a mockup that was representative of the proposed CEV docking system, with added retroreflectors for the AVGS.' The multi-sensor test configuration used 35 open-loop test trajectories covering three major objectives: (l) sensor characterization trajectories designed to test a wide range of performance parameters; (2) CEV-specific trajectories designed to test performance during CEV-like approach and departure profiles; and (3) sensor characterization tests designed for evaluating sensor performance under more extreme conditions as might be induced during a spacecraft failure or during contingency situations. This paper describes the test development, test facility, test preparations, test execution, and test results of the multisensor series oftrajectories

  18. Synaptotagmin-1 docks secretory vesicles to syntaxin-1/SNAP-25 acceptor complexes

    DEFF Research Database (Denmark)

    de Wit, Heidi; Walter, Alexander M; Milosevic, Ira

    2009-01-01

    Docking, the initial association of secretory vesicles with the plasma membrane, precedes formation of the SNARE complex, which drives membrane fusion. For many years, the molecular identity of the docked state, and especially the vesicular docking protein, has been unknown, as has the link...... to SNARE complex assembly. Here, using adrenal chromaffin cells, we identify the vesicular docking partner as synaptotagmin-1, the calcium sensor for exocytosis, and SNAP-25 as an essential plasma membrane docking factor, which, together with the previously known docking factors Munc18-1 and syntaxin, form...... the minimal docking machinery. Moreover, we show that the requirement for Munc18-1 in docking, but not fusion, can be overcome by stabilizing syntaxin/SNAP-25 acceptor complexes. These findings, together with cross-rescue, double-knockout, and electrophysiological data, lead us to propose that vesicles dock...

  19. Comprehensive assessment of flexible-ligand docking algorithms: current effectiveness and challenges.

    Science.gov (United States)

    Huang, Sheng-You

    2017-03-14

    Protein-ligand docking has been playing an important role in modern drug discovery. To model drug-target binding in real systems, a number of flexible-ligand docking algorithms with different sampling strategies and scoring methods have been subsequently developed over the past three decades, while rigid-ligand docking is still being used because of its compelling computational efficiency. Here, a comprehensive assessment has been conducted to investigate the effectiveness of flexible-ligand docking versus rigid-ligand docking for three representative docking algorithms (global optimization, incremental construction and multi-conformer docking) in virtual screening and pose prediction on the Directory of Useful Decoys. It was found that overall flexible-ligand docking did not achieve a statistically significant improvement in enrichments over rigid-ligand docking in virtual screening, but all docking programs significantly improved the success rates when considering ligand flexibility in pose prediction. The worse effectiveness of flexible-ligand docking in virtual screening than in pose prediction suggests that the challenges of current docking algorithms exist in ranking more than docking, although the use of flexible-ligand docking in virtual screening was justified by its better effectiveness for more flexible ligand in virtual screening. Challenges for scoring, including internal energy, charge polarization, entropy and flexibility, were investigated and discussed. An empirical way was also proposed to consider loss of ligand conformational entropy for virtual screening. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  20. Machine Vision for Relative Spacecraft Navigation During Approach to Docking

    Science.gov (United States)

    Chien, Chiun-Hong; Baker, Kenneth

    2011-01-01

    This paper describes a machine vision system for relative spacecraft navigation during the terminal phase of approach to docking that: 1) matches high contrast image features of the target vehicle, as seen by a camera that is bore-sighted to the docking adapter on the chase vehicle, to the corresponding features in a 3d model of the docking adapter on the target vehicle and 2) is robust to on-orbit lighting. An implementation is provided for the case of the Space Shuttle Orbiter docking to the International Space Station (ISS) with quantitative test results using a full scale, medium fidelity mock-up of the ISS docking adapter mounted on a 6-DOF motion platform at the NASA Marshall Spaceflight Center Flight Robotics Laboratory and qualitative test results using recorded video from the Orbiter Docking System Camera (ODSC) during multiple orbiter to ISS docking missions. The Natural Feature Image Registration (NFIR) system consists of two modules: 1) Tracking which tracks the target object from image to image and estimates the position and orientation (pose) of the docking camera relative to the target object and 2) Acquisition which recognizes the target object if it is in the docking camera Field-of-View and provides an approximate pose that is used to initialize tracking. Detected image edges are matched to the 3d model edges whose predicted location, based on the pose estimate and its first time derivative from the previous frame, is closest to the detected edge1 . Mismatches are eliminated using a rigid motion constraint. The remaining 2d image to 3d model matches are used to make a least squares estimate of the change in relative pose from the previous image to the current image. The changes in position and in attitude are used as data for two Kalman filters whose outputs are smoothed estimate of position and velocity plus attitude and attitude rate that are then used to predict the location of the 3d model features in the next image.

  1. CtIP-Specific Roles during Cell Reprogramming Have Long-Term Consequences in the Survival and Fitness of Induced Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Daniel Gómez-Cabello

    2017-02-01

    Full Text Available Acquired genomic instability is one of the major concerns for the clinical use of induced pluripotent stem cells (iPSCs. All reprogramming methods are accompanied by the induction of DNA damage, of which double-strand breaks are the most cytotoxic and mutagenic. Consequently, DNA repair genes seem to be relevant for accurate reprogramming to minimize the impact of such DNA damage. Here, we reveal that reprogramming is associated with high levels of DNA end resection, a critical step in homologous recombination. Moreover, the resection factor CtIP is essential for cell reprogramming and establishment of iPSCs, probably to repair reprogramming-induced DNA damage. Our data reveal a new role for DNA end resection in maintaining genomic stability during cell reprogramming, allowing DNA repair fidelity to be retained in both human and mouse iPSCs. Moreover, we demonstrate that reprogramming in a resection-defective environment has long-term consequences on stem cell self-renewal and differentiation.

  2. Characterization of interaction between isoliquiritigenin and bovine serum albumin: Spectroscopic and molecular docking methods

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Jie-hua, E-mail: shijh@zjut.edu.cn [College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310032 (China); State Key Laboratory Breeding Base of Green Chemistry Synthesis Technology, Zhejiang University of Technology, Hangzhou 310032 (China); Wang, Jing; Zhu, Ying-yao; Chen, Jun [College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310032 (China)

    2014-01-15

    The intermolecular interaction between isoliquiritigenin (ISL) and bovine serum albumin (BSA) under imitated physiological conditions was investigated using fluorescence, circular dichromism (CD) and molecular docking methods. The results revealed that the fluorescence quenching of BSA at 338 nm by ISL resulted from the formation of ISL–BSA complex. The number of binding sites (n) for ISL binding on BSA was approximately equal to 1. The experimental and molecular docking results revealed that after binding ISL to BSA, ISL was close to Tyr residue than Trp residue, the binding of ISL to BSA induced a slight change in conformation of BSA but the BSA still retains its secondary structure, the binding process of ISL with BSA is spontaneous, and ISL could be inserted into the hydrophobic cavity of BSA (Site I) in the binding process of ISL with BSA. The enthalpic change (ΔH{sup 0}) and entropic change (ΔS{sup 0}) in the process of interaction of BSA with ISL were –116.74 kJ mol{sup –1} and –286.32 J mol{sup –1} K{sup –1}, respectively, indicating that the main interaction forces of ISL with BSA were Van der Waals and hydrogen bonding interactions. And, it can be suggested from the molecular docking results that the flexibility of ISL plays an important role in increasing the stability of the whole system upon association of ISL with BSA. -- Highlights: • ISL binds to hydrophobic cavity (site I) in BSA and forms 1:1 complex with it. • The fluorescence quenching of BSA induced by ISL is static quenching. • ISL binding results in a decreased α-helix. • The main interaction forces were Van der Waals and hydrogen bonding interactions. • The flexibility of ISL plays an important role in increasing the ISL–BSA stability.

  3. ACSM Fit Society Page

    Science.gov (United States)

    ... 2011 -- Exercise for Special Populations 2011 -- Behavior Change & Exercise Adherence 2011 -- Nutrition 2011 -- Winter Health 2010 -- Healthy Aging 2010 -- Weight Loss & Weight Management 2010 -- Fitness Assessment & Injury Prevention 2009 -- Strength Training 2009 -- Menopause ...

  4. Getting Fit Before Pregnancy

    Science.gov (United States)

    ... Global Map Premature birth report card Careers Archives Pregnancy Before or between pregnancies Nutrition, weight & fitness Prenatal ... virus and pregnancy Folic acid Medicine safety and pregnancy Birth defects prevention Learn how to help reduce ...

  5. Molecular docking assessment of pyridone derivatives as glucokinase activators

    Directory of Open Access Journals (Sweden)

    Y. Nanda Kumar

    2012-10-01

    Full Text Available Background: Mutations in glucokinase (GK gene results in maturity onset diabetes of the young 2 (MODY2. It has been observed that GK activators (GKAs can activate GK structure and promote glucose phosphorylation and bring blood glucose levels to normal condition. The present study is aimed to identify the binding mode of pyridone derivatives (PDs as GKAs through molecular docking study. Methods: GK structure was retrieved from the Protein Data Bank (PDB, protonated and energy minimized. A database was constructed with 29 PDs and docked into the allosteric site specified with Y61, R63, S69 and Y215 residues using Molecular Operating Environment (MOE software. Docking conformations were generated using triangle match algorithm and ranked by London dG scoring function. The binding orientations and strength of interactions were evaluated by ligand interaction module of MOE. Results: Molecular docking of 29 PDs in allosteric site of GK gave reliable docking scores, interestingly arene cationic interactions were observed with the compounds PD1, PD12, PD20 and PD21. R63 residue of allosteric site played a predominant role in binding with PDs. Conclusions: PDs can be potentially useful agents in future management strategies of type 2 diabetes mellitus.

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

    Directory of Open Access Journals (Sweden)

    Marco Zucca

    2017-01-01

    Full Text Available 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 rehabilitation works executed after the severe earthquake of 1908 and, finally, the works carried out to increase the size of the dry dock in 1950. After this first step, numerical seismic analyses were done with some implemented finite element models (FEM of the structure. In each FEM, the vertical loads were applied according to the “construction stages” analysis technique, in order to achieve an appropriate representation of the soil stresses around the structure. The analysis results were evaluated according to the Italian design code (NTC 2008 in order to determine the seismic vulnerability of the dry dock.

  7. 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.

  8. On the laboratory rearing of green dock leaf beetles Gastrophysa viridula (Coleoptera: Chrysomelidae)

    Institute of Scientific and Technical Information of China (English)

    Dagmar Voigt; Naoe Hosoda; Jan Schuppert; Stanislav Gorb

    2011-01-01

    Leaf beetles Gastrophysa viridula have attracted recently increased research interest from various points of view, since they are: (i) pest insects in rhubarb crops; (ii) potential biocontrol agents of dock plants Rumex spp. in grasslands; and (iii) a model species in ecological studies on insect population dynamics, biochemistry, behavior, biomechanics and biomimetics. The continuous rearing of beetles at standardized conditions may help to unify the fitness state of different individuals, allowing a better comparison of experimental results. The present communication suggests a modular space- and time-saving rearing method of G. viridula in stackable faunariums under laboratory conditions, which has been successfully established and continuously used over the last 5 years. Several developmental stages were kept in separate boxes, and multiple generations were kept simultaneously, depending on the required number of beetles.

  9. Fitting Galaxies on GPUs

    Science.gov (United States)

    Barsdell, B. R.; Barnes, D. G.; Fluke, C. J.

    2011-07-01

    Structural parameters are normally extracted from observed galaxies by fitting analytic light profiles to the observations. Obtaining accurate fits to high-resolution images is a computationally expensive task, requiring many model evaluations and convolutions with the imaging point spread function. While these algorithms contain high degrees of parallelism, current implementations do not exploit this property. With ever-growing volumes of observational data, an inability to make use of advances in computing power can act as a constraint on scientific outcomes. This is the motivation behind our work, which aims to implement the model-fitting procedure on a graphics processing unit (GPU). We begin by analysing the algorithms involved in model evaluation with respect to their suitability for modern many-core computing architectures like GPUs, finding them to be well-placed to take advantage of the high memory bandwidth offered by this hardware. Following our analysis, we briefly describe a preliminary implementation of the model fitting procedure using freely-available GPU libraries. Early results suggest a speed-up of around 10× over a CPU implementation. We discuss the opportunities such a speed-up could provide, including the ability to use more computationally expensive but better-performing fitting routines to increase the quality and robustness of fits.

  10. Plugin-docking system for autonomous charging using particle filter

    Science.gov (United States)

    Koyasu, Hiroshi; Wada, Masayoshi

    2017-03-01

    Autonomous charging of the robot battery is one of the key functions for the sake of expanding working areas of the robots. To realize it, most of existing systems use custom docking stations or artificial markers. By the other words, they can only charge on a few specific outlets. If the limit can be removed, working areas of the robots significantly expands. In this paper, we describe a plugin-docking system for the autonomous charging, which does not require any custom docking stations or artificial markers. A single camera is used for recognizing the 3D position of an outlet socket. A particle filter-based image tracking algorithm which is robust to the illumination change is applied. The algorithm is implemented on a robot with an omnidirectional moving system. The experimental results show the effectiveness of our system.

  11. Molecular docking and structure-based drug design strategies.

    Science.gov (United States)

    Ferreira, Leonardo G; Dos Santos, Ricardo N; Oliva, Glaucius; Andricopulo, Adriano D

    2015-07-22

    Pharmaceutical research has successfully incorporated a wealth of molecular modeling methods, within a variety of drug discovery programs, to study complex biological and chemical systems. The integration of computational and experimental strategies has been of great value in the identification and development of novel promising compounds. Broadly used in modern drug design, molecular docking methods explore the ligand conformations adopted within the binding sites of macromolecular targets. This approach also estimates the ligand-receptor binding free energy by evaluating critical phenomena involved in the intermolecular recognition process. Today, as a variety of docking algorithms are available, an understanding of the advantages and limitations of each method is of fundamental importance in the development of effective strategies and the generation of relevant results. The purpose of this review is to examine current molecular docking strategies used in drug discovery and medicinal chemistry, exploring the advances in the field and the role played by the integration of structure- and ligand-based methods.

  12. Spacecraft Rendevouz and Docking. An Autonomy assisted Human Operator Approach

    DEFF Research Database (Denmark)

    Jørgensen, John Leif; Thuesen, Gøsta

    1999-01-01

    The phenomena and problems encountered when a rendezvous maneuver, 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 analyzed. So far, all solutions that have been brought into realization have 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 procedures...... information to assist the human operator during the docking phase.The closed loop and operator assistance performance of the system have been assessed using a test bench including human operator, navigation module and high fidelity visualization module.The tests performed verified the general accuracy, real...

  13. Solvent structure improves docking prediction in lectin-carbohydrate complexes.

    Science.gov (United States)

    Gauto, Diego F; Petruk, Ariel A; Modenutti, Carlos P; Blanco, Juan I; Di Lella, Santiago; Martí, Marcelo A

    2013-02-01

    Recognition and complex formation between proteins and carbohydrates is a key issue in many important biological processes. Determination of the three-dimensional structure of such complexes is thus most relevant, but particularly challenging because of their usually low binding affinity. In silico docking methods have a long-standing tradition in predicting protein-ligand complexes, and allow a potentially fast exploration of a number of possible protein-carbohydrate complex structures. However, determining which of these predicted complexes represents the correct structure is not always straightforward. In this work, we present a modification of the scoring function provided by AutoDock4, a widely used docking software, on the basis of analysis of the solvent structure adjacent to the protein surface, as derived from molecular dynamics simulations, that allows the definition and characterization of regions with higher water occupancy than the bulk solvent, called water sites. They mimic the interaction held between the carbohydrate -OH groups and the protein. We used this information for an improved docking method in relation to its capacity to correctly predict the protein-carbohydrate complexes for a number of tested proteins, whose ligands range in size from mono- to tetrasaccharide. Our results show that the presented method significantly improves the docking predictions. The resulting solvent-structure-biased docking protocol, therefore, appears as a powerful tool for the design and optimization of development of glycomimetic drugs, while providing new insights into protein-carbohydrate interactions. Moreover, the achieved improvement also underscores the relevance of the solvent structure to the protein carbohydrate recognition process.

  14. Fitness is Recovered with the Decline of Dimethachlon Resistance in Laboratory-induced Mutants of Sclerotinia sclerotiorum after Long-term Cold Storage

    Directory of Open Access Journals (Sweden)

    Jin-Li Li

    2015-09-01

    Full Text Available After four years of cold storage, dimethachlon resistance of two laboratory-induced resistant Sclerotinia sclerotiorum isolates SCG7 and LA50 declined by 99.5% and 98.9%, respectively, and cross resistance to iprodione and procymidone also declined dramatically. Along with the decline of fungicide resistance, osmotic sensitivity to sodium chloride and glucose decreased tremendously; mycelial growth rate, sclerotia number and weight per potato dextrose agar (PDA plate increased on average by 118.6%, 85. 5% and 64.5%, respectively; and virulence to detached leaves of oilseed rape increased by 72.7% on average. Significant negative correlations were detected between dimethachlon resistance levels and mycelial growth rate on PDA (r = −0.980, P = 0.021, and between resistance levels and lesion diameters on detached leaves of oilseed rape plants (r = −0.997, P = 0.002. These results have profound implications for assessing the potential risk for resistance development to dicarboximide fungicides in S. sclerotiorum.

  15. Improved Evolutionary Hybrids for Flexible Ligand Docking in Autodock

    Energy Technology Data Exchange (ETDEWEB)

    Belew, R.K.; Hart, W.E.; Morris, G.M.; Rosin, C.

    1999-01-27

    In this paper we evaluate the design of the hybrid evolutionary algorithms (EAs) that are currently used to perform flexible ligand binding in the Autodock docking software. Hybrid EAs incorporate specialized operators that exploit domain-specific features to accelerate an EA's search. We consider hybrid EAs that use an integrated local search operator to reline individuals within each iteration of the search. We evaluate several factors that impact the efficacy of a hybrid EA, and we propose new hybrid EAs that provide more robust convergence to low-energy docking configurations than the methods currently available in Autodock.

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

    DEFF Research Database (Denmark)

    Petersen, Hanne Løhmann; Røpke, Stefan

    2011-01-01

    In this paper, we consider the pickup and delivery problem with cross-docking opportunity (PDPCD). The problem arises from an industry application, and includes pickup requests, delivery requests, and pickup-and-delivery requests. Each pickup-and-delivery request can be served either as direct...... 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...

  17. SYNTHESIS, DOCKING AND BIOLOGICAL STUDIES OF THE LINEAR TETRAPEPTIDE PWPV

    Directory of Open Access Journals (Sweden)

    M. Himaja

    2012-06-01

    Full Text Available Linear Tetrapeptides L-PWPV (Pro-Trp-Pro-Val was designed and synthesized by solution phase peptide synthesis based on dock score. The molecular docking studies of the designed tetrapeptide L-PWPV was carried out using Molegro Virtual Docker software for tumor cancer protein(1OLG. The linear tetrapeptide was synthesized by coupling protected amino acids (dipeptides using EDC (ethyl-3-(N,N-dimethylaminopropyl carbodiimide as coupling reagent. The compounds were analyzed by FTIR, 1H NMR and MASS data and subjected to antioxidant activity using 1,1-dipheny-2-picryl-hydrazil (DPPH method and insecticidal activity using Morita et al method.

  18. Nanoscale rotary apparatus formed from tight-fitting 3D DNA components

    Science.gov (United States)

    Ketterer, Philip; Willner, Elena M.; Dietz, Hendrik

    2016-01-01

    We report a nanoscale rotary mechanism that reproduces some of the dynamic properties of biological rotary motors in the absence of an energy source, such as random walks on a circle with dwells at docking sites. Our mechanism is built modularly from tight-fitting components that were self-assembled using multilayer DNA origami. The apparatus has greater structural complexity than previous mechanically interlocked objects and features a well-defined angular degree of freedom without restricting the range of rotation. We studied the dynamics of our mechanism using single-particle experiments analogous to those performed previously with actin-labeled adenosine triphosphate synthases. In our mechanism, rotor mobility, the number of docking sites, and the dwell times at these sites may be controlled through rational design. Our prototype thus realizes a working platform toward creating synthetic nanoscale rotary motors. Our methods will support creating other complex nanoscale mechanisms based on tightly fitting, sterically constrained, but mobile, DNA components. PMID:26989778

  19. 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.

  20. DOCKING STUDIES OF CURCUMIN AS A POTENTIAL LEAD COMPOUND TO DEVELOP NOVEL DIPEPTYDYL PEPTIDASE-4 INHIBITORS

    Directory of Open Access Journals (Sweden)

    Enade Perdana Istyastono

    2010-06-01

    Full Text Available Interaction of curcumin to dipeptydyl peptidase-4 (DPP-4 has been studied by employing docking method using Molecular Operating Environment (MOE and AutoDock as the docking software applications. Although MOE can sample more conformational spaces that represent the original interaction poses than AutoDock, both softwares serve as valid and acceptable docking applications to study the interactions of small compound to DPP-4. The calculated free energy of binding (DGbinding results from MOE and AutoDock shows that curcumin is needed to be optimized to reach similar or better DGbinding compare to the reference compound. Curcumin can be considered as a good lead compound in the development of new DPP-4 inhibitor. The results of these studies can serve as an initial effort of the further study.     Keywords: curcumin, docking, molecular operating environment (MOE, AutoDock, dipeptydyl peptidase-4 (DPP-4

  1. Immune regulatory functions of DOCK family proteins in health and disease.

    Science.gov (United States)

    Nishikimi, Akihiko; Kukimoto-Niino, Mutsuko; Yokoyama, Shigeyuki; Fukui, Yoshinori

    2013-09-10

    DOCK proteins constitute a family of evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho family of GTPases. Although DOCK family proteins do not contain the Dbl homology domain typically found in GEFs, they mediate the GTP-GDP exchange reaction through DHR-2 domain. Accumulating evidence indicates that the DOCK proteins act as major GEFs in varied biological settings. For example, DOCK2, which is predominantly expressed in hematopoietic cells, regulates migration and activation of leukocytes through Rac activation. On the other hand, it was recently reported that mutations of DOCK8, another member of the DOCK family proteins, cause a combined immunodeficiency syndrome in humans. This article reviews the structure, functions and signaling of DOCK2 and DOCK8, especially focusing on their roles in immune responses. © 2013 Elsevier Inc. All rights reserved.

  2. Alternative Astronomical FITS imaging

    CERN Document Server

    Varsaki, Eleni E; Fotopoulos, Vassilis; Skodras, Athanassios N

    2012-01-01

    Astronomical radio maps are presented mainly in FITS format. Astronomical Image Processing Software (AIPS) uses a set of tables attached to the output map to include all sorts of information concerning the production of the image. However this information together with information on the flux and noise of the map is lost as soon as the image of the radio source in fits or other format is extracted from AIPS. This information would have been valuable to another astronomer who just uses NED, for example, to download the map. In the current work, we show a method of data hiding inside the radio map, which can be preserved under transformations, even for example while the format of the map is changed from fits to other lossless available image formats.

  3. Fitting Galaxies on GPUs

    CERN Document Server

    Barsdell, Benjamin R; Fluke, Christopher J

    2011-01-01

    Structural parameters are normally extracted from observed galaxies by fitting analytic light profiles to the observations. Obtaining accurate fits to high-resolution images is a computationally expensive task, requiring many model evaluations and convolutions with the imaging point spread function. While these algorithms contain high degrees of parallelism, current implementations do not exploit this property. With evergrowing volumes of observational data, an inability to make use of advances in computing power can act as a constraint on scientific outcomes. This is the motivation behind our work, which aims to implement the model-fitting procedure on a graphics processing unit (GPU). We begin by analysing the algorithms involved in model evaluation with respect to their suitability for modern many-core computing architectures like GPUs, finding them to be well-placed to take advantage of the high memory bandwidth offered by this hardware. Following our analysis, we briefly describe a preliminary implementa...

  4. Fitting the Phenomenological MSSM

    CERN Document Server

    AbdusSalam, S S; Quevedo, F; Feroz, F; Hobson, M

    2010-01-01

    We perform a global Bayesian fit of the phenomenological minimal supersymmetric standard model (pMSSM) to current indirect collider and dark matter data. The pMSSM contains the most relevant 25 weak-scale MSSM parameters, which are simultaneously fit using `nested sampling' Monte Carlo techniques in more than 15 years of CPU time. We calculate the Bayesian evidence for the pMSSM and constrain its parameters and observables in the context of two widely different, but reasonable, priors to determine which inferences are robust. We make inferences about sparticle masses, the sign of the $\\mu$ parameter, the amount of fine tuning, dark matter properties and the prospects for direct dark matter detection without assuming a restrictive high-scale supersymmetry breaking model. We find the inferred lightest CP-even Higgs boson mass as an example of an approximately prior independent observable. This analysis constitutes the first statistically convergent pMSSM global fit to all current data.

  5. Molecular docking studies for the identification of novel melatoninergic inhibitors for acetylserotonin-O-methyltransferase using different docking routines

    Science.gov (United States)

    2013-01-01

    Background N-Acetylserotonin O-methyltransferase (ASMT) is an enzyme which by converting nor-melatonin to melatonin catalyzes the final reaction in melatonin biosynthesis in tryptophan metabolism pathway. High Expression of ASMT gene is evident in PPTs. The presence of abnormally high levels of ASMT in pineal gland could serve as an indication of the existence of pineal parenchymal tumors (PPTs) in the brain (J Neuropathol Exp Neurol 65: 675–684, 2006). Different levels of melatonin are used as a trait marker for prescribing the mood disorders e.g. Seasonal affective disorder, bipolar disorder, or major depressive disorder. In addition, melatonin levels can also be used to calculate the severity of a patient’s illness at a given point in time. Methods Seventy three melatoninergic inhibitors were docked with acetylserotonin-O-methyltransferase in order to identify the potent inhibitor against the enzyme. The chemical nature of the protein and ligands greatly influence the performance of docking routines. Keeping this fact in view, critical evaluation of the performance of four different commonly used docking routines: AutoDock/Vina, GOLD, FlexX and FRED were performed. An evaluation criterion was based on the binding affinities/docking scores and experimental bioactivities. Results and conclusion Results indicated that both hydrogen bonding and hydrophobic interactions contributed significantly for its ligand binding and the compound selected as potent inhibitor is having minimum binding affinity, maximum GoldScore and minimum FlexX energy. The correlation value of r2 = 0. 66 may be useful in the selection of correct docked complexes based on the energy without having prior knowledge of the active site. This may lead to further understanding of structures, their reliability and Biomolecular activity especially in connection with bipolar disorders. PMID:24156411

  6. 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

  7. The universal Higgs fit

    DEFF Research Database (Denmark)

    Giardino, P. P.; Kannike, K.; Masina, I.;

    2014-01-01

    We perform a state-of-the-art global fit to all Higgs data. We synthesise them into a 'universal' form, which allows to easily test any desired model. We apply the proposed methodology to extract from data the Higgs branching ratios, production cross sections, couplings and to analyse composite H...... as an alternative to the Higgs, and disfavour fits with negative Yukawa couplings. We derive for the first time the SM Higgs boson mass from the measured rates, rather than from the peak positions, obtaining M-h = 124.4 +/- 1.6 GeV....

  8. Linking the Fits, Fitting the Links: Connecting Different Types of PO Fit to Attitudinal Outcomes

    Science.gov (United States)

    Leung, Aegean; Chaturvedi, Sankalp

    2011-01-01

    In this paper we explore the linkages among various types of person-organization (PO) fit and their effects on employee attitudinal outcomes. We propose and test a conceptual model which links various types of fits--objective fit, perceived fit and subjective fit--in a hierarchical order of cognitive information processing and relate them to…

  9. Spectroscopy and molecular docking studies on the binding of propyl gallate to human serum albumin

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Guo-fei; Wang, Yu; Xi, Lei; Liu, Jin; Wang, Hao; Du, Lin-fang, E-mail: dulinfang@scu.edu.cn

    2015-03-15

    The interaction of propyl gallate (PG) with human serum albumin (HSA) was investigated by fluorescence, far-UV CD and FT-IR spectroscopic methods as well as molecular docking. Fluorescence emission spectra demonstrated that the HSA fluorescence was quenched by PG through static quenching and energy transfer with the binding constants in the order of 10{sup 5} L mol{sup −1}. The thermodynamic parameters (ΔH=−29.64 KJ mol{sup −1}, ΔS=2.7 J mol{sup −1} K{sup −1}) indicated that both hydrophobic force and hydrogen bond interactions played a leading role in the formation of PG–HSA complex. The results also showed the existence of a single binding site, which was located in subdomain IIA (site I) as revealed by molecular docking and competitive binding experiments. Molecular docking studies further showed the participation of several amino acids in PG–HSA complexation, which stabilized by H-bonding systems. The synchronous fluorescence spectra showed that the binding of drug caused the environment of tryptophan residues became more polar. FT-IR and CD spectroscopic further showed that drug complexation altered protein conformation by a major reduction of α-helix inducing a partial protein destabilization. - Highlights: • The interaction between propyl gallate and HSA has been investigated. • HSA fluorescence is quenched by propyl gallate through static quenching mechanism. • Both hydrophobic force and hydrogen bond play major role in the binding process. • Site I of the HSA is found to be the main binding site for propyl gallate. • The structure of HSA has been changed upon the interaction with propyl gallate.

  10. In silico docking of forchlorfenuron (FCF to septins suggests that FCF interferes with GTP binding.

    Directory of Open Access Journals (Sweden)

    Dimitrios Angelis

    Full Text Available Septins are GTP-binding proteins that form cytoskeleton-like filaments, which are essential for many functions in eukaryotic organisms. Small molecule compounds that disrupt septin filament assembly are valuable tools for dissecting septin functions with high temporal control. To date, forchlorfenuron (FCF is the only compound known to affect septin assembly and functions. FCF dampens the dynamics of septin assembly inducing the formation of enlarged stable polymers, but the underlying mechanism of action is unknown. To investigate how FCF binds and affects septins, we performed in silico simulations of FCF docking to all available crystal structures of septins. Docking of FCF with SEPT2 and SEPT3 indicated that FCF interacts preferentially with the nucleotide-binding pockets of septins. Strikingly, FCF is predicted to form hydrogen bonds with residues involved in GDP-binding, mimicking nucleotide binding. FCF docking with the structure of SEPT2-GppNHp, a nonhydrolyzable GTP analog, and SEPT7 showed that FCF may assume two alternative non-overlapping conformations deeply into and on the outer side of the nucleotide-binding pocket. Surprisingly, FCF was predicted to interact with the P-loop Walker A motif GxxxxGKS/T, which binds the phosphates of GTP, and the GTP specificity motif AKAD, which interacts with the guanine base of GTP, and highly conserved amino acids including a threonine, which is critical for GTP hydrolysis. Thus, in silico FCF exhibits a conserved mechanism of binding, interacting with septin signature motifs and residues involved in GTP binding and hydrolysis. Taken together, our results suggest that FCF stabilizes septins by locking them into a conformation that mimics a nucleotide-bound state, preventing further GTP binding and hydrolysis. Overall, this study provides the first insight into how FCF may bind and stabilize septins, and offers a blueprint for the rational design of FCF derivatives that could target septins with

  11. Docking and Molecular Dynamics Simulations of Celastrol Binding to p23

    Energy Technology Data Exchange (ETDEWEB)

    Han, Sang Hwa [Seoul National University, Seoul (Korea, Republic of)

    2012-01-15

    Blind docking simulations identified a binding site of CSL-COO{sup -} on p23. Further structural refinement by MD simulations revealed an extensive hydrogen bonding network between the ligand and nearby residues including Arg88 and Thr90. Hydrophobic interaction is implied between the hydrocarbon skeleton and the hydrophobic surface of the protein. The complex stayed stable during 20 ns of MD simulation suggesting that the binding is strong in both docking and MD simulations. Celastrol (CSL), a quinone methide triterpenoid from thunder god vine, is a natural product with high antiinflammatory and anti-cancer potential. One of CSL's major targets is the Hsp90 chaperoning system and its inhibition by CSL results in destabilization of the Hsp90 client proteins involved in inflammation and cancer. Early reports suggest that CSL binds to the N-terminal domain of Hsp90 to interfere with the Hsp90-Cdc37 association. Later it was demonstrated that CSL reacts with cysteine residues of Cdc37 causing aggregation of Cdc37. Recently Chadli et al. showed that CSL induces fibrillization of p23, an Hsp90 co-chaperone that is specific for steroid receptors. Although CSL can react with cysteine residues of p23, non-covalent association is implicated in the fibrillization because reduced CSL is equally effective. The authors identified the amino acid residues whose NMR signals were perturbed upon CSL-COO{sup -} binding. Structure of the p23-CSL complex has not been determined, however. We previously performed docking and molecular dynamics simulations to identify the CSL binding site of Erk2 and found that CSL inhibits FceRI signaling by blocking the Erk2's ATP binding site. A similar strategy was employed in this study to model the structure of the p23-CSL complex.

  12. Combining pharmacophore search, automated docking, and molecular dynamics simulations as a novel strategy for flexible docking. Proof of concept: docking of arginine-glycine-aspartic acid-like compounds into the alphavbeta3 binding site.

    Science.gov (United States)

    Moitessier, Nicolas; Henry, Christophe; Maigret, Bernard; Chapleur, Yves

    2004-08-12

    A novel and highly efficient flexible docking approach is presented where the conformations (internal degrees of freedom) and orientations (external degrees of freedom) of the ligands are successively considered. This hybrid method takes advantage of the synergistic effects of structure-based and ligand-based drug design techniques. Preliminary antagonist-derived pharmacophore determination provides the postulated bioactive conformation. Subsequent docking of this pharmacophore to the receptor crystal structure results in a postulated pharmacophore/receptor binding mode. Pharmacophore-oriented docking of antagonists is subsequently achieved by matching ligand interacting groups with pharmacophore points. Molecular dynamics in water refines the proposed complexes. To validate the method, arginine-glycine-aspartic acid (RGD) containing peptides, pseudopeptides, and RGD-like antagonists were docked to the crystal structure of alphavbeta3 holoprotein and apoprotein. The proposed directed docking was found to be more accurate, faster, and less biased with respect to the protein structure (holo and apoprotein) than DOCK, Autodock, and FlexX docking methods. The successful docking of an antagonist recently cocrystallized with the receptor to both apo and holoprotein is particularly appealing. The results summarized in this report illustrated the efficiency of our light CoMFA/rigid body docking hybrid method.

  13. Economic Impacts from Spending by Community Dock Owners at Table Rock Lake

    Science.gov (United States)

    2008-01-01

    Rock Lake, community dock • Rough River Lake, community dock • Pomme de Terre Lake, community dock • Harry S. Truman Dam and Reservoir, marina...owners at Table Rock Lake (Missouri/Arkansas), Rough River Lake (Kentucky), and Pomme de Terre Lake (Missouri). The ERB staff designed the survey

  14. pso@autodock: a fast flexible molecular docking program based on Swarm intelligence.

    Science.gov (United States)

    Namasivayam, Vigneshwaran; Günther, Robert

    2007-12-01

    On the quest of novel therapeutics, molecular docking methods have proven to be valuable tools for screening large libraries of compounds determining the interactions of potential drugs with the target proteins. A widely used docking approach is the simulation of the docking process guided by a binding energy function. On the basis of the molecular docking program autodock, we present pso@autodock as a tool for fast flexible molecular docking. Our novel Particle Swarm Optimization (PSO) algorithms varCPSO and varCPSO-ls are suited for rapid docking of highly flexible ligands. Thus, a ligand with 23 rotatable bonds was successfully docked within as few as 100 000 computing steps (rmsd = 0.87 A), which corresponds to only 10% of the computing time demanded by autodock. In comparison to other docking techniques as gold 3.0, dock 6.0, flexx 2.2.0, autodock 3.05, and sodock, pso@autodock provides the smallest rmsd values for 12 in 37 protein-ligand complexes. The average rmsd value of 1.4 A is significantly lower then those obtained with the other docking programs, which are all above 2.0 A. Thus, pso@autodock is suggested as a highly efficient docking program in terms of speed and quality for flexible peptide-protein docking and virtual screening studies.

  15. Synchronization in cross-docking networks : A research classification and framework

    NARCIS (Netherlands)

    Buijs, Paul; Vis, Iris F. A.; Carlo, Hector J.

    2014-01-01

    Cross-docking is a distribution strategy that enables the consolidation of less-than-truckload shipments into full truckloads without long-term storage. Due to the absence of a storage buffer inside a cross-dock, local and network-wide cross-docking operations need to be carefully synchronized. This

  16. 19 CFR 4.1 - Boarding of vessels; cutter and dock passes.

    Science.gov (United States)

    2010-04-01

    ... 19 Customs Duties 1 2010-04-01 2010-04-01 false Boarding of vessels; cutter and dock passes. 4.1... vessels; cutter and dock passes. (a) Every vessel arriving at a Customs port will be subject to such... charge until the vessel has been properly inspected by Customs and brought into the dock or anchorage at...

  17. 48 CFR 52.247-40 - Ex Dock, Pier, or Warehouse, Port of Importation.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Ex Dock, Pier, or... Provisions and Clauses 52.247-40 Ex Dock, Pier, or Warehouse, Port of Importation. As prescribed in 47.303-12(c), insert the following clause in solicitations and contracts when the delivery term is ex dock...

  18. 19 CFR 18.24 - Retention of goods on dock; splitting of shipments.

    Science.gov (United States)

    2010-04-01

    ... 19 Customs Duties 1 2010-04-01 2010-04-01 false Retention of goods on dock; splitting of shipments... Transit Through the United States to Foreign Countries § 18.24 Retention of goods on dock; splitting of... dock, the port director, in his discretion, may allow in-transit merchandise, including merchandise...

  19. 48 CFR 47.303-12 - Ex dock, pier, or warehouse, port of importation.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Ex dock, pier, or... ACQUISITION REGULATION CONTRACT MANAGEMENT TRANSPORTATION Transportation in Supply Contracts 47.303-12 Ex dock, pier, or warehouse, port of importation. (a) Explanation of delivery term. Ex dock, pier, or warehouse...

  20. 29 CFR 1915.75 - Access to and guarding of dry docks and marine railways.

    Science.gov (United States)

    2010-07-01

    ... 29 Labor 7 2010-07-01 2010-07-01 false Access to and guarding of dry docks and marine railways... Scaffolds, Ladders and Other Working Surfaces § 1915.75 Access to and guarding of dry docks and marine... strength, maintained in safe repair and securely fastened, shall be provided between a floating dry dock...

  1. Talking Sport and Fitness

    Science.gov (United States)

    Dixon-Watmough, Rebecca; Keogh, Brenda; Naylor, Stuart

    2012-01-01

    For some time the Association for Science Education (ASE) has been aware that it would be useful to have some resources available to get children talking and thinking about issues related to health, sport and fitness. Some of the questions about pulse, breathing rate and so on are pretty obvious to everyone, and there is a risk of these being…

  2. Water Fit to Drink.

    Science.gov (United States)

    Donovan, Edward P.

    The major objective of this module is to help students understand how water from a source such as a lake is treated to make it fit to drink. The module, consisting of five major activities and a test, is patterned after Individualized Science Instructional System (ISIS) modules. The first activity (Planning) consists of a brief introduction and a…

  3. Fit for Life.

    Science.gov (United States)

    Vail, Kathleen

    1999-01-01

    Children who hate gym grow into adults who associate physical activity with ridicule and humiliation. Physical education is reinventing itself, stressing enjoyable activities that continue into adulthood: aerobic dance, weight training, fitness walking, mountain biking, hiking, inline skating, karate, rock-climbing, and canoeing. Cooperative,…

  4. Finding What Fits

    Science.gov (United States)

    Casey, Stephanie A.

    2016-01-01

    Statistical association between two variables is one of the fundamental statistical ideas in school curricula. Reasoning about statistical association has been deemed one of the most important cognitive activities that humans perform. Students are typically introduced to statistical association through the study of the line of best fit because it…

  5. Fitting a Gompertz curve

    NARCIS (Netherlands)

    Ph.H.B.F. Franses (Philip Hans)

    1994-01-01

    textabstractIn this paper, a simple Gompertz curve-fitting procedure is proposed. Its advantages include the facts that the stability of the saturation level over the sample period can be checked, and that no knowledge of its value is necessary for forecasting. An application to forecasting the stoc

  6. Kids Weigh to Fitness.

    Science.gov (United States)

    Maione, Mary Jane

    A description is given of a program that provides preventive measures to check obesity in children and young people. The 24-week program is divided into two parts--a nutrition component and an exercise component. At the start and end of the program, tests are given to assess the participants' height, weight, body composition, fitness level, and…

  7. Manual for physical fitness

    Science.gov (United States)

    Coleman, A. E.

    1981-01-01

    Training manual used for preflight conditioning of NASA astronauts is written for audience with diverse backgrounds and interests. It suggests programs for various levels of fitness, including sample starter programs, safe progression schedules, and stretching exercises. Related information on equipment needs, environmental coonsiderations, and precautions can help readers design safe and effective running programs.

  8. Design of a Docking Wall-Climbing Robot

    Directory of Open Access Journals (Sweden)

    Rong Liu

    2013-02-01

    Full Text Available This paper introduces an innovative wall-climbing robot. The robot consists of two single-body negative pressure adsorption robots which could dock together as a mother-robot or separate into two independent child-robots. The child-robots connect with each other through a docking mechanism which can not only lock solidly and unlock smoothly but which can also adjust the relative position of the two child-robots. This design guarantees that while in dock mode the mother robot will be able to cross some barriers which are impossible to surmount for a single-body wall-climbing robot, while in separate mode the child-robots maintain agility and mobility compared to other two-body robots. In this paper, an overview of the mechanical structure of the robot is first presented and then three possible mechanisms for barrier-crossing are discussed and a reasonable one is selected. An analysis of the initial docking condition of the selected design is also given which provides the basis for the experiments and research for the future.

  9. Simulation of carbohydrates, from molecular docking to dynamics in water.

    Science.gov (United States)

    Sapay, Nicolas; Nurisso, Alessandra; Imberty, Anne

    2013-01-01

    Modeling of carbohydrates is particularly challenging because of the variety of structures resulting for the high number of monosaccharides and possible linkages and also because of their intrinsic flexibility. The development of carbohydrate parameters for molecular modeling is still an active field. Nowadays, main carbohydrates force fields are GLYCAM06, CHARMM36, and GROMOS 45A4. GLYCAM06 includes the largest choice of compounds and is compatible with the AMBER force fields and associated. Furthermore, AMBER includes tools for the implementation of new parameters. When looking at protein-carbohydrate interaction, the choice of the starting structure is of importance. Such complex can be sometimes obtained from the Protein Data Bank-although the stereochemistry of sugars may require some corrections. When no experimental data is available, molecular docking simulation is generally used to the obtain protein-carbohydrate complex coordinates. As molecular docking parameters are not specifically dedicated to carbohydrates, inaccuracies should be expected, especially for the docking of polysaccharides. This issue can be addressed at least partially by combining molecular docking with molecular dynamics simulation in water.

  10. I-AUV Docking and Panel Intervention at Sea

    Directory of Open Access Journals (Sweden)

    Narcís Palomeras

    2016-10-01

    Full Text Available The use of commercially available autonomous underwater vehicles (AUVs has increased during the last fifteen years. While they are mainly used for routine survey missions, there is a set of applications that nowadays can be only addressed by manned submersibles or work-class remotely operated vehicles (ROVs equipped with teleoperated arms: the intervention applications. To allow these heavy vehicles controlled by human operators to perform intervention tasks, underwater structures like observatory facilities, subsea panels or oil-well Christmas trees have been adapted, making them more robust and easier to operate. The TRITON Spanish founded project proposes the use of a light-weight intervention AUV (I-AUV to carry out intervention applications simplifying the adaptation of these underwater structures and drastically reducing the operational cost. To prove this concept, the Girona 500 I-AUV is used to autonomously dock into an adapted subsea panel and once docked perform an intervention composed of turning a valve and plugging in/unplugging a connector. The techniques used for the autonomous docking and manipulation as well as the design of an adapted subsea panel with a funnel-based docking system are presented in this article together with the results achieved in a water tank and at sea.

  11. Spacecraft Rendevouz and Docking. An Autonomy assisted Human Operator Approach

    DEFF Research Database (Denmark)

    Jørgensen, John Leif; Thuesen, Gøsta

    1999-01-01

    The phenomena and problems encountered when a rendezvous maneuver, 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 analyzed. So far, all solutions that have been brought into realization have bee...

  12. A fast flexible docking method using an incremental construction algorithm.

    Science.gov (United States)

    Rarey, M; Kramer, B; Lengauer, T; Klebe, G

    1996-08-23

    We present an automatic method for docking organic ligands into protein binding sites. The method can be used in the design process of specific protein ligands. It combines an appropriate model of the physico-chemical properties of the docked molecules with efficient methods for sampling the conformational space of the ligand. If the ligand is flexible, it can adopt a large variety of different conformations. Each such minimum in conformational space presents a potential candidate for the conformation of the ligand in the complexed state. Our docking method samples the conformation space of the ligand on the basis of a discrete model and uses a tree-search technique for placing the ligand incrementally into the active site. For placing the first fragment of the ligand into the protein, we use hashing techniques adapted from computer vision. The incremental construction algorithm is based on a greedy strategy combined with efficient methods for overlap detection and for the search of new interactions. We present results on 19 complexes of which the binding geometry has been crystallographically determined. All considered ligands are docked in at most three minutes on a current workstation. The experimentally observed binding mode of the ligand is reproduced with 0.5 to 1.2 A rms deviation. It is almost always found among the highest-ranking conformations computed.

  13. Dissecting Nck/Dock Signaling Pathways in Drosophila Visual System

    Directory of Open Access Journals (Sweden)

    2005-04-01

    Full Text Available The establishment of neuronal connections during embryonic development requires the precise guidance and targeting of the neuronal growth cone, an expanded cellular structure at the leading tip of a growing axon. The growth cone contains sophisticated signaling systems that allow the rapid communication between guidance receptors and the actin cytoskeleton in generating directed motility. Previous studies demonstrated a specific role for the Nck/Dock SH2/SH3 adapter protein in photoreceptor (R cell axon guidance and target recognition in the Drosophila visual system, suggesting strongly that Nck/Dock is one of the long-sought missing links between cell surface receptors and the actin cytoskeleton. In this review, I discuss the recent progress on dissecting the Nck/Dock signaling pathways in R-cell growth cones. These studies have identified additional key components of the Nck/Dock signaling pathways for linking the receptor signaling to the remodeling of the actin cytoskeleton in controlling growth-cone motility.

  14. Space module assembly apparatus with docking alignment flexibility and restraint

    Science.gov (United States)

    Whitaker, Willie D. (Inventor)

    1989-01-01

    A berthing mechanism especially for use in berthing and compliant air-tight securing between manned space vehicle and modules is disclosed. The interface is provided by a pair of annular rings, one of which is typically, mechanically attached to the vehicle and the other to the module to which it is to be docked and secured. One of the two rings is attached to a base by resilient bellows. The facing surface of one annular ring is joined to a base by a cable laced through alternating pulleys attached circumferentially so that the interface surface of that ring may be tilted to accommodate angular misalignment as the annular rings are brought into docking (berthing) contact. Interleaving guide flanges with chambered sides provide at least some rotational mialignmnet correction. A plurality of electromechanical actuator/attenuator units provide means for extending one annular ring toward the other in the final stages of docking, for absorbing the initial docking shock and for drawing the annular rings into tight interface contact. Locking hooks provide for securing the interfaces.

  15. 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.

  16. I-AUV Docking and Panel Intervention at Sea

    Science.gov (United States)

    Palomeras, Narcís; Peñalver, Antonio; Massot-Campos, Miquel; Negre, Pep Lluís; Fernández, José Javier; Ridao, Pere; Sanz, Pedro J.; Oliver-Codina, Gabriel

    2016-01-01

    The use of commercially available autonomous underwater vehicles (AUVs) has increased during the last fifteen years. While they are mainly used for routine survey missions, there is a set of applications that nowadays can be only addressed by manned submersibles or work-class remotely operated vehicles (ROVs) equipped with teleoperated arms: the intervention applications. To allow these heavy vehicles controlled by human operators to perform intervention tasks, underwater structures like observatory facilities, subsea panels or oil-well Christmas trees have been adapted, making them more robust and easier to operate. The TRITON Spanish founded project proposes the use of a light-weight intervention AUV (I-AUV) to carry out intervention applications simplifying the adaptation of these underwater structures and drastically reducing the operational cost. To prove this concept, the Girona 500 I-AUV is used to autonomously dock into an adapted subsea panel and once docked perform an intervention composed of turning a valve and plugging in/unplugging a connector. The techniques used for the autonomous docking and manipulation as well as the design of an adapted subsea panel with a funnel-based docking system are presented in this article together with the results achieved in a water tank and at sea. PMID:27754348

  17. Normal mode-based approaches in receptor ensemble docking.

    Science.gov (United States)

    Cavasotto, Claudio N

    2012-01-01

    Explicitly accounting for target flexibility in docking still constitutes a difficult challenge due to the high dimensionality of the conformational space to be sampled. This especially applies to the high-throughput scenario, where the screening of hundreds of thousands compounds takes place. The use of multiple receptor conformations (MRCs) to perform ensemble docking in a sequential fashion is a simple but powerful approach that allows to incorporate binding site structural diversity in the docking process. Whenever enough experimental structures to build a diverse ensemble are not available, normal mode analysis provides an appealing and efficient approach to in silico generate MRCs by distortion along few low-frequency modes that represent collective mid- and large-scale displacements. In this way, the dimension of the conformational space to be sampled is heavily reduced. This methodology is especially suited to incorporate target flexibility at the backbone level. In this chapter, the main components of normal mode-based approaches in the context of ensemble docking are presented and explained, including the theoretical and practical considerations needed for the successful development and implementation of this methodology.

  18. Vision Based Navigation Sensors for Spacecraft Rendezvous and Docking

    DEFF Research Database (Denmark)

    Benn, Mathias

    is a technological demonstration mission, where all aspects of space rendezvous and docking to both a cooperative and a non-cooperative target is researched, with the use of novel methods, instruments and technologies. Amongst other equipment, DTU has delivered a vision based sensor package to the Main spacecraft...

  19. System for deflection measurements of floating dry docks

    Science.gov (United States)

    Gorbachev, Alexey A.; Pantyushin, Anton V.; Serikova, Mariya G.; Korotaev, Valery V.; Timofeev, Aleksandr N.

    2015-05-01

    In this paper we introduce a system for deflection measurement of floating dry docks. The system contains two measurement channels observing opposite directions of the dock. It also includes set of reference marks, an industrial computer and a display. Each channel contains CMOS camera with long focal-length lens. Reference marks are implemented as IR LED arrays with 940 nm working wavelength for better performance within bad weather conditions (e.g. fog, rain, high humidity etc.). In the paper we demonstrate results of an analysis of different optical schemes for coupling the oppositely directed channels of the measurement unit and show that the scheme with two image sensors with separated lenses is an optimal option, because it allows usage of nonequidistant location of reference marks and demonstrates the least value of parasitic shift caused by rotations of the measuring unit. The developed system was tested both on specially-designed setup and in real infrastructure of a floating dry dock. The conducted tests proved that a measuring error of the system is smaller than +/- 1.5 mm within the measurement range of +/- 150 mm when deflection of 100 m dock is measured. Obtained results showed that the system demonstrates an ability to work in a harsh environment including poor weather conditions.

  20. Synthesis, Pharmacological Profile and Docking Studies of New Sulfonamides Designed as Phosphodiesterase-4 Inhibitors

    Science.gov (United States)

    Cardozo, Suzana Vanessa S.; Carvalho, Vinicius de Frias; Romeiro, Nelilma Correia; Silva, Patrícia Machado Rodrigues e; Martins, Marco Aurélio; Barreiro, Eliezer J.; Lima, Lídia Moreira

    2016-01-01

    Prior investigations showed that increased levels of cyclic AMP down-regulate lung inflammatory changes, stimulating the interest in phosphodiesterase (PDE)4 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. PMID:27695125

  1. 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.

  2. 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.

  3. Prediction of substrates for glutathione transferases by covalent docking.

    Science.gov (United States)

    Dong, Guang Qiang; Calhoun, Sara; Fan, Hao; Kalyanaraman, Chakrapani; Branch, Megan C; Mashiyama, Susan T; London, Nir; Jacobson, Matthew P; Babbitt, Patricia C; Shoichet, Brian K; Armstrong, Richard N; Sali, Andrej

    2014-06-23

    Enzymes in the glutathione transferase (GST) superfamily catalyze the conjugation of glutathione (GSH) to electrophilic substrates. As a consequence they are involved in a number of key biological processes, including protection of cells against chemical damage, steroid and prostaglandin biosynthesis, tyrosine catabolism, and cell apoptosis. Although virtual screening has been used widely to discover substrates by docking potential noncovalent ligands into active site clefts of enzymes, docking has been rarely constrained by a covalent bond between the enzyme and ligand. In this study, we investigate the accuracy of docking poses and substrate discovery in the GST superfamily, by docking 6738 potential ligands from the KEGG and MetaCyc compound libraries into 14 representative GST enzymes with known structures and substrates using the PLOP program [ Jacobson Proteins 2004 , 55 , 351 ]. For X-ray structures as receptors, one of the top 3 ranked models is within 3 Å all-atom root mean square deviation (RMSD) of the native complex in 11 of the 14 cases; the enrichment LogAUC value is better than random in all cases, and better than 25 in 7 of 11 cases. For comparative models as receptors, near-native ligand-enzyme configurations are often sampled but difficult to rank highly. For models based on templates with the highest sequence identity, the enrichment LogAUC is better than 25 in 5 of 11 cases, not significantly different from the crystal structures. In conclusion, we show that covalent docking can be a useful tool for substrate discovery and point out specific challenges for future method improvement.

  4. 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.

  5. Alternative to consensus scoring--a new approach toward the qualitative combination of docking algorithms.

    Science.gov (United States)

    Wolf, Antje; Zimmermann, Marc; Hofmann-Apitius, Martin

    2007-01-01

    Since the development of the first docking algorithm in the early 1980s a variety of different docking approaches and tools has been created in order to solve the docking problem. Subsequent studies have shown that the docking performance of most tools strongly depends on the considered target. Thus it is hard to choose the best algorithm in the situation at hand. The docking tools FlexX and AutoDock are among the most popular programs for docking flexible ligands into target proteins. Their analysis, comparison, and combination are the topics of this study. In contrast to standard consensus scoring techniques which integrate different scoring algorithms usually only by their rank, we focus on a more general approach. Our new combined docking workflow-AutoxX-unifies the interaction models of AutoDock and FlexX rather than combining the scores afterward which allows interpretability of the results. The performance of FlexX, AutoDock, and the combined algorithm AutoxX was evaluated on the basis of a test set of 204 structures from the Protein Data Bank (PDB). AutoDock and FlexX show a highly diverse redocking accuracy at the different complexes which assures again the usefulness of taking several docking algorithms into account. With the combined docking the number of complexes reproduced below an rmsd of 2.5 A could be raised by 10. AutoxX had a strong positive effect on several targets. The highest performance increase could be found when redocking 20 protein-ligand complexes of alpha-thrombin, plasmepsin, neuraminidase, and d-xylose isomerase. A decrease was found for gamma-chymotrypsin. The results show that--applied to the right target-AutoxX can improve the docking performance compared to AutoDock and FlexX alone.

  6. A Practical Guide to Molecular Docking and Homology Modelling for Medicinal Chemists.

    Science.gov (United States)

    Lohning, Anna E; Levonis, Stephan M; Williams-Noonan, Billy; Schweiker, Stephanie S

    2017-01-01

    Elucidating details of the relationship between molecular structure and a particular biological end point is essential for successful, rational drug discovery. Molecular docking is a widely accepted tool for lead identification however, navigating the intricacies of the software can be daunting. Our objective was therefore to provide a step-by-step guide for those interested in incorporating contemporary basic molecular docking and homology modelling into their design strategy. Three molecular docking programs, AutoDock4, SwissDock and Surflex-Dock, were compared in the context of a case study where a set of steroidal and non-steroidal ligands were docked into the human androgen receptor (hAR) using both rigid and flexible target atoms. Metrics for comparison included how well each program predicted the X-ray structure orientation via root mean square deviation (rmsd), predicting known actives via ligand ranking and comparison to biological data where available. Benchmarking metrics were discussed in terms of identifying accurate and reliable results. For cases where no three dimensional structure exists, we provided a practical example for creating a homology model using Swiss-Model. Results showed an rmsd between X-ray ligands from wild-type and mutant receptors and docked poses were 4.15Å and 0.83Å (SwissDock), 2.69Å and 8.80Å (AutoDock4) and 0.39Å and 0.71Å (Surflex-Dock) respectively. Surflex-Dock performed consistently well in pose prediction (less than 2Å) while Auto- Dock4 predicted known active non-steroidal antiandrogens most accurately. Introducing flexibility into target atoms produced the largest degree of change in ligand ranking in Surflex-Dock. We produced a viable homology model of the P2X1 purireceptor for subsequent docking analysis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  7. Human nucleoporins promote HIV-1 docking at the nuclear pore, nuclear import and integration.

    Directory of Open Access Journals (Sweden)

    Francesca Di Nunzio

    Full Text Available The nuclear pore complex (NPC mediates nucleo-cytoplasmic transport of macromolecules and is an obligatory point of passage and functional bottleneck in the replication of some viruses. The Human Immunodeficiency Virus (HIV has evolved the required mechanisms for active nuclear import of its genome through the NPC. However the mechanisms by which the NPC allows or even assists HIV translocation are still unknown. We investigated the involvement of four key nucleoporins in HIV-1 docking, translocation, and integration: Nup358/RanBP2, Nup214/CAN, Nup98 and Nup153. Although all induce defects in infectivity when depleted, only Nup153 actually showed any evidence of participating in HIV-1 translocation through the nuclear pore. We show that Nup358/RanBP2 mediates docking of HIV-1 cores on NPC cytoplasmic filaments by interacting with the cores and that the C-terminus of Nup358/RanBP2 comprising a cyclophilin-homology domain contributes to binding. We also show that Nup214/CAN and Nup98 play no role in HIV-1 nuclear import per se: Nup214/CAN plays an indirect role in infectivity read-outs through its effect on mRNA export, while the reduction of expression of Nup98 shows a slight reduction in proviral integration. Our work shows the involvement of nucleoporins in diverse and functionally separable steps of HIV infection and nuclear import.

  8. Synthesis of novel bisindolylmethanes: New carbonic anhydrase II inhibitors, docking, and 3D pharmacophore studies.

    Science.gov (United States)

    Imran, Syahrul; Taha, Muhammad; Ismail, Nor Hadiani; Fayyaz, Sharmeen; Khan, Khalid Mohammed; Choudhary, Muhammad Iqbal

    2016-10-01

    In this study, 45 bisindolylmethanes having sulfonamide moiety had been synthesized through 3 steps. In vitro assay for inhibition of carbonic anhydrase showed that some of the compounds having sulfonamide moiety are capable of inhibiting carbonic anhydrase II. Bisindoles having halogens at fifth position showed better inhibitory activity as compared to unsubstituted bisindoles. The results obtained from in vitro inhibitory activity were subjected through 3D QSAR and docking studies to identify important features contributing to the activity and further improve the structure. Pharmacophore studies suggest that bisindolylmethane moiety is contributing significantly towards the inhibition activity. Docking studies showed that compounds having nitro substituent (5g and 5i) were found to be able interact with Zn(2+) ion, Thr199, His94, His96, and His119, which interferes with the ZnOHThr199Glu106 hydrogen bond network. Bulky nitro substituent at ortho position for compound 5g prevents the compound from interacting with other residues like Thr199 and Thr200. Methyl substituent at ortho position for Compound 5i induces less steric hindrance effect, thus allowing second oxygen atom of sulfonamide to interact with Thr199 (2.51Å). Hydrogen bonding between NH on indole ring with Glu69 might have increased stability of ligand-receptor complex. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Extensive fitness and human cooperation

    NARCIS (Netherlands)

    van Hateren, J. H.

    2015-01-01

    Evolution depends on the fitness of organisms, the expected rate of reproducing. Directly getting offspring is the most basic form of fitness, but fitness can also be increased indirectly by helping genetically related individuals (such as kin) to increase their fitness. The combined effect is known

  10. MixFit

    DEFF Research Database (Denmark)

    Haller, Toomas; Leitsalu, Liis; Fischer, Krista

    2017-01-01

    Ancestry information at the individual level can be a valuable resource for personalized medicine, medical, demographical and history research, as well as for tracing back personal history. We report a new method for quantitatively determining personal genetic ancestry based on genome-wide data....... Numerical ancestry component scores are assigned to individuals based on comparisons with reference populations. These comparisons are conducted with an existing analytical pipeline making use of genotype phasing, similarity matrix computation and our addition-multidimensional best fitting by Mix......Fit. The method is demonstrated by studying Estonian and Finnish populations in geographical context. We show the main differences in the genetic composition of these otherwise close European populations and how they have influenced each other. The components of our analytical pipeline are freely available...

  11. Return to fitness.

    Science.gov (United States)

    Dinubile, Nicholas A

    2008-12-01

    The cornerstone of personal health is prevention. The concept of exercise as medicine is a lesson I have preached throughout my career, both with my patients in my private practice as well as through my years working with athletes at all levels including the Philadelphia 76ers basketball team and the Pennsylvania Ballet. It is also a message I relayed as a Special Advisor to the President's Council on Physical Fitness and Sports (PCPFS) during the first Bush administration, working closely with my old friend-and fitness advocate and visionary himself-Governor Arnold Schwarzenegger, who served as Chairman to the PCPFS. Arnold's impact on our nation's health was an extremely positive one that was felt in communities from coast-to-coast. Exercise, activity, and prevention were key components of his prescription for change and improved health for our country. He has also always personally inspired me to see my role as a physician and "healer" in a much broader context.

  12. Virtual Fitting Rooms

    OpenAIRE

    Becerra Rodríguez, Carlos Alfredo

    2016-01-01

    In the last decade a considerable number of efforts have been devoted into developing Virtual Fitting Rooms (VFR) due to the great popularity of Virtual Reality (VR) and Augmented Reality (AR) in the fashion design industry. The existence of new technologies such as Kinect, powerful web cameras and smartphones permit us to examine new ways to try on clothes without doing it physically in a store center. This research is primarily dedicated to review some important aspects about...

  13. BESⅢ track fitting algorithm

    Institute of Scientific and Technical Information of China (English)

    WANG Ji-Ke; MAO Ze-Pu; BIAN Jian-Ming; CAO Guo-Fu; CAO Xue-Xiang; CHEN Shen-Jian; DENG Zi-Yan; FU Cheng-Dong; GAO Yuan-Ning; HE Kang-Lin; HE Miao; HUA Chun-Fei; HUANG Bin; HUANG Xing-Tao; JI Xiao-Sin; LI Fei; LI Hai-Bo; LI Wei-Dong; LIANG Yu-Tie; LIU Chun-Xiu; LIU Huai-Min; LIU Suo; LIU Ying-Jie; MA Qiu-Mei; MA Xiang; MAO Ya-Jun; MO Xiao-Hu; PAN Ming-Hua; PANG Cai-Ying; PING Rong-Gang; QIN Ya-Hong; QIU Jin-Fa; SUN Sheng-Sen; SUN Yong-Zhao; WANG Liang-Liang; WEN Shuo-Pin; WU Ling-Hui; XIE Yu-Guang; XU Min; YAN Liang; YOU Zheng-Yun; YUAN Chang-Zheng; YUAN Ye; ZHANG Bing-Yun; ZHANG Chang-Chun; ZHANG Jian-Yong; ZHANG Xue-Yao; ZHANG Yao; ZHENG Yang-Heng; ZHU Ke-Jun; ZHU Yong-Sheng; ZHU Zhi-Li; ZOU Jia-Heng

    2009-01-01

    A track fitting algorithm based on the Kalman filter method has been developed for BESⅢ of BEPCⅡ.The effects of multiple scattering and energy loss when the charged particles go through the detector,non-uniformity of magnetic field (NUMF) and wire sag, etc., have been carefully handled.This algorithm works well and the performance satisfies the physical requirements tested by the simulation data.

  14. 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.

  15. Made to fit

    DEFF Research Database (Denmark)

    Bjerck, Mari; Klepp, Ingun Grimstad; Skoland, Eli

    Denne rapporten formidler funn fra en litteraturstudie, brukerundersøkelse og markedsundersøkelse gjort i prosjektet Made to Fit. Rapporten svarer på prosjektets hovedmål og delmål som retter seg mot å formidle kunnskap om tilpasning og fremstilling av funksjonelle og gode produkter for handikapp......Denne rapporten formidler funn fra en litteraturstudie, brukerundersøkelse og markedsundersøkelse gjort i prosjektet Made to Fit. Rapporten svarer på prosjektets hovedmål og delmål som retter seg mot å formidle kunnskap om tilpasning og fremstilling av funksjonelle og gode produkter...... for handikappede. Herunder potensialet for å utvikle spesialtilpassede klær i konseptet «Made to Fit», utprøving av metoder og identifisering av kunnskapsstatus på feltet. Rapporten er således delt inn i tre hoveddeler. Første delen bygger videre på prosjektnotatet til Vestvik, Hebrok og Klepp (2013) fra...

  16. Gender Induced Differences in Naval Fitness Reports

    Science.gov (United States)

    1991-06-01

    Epstein, Cynthia F., "Ways Men and Women Lead," Harvard Business Review, January/February 1990, pp. 150-160. 20. Bargh , John A., and Paul Pietromonaco...Formation," Journal of Personality and Social Psvchologv, Vol. 43, No. 3, pp. 437-449. 21. Higgins, E. Tory, William S. Rhodes and Carl R. Jones, "Category

  17. Virtual fragment screening: an exploration of various docking and scoring protocols for fragments using Glide

    Science.gov (United States)

    Kawatkar, Sameer; Wang, Hongming; Czerminski, Ryszard; Joseph-McCarthy, Diane

    2009-08-01

    Fragment-based drug discovery approaches allow for a greater coverage of chemical space and generally produce high efficiency ligands. As such, virtual and experimental fragment screening are increasingly being coupled in an effort to identify new leads for specific therapeutic targets. Fragment docking is employed to create target-focussed subset of compounds for testing along side generic fragment libraries. The utility of the program Glide with various scoring schemes for fragment docking is discussed. Fragment docking results for two test cases, prostaglandin D2 synthase and DNA ligase, are presented and compared to experimental screening data. Self-docking, cross-docking, and enrichment studies are performed. For the enrichment runs, experimental data exists indicating that the docking decoys in fact do not inhibit the corresponding enzyme being examined. Results indicate that even for difficult test cases fragment docking can yield enrichments significantly better than random.

  18. ATTRACT and PTools: open source programs for protein-protein docking.

    Science.gov (United States)

    Schneider, Sebastian; Saladin, Adrien; Fiorucci, Sébastien; Prévost, Chantal; Zacharias, Martin

    2012-01-01

    The prediction of the structure of protein-protein complexes based on structures or structural models of isolated partners is of increasing importance for structural biology and bioinformatics. The ATTRACT program can be used to perform systematic docking searches based on docking energy minimization. It is part of the object-oriented PTools library written in Python and C++. The library contains various routines to manipulate protein structures, to prepare and perform docking searches as well as analyzing docking results. It also intended to facilitate further methodological developments in the area of macromolecular docking that can be easily integrated. Here, we describe the application of PTools to perform systematic docking searches and to analyze the results. In addition, the possibility to perform multi-component docking will also be presented.

  19. 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...... by independent scientists comparing the performance of the docking programs by using default 'black box' protocols supplied by the software companies. Such studies have to be considered carefully as the docking programs can be tweaked towards optimum performance by selecting the parameters suitable...... for the target of interest. In this study we address the problem of selecting an appropriate docking and scoring function combination (88 docking algorithm-scoring functions) for substrate specificity predictions for feruloyl esterases, an industrially relevant enzyme family. We also propose the 'Key Interaction...

  20. QSAR based docking studies of marine algal anticancer compounds as inhibitors of protein kinase B (PKBβ).

    Science.gov (United States)

    Davis, G Dicky John; Vasanthi, A Hannah Rachel

    2015-08-30

    Marine algae are prolific source of bioactive secondary metabolites and are found to be active against different cancer cell lines. QSAR studies will explicate the significance of a particular class of descriptor in eliciting anticancer activity against a cancer type. Marine algal compounds showing anticancer activity against six different cancer cell lines namely MCF-7, A431, HeLa, HT-29, P388 and A549 taken from Seaweed metabolite database were subjected to comprehensive QSAR modeling studies. A hybrid-GA (genetic algorithm) optimization technique for descriptor space reduction and multiple linear regression analysis (MLR) approach was used as fitness functions. Cell lines HeLa and MCF-7 showed good statistical quality (R(2)∼0.75, Q(2)∼0.65) followed by A431, HT29 and P388 cell lines with reasonable statistical values (R(2)∼0.70, Q(2)∼0.60). The models developed were interpretable, with good statistical and predictive significance. Molecular descriptor analyses revealed that Baumann's alignment-independent topological descriptors had a major role in variation of activity along with other descriptors. Incidentally, earlier QSAR analysis on a variety of chemically diverse PKBα inhibitors revealed Baumann's alignment-independent topological descriptors that differentiated the molecules binding to Protein kinase B (PKBα) kinase or PH domain, hence a docking study of two crystal structures of PKBβ was performed for identification of novel ATP-competitive inhibitors of PKBβ. Five compounds had a good docking score and Callophycin A showed better ligand efficiency than other PKBβ inhibitors. Furthermore in silico pharmacokinetic and toxicity studies also showed that Callophycin A had a high drug score (0.85) compared to the other inhibitors. These results encourages discovering novel inhibitors for cancer therapeutic targets by screening metabolites from marine algae.

  1. Design of an Automatic Autonomous Mini Prone-cone Microsatellite Docking Mechanism

    Institute of Scientific and Technical Information of China (English)

    LAI Yinan; DAI Ye; TIAN Hao; ZHANG Dawei

    2010-01-01

    The capability of docking, refueling, repairing, and updating microsatellites using automatic autonomous vehicles will be of significance critical value for design and operation of several space systems in the near feature. Automatic docking capability was successfully tested by many institutions such as National Space Development Agency in Japan, European Space Agency, National Aeronautics and Space Administration in USA, etc. However, there is still much more space for improvement of degree of automation during the process of docking with large deviations of the initial attitude. A novel automatic autonomous probe-cone docking mechanism used for microsatellite docking is proposed. This docking mechanism is designed according to the design indices such as miniaturization, degree of automation and automatic capture capability within large deviation of the initial attitude. On the basis of the virtual work principle, the dynamics modeling of the docking process is presented. The position of the contact point is then analyzed. Comprehensive system level simulation is conducted in the 13 kinds of typical operating conditions with the initial deviations. Capture performance is analyzed. The simulation results show that the docking mechanism can be smoothly captured within 2 s in all cases of large attitude deviation between the active and passive spacecrafts. A virtual prototype model of the docking mechanism is established through ADAMS for further verifying the correctness of the buffer parameter model and the autonomous docking capability. A laboratory platform is designed for on-the-ground experimental validation of the property of mini probe-cone docking mechanism. Repeated docking tests prove the proposed design of the mini probe-cone docking mechanism system for its high reliability, and automatic capture capability within large attitude range. The kinetic model of the docking capture process and the mechanism structure could provide some References for similar

  2. Homology modeling and metabolism prediction of human carboxylesterase-2 using docking analyses by GriDock: a parallelized tool based on AutoDock 4.0.

    Science.gov (United States)

    Vistoli, Giulio; Pedretti, Alessandro; Mazzolari, Angelica; Testa, Bernard

    2010-09-01

    Metabolic problems lead to numerous failures during clinical trials, and much effort is now devoted to developing in silico models predicting metabolic stability and metabolites. Such models are well known for cytochromes P450 and some transferases, whereas less has been done to predict the activity of human hydrolases. The present study was undertaken to develop a computational approach able to predict the hydrolysis of novel esters by human carboxylesterase hCES2. The study involved first a homology modeling of the hCES2 protein based on the model of hCES1 since the two proteins share a high degree of homology (congruent with 73%). A set of 40 known substrates of hCES2 was taken from the literature; the ligands were docked in both their neutral and ionized forms using GriDock, a parallel tool based on the AutoDock4.0 engine which can perform efficient and easy virtual screening analyses of large molecular databases exploiting multi-core architectures. Useful statistical models (e.g., r (2) = 0.91 for substrates in their unprotonated state) were calculated by correlating experimental pK(m) values with distance between the carbon atom of the substrate's ester group and the hydroxy function of Ser228. Additional parameters in the equations accounted for hydrophobic and electrostatic interactions between substrates and contributing residues. The negatively charged residues in the hCES2 cavity explained the preference of the enzyme for neutral substrates and, more generally, suggested that ligands which interact too strongly by ionic bonds (e.g., ACE inhibitors) cannot be good CES2 substrates because they are trapped in the cavity in unproductive modes and behave as inhibitors. The effects of protonation on substrate recognition and the contrasting behavior of substrates and products were finally investigated by MD simulations of some CES2 complexes.

  3. Invasion fitness, inclusive fitness, and reproductive numbers in heterogeneous populations.

    Science.gov (United States)

    Lehmann, Laurent; Mullon, Charles; Akçay, Erol; Van Cleve, Jeremy

    2016-08-01

    How should fitness be measured to determine which phenotype or "strategy" is uninvadable when evolution occurs in a group-structured population subject to local demographic and environmental heterogeneity? Several fitness measures, such as basic reproductive number, lifetime dispersal success of a local lineage, or inclusive fitness have been proposed to address this question, but the relationships between them and their generality remains unclear. Here, we ascertain uninvadability (all mutant strategies always go extinct) in terms of the asymptotic per capita number of mutant copies produced by a mutant lineage arising as a single copy in a resident population ("invasion fitness"). We show that from invasion fitness uninvadability is equivalently characterized by at least three conceptually distinct fitness measures: (i) lineage fitness, giving the average individual fitness of a randomly sampled mutant lineage member; (ii) inclusive fitness, giving a reproductive value weighted average of the direct fitness costs and relatedness weighted indirect fitness benefits accruing to a randomly sampled mutant lineage member; and (iii) basic reproductive number (and variations thereof) giving lifetime success of a lineage in a single group, and which is an invasion fitness proxy. Our analysis connects approaches that have been deemed different, generalizes the exact version of inclusive fitness to class-structured populations, and provides a biological interpretation of natural selection on a mutant allele under arbitrary strength of selection.

  4. The assessment of facial expressions in piglets undergoing tail docking and castration: towards the development of the Piglet Grimace Scale

    Directory of Open Access Journals (Sweden)

    Pierpaolo Di Giminiani

    2016-11-01

    Full Text Available Many piglets are exposed to potentially painful husbandry procedures within the first week of life, including tail docking and castration, without the provision of either anaesthesia or analgesia. The assessment methods used to evaluate pain experienced by piglets are often affected by low specificity and practical limitations, prompting the investigation of alternative methodologies. The assessment of changes in facial expression following a painful event has been successfully applied to several species. The objective of this pilot study was to evaluate the utility of a Grimace Scale applied to neonatal pigs to evaluate pain evoked by tail docking and castration.Eight female piglets, sus scrofa domesticus (Landrace/Large White X synthetic sire line underwent tail docking and 15 male piglets (75% Large White and 25% Belgian Landrace were exposed to the castration procedure. Clear images of the faces of the piglets were collected immediately pre- and post-procedure. The images were used by experienced observers to identify Facial Action Units (FAU which changed in individuals over this period and a scoring scale was depicted in a training manual. A set of randomly selected images were then combined in a scorebook, which was evaluated after training by 30 scorers, blind to the treatment. The scale for most FAU was used with a high level of consistency across all observers. Tail docking induced a significant change (P<0.05 only in the ‘orbital tightening’ Action Unit, whereas no change in any unit was observed in castrated piglets. In this initial stage of development, orbital tightening at least seems to have the potential to be applied to investigate painful conditions in neonatal pigs. Nonetheless, more studies are needed to assess its full effectiveness and to evaluate the influence of possible confounds (e.g. handling stress on the observed changes in facial expressions.

  5. Fit for work

    DEFF Research Database (Denmark)

    Brorholt, Grete

    "Fit for work - Attraktiv sundhed og sikkerhed på en hospitalsafdeling i Region Hovedstaden" undersøger hvorledes sundhedsvæsenets forandringer påvirker medarbejdere, ledere og organisation. Udgangspunktet for afhandlingen er en interesse for psykisk arbejdsmiljø, og hvordan reformerne i kølvandet...... også belastende arbejdsmiljø. Afhandlingen er baseret på 8 måneders deltagerobservation og interviews på en anæstesiologisk afdeling kombineret med omfattende dokumentlæsning....

  6. Adaptive Vertex Fitting

    CERN Document Server

    Frühwirth, R; Vanlaer, Pascal

    2007-01-01

    Vertex fitting frequently has to deal with both mis-associated tracks and mis-measured track errors. A robust, adaptive method is presented that is able to cope with contaminated data. The method is formulated as an iterative re-weighted Kalman filter. Annealing is introduced to avoid local minima in the optimization. For the initialization of the adaptive filter a robust algorithm is presented that turns out to perform well in a wide range of applications. The tuning of the annealing schedule and of the cut-off parameter is described, using simulated data from the CMS experiment. Finally, the adaptive property of the method is illustrated in two examples.

  7. Communications, tracking, and docking on the Space Station

    Science.gov (United States)

    Erwin, H. O.; Coden, M. H.; Scholl, F. W.

    1982-01-01

    Many of the communications, tracking, and docking functions on a large manned orbiting Space Station - one that is modular and made of metal - will have to be performed by optical systems out of necessity. This paper discusses four practical approaches to accomplishing Space Station functions using optical communications technology. It also provides the results of preliminary experiments involved in the design of particular systems. Major operational factors considered in each system design include: (a) electromagnetic interference problems, (b) data bandwidth requirements, (c) zero-gravity operations, (d) free-space operations, (e) data security, and (f) modular expansion of the Space Station structure. The technologies discussed are the following: (a) local infrared communications, (b) optical tracking and docking techniques, (c) long distance free space optical communications, and (d) local area optical networks.

  8. Combined 3D-QSAR modeling and molecular docking study on multi-acting quinazoline derivatives as HER2 kinase inhibitors.

    Science.gov (United States)

    Mirzaie, Sako; Monajjemi, Majid; Hakhamaneshi, Mohammad Saeed; Fathi, Fardin; Jamalan, Mostafa

    2013-01-01

    A series of new quinazoline derivatives has been recently reported as potent multi-acting histone deacetylase (HDAC), epidermal growth factor receptor (EGFR), and human epidermal growth factor receptor 2 (HER2) inhibitors. HER2 is one of the major targets for the treatment of breast cancer and other carcinomas. Three-dimensional structure-activity relationship (3D-QSAR) is a well-known technique, which is used to drug design and development. This technique is used for quantitatively predicting the interaction between a molecule and the active site of a specific target. For each 3D-QSAR study, a three-dimensional model is created from a large curve fit to find a fitting between computational descriptors and biological activity. This model could be used as a predictive tool in drug design. The best model has the highest correlation between theoretical and experimental data. Self-Organizing Molecular Field Analysis (SOMFA), a grid-based and alignment-dependent 3D-QSAR method, is employed to study the correlation between the molecular properties and HER2 inhibitory potency of the quinazoline derivatives. Before presentation of inhibitor structures to SOMFA study, conformation of inhibitors was determined by AutoDock4, HyperChem and AutoDock Vina, separately. Overall, six independent models were produced and evaluated by the statistical partial least square (PLS) analysis. Among the several generated 3D-QSARs, the best model was selected on the basis of its statistical significance and predictive potential. The model derived from the superposition of docked conformation with AutoDock Vina with reasonable cross-validated q(2) (0.767), non cross-validated r(2) (0.815) and F-test (97.22) values showed a desirable predictive capability. Analysis of SOMFA model could provide some useful information in the design of novel HER2 kinase inhibitors with better spectrum of activity.

  9. Docking Studies of Phthalimide Pharmacophore as a Sodium Channel Blocker

    Directory of Open Access Journals (Sweden)

    Maryam Iman

    2013-09-01

    Full Text Available   Objective(s: Recently, phthalimide derivatives were designed based on ameltolide and thalidomide as they possess a similar degree of anticonvulsant potency due to their phenytoin-like profile. The ability of phthalimide pharmacophore to interact with neuronal voltage-dependent sodium channels was studied in the batrachotoxin affinity assay. Therefore, in the present study, a series of 19 compounds of phthalimide pharmacophore possessing a variety of substituents (NO2, NH2 , Me, Cl, COOH, MeO at 2-, 3-, and 4- position of the N-phenyl ring and N-(3-amino-2-methylphenyl succinimide, were subjected to docking studies in order to inhibit voltage-gated sodium channels.   Materials and Methods : Chemical structures of all compounds were designed using HYPERCHEM program and Conformational studies were performed through semi-empirical molecular orbital calculations method followed by PM3 force field. Total energy gradient calculated as a root mean square (RMS value, until the RMS gradient was 0.01 kcal mol-1. Among all energy minima conformers, the global minimum of compounds was used in docking calculations. Using a model of the open pore of Na channels, docking study was performed by AUTODOCK4.2 program. Results : Docking studies have revealed that these types of ligands interacted mainly with II-S6 residues of NaV1.2 through making hydrogen bonds and have additional hydrophobic interactions with domain I, II, III and IV in the channel's inner pore. Conclusion   : These computational studies have displayed that these compounds are capable of inhibiting Na channel, efficiently.

  10. Genetic, Clinical, and Laboratory Markers for DOCK8 Immunodeficiency Syndrome

    Directory of Open Access Journals (Sweden)

    Jeremiah C. Davis

    2010-01-01

    Full Text Available DOCK8 immunodeficiency syndrome (DIDS is a combined immunodeficiency characterized by recurrent viral infections, severe atopy, and early onset malignancy. Genetic studies revealed large, unique deletions in patients from different families and ethnic backgrounds. Clinical markers of DIDS include atopic dermatitis, allergies, cutaneous viral infections, recurrent respiratory tract infections, and malignancy. Immune assessments showed T cell lymphopenia, hyper-IgE, hypo-IgM, and eosinophilia. The impaired lymphocyte functions in DIDS patients appear central for disease pathogenesis.

  11. Machine learning and docking models for Mycobacterium tuberculosis topoisomerase I.

    Science.gov (United States)

    Ekins, Sean; Godbole, Adwait Anand; Kéri, György; Orfi, Lászlo; Pato, János; Bhat, Rajeshwari Subray; Verma, Rinkee; Bradley, Erin K; Nagaraja, Valakunja

    2017-03-01

    There is a shortage of compounds that are directed towards new targets apart from those targeted by the FDA approved drugs used against Mycobacterium tuberculosis. Topoisomerase I (Mttopo I) is an essential mycobacterial enzyme and a promising target in this regard. However, it suffers from a shortage of known inhibitors. We have previously used computational approaches such as homology modeling and docking to propose 38 FDA approved drugs for testing and identified several active molecules. To follow on from this, we now describe the in vitro testing of a library of 639 compounds. These data were used to create machine learning models for Mttopo I which were further validated. The combined Mttopo I Bayesian model had a 5 fold cross validation receiver operator characteristic of 0.74 and sensitivity, specificity and concordance values above 0.76 and was used to select commercially available compounds for testing in vitro. The recently described crystal structure of Mttopo I was also compared with the previously described homology model and then used to dock the Mttopo I actives norclomipramine and imipramine. In summary, we describe our efforts to identify small molecule inhibitors of Mttopo I using a combination of machine learning modeling and docking studies in conjunction with screening of the selected molecules for enzyme inhibition. We demonstrate the experimental inhibition of Mttopo I by small molecule inhibitors and show that the enzyme can be readily targeted for lead molecule development. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Ultrafast de novo docking combining pharmacophores and combinatorics.

    Science.gov (United States)

    Gastreich, Marcus; Lilienthal, Markus; Briem, Hans; Claussen, Holger

    2006-12-01

    We report on a successful de novo design approach which relies on the combination of multi-million compound combinatorial docking under receptor-based pharmacophore constraints. Inspired by a rationale by A.R. Leach et al., we document on the unification of two steps into one for ligand assembly. In the original work, fragments known to bind in protein active sites were connected forming novel ligand compounds by means of generic skeleton linkers and following a combinatorial approach. In our approach, the knowledge of fragments binding to the protein has been expressed in terms of a receptor-based pharmacophore definition. The combinatorial linking step is performed in situ during docking, starting from combinatorial libraries. Three sample scenarios growing in size and complexity (combinatorial libraries of 1 million, 1.3 million, and 22.4 million compounds) have been created to illustrate the method. Docking could be accomplished between minutes and several hours depending on the outset; the results were throughout promising. Technically, a module compatibility between FlexX(C) and FlexX-Pharm has been established. The background is explained, and the crucial points from an information scientist's perspective are highlighted.

  13. Molecular Docking and Structure-Based Drug Design Strategies

    Directory of Open Access Journals (Sweden)

    Leonardo G. Ferreira

    2015-07-01

    Full Text Available Pharmaceutical research has successfully incorporated a wealth of molecular modeling methods, within a variety of drug discovery programs, to study complex biological and chemical systems. The integration of computational and experimental strategies has been of great value in the identification and development of novel promising compounds. Broadly used in modern drug design, molecular docking methods explore the ligand conformations adopted within the binding sites of macromolecular targets. This approach also estimates the ligand-receptor binding free energy by evaluating critical phenomena involved in the intermolecular recognition process. Today, as a variety of docking algorithms are available, an understanding of the advantages and limitations of each method is of fundamental importance in the development of effective strategies and the generation of relevant results. The purpose of this review is to examine current molecular docking strategies used in drug discovery and medicinal chemistry, exploring the advances in the field and the role played by the integration of structure- and ligand-based methods.

  14. In silico docking analysis of piperine with cyclooxygenases

    Directory of Open Access Journals (Sweden)

    Prashantha Karunakar

    2012-08-01

    Full Text Available The structure of 1-[5-(1,3-benzodioxol- 5-yl-1-oxo-2,4-pentadienyl]piperidine (Piperine, C17H19O3N, a versatile bioactive molecule has been redetermined at 100(2 K by X-raycrystallography to explore their potential utilization in inhibition of prostaglandin release. The crystal structure is stabilized by weaknonclassical intermolecular C-H…O hydrogen bonds and also intermolecular C-H…π interactions. The crystallographiccoordinates of the compound were extrapolated to docking studies to elucidate the action of piperine against the enzymes,cyclooxygenases (COX-1 and COX-2 involved in biosynthesis of prostaglandin release. Using AutoDock suite, piperine was docked at the binding site of COX-1 and COX-2 enzyme and a strong affinity (-9.06kcal/mol, Ki =227.73nM and -8.77kcal/mol, Ki = 375.62nM, respectively was formed by Hydrogen bonds and hydrophobic interactions. These results suggest that piperine can be a promising lead for the development of COX family inhibitors.

  15. A simple click by click protocol to perform docking: AutoDock 4.2 made easy for non-bioinformaticians.

    Science.gov (United States)

    Rizvi, Syed Mohd Danish; Shakil, Shazi; Haneef, Mohd

    2013-01-01

    Recently, bioinformatics has advanced to the level that it allows almost accurate prediction of molecular interactions that hold together a protein and a ligand in the bound state. For instance, the program AutoDock has been developed to provide a procedure for predicting the interaction of small molecules with macromolecular targets which can easily separate compounds with micromolar and nanomolar binding constants from those with millimolar binding constants and can often rank molecules with finer differences in affinity. AutoDock can be used to screen a variety of possible compounds, searching for new compounds with specific binding properties or testing a range of modifications of an existing compound. The present work is a detailed outline of the protocol to use AutoDock in a more user-friendly manner. The first step is to retrieve required Ligand and Target.pdb files from major databases. The second step is preparing PDBQT format files for Target and Ligand (Target.pdbqt, Ligand.pdbqt) and Grid and Docking Parameter file (a.gpf and a.dpf) using AutoDock 4.2. The third step is to perform molecular docking using Cygwin and finally the results are analyzed. With due confidence, this is our humble claim that a researcher with no previous background in bioinformatics research would be able to perform molecular docking using AutoDock 4.2 program by following stepwise guidelines given in this article.

  16. 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.

  17. Comparison of neural histomorphology in tail tips from pigs docked using clippers or cautery iron.

    Science.gov (United States)

    Kells, N J; Beausoleil, N J; Johnson, C B; Sutherland, M A; Morrison, R S; Roe, W

    2016-12-01

    Tail docking of pigs is commonly performed to reduce the incidence of unwanted tail-biting behaviour. Two docking methods are commonly used: blunt trauma cutting (i.e. using side clippers), or cutting and concurrent cauterisation using a hot cautery iron. A potential consequence of tail amputation is the development of neuromas at the docking site. Neuromas have been linked to neuropathic pain, which can influence the longer-term welfare of affected individuals. To determine whether method of tail docking influences the extent of neuroma formation, 75 pigs were allocated to one of three treatments at birth: tail docked using clippers; tail docked using cautery iron; tail left intact. Tail docking was performed at 2 days of age and pigs were kept under conventional conditions until slaughter at 21 weeks of age. Tails were removed following slaughter and subjected to histological examination. Nerve histomorphology was scored according to the following scale: 1=discrete well-organised nerve bundles; 2=moderate neural proliferation and disorganisation affecting more than half of the circumference of the tail; 3=marked neural proliferation to form almost continuous disorganised bundles or non-continuous enlarged bundles compressing the surrounding connective tissue. Scores of 2 or 3 indicated neuroma formation. Scores were higher in docked pigs than undocked pigs (Pclippers and those docked using cautery (P=0.23). The results indicate that tail docking using either clippers or cautery results in neuroma formation, thus having the potential to affect long-term pig welfare.

  18. Regulation of synaptic vesicle docking by different classes of macromolecules in active zone material.

    Science.gov (United States)

    Szule, Joseph A; Harlow, Mark L; Jung, Jae Hoon; De-Miguel, Francisco F; Marshall, Robert M; McMahan, Uel J

    2012-01-01

    The docking of synaptic vesicles at active zones on the presynaptic plasma membrane of axon terminals is essential for their fusion with the membrane and exocytosis of their neurotransmitter to mediate synaptic impulse transmission. Dense networks of macromolecules, called active zone material, (AZM) are attached to the presynaptic membrane next to docked vesicles. Electron tomography has shown that some AZM macromolecules are connected to docked vesicles, leading to the suggestion that AZM is somehow involved in the docking process. We used electron tomography on the simply arranged active zones at frog neuromuscular junctions to characterize the connections of AZM to docked synaptic vesicles and to search for the establishment of such connections during vesicle docking. We show that each docked vesicle is connected to 10-15 AZM macromolecules, which fall into four classes based on several criteria including their position relative to the presynaptic membrane. In activated axon terminals fixed during replacement of docked vesicles by previously undocked vesicles, undocked vesicles near vacated docking sites on the presynaptic membrane have connections to the same classes of AZM macromolecules that are connected to docked vesicles in resting terminals. The number of classes and the total number of macromolecules to which the undocked vesicles are connected are inversely proportional to the vesicles' distance from the presynaptic membrane. We conclude that vesicle movement toward and maintenance at docking sites on the presynaptic membrane are directed by an orderly succession of stable interactions between the vesicles and distinct classes of AZM macromolecules positioned at different distances from the membrane. Establishing the number, arrangement and sequence of association of AZM macromolecules involved in vesicle docking provides an anatomical basis for testing and extending concepts of docking mechanisms provided by biochemistry.

  19. Automated docking to multiple target structures: incorporation of protein mobility and structural water heterogeneity in AutoDock.

    Science.gov (United States)

    Osterberg, Fredrik; Morris, Garrett M; Sanner, Michel F; Olson, Arthur J; Goodsell, David S

    2002-01-01

    Protein motion and heterogeneity of structural waters are approximated in ligand-docking simulations, using an ensemble of protein structures. Four methods of combining multiple target structures within a single grid-based lookup table of interaction energies are tested. The method is evaluated using complexes of 21 peptidomimetic inhibitors with human immunodeficiency virus type 1 (HIV-1) protease. Several of these structures show motion of an arginine residue, which is essential for binding of large inhibitors. A structural water is also present in 20 of the structures, but it must be absent in the remaining one for proper binding. Mean and minimum methods perform poorly, but two weighted average methods permit consistent and accurate ligand docking, using a single grid representation of the target protein structures. Copyright 2001 Wiley-Liss, Inc.

  20. Scheduling trucks in cross docking systems with temporary storage and dock repeat truck holding pattern using GRASP method

    Directory of Open Access Journals (Sweden)

    Hassan Javanshir

    2012-10-01

    Full Text Available Cross docking play an important role in management of supply chains where items delivered to a warehouse by inbound trucks are directly sorted out, reorganized based on customer demands, routed and loaded into outbound trucks for delivery to customers without virtually keeping them at the warehouse. If any item is held in storage, it is usually for a short time, which is normally less than 24 hours. The proposed model of this paper considers a special case of cross docking where there is temporary storage and uses GRASP technique 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 GRASP method. The preliminary test results indicate that the GRASP method performs better than alternative solution strategies.

  1. Drosophila DOCK Family Protein Zizimin Involves in Pigment Cell Differentiation in Pupal Retinae.

    Science.gov (United States)

    Ozasa, Fumito; Morishita, Kazushige; Dang, Ngoc Anh Suong; Miyata, Seiji; Yoshida, Hideki; Yamaguchi, Masamitsu

    2017-08-26

    The dedicator of cytokinesis (DOCK) family proteins are known as one of guanine nucleotide exchange factors (GEFs), that contribute to cellular signaling processes by activating small G proteins. Although mammalian Zizimin is known to be a GEF for Cdc42 of Rho family small GTPase, its role in vivo is not well understood. Here we studied in vivo function of Drosophila Zizimin (Ziz). Knockdown of Ziz in eye imaginal discs induced the rough eye phenotype accompanied with fusion of ommatidia, loss of bristles and loss of pigments. Immunostaining analyses revealed that Ziz mainly localizes in the secondary pigment cells (SPCs) and tertiary pigment cells (TPCs) in pupal retinae. Ziz-knockdown induced SPC- and TPC-like cells with aberrant morphology in the pupal retina. Delta (Dl), a downstream target of EGFR signaling is known to regulate pigment cell differentiation. Loss-of-function mutation of Dl suppressed the rough eye phenotype and the defect in differentiation of SPCs and TPCs in Ziz-knockdown flies. Moreover, Ziz-knockdown increased Dl expression level especially in SPCs and TPCs. In addition, mutations of rhomboid-1 and roughoid that are activators of EGFR signaling pathway also suppressed both the rough eye phenotype and the defect in differentiation of SPCs and TPCs in Ziz-knockdown flies. Activation of EGFR signaling in Ziz-knockdown flies were further confirmed by immunostaining with anti-diphospho ERK IgG. These results indicate that Ziz negatively regulates the Dl expression in SPCs and TPCs to control differentiation of pigment cells and this regulation is mediated by EGFR signaling pathway.Key words: Zizimin, DOCK, EGFR signaling pathway, pigment cell, Drosophila.

  2. Docking validation resources: protein family and ligand flexibility experiments.

    Science.gov (United States)

    Mukherjee, Sudipto; Balius, Trent E; Rizzo, Robert C

    2010-11-22

    A database consisting of 780 ligand-receptor complexes, termed SB2010, has been derived from the Protein Databank to evaluate the accuracy of docking protocols for regenerating bound ligand conformations. The goal is to provide easily accessible community resources for development of improved procedures to aid virtual screening for ligands with a wide range of flexibilities. Three core experiments using the program DOCK, which employ rigid (RGD), fixed anchor (FAD), and flexible (FLX) protocols, were used to gauge performance by several different metrics: (1) global results, (2) ligand flexibility, (3) protein family, and (4) cross-docking. Global spectrum plots of successes and failures vs rmsd reveal well-defined inflection regions, which suggest the commonly used 2 Å criteria is a reasonable choice for defining success. Across all 780 systems, success tracks with the relative difficulty of the calculations: RGD (82.3%) > FAD (78.1%) > FLX (63.8%). In general, failures due to scoring strongly outweigh those due to sampling. Subsets of SB2010 grouped by ligand flexibility (7-or-less, 8-to-15, and 15-plus rotatable bonds) reveal that success degrades linearly for FAD and FLX protocols, in contrast to RGD, which remains constant. Despite the challenges associated with FLX anchor orientation and on-the-fly flexible growth, success rates for the 7-or-less (74.5%) and, in particular, the 8-to-15 (55.2%) subset are encouraging. Poorer results for the very flexible 15-plus set (39.3%) indicate substantial room for improvement. Family-based success appears largely independent of ligand flexibility, suggesting a strong dependence on the binding site environment. For example, zinc-containing proteins are generally problematic, despite moderately flexible ligands. Finally, representative cross-docking examples, for carbonic anhydrase, thermolysin, and neuraminidase families, show the utility of family-based analysis for rapid identification of particularly good or bad

  3. Ground Demonstration on the Autonomous Docking of Two 3U CubeSats Using a Novel Permanent-Magnet Docking Mechanism

    Science.gov (United States)

    Pei, Jing; Murchison, Luke; BenShabat, Adam; Stewart, Victor; Rosenthal, James; Follman, Jacob; Branchy, Mark; Sellers, Drew; Elandt, Ryan; Elliott, Sawyer; Choueiri, Marc; Finch, Peter

    2017-01-01

    Small spacecraft autonomous rendezvous and docking is an essential technology for future space structure assembly missions. A novel magnetic capture and latching mechanism is analyzed that allows for docking of two CubeSats without precise sensors and actuators. The proposed magnetic docking hardware not only provides the means to latch the CubeSats but it also significantly increases the likelihood of successful docking in the presence of relative attitude and position errors. The simplicity of the design allows it to be implemented on many CubeSat rendezvous missions. A CubeSat 3-DOF ground demonstration effort is on-going at NASA Langley Research Center that enables hardware-in-the loop testing of the autonomous approach and docking of a follower CubeSat to an identical leader CubeSat. The test setup consists of a 3 meter by 4 meter granite table and two nearly frictionless air bearing systems that support the two CubeSats. Four cold-gas on-off thrusters are used to translate the follower towards the leader, while a single reaction wheel is used to control the attitude of each CubeSat. An innovative modified pseudo inverse control allocation scheme was developed to address interactions between control effectors. The docking procedure requires relatively high actuator precision, a novel minimal impulse bit mitigation algorithm was developed to minimize the undesirable deadzone effects of the thrusters. Simulation of the ground demonstration shows that the Guidance, Navigation, and Control system along with the docking subsystem leads to successful docking under 3-sigma dispersions for all key system parameters. Extensive simulation and ground testing will provide sufficient confidence that the proposed docking mechanism along with the choosen suite of sensors and actuators will perform successful docking in the space environment.

  4. Methodology review: evaluating person fit

    NARCIS (Netherlands)

    Meijer, R.R.; Sijtsma, Klaas

    2001-01-01

    Person-fit methods based on classical test theory-and item response theory (IRT), and methods investigating particular types of response behavior on tests, are examined. Similarities and differences among person-fit methods and their advantages and disadvantages are discussed. Sound person-fit

  5. SE-FIT

    Science.gov (United States)

    Chen, Yongkang; Weislogel, Mark; Schaeffer, Ben; Semerjian, Ben; Yang, Lihong; Zimmerli, Gregory

    2012-01-01

    The mathematical theory of capillary surfaces has developed steadily over the centuries, but it was not until the last few decades that new technologies have put a more urgent demand on a substantially more qualitative and quantitative understanding of phenomena relating to capillarity in general. So far, the new theory development successfully predicts the behavior of capillary surfaces for special cases. However, an efficient quantitative mathematical prediction of capillary phenomena related to the shape and stability of geometrically complex equilibrium capillary surfaces remains a significant challenge. As one of many numerical tools, the open-source Surface Evolver (SE) algorithm has played an important role over the last two decades. The current effort was undertaken to provide a front-end to enhance the accessibility of SE for the purposes of design and analysis. Like SE, the new code is open-source and will remain under development for the foreseeable future. The ultimate goal of the current Surface Evolver Fluid Interface Tool (SEFIT) development is to build a fully integrated front-end with a set of graphical user interface (GUI) elements. Such a front-end enables the access to functionalities that are developed along with the GUIs to deal with pre-processing, convergence computation operation, and post-processing. In other words, SE-FIT is not just a GUI front-end, but an integrated environment that can perform sophisticated computational tasks, e.g. importing industry standard file formats and employing parameter sweep functions, which are both lacking in SE, and require minimal interaction by the user. These functions are created using a mixture of Visual Basic and the SE script language. These form the foundation for a high-performance front-end that substantially simplifies use without sacrificing the proven capabilities of SE. The real power of SE-FIT lies in its automated pre-processing, pre-defined geometries, convergence computation operation

  6. Structural and Functional Characterization of the PaaI Thioesterase from Streptococcus pneumoniae Reveals a Dual Specificity for Phenylacetyl-CoA and Medium-chain Fatty Acyl-CoAs and a Novel CoA-induced Fit Mechanism.

    Science.gov (United States)

    Khandokar, Yogesh B; Srivastava, Parul; Sarker, Subir; Swarbrick, Crystall M D; Aragao, David; Cowieson, Nathan; Forwood, Jade K

    2016-01-22

    PaaI thioesterases are members of the TE13 thioesterase family that catalyze the hydrolysis of thioester bonds between coenzyme A and phenylacetyl-CoA. In this study we characterize the PaaI thioesterase from Streptococcus pneumoniae (SpPaaI), including structural analysis based on crystal diffraction data to 1.8-Å resolution, to reveal two double hotdog domains arranged in a back to back configuration. Consistent with the crystallography data, both size exclusion chromatography and small angle x-ray scattering data support a tetrameric arrangement of thioesterase domains in solution. Assessment of SpPaaI activity against a range of acyl-CoA substrates showed activity for both phenylacetyl-CoA and medium-chain fatty-acyl CoA substrates. Mutagenesis of putative active site residues reveals Asn(37), Asp(52), and Thr(68) are important for catalysis, and size exclusion chromatography analysis and x-ray crystallography confirm that these mutants retain the same tertiary and quaternary structures, establishing that the reduced activity is not a result of structural perturbations. Interestingly, the structure of SpPaaI in the presence of CoA provides a structural basis for the observed substrate specificity, accommodating a 10-carbon fatty acid chain, and a large conformational change of up to 38 Å in the N terminus, and a loop region involving Tyr(38)-Tyr(39). This is the first time PaaI thioesterases have displayed a dual specificity for medium-chain acyl-CoAs substrates and phenylacetyl-CoA substrates, and we provide a structural basis for this specificity, highlighting a novel induced fit mechanism that is likely to be conserved within members of this enzyme family.

  7. Virtual screening for HIV protease inhibitors: a comparison of AutoDock 4 and Vina.

    Science.gov (United States)

    Chang, Max W; Ayeni, Christian; Breuer, Sebastian; Torbett, Bruce E

    2010-08-04

    The AutoDock family of software has been widely used in protein-ligand docking research. This study compares AutoDock 4 and AutoDock Vina in the context of virtual screening by using these programs to select compounds active against HIV protease. Both programs were used to rank the members of two chemical libraries, each containing experimentally verified binders to HIV protease. In the case of the NCI Diversity Set II, both AutoDock 4 and Vina were able to select active compounds significantly better than random (AUC = 0.69 and 0.68, respectively; pAutoDock 4 and Vina were equally capable, though both exhibited a size-related bias in scoring. However, as Vina executes more quickly and is able to more accurately rank larger molecules, researchers should look to it first when undertaking a virtual screen.

  8. 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.

  9. Androgynous, Reconfigurable Closed Loop Feedback Controlled Low Impact Docking System With Load Sensing Electromagnetic Capture Ring

    Science.gov (United States)

    Lewis, James L. (Inventor); Carroll, Monty B. (Inventor); Morales, Ray H. (Inventor); Le, Thang D. (Inventor)

    2002-01-01

    The present invention relates to a fully androgynous, reconfigurable closed loop feedback controlled low impact docking system with load sensing electromagnetic capture ring. The docking system of the present invention preferably comprises two Docking- assemblies, each docking assembly comprising a load sensing ring having an outer face, one of more electromagnets, one or more load cells coupled to said load sensing ring. The docking assembly further comprises a plurality of actuator arms coupled to said load sensing ring and capable of dynamically adjusting the orientation of said load sensing ring and a reconfigurable closed loop control system capable of analyzing signals originating from said plurality of load cells and of outputting real time control for each of the actuators. The docking assembly of the present invention incorporates an active load sensing system to automatically dynamically adjust the load sensing ring during capture instead of requiring significant force to push and realign the ring.

  10. Casual dock work: profile of diseases and injuries and perception of influence on health.

    Science.gov (United States)

    Cezar-Vaz, Marta Regina; de Almeida, Marlise Capa Verde; Bonow, Clarice Alves; Rocha, Laurelize Pereira; Borges, Anelise Miritz; Piexak, Diéssica Roggia

    2014-02-19

    The present study aimed to identify the profile of diseases and injuries that affect casual dock workers and identify casual dock workers' perceptions of positive and negative work influences on their health. This study consisted of two phases. The first phase was a quantitative study composed of a retrospective analysis, conducted with 953 medical records. The second phase of the research is a non-random sample with 51 casual dock workers. Data analysis was performed with SPSS 19.0. The average age of the casual dock workers was 48.7. Concerning working time, the majority had more than 19.6 years of dock work experience. In the first phase, 527 pathologic diagnoses were identified. The diagnoses that affected the musculoskeletal system (15.8%, N = 152; p dock work perception and have motivated an introduction of preventive measures.

  11. Molecular docking study investigating the possible mode of binding of C.I. Acid Red 73 with DNA.

    Science.gov (United States)

    Guo, Yumei; Yue, Qinyan; Gao, Baoyu

    2011-07-01

    C.I. Acid Red 73 is a reactive azo dye with a variable potential carcinogenicity. The mechanism mediating interactions that occur between the dye and DNA have not been completely understood thus far. In this study, molecular docking techniques were applied to describe the most probable mode of DNA binding as well as the sequence selectivity of the C.I. Acid Red 73 dye. These docking experiments revealed that the dye is capable of interacting with the minor groove of the DNA on the basis of its curved shape, which fits well with the topology of double-stranded DNA. In addition, the dye can bind selectively to the minor groove of the DNA by applying CGT sequence selectivity. Further, the minor groove can be recognized although DNA targets present intercalation gaps. However, intercalative binding can also occur when the DNA target possesses an appropriate intercalation gap. Compared with the other eight DNA sequences that were studied, the DNA dodecamer d(CGCGATATCGCG)(2) (PDB ID: 1DNE) presents a very favorable target for the binding of C.I. Acid Red 73 to the minor groove, with the lowest binding free energy -9.19 kcal/mol. Results reported from this study are expected to provide useful information for research involving further simulations of molecular dynamics and toxicology investigations of the dye.

  12. ASTP crewmen in Docking Module trainer during training session at JSC

    Science.gov (United States)

    1975-01-01

    An interior view of the Docking Module trainer in bldg 35 during Apollo Soyuz Test Project (ASTP) joint crew training at JSC. Astronaut Donald K. Slayton (right) is the docking module pilot of the American ASTP prime crew. The other man is Cosmonaut Valeriy N. Kubasov, engineer on the Soviet ASTP first (prime) crew. The training session simulated activities on the second day in space. The Docking module is designed to link the Apollo and Soyuz spacecraft.

  13. Radiant Cooling for Closed-Loop Water Containment: Exploration of Possible Application in Dry Docks

    Science.gov (United States)

    2015-08-20

    Radiant Cooling For Closed-Loop Water Containment: Exploration of Possible Application in Dry Docks by Trevor R. Murphy, Mechanical...Organization: SPAWAR Sponsoring Organization: NESDI Keywords: Dry Dock Cooling, Heat Transfer, Closed Loop, Pipe System, Cost, Pareto List of Programs...provide data for estimating the cost of implementing a closed-loop radiant cooling system for ships in dry docks . Depending on the material used, pipe

  14. Molecular Recognition Analyzed by Docking Simulations: The Aspartate Receptor and Isocitrate Dehydrogenase from Escherichia coli

    Science.gov (United States)

    Stoddard, Barry L.; Koshland, Daniel E., Jr.

    1993-02-01

    Protein docking protocols are used for the prediction of both small molecule binding to DNA and protein macromolecules and of complexes between macromolecules. These protocols are becoming increasingly automated and powerful tools for computer-aided drug design. We review the basic methodologies and strategies used for analyzing molecular recognition by computer docking algorithms and discuss recent experiments in which (i) substrate and substrate analogues are docked to the active site of isocitrate dehydrogenase and (ii) maltose binding protein is docked to the extracellular domain of the receptor, which signals maltose chemotaxis.

  15. SPACECRAFT DOCKING SIMULATION USING HARDWARE-IN-THE-LOOP SIMULATOR WITH STEWART PLATFORM

    Institute of Scientific and Technical Information of China (English)

    Huang Qitao; Jiang Hongzhou; Zhang Shangying; Han Junwei

    2005-01-01

    A ground-based hardware-in-the-loop (HIL) simulation system with hydraulically driven Stewart platform for spacecraft docking simulation is presented. The system is used for simulating docking process of the on-orbit spacecraft. Principle and structure of the six-degree-of-freedom simulation system are introduced. The docking process dynamic of the vehicles is modeled. Experiment results and mathematical simulation data are compared to validating the simulation system. The comparisons of the results prove that the simulation system proposed can effectively simulate the on-orbit docking process of the spacecraft.

  16. Hypomorphic function and somatic reversion of DOCK8 cause combined immunodeficiency without hyper-IgE.

    Science.gov (United States)

    Kienzler, Anne-Kathrin; van Schouwenburg, Pauline A; Taylor, John; Marwah, Ishita; Sharma, Richa U; Noakes, Charlotte; Thomson, Kate; Sadler, Ross; Segal, Shelley; Ferry, Berne; Taylor, Jenny C; Blair, Edward; Chapel, Helen; Patel, Smita Y

    2016-02-01

    Loss-of-function mutations in DOCK8 are linked to hyper-IgE syndrome. Patients typically present with recurrent sinopulmonary infections, severe cutaneous viral infections, food allergies and elevated serum IgE. Although patients may present with a spectrum of disease-related symptoms, molecular mechanisms explaining phenotypic variability in patients are poorly defined. Here we characterized a novel compound heterozygous mutation in DOCK8 in a patient diagnosed with primary combined immunodeficiency which was not typical of classical DOCK8 deficiency. In contrast to previously identified mutations in DOCK8 which result in complete loss of function, the newly identified single nucleotide insertion results in expression of a truncated DOCK8 protein. Functional evaluation of the truncated DOCK8 protein revealed its hypomorphic function. In addition we found somatic reversion of DOCK8 predominantly in T cells. The combination of somatic reversion and hypomorphic DOCK8 function explains the milder and atypical phenotype of the patient and further broadens the spectrum of DOCK8-associated disease.

  17. Ligand docking and binding site analysis with PyMOL and Autodock/Vina.

    Science.gov (United States)

    Seeliger, Daniel; de Groot, Bert L

    2010-05-01

    Docking of small molecule compounds into the binding site of a receptor and estimating the binding affinity of the complex is an important part of the structure-based drug design process. For a thorough understanding of the structural principles that determine the strength of a protein/ligand complex both, an accurate and fast docking protocol and the ability to visualize binding geometries and interactions are mandatory. Here we present an interface between the popular molecular graphics system PyMOL and the molecular docking suites Autodock and Vina and demonstrate how the combination of docking and visualization can aid structure-based drug design efforts.

  18. Effects of protein conformation in docking: improved pose prediction through protein pocket adaptation.

    Science.gov (United States)

    Jain, Ajay N

    2009-06-01

    Computational methods for docking ligands have been shown to be remarkably dependent on precise protein conformation, where acceptable results in pose prediction have been generally possible only in the artificial case of re-docking a ligand into a protein binding site whose conformation was determined in the presence of the same ligand (the "cognate" docking problem). In such cases, on well curated protein/ligand complexes, accurate dockings can be returned as top-scoring over 75% of the time using tools such as Surflex-Dock. A critical application of docking in modeling for lead optimization requires accurate pose prediction for novel ligands, ranging from simple synthetic analogs to very different molecular scaffolds. Typical results for widely used programs in the "cross-docking case" (making use of a single fixed protein conformation) have rates closer to 20% success. By making use of protein conformations from multiple complexes, Surflex-Dock yields an average success rate of 61% across eight pharmaceutically relevant targets. Following docking, protein pocket adaptation and rescoring identifies single pose families that are correct an average of 67% of the time. Consideration of the best of two pose families (from alternate scoring regimes) yields a 75% mean success rate.

  19. DOCK/PIERR: web server for structure prediction of protein-protein complexes.

    Science.gov (United States)

    Viswanath, Shruthi; Ravikant, D V S; Elber, Ron

    2014-01-01

    In protein docking we aim to find the structure of the complex formed when two proteins interact. Protein-protein interactions are crucial for cell function. Here we discuss the usage of DOCK/PIERR. In DOCK/PIERR, a uniformly discrete sampling of orientations of one protein with respect to the other, are scored, followed by clustering, refinement, and reranking of structures. The novelty of this method lies in the scoring functions used. These are obtained by examining hundreds of millions of correctly and incorrectly docked structures, using an algorithm based on mathematical programming, with provable convergence properties.

  20. Controlling broad-leaved dock (Rumex obtusifolius) in grass clover mixtures

    OpenAIRE

    van Eekeren, Nick; Fehér, L.; Smeding, Frans; Prins, Udo; Jansonius, PieterJans

    2006-01-01

    This article describes three experiments on the control of broad-leaved dock. Experiment 1: Dock seeds were ensiled in grass silages of different dry matter percentages; 23, 34 and 60% respectively. All silages showed a decline of seed vitality in time. Grass clover with dock seeds should be ensiled at a low dry matter percentage or remain in the silage bin for a longer period than 8 weeks. Experiment 2: In a potassium fertilisation trial on grass clover the development of dock was followed. ...

  1. 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

    2017-08-01

    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.

  2. Vina-Carb: Improving Glycosidic Angles during Carbohydrate Docking.

    Science.gov (United States)

    Nivedha, Anita K; Thieker, David F; Makeneni, Spandana; Hu, Huimin; Woods, Robert J

    2016-02-09

    Molecular docking programs are primarily designed to align rigid, drug-like fragments into the binding sites of macromolecules and frequently display poor performance when applied to flexible carbohydrate molecules. A critical source of flexibility within an oligosaccharide is the glycosidic linkages. Recently, Carbohydrate Intrinsic (CHI) energy functions were reported that attempt to quantify the glycosidic torsion angle preferences. In the present work, the CHI-energy functions have been incorporated into the AutoDock Vina (ADV) scoring function, subsequently termed Vina-Carb (VC). Two user-adjustable parameters have been introduced, namely, a CHI- energy weight term (chi_coeff) that affects the magnitude of the CHI-energy penalty and a CHI-cutoff term (chi_cutoff) that negates CHI-energy penalties below a specified value. A data set consisting of 101 protein-carbohydrate complexes and 29 apoprotein structures was used in the development and testing of VC, including antibodies, lectins, and carbohydrate binding modules. Accounting for the intramolecular energies of the glycosidic linkages in the oligosaccharides during docking led VC to produce acceptable structures within the top five ranked poses in 74% of the systems tested, compared to a success rate of 55% for ADV. An enzyme system was employed in order to illustrate the potential application of VC to proteins that may distort glycosidic linkages of carbohydrate ligands upon binding. VC represents a significant step toward accurately predicting the structures of protein-carbohydrate complexes. Furthermore, the described approach is conceptually applicable to any class of ligands that populate well-defined conformational states.

  3. 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.

  4. Solving Molecular Docking Problems with Multi-Objective Metaheuristics

    Directory of Open Access Journals (Sweden)

    María Jesús García-Godoy

    2015-06-01

    Full Text Available Molecular docking is a hard optimization problem that has been tackled in the past with metaheuristics, demonstrating new and challenging results when looking for one objective: the minimum binding energy. However, only a few papers can be found in the literature that deal with this problem by means of a multi-objective approach, and no experimental comparisons have been made in order to clarify which of them has the best overall performance. In this paper, we use and compare, for the first time, a set of representative multi-objective optimization algorithms applied to solve complex molecular docking problems. The approach followed is focused on optimizing the intermolecular and intramolecular energies as two main objectives to minimize. Specifically, these algorithms are: two variants of the non-dominated sorting genetic algorithm II (NSGA-II, speed modulation multi-objective particle swarm optimization (SMPSO, third evolution step of generalized differential evolution (GDE3, multi-objective evolutionary algorithm based on decomposition (MOEA/D and S-metric evolutionary multi-objective optimization (SMS-EMOA. We assess the performance of the algorithms by applying quality indicators intended to measure convergence and the diversity of the generated Pareto front approximations. We carry out a comparison with another reference mono-objective algorithm in the problem domain (Lamarckian genetic algorithm (LGA provided by the AutoDock tool. Furthermore, the ligand binding site and molecular interactions of computed solutions are analyzed, showing promising results for the multi-objective approaches. In addition, a case study of application for aeroplysinin-1 is performed, showing the effectiveness of our multi-objective approach in drug discovery.

  5. Solving molecular docking problems with multi-objective metaheuristics.

    Science.gov (United States)

    García-Godoy, María Jesús; López-Camacho, Esteban; García-Nieto, José; Aldana-Montes, Antonio J Nebroand José F

    2015-06-02

    Molecular docking is a hard optimization problem that has been tackled in the past with metaheuristics, demonstrating new and challenging results when looking for one objective: the minimum binding energy. However, only a few papers can be found in the literature that deal with this problem by means of a multi-objective approach, and no experimental comparisons have been made in order to clarify which of them has the best overall performance. In this paper, we use and compare, for the first time, a set of representative multi-objective optimization algorithms applied to solve complex molecular docking problems. The approach followed is focused on optimizing the intermolecular and intramolecular energies as two main objectives to minimize. Specifically, these algorithms are: two variants of the non-dominated sorting genetic algorithm II (NSGA-II), speed modulation multi-objective particle swarm optimization (SMPSO), third evolution step of generalized differential evolution (GDE3), multi-objective evolutionary algorithm based on decomposition (MOEA/D) and S-metric evolutionary multi-objective optimization (SMS-EMOA). We assess the performance of the algorithms by applying quality indicators intended to measure convergence and the diversity of the generated Pareto front approximations. We carry out a comparison with another reference mono-objective algorithm in the problem domain (Lamarckian genetic algorithm (LGA) provided by the AutoDock tool). Furthermore, the ligand binding site and molecular interactions of computed solutions are analyzed, showing promising results for the multi-objective approaches. In addition, a case study of application for aeroplysinin-1 is performed, showing the effectiveness of our multi-objective approach in drug discovery.

  6. Design, synthesis and molecular docking of α,β-unsaturated cyclohexanone analogous of curcumin as potent EGFR inhibitors with antiproliferative activity.

    Science.gov (United States)

    Xu, Yun-Yun; Cao, Yi; Ma, Hailkuo; Li, Huan-Qiu; Ao, Gui-Zhen

    2013-01-15

    A type of novel α,β-unsaturated cyclohexanone analogous, which designed based on the curcumin core structure, have been discovered as potential EGFR inhibitors. These compounds exhibit potent antiproliferative activity in two human tumor cell lines (Hep G2 and B16-F10). Among them, compounds I(3) and I(12) displayed the most potent EGFR inhibitory activity (IC(50) = 0.43 μM and 1.54 μM, respectively). Molecular docking of I(12) into EGFR TK active site was also performed. This inhibitor nicely fitting the active site might well explain its excellent inhibitory activity.

  7. SYNTHESIS, DOCKING STUDIES AND ANTIOXIDANT ACTIVITY OF LINEAR TETRAPEPTIDE FAYV

    Directory of Open Access Journals (Sweden)

    Sreekanth K.

    2011-07-01

    Full Text Available The linear tetrapeptide Phe-Ala-Tyr-Val (FAYV was designed based on docking results using Schrodinger Software tool. The tetrapeptide was conveniently synthesized by solution phase peptide synthesis using Dicyclohexylcarbidomide (DCC as coupling agent and triethyl amine as the base. Qikprop (a tool to predict drug like properties results showed that the ligands mostly show antihypertensive and antidiabetic properties. The compounds were evaluated for antioxidant property by using 1,1-diphenyl-2-picryl-hydrazil (DPPH. method and were found to possess significant antioxidant activity.

  8. StarDock: shipping customized computing environments to the data

    Science.gov (United States)

    Young, Michael D.; Hayashi, Soichi; Gopu, Arvind

    2016-08-01

    Surging data volumes make it increasingly unfeasible to transfer astronomical datasets to the local systems of individual scientists. Centralized pipelines offer some relief, but lack flexibility to fulfill the needs of all users. We have developed a system that leverages the Docker container application virtualization software. Along with a suite of commonly used astronomy applications, users can configure a container with their own custom software and analysis tools. Our StarDock system will move the users container to the data, and expose the requested dataset, allowing our users to safely and securely process their data without needlessly transferring hundreds of gigabytes.

  9. Docking study of HIV-1 reverse transcriptase with phytochemicals.

    Science.gov (United States)

    Seal, Abhik; Aykkal, Riju; Babu, Rosana O; Ghosh, Mriganka

    2011-02-15

    Natural products are important sources of drug discovery. In this context groups of different set of phytochemicals were taken and docked into the different cavities of the Reverse transcriptase (PDB ID: 1REV) of Human immunodeficiency virus (HIV) and results were discussed. Natural compounds such as Curcumin, Geranin, Gallotannin, Tiliroside, Kaempferol-3-o-glucoside and Trachelogenin were found to very effective according to its binding energy and ligand efficiency score. Those compounds also were found to have no adverse effect as carcinogenicity and mutagenicity and favorable drug likeness score. Hence, considering the facts those compounds could use effectively for HIV-1 drug discovery.

  10. Synthesis, antiproliferative activity and molecular docking of Colchicine derivatives.

    Science.gov (United States)

    Huczyński, Adam; Majcher, Urszula; Maj, Ewa; Wietrzyk, Joanna; Janczak, Jan; Moshari, Mahshad; Tuszynski, Jack A; Bartl, Franz

    2016-02-01

    In order to create more potent anticancer agents, a series of five structurally different derivatives of Colchicine have been synthesised. These compounds were characterised spectroscopically and structurally and their antiproliferative activity against four human tumour cell lines (HL-60, HL-60/vinc, LoVo, LoVo/DX) was evaluated. Additionally the activity of the studied compounds was calculated using computational methods involving molecular docking of the Colchicine derivatives to β-tubulin. The experimental and computational results are in very good agreement indicating that the antimitotic activity of Colchicine derivatives can be readily predicted using computational modeling methods.

  11. APOLLO 14: Docking trouble (pt 1/2)

    Science.gov (United States)

    1974-01-01

    APOLLO 14: The crew are having problems docking the command module to the lunar module: the locking mechanism will not engage. From the film documentary 'APOLLO 14: 'Mission to Fra Mauro'', part of a documentary series on the APOLLO missions made in the early '70's and narrated by Burgess Meredith. APOLO 14: Third manned lunar landing with Alan B. Shepard, Jr.,Stuart A. Roosa, and Edgar D. Mitchell. Landed in the Fra Mauro area on Ferurary 5, 1971; performed EVA, deployed lunar experiments, returned lunar samples. Mission Duration 216 hrs 1 min 58 sec

  12. Bio-inspired algorithms applied to molecular docking simulations.

    Science.gov (United States)

    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.

  13. 3D-QSAR and docking studies of estrogen compounds based on estrogen receptor β

    Institute of Scientific and Technical Information of China (English)

    YANG XuShu; WANG XiaoDong; LUO Si; JI Li; QIN Liang; LI Rong; SUN Cheng; WANG LianSheng

    2009-01-01

    Close attention has been paid to estrogen compounds because these chemicals may pose a serious threat to the health of humans and wildlife.Estrogen receptor (ER) exists as two subtypes,ERo and ERβ.The difference in amino acids sequence of the binding sites of ERo and ERβ might lead to a result that some synthetic estrogens and naturally occurring steroidal ligands have different relative affinities and binding modes for ERa and ERβ.In this investigation,comparative molecular similarity indices analysis (CoMSIA) was performed on 50 estrogen compounds binding ERβ to find out the structural relationship with the activities.We also compared two alignment schemes employed in CoMSIA analysis,namely,atom-fit and receptor-based alignment,with respect to the predictive capability of their respective models for structurally diverse data sets.The model with the significant correlation and the best predictive power (R2=0.961,q2LOO=0.671,Rp2red=0.722) was achieved.The CoMSIA and docking results revealed the structural features related to an activity and provided an insight into molecular mechanisms of estrogenic activities for estrogen compounds.

  14. 3D-QSAR and docking studies of estrogen compounds based on estrogen receptor β

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Close attention has been paid to estrogen compounds because these chemicals may pose a serious threat to the health of humans and wildlife. Estrogen receptor (ER) exists as two subtypes, ERα and ERβ. The difference in amino acids sequence of the binding sites of ERα and ERβ might lead to a result that some synthetic estrogens and naturally occurring steroidal ligands have different relative affinities and binding modes for ERα and ERβ. In this investigation, comparative molecular similarity indices analysis (CoMSIA) was performed on 50 estrogen compounds binding ERβ to find out the structural relationship with the activities. We also compared two alignment schemes employed in CoMSIA analy-sis, namely, atom-fit and receptor-based alignment, with respect to the predictive capability of their respective models for structurally diverse data sets. The model with the significant correlation and the best predictive power (R2=0.961, qL 2OO=0.671, RP 2red=0.722) was achieved. The CoMSIA and docking results revealed the structural features related to an activity and provided an insight into molecular mechanisms of estrogenic activities for estrogen compounds.

  15. Ligand-induced conformational changes: Improved predictions of ligand binding conformations and affinities

    DEFF Research Database (Denmark)

    Frimurer, T.M.; Peters, Günther H.J.; Iversen, L.F.

    2003-01-01

    A computational docking strategy using multiple conformations of the target protein is discussed and evaluated. A series of low molecular weight, competitive, nonpeptide protein tyrosine phosphatase inhibitors are considered for which the x-ray crystallographic structures in complex with protein...... tyrosine phosphatase 1 B (PTP1B) are known. To obtain a quantitative measure of the impact of conformational changes induced by the inhibitors, these were docked to the active site region of various structures of PTP1B using the docking program FlexX. Firstly, the inhibitors were docked to a PTP1B crystal...... predicted binding energy and a correct docking mode. Thirdly, to improve the predictability of the docking procedure in the general case, where only a single target protein structure is known, we evaluate an approach which takes possible protein side-chain conformational changes into account. Here, side...

  16. Molecular docking of intercalators and groove-binders to nucleic acids using Autodock and Surflex.

    Science.gov (United States)

    Holt, Patrick A; Chaires, Jonathan B; Trent, John O

    2008-08-01

    The molecular docking tools Autodock and Surflex accurately reproduce the crystallographic structures of a collection of small molecule ligands that have been shown to bind nucleic acids. Docking studies were performed with the intercalators daunorubicin and ellipticine and the minor groove binders distamycin and pentamidine. Autodock and Surflex dock daunorubicin and distamycin to their nucleic acid targets within a resolution of approximately 2 A, which is similar to the limit of the crystal structure resolution. However, for the top ranked poses, Autodock and Surflex both dock ellipticine into the correct site but in a different orientation compared to the crystal structure. This appears not only to be partly related to the symmetry of the target nucleic acid, as ellipticine is able to dock from either side of the intercalation site, but also due to the shape of the ligand and docking accuracy. Surflex docks pentamidine in a symmetrically equivalent orientation relative to the crystal structure, while Autodock was able to dock this molecule in the original orientation. In the case of the Surflex docking of pentamidine, the initial rmsd is misleading, given the symmetrical structure of pentamidine. Importantly, the ranking functions of both of these programs are able to return a top pose within approximately 2 A rmsd for daunorubicin, distamycin, and pentamidine and approximately 3 A rmsd for ellipticine compared to their respective crystal structures. Some docking challenges and potential pitfalls are explored, such as the importance of hydrogen treatment on ligands as well as the scoring functions of Autodock and Surflex. Overall for this set of complexes, Surflex is preferred over Autodock for virtual screening, as although the results are comparable, Surflex has significantly faster performance and ease of use under the optimal software conditions tested. These experiments show that molecular docking techniques can be successfully extended to include nucleic

  17. Accurate refinement of docked protein complexes using evolutionary information and deep learning.

    Science.gov (United States)

    Akbal-Delibas, Bahar; Farhoodi, Roshanak; Pomplun, Marc; Haspel, Nurit

    2016-06-01

    One of the major challenges for protein docking methods is to accurately discriminate native-like structures from false positives. Docking methods are often inaccurate and the results have to be refined and re-ranked to obtain native-like complexes and remove outliers. In a previous work, we introduced AccuRefiner, a machine learning based tool for refining protein-protein complexes. Given a docked complex, the refinement tool produces a small set of refined versions of the input complex, with lower root-mean-square-deviation (RMSD) of atomic positions with respect to the native structure. The method employs a unique ranking tool that accurately predicts the RMSD of docked complexes with respect to the native structure. In this work, we use a deep learning network with a similar set of features and five layers. We show that a properly trained deep learning network can accurately predict the RMSD of a docked complex with 1.40 Å error margin on average, by approximating the complex relationship between a wide set of scoring function terms and the RMSD of a docked structure. The network was trained on 35000 unbound docking complexes generated by RosettaDock. We tested our method on 25 different putative docked complexes produced also by RosettaDock for five proteins that were not included in the training data. The results demonstrate that the high accuracy of the ranking tool enables AccuRefiner to consistently choose the refinement candidates with lower RMSD values compared to the coarsely docked input structures.

  18. Discovery of peptide ligands through docking and virtual screening at nicotinic acetylcholine receptor homology models.

    Science.gov (United States)

    Leffler, Abba E; Kuryatov, Alexander; Zebroski, Henry A; Powell, Susan R; Filipenko, Petr; Hussein, Adel K; Gorson, Juliette; Heizmann, Anna; Lyskov, Sergey; Tsien, Richard W; Poget, Sébastien F; Nicke, Annette; Lindstrom, Jon; Rudy, Bernardo; Bonneau, Richard; Holford, Mandë

    2017-09-19

    Venom peptide toxins such as conotoxins play a critical role in the characterization of nicotinic acetylcholine receptor (nAChR) structure and function and have potential as nervous system therapeutics as well. However, the lack of solved structures of conotoxins bound to nAChRs and the large size of these peptides are barriers to their computational docking and design. We addressed these challenges in the context of the α4β2 nAChR, a widespread ligand-gated ion channel in the brain and a target for nicotine addiction therapy, and the 19-residue conotoxin α-GID that antagonizes it. We developed a docking algorithm, ToxDock, which used ensemble-docking and extensive conformational sampling to dock α-GID and its analogs to an α4β2 nAChR homology model. Experimental testing demonstrated that a virtual screen with ToxDock correctly identified three bioactive α-GID mutants (α-GID[A10V], α-GID[V13I], and α-GID[V13Y]) and one inactive variant (α-GID[A10Q]). Two mutants, α-GID[A10V] and α-GID[V13Y], had substantially reduced potency at the human α7 nAChR relative to α-GID, a desirable feature for α-GID analogs. The general usefulness of the docking algorithm was highlighted by redocking of peptide toxins to two ion channels and a binding protein in which the peptide toxins successfully reverted back to near-native crystallographic poses after being perturbed. Our results demonstrate that ToxDock can overcome two fundamental challenges of docking large toxin peptides to ion channel homology models, as exemplified by the α-GID:α4β2 nAChR complex, and is extendable to other toxin peptides and ion channels. ToxDock is freely available at rosie.rosettacommons.org/tox_dock.

  19. 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

  20. Spectroscopic and molecular docking studies on chlorambucil interaction with DNA.

    Science.gov (United States)

    Charak, Sonika; Shandilya, Manish; Tyagi, Gunjan; Mehrotra, Ranjana

    2012-11-01

    Chlorambucil (CMB) is an anticancer drug used for the treatment of variety of cancers. Structural and conformational changes associated with DNA after binding with CMB were explored using spectroscopic techniques to get insight into the mechanism of action of CMB at molecular level. Different molar ratios of CMB-DNA complex were prepared with constant DNA concentration under physiological conditions. FTIR spectroscopy, UV-visible spectroscopy, CD spectroscopy and molecular docking studies were employed to determine the binding site and binding constant of CMB with DNA. The results show CMB binds DNA through nitrogenous bases (thymine, guanine and cytosine). The binding constant was calculated to be 1.3 × 10³ M⁻¹, which suggests weak binding of CMB with DNA double helix. FTIR and CD results show that CMB do not disturb native B-conformation of DNA and it continues to remain in its B conformation even at higher concentrations of CMB. The molecular docking results are in corroboration with our experimental results and provides structural insight into the interaction site. Copyright © 2012 Elsevier B.V. All rights reserved.

  1. Docking-based classification models for exploratory toxicology ...

    Science.gov (United States)

    Background: Exploratory toxicology is a new emerging research area whose ultimate mission is that of protecting human health and environment from risks posed by chemicals. In this regard, the ethical and practical limitation of animal testing has encouraged the promotion of computational methods for the fast screening of huge collections of chemicals available on the market. Results: We derived 24 reliable docking-based classification models able to predict the estrogenic potential of a large collection of chemicals having high quality experimental data, kindly provided by the U.S. Environmental Protection Agency (EPA). The predictive power of our docking-based models was supported by values of AUC, EF1% (EFmax = 7.1), -LR (at SE = 0.75) and +LR (at SE = 0.25) ranging from 0.63 to 0.72, from 2.5 to 6.2, from 0.35 to 0.67 and from 2.05 to 9.84, respectively. In addition, external predictions were successfully made on some representative known estrogenic chemicals. Conclusion: We show how structure-based methods, widely applied to drug discovery programs, can be adapted to meet the conditions of the regulatory context. Importantly, these methods enable one to employ the physicochemical information contained in the X-ray solved biological target and to screen structurally-unrelated chemicals. Shows how structure-based methods, widely applied to drug discovery programs, can be adapted to meet the conditions of the regulatory context. Evaluation of 24 reliable dockin

  2. A "Dock and Lock" Approach to Preparation of Targeted Liposomes.

    Science.gov (United States)

    Backer, Marina V; Backer, Joseph M

    2017-01-01

    We developed a strategy for covalent coupling of targeting proteins to liposomes decorated with a standard adapter protein. This strategy is based on "dock and lock" interactions between two mutated fragments of human RNase I, a 1-15 aa fragment with the R4C amino acid substitution (Cys-tag), and a 21-127-aa fragment with the V118C substitution, (Ad-C). Upon binding to each other, Cys-tag and Ad-C spontaneously form a disulfide bond between the complementary 4C and 118C residues. Therefore, any targeting protein expressed with Cys-tag can be easily coupled to liposomes decorated with Ad-C. Here we describe the preparation of Ad-liposomes followed by coupling them to two Cys-tagged targeted proteins, human vascular endothelial growth factor expressed with N-terminal Cys-tag and a 254-aa long N-terminal fragment of anthrax lethal factor carrying C-terminal Cys-tag. Both proteins retain functional activity after coupling to Ad-C-decorated drug-loaded liposomes. We expect that our "dock and lock" strategy will open new opportunities for development of targeted therapeutic liposomes for research and clinical use.

  3. Docks and Piers, Port of Green Bay docks along the Fox River are complete, Published in 2008, 1:1200 (1in=100ft) scale, Brown County, WI.

    Data.gov (United States)

    NSGIC GIS Inventory (aka Ramona) — This Docks and Piers dataset, published at 1:1200 (1in=100ft) scale, was produced all or in part from Orthoimagery information as of 2008. It is described as 'Port...

  4. "Flexible Ligand Docking Studies of Matrix Metalloproteinase Inhibitors Using Lamarckian Genetic Algorithm "

    Directory of Open Access Journals (Sweden)

    lOrkideh Ghorban Dadrass

    2004-06-01

    Full Text Available As important therapeutic drug targets, matrix metalloproteinases (MMPs have recently attracted great interest in the search for potent and selective inhibitors using computer-aided molecular modelling and docking techniques. Availability of more than 60 X-ray crystal structures or NMR solution structures related to MMPs in Protein Data Bank (PDB of which more than half of them are in complex with various MMP inhibitors (MMPIs, provides a great opportunity for docking studies. In this study AutoDock 3.0.5 along with its LGA algorithm were used for automated flexible ligand docking of 32 MMPI-MMP complexes and docking accuracy and reliability of the estimated inhibition constants were evaluated. Twenty-six out of 32 docks had RMSD less than 3.0 Å which is considered as well-docked, however, for the most of the cases (15 out of 27, predicted pKi values were considerably overestimated in comparison to experimental values. To improve pKi prediction regarding MMPI-MMP complexes, inclusion of at least one such a complex in calibration of empirical free energy function in the next release of AutoDock is highly recommended.

  5. Economic Impacts from Spending by Community Dock Owners at Rough River Lake

    Science.gov (United States)

    2008-01-01

    community dock • Pomme de Terre Lake, community dock • Harry S. Truman Dam and Reservoir, marina • Raystown Lake, marina • Hartwell Lake, private...Rock Lake (Missouri/Arkansas), Rough River Lake (Kentucky), and Pomme de Terre Lake (Missouri). The ERB staff designed the survey, constructed the

  6. Attitudes of Dutch Pig Farmers Towards Tail Biting and Tail Docking

    NARCIS (Netherlands)

    Bracke, M.B.M.; Lauwere, de C.C.; Wind, S.M.M.; Zonderland, J.J.

    2013-01-01

    The Dutch policy objective of a fully sustainable livestock sector without mutilations by 2023 is not compatible with the routine practice of tail docking to minimize the risk of tail biting. To examine farmer attitudes towards docking, a telephone survey was conducted among 487 conventional and 33

  7. DOCK8 Deficiency : Clinical and Immunological Phenotype and Treatment Options - a Review of 136 Patients

    NARCIS (Netherlands)

    Aydin, Susanne E.; Kilic, Sara Sebnem; Aytekin, Caner; Kumar, Ashish; Porras, Oscar; Kainulainen, Leena; Kostyuchenko, Larysa; Genel, Ferah; Kutukculer, Necil; Karaca, Neslihan; Gonzalez-Granado, Luis; Abbott, Jordan; Al-Zahrani, Daifulah; Rezaei, Nima; Baz, Zeina; Thiel, Jens; Ehl, Stephan; Marodi, Laszlo; Orange, Jordan S.; Sawalle-Belohradsky, Julie; Keles, Sevgi; Holland, Steven M.; Sanal, Ozden; Ayvaz, Deniz C.; Tezcan, Ilhan; Al-Mousa, Hamoud; Alsum, Zobaida; Hawwari, Abbas; Metin, Ayse; Matthes-Martin, Susanne; Hoenig, Manfred; Schulz, Ansgar; Picard, Capucine; Barlogis, Vincent; Gennery, Andrew; Ifversen, Marianne; van Montfrans, JM; Kuijpers, Taco; Bredius, Robbert; Duckers, Gregor; Al-Herz, Waleed; Pai, Sung-Yun; Geha, Raif; Notheis, Gundula; Schwarze, Carl-Philipp; Tavil, Betul; Azik, Fatih; Bienemann, Kirsten; Grimbacher, Bodo; Heinz, Valerie; Gaspar, H. Bobby; Aydin, Roland; Hagl, Beate; Gathmann, Benjamin; Belohradsky, Bernd H.; Ochs, Hans D.; Chatila, Talal; Renner, Ellen D.; Su, Helen; Freeman, Alexandra F.; Engelhardt, Karin; Albert, Michael H.

    2015-01-01

    Mutations in DOCK8 result in autosomal recessive Hyper-IgE syndrome with combined immunodeficiency (CID). However, the natural course of disease, long-term prognosis, and optimal therapeutic management have not yet been clearly defined. In an international retrospective survey of patients with DOCK8

  8. PSOVina: The hybrid particle swarm optimization algorithm for protein-ligand docking.

    Science.gov (United States)

    Ng, Marcus C K; Fong, Simon; Siu, Shirley W I

    2015-06-01

    Protein-ligand docking is an essential step in modern drug discovery process. The challenge here is to accurately predict and efficiently optimize the position and orientation of ligands in the binding pocket of a target protein. In this paper, we present a new method called PSOVina which combined the particle swarm optimization (PSO) algorithm with the efficient Broyden-Fletcher-Goldfarb-Shannon (BFGS) local search method adopted in AutoDock Vina to tackle the conformational search problem in docking. Using a diverse data set of 201 protein-ligand complexes from the PDBbind database and a full set of ligands and decoys for four representative targets from the directory of useful decoys (DUD) virtual screening data set, we assessed the docking performance of PSOVina in comparison to the original Vina program. Our results showed that PSOVina achieves a remarkable execution time reduction of 51-60% without compromising the prediction accuracies in the docking and virtual screening experiments. This improvement in time efficiency makes PSOVina a better choice of a docking tool in large-scale protein-ligand docking applications. Our work lays the foundation for the future development of swarm-based algorithms in molecular docking programs. PSOVina is freely available to non-commercial users at http://cbbio.cis.umac.mo .

  9. Carborane Clusters in Computational Drug Design: A Comparative Docking Evaluation Using Autodock, Flexx, Glide and Surflex#

    Science.gov (United States)

    Tiwari, Rohit; Mahasenan, Kiran; Pavlovicz, Ryan; Li, Chenglong; Tjarks, Werner

    2009-01-01

    Compounds containing boron atoms play increasingly important roles in the therapy and diagnosis of various diseases, particularly cancer. However, computational drug design of boron-containing therapeutics and diagnostics is hampered by the fact that many software packages used for this purpose lack parameters for all or part of the various types of boron atoms. In the present paper, we describe simple and efficient strategies to overcome this problem, which are based on the replacement of the boron atom types with carbon atom types. The developed methods were validated by docking closo- and nido-carboranyl antifolates into the active site of a human dihydrofolate reductase (hDHFR) using AutoDock, Glide, FlexX, and Surflex and comparing the obtained docking poses with the poses of their counterparts in the original hDHFR-carboranyl antifolate crystal structures. Under optimized conditions, AutoDock and Glide were equally good in docking of the closo-carboranyl antifolates followed by Surflex and FlexX whereas Autodock, Glide, and Surflex proved to be comparably efficient in the docking of nido-carboranyl antifolates followed by FlexX. Differences in geometries and partial atom charges in the structures of the carboranyl antifolates resulting from different data sources and/or optimization methods did not impact the docking performances of AutoDock or Glide significantly. Scoring functions generated by all four programs were in accordance with experimental data. PMID:19449853

  10. jMetalCpp: optimizing molecular docking problems with a C++ metaheuristic framework.

    Science.gov (United States)

    López-Camacho, Esteban; García Godoy, María Jesús; Nebro, Antonio J; Aldana-Montes, José F

    2014-02-01

    Molecular docking is a method for structure-based drug design and structural molecular biology, which attempts to predict the position and orientation of a small molecule (ligand) in relation to a protein (receptor) to produce a stable complex with a minimum binding energy. One of the most widely used software packages for this purpose is AutoDock, which incorporates three metaheuristic techniques. We propose the integration of AutoDock with jMetalCpp, an optimization framework, thereby providing both single- and multi-objective algorithms that can be used to effectively solve docking problems. The resulting combination of AutoDock + jMetalCpp allows users of the former to easily use the metaheuristics provided by the latter. In this way, biologists have at their disposal a richer set of optimization techniques than those already provided in AutoDock. Moreover, designers of metaheuristic techniques can use molecular docking for case studies, which can lead to more efficient algorithms oriented to solving the target problems.  jMetalCpp software adapted to AutoDock is freely available as a C++ source code at http://khaos.uma.es/AutodockjMetal/.

  11. Attitudes of Dutch Pig Farmers Towards Tail Biting and Tail Docking

    NARCIS (Netherlands)

    Bracke, M.B.M.; Lauwere, de C.C.; Wind, S.M.M.; Zonderland, J.J.

    2013-01-01

    The Dutch policy objective of a fully sustainable livestock sector without mutilations by 2023 is not compatible with the routine practice of tail docking to minimize the risk of tail biting. To examine farmer attitudes towards docking, a telephone survey was conducted among 487 conventional and 33

  12. Molecular mechanism of serotonin transporter inhibition elucidated by a new flexible docking protocol.

    Science.gov (United States)

    Gabrielsen, Mari; Kurczab, Rafał; Ravna, Aina W; Kufareva, Irina; Abagyan, Ruben; Chilmonczyk, Zdzisław; Bojarski, Andrzej J; Sylte, Ingebrigt

    2012-01-01

    The two main groups of antidepressant drugs, the tricyclic antidepressants (TCAs) and the selective serotonin reuptake inhibitors (SSRIs), as well as several other compounds, act by inhibiting the serotonin transporter (SERT). However, the binding mode and molecular mechanism of inhibition in SERT are not fully understood. In this study, five classes of SERT inhibitors were docked into an outward-facing SERT homology model using a new 4D ensemble docking protocol. Unlike other docking protocols, where protein flexibility is not considered or is highly dependent on the ligand structure, flexibility was here obtained by side chain sampling of the amino acids of the binding pocket using biased probability Monte Carlo (BPMC) prior to docking. This resulted in the generation of multiple binding pocket conformations that the ligands were docked into. The docking results showed that the inhibitors were stacked between the aromatic amino acids of the extracellular gate (Y176, F335) presumably preventing its closure. The inhibitors interacted with amino acids in both the putative substrate binding site and more extracellular regions of the protein. A general structure-docking-based pharmacophore model was generated to explain binding of all studied classes of SERT inhibitors. Docking of a test set of actives and decoys furthermore showed that the outward-facing ensemble SERT homology model consistently and selectively scored the majority of active compounds above decoys, which indicates its usefulness in virtual screening.

  13. Extracellular domains play different roles in gap junction formation and docking compatibility.

    Science.gov (United States)

    Bai, Donglin; Wang, Ao Hong

    2014-02-15

    GJ (gap junction) channels mediate direct intercellular communication and play an important role in many physiological processes. Six connexins oligomerize to form a hemichannel and two hemichannels dock together end-to-end to form a GJ channel. Connexin extracellular domains (E1 and E2) have been shown to be important for the docking, but the molecular mechanisms behind the docking and formation of GJ channels are not clear. Recent developments in atomic GJ structure and functional studies on a series of connexin mutants revealed that E1 and E2 are likely to play different roles in the docking. Non-covalent interactions at the docking interface, including hydrogen bonds, are predicted to form between interdocked extracellular domains. Protein sequence alignment analysis on the docking compatible/incompatible connexins indicate that the E1 domain is important for the formation of the GJ channel and the E2 domain is important in the docking compatibility in heterotypic channels. Interestingly, the hydrogen-bond forming or equivalent residues in both E1 and E2 domains are mutational hot spots for connexin-linked human diseases. Understanding the molecular mechanisms of GJ docking can assist us to develop novel strategies in rescuing the disease-linked connexin mutants.

  14. Connecting in Space: Docking with the International Space Station. Educational Brief.

    Science.gov (United States)

    National Aeronautics and Space Administration, Washington, DC.

    This brief discusses the space shuttle and the docking procedures used with the International Space Station (ISS). Using this activity designed for grades 5-12, students demonstrate and identify procedures for determining the best method for completing the docking activity. Students will also study and identify Newton's Laws of Motion. A mockup…

  15. Epigallocatechin gallate affects glucose metabolism and increases fitness and lifespan in Drosophila melanogaster.

    Science.gov (United States)

    Wagner, Anika E; Piegholdt, Stefanie; Rabe, Doerte; Baenas, Nieves; Schloesser, Anke; Eggersdorfer, Manfred; Stocker, Achim; Rimbach, Gerald

    2015-10-13

    In this study, we tested whether a standardized epigallocatechin-3-gallate (EGCG) rich green tea extract (comprising > 90% EGCG) affects fitness and lifespan as well as parameters of glucose metabolism and energy homeostasis in the fruit fly, Drosophila melanogaster. Following the application of the green tea extract a significant increase in the mean lifespan (+ 3.3 days) and the 50% survival (+ 4.3 days) as well as improved fitness was detected. These effects went along an increased expression of Spargel, the homolog of mammalian PGC1α, which has been reported to affect lifespan in flies. Intriguingly, in flies, treatment with the green tea extract decreased glucose concentrations, which were accompanied by an inhibition of α-amylase and α-glucosidase activity. Computational docking analysis proved the potential of EGCG to dock into the substrate binding pocket of α-amylase and to a greater extent into α-glucosidase. Furthermore, we demonstrate that EGCG downregulates insulin-like peptide 5 and phosphoenolpyruvate carboxykinase, major regulators of glucose metabolism, as well as the Drosophila homolog of leptin, unpaired 2. We propose that a decrease in glucose metabolism in connection with an upregulated expression of Spargel contribute to the better fitness and the extended lifespan in EGCG-treated flies.

  16. Optimization of military garment fit

    NARCIS (Netherlands)

    Daanen, H.A.M.

    2014-01-01

    In the Dutch armed forces clothing sizes are determined using 3D body scans. To evaluate if the predicted size based on the scan analysis matches the best fit, 35 male soldiers fitted a combat jacket and combat pants. It was shown that the predicted jacket size was slightly too large. Therefore, an

  17. Reeling of tight fit pipe

    NARCIS (Netherlands)

    Focke, E.S.

    2007-01-01

    If it would be possible to install Tight Fit Pipe by means of reeling, it would be an attractive new option for the exploitation of offshore oil and gas fields containing corrosive hydrocarbons. Tight Fit Pipe is a mechanically bonded double walled pipe where a corrosion resistant alloy liner pipe

  18. Definitions of Health Terms: Fitness

    Science.gov (United States)

    ... this page: https://medlineplus.gov/definitions/fitnessdefinitions.html Definitions of Health Terms: Fitness To use the sharing features on ... the most of your exercise routine. Find more definitions on Fitness | General Health | Minerals | Nutrition | Vitamins Activity Count Physical activity is ...

  19. DockBench: An Integrated Informatic Platform Bridging the Gap between the Robust Validation of Docking Protocols and Virtual Screening Simulations

    Directory of Open Access Journals (Sweden)

    Alberto Cuzzolin

    2015-05-01

    Full Text Available Virtual screening (VS is a computational methodology that streamlines the drug discovery process by reducing costs and required resources through the in silico identification of potential drug candidates. Structure-based VS (SBVS exploits knowledge about the three-dimensional (3D structure of protein targets and uses the docking methodology as search engine for novel hits. The success of a SBVS campaign strongly depends upon the accuracy of the docking protocol used to select the candidates from large chemical libraries. The identification of suitable protocols is therefore a crucial step in the setup of SBVS experiments. Carrying out extensive benchmark studies, however, is usually a tangled task that requires users’ proficiency in handling different file formats and philosophies at the basis of the plethora of existing software packages. We present here DockBench 1.0, a platform available free of charge that eases the pipeline by automating the entire procedure, from docking benchmark to VS setups. In its current implementation, DockBench 1.0 handles seven docking software packages and offers the possibility to test up to seventeen different protocols. The main features of our platform are presented here and the results of the benchmark study of human Checkpoint kinase 1 (hChk1 are discussed as validation test.

  20. PaFlexPepDock: parallel ab-initio docking of peptides onto their receptors with full flexibility based on Rosetta.

    Directory of Open Access Journals (Sweden)

    Haiou Li

    Full Text Available Structural information related to protein-peptide complexes can be very useful for novel drug discovery and design. The computational docking of protein and peptide can supplement the structural information available on protein-peptide interactions explored by experimental ways. Protein-peptide docking of this paper can be described as three processes that occur in parallel: ab-initio peptide folding, peptide docking with its receptor, and refinement of some flexible areas of the receptor as the peptide is approaching. Several existing methods have been used to sample the degrees of freedom in the three processes, which are usually triggered in an organized sequential scheme. In this paper, we proposed a parallel approach that combines all the three processes during the docking of a folding peptide with a flexible receptor. This approach mimics the actual protein-peptide docking process in parallel way, and is expected to deliver better performance than sequential approaches. We used 22 unbound protein-peptide docking examples to evaluate our method. Our analysis of the results showed that the explicit refinement of the flexible areas of the receptor facilitated more accurate modeling of the interfaces of the complexes, while combining all of the moves in parallel helped the constructing of energy funnels for predictions.

  1. DockBench: An Integrated Informatic Platform Bridging the Gap between the Robust Validation of Docking Protocols and Virtual Screening Simulations.

    Science.gov (United States)

    Cuzzolin, Alberto; Sturlese, Mattia; Malvacio, Ivana; Ciancetta, Antonella; Moro, Stefano

    2015-05-29

    Virtual screening (VS) is a computational methodology that streamlines the drug discovery process by reducing costs and required resources through the in silico identification of potential drug candidates. Structure-based VS (SBVS) exploits knowledge about the three-dimensional (3D) structure of protein targets and uses the docking methodology as search engine for novel hits. The success of a SBVS campaign strongly depends upon the accuracy of the docking protocol used to select the candidates from large chemical libraries. The identification of suitable protocols is therefore a crucial step in the setup of SBVS experiments. Carrying out extensive benchmark studies, however, is usually a tangled task that requires users' proficiency in handling different file formats and philosophies at the basis of the plethora of existing software packages. We present here DockBench 1.0, a platform available free of charge that eases the pipeline by automating the entire procedure, from docking benchmark to VS setups. In its current implementation, DockBench 1.0 handles seven docking software packages and offers the possibility to test up to seventeen different protocols. The main features of our platform are presented here and the results of the benchmark study of human Checkpoint kinase 1 (hChk1) are discussed as validation test.

  2. A High Performance Cloud-Based Protein-Ligand Docking Prediction Algorithm

    Directory of Open Access Journals (Sweden)

    Jui-Le Chen

    2013-01-01

    Full Text Available The potential of predicting druggability for a particular disease by integrating biological and computer science technologies has witnessed success in recent years. Although the computer science technologies can be used to reduce the costs of the pharmaceutical research, the computation time of the structure-based protein-ligand docking prediction is still unsatisfied until now. Hence, in this paper, a novel docking prediction algorithm, named fast cloud-based protein-ligand docking prediction algorithm (FCPLDPA, is presented to accelerate the docking prediction algorithm. The proposed algorithm works by leveraging two high-performance operators: (1 the novel migration (information exchange operator is designed specially for cloud-based environments to reduce the computation time; (2 the efficient operator is aimed at filtering out the worst search directions. Our simulation results illustrate that the proposed method outperforms the other docking algorithms compared in this paper in terms of both the computation time and the quality of the end result.

  3. Developing a cross-docking network design model under uncertain environment

    Science.gov (United States)

    Seyedhoseini, S. M.; Rashid, Reza; Teimoury, E.

    2014-09-01

    Cross-docking is a logistic concept, which plays an important role in supply chain management by decreasing inventory holding, order packing, transportation costs and delivery time. Paying attention to these concerns, and importance of the congestion in cross docks, we present a mixed-integer model to optimize the location and design of cross docks at the same time to minimize the total transportation and operating costs. The model combines queuing theory for design aspects, for that matter, we consider a network of cross docks and customers where two M/M/c queues have been represented to describe operations of indoor trucks and outdoor trucks in each cross dock. To prepare a perfect illustration for performance of the model, a real case also has been examined that indicated effectiveness of the proposed model.

  4. Docking of B-cell epitope antigen to specific hepatitis B antibody

    Indian Academy of Sciences (India)

    R Rajkannan; E J Padma Malar

    2007-09-01

    The interaction of pres1 region of hepatitis B virus B-cell epitope antigen with specific hepatitis B neutralizing monoclonal antibody was examined by docking study. We modelled the 3D complex structure of B-cell epitope antigen residues CTTPAQGNSMFPSCCCTKPTDGNCY by homology modelling and docked it with the crystal structure of monoclonal antibody specific for the pres1 region of the hepatitis B virus. At the optimized docked conformation, the interactions between the amino acids of antigen and antibody were examined. It is found that the docked complex is stabilized by 59.3 kcal/mol. The stability of the docked antigen-antibody complex is due to hydrogen bonding and van der Waals interactions. The amino acids of the antigen and antibody responsible for the interaction were identified.

  5. Theoretical Studies on Docking Dynamics and Electronic Structure in Metalloprotein Complexes

    Science.gov (United States)

    Sugiyama, Ayumu; Nishikawa, Keigo; Yamamoto, Tetsunori; Purqon, Acep; Nishikawa, Kiyoshi; Nagao, Hidemi

    2007-12-01

    An investigating of docking structure and dynamics between metalloprotein is interested from the viewpoint of searching the function of protein. We investigate the cytochrome c551 and azurin complexes by three computational methods, quantum mechanical calculation, docking searching algorism and molecular dynamics simulation. At first we present the docking structure of the cytochrome c551-azurin complexes expected by ZDOCK searching algorism. Quantum chemical calculation is tools to estimate the charge distrubution around the active site for each protein and force field parameters. From these parameters, we reproduce the protein docking dynamics by molecular dynamics simulation. We analyze some physical properties of complex system such as binding free energy, dynamical cross correlation map, and so on. We discuss the docking stability and dynamical effect of the cytochrome c551-azurin complexes.

  6. Accessible high-throughput virtual screening molecular docking software for students and educators.

    Directory of Open Access Journals (Sweden)

    Reed B Jacob

    2012-05-01

    Full Text Available We survey low cost high-throughput virtual screening (HTVS computer programs for instructors who wish to demonstrate molecular docking in their courses. Since HTVS programs are a useful adjunct to the time consuming and expensive wet bench experiments necessary to discover new drug therapies, the topic of molecular docking is core to the instruction of biochemistry and molecular biology. The availability of HTVS programs coupled with decreasing costs and advances in computer hardware have made computational approaches to drug discovery possible at institutional and non-profit budgets. This paper focuses on HTVS programs with graphical user interfaces (GUIs that use either DOCK or AutoDock for the prediction of DockoMatic, PyRx, DockingServer, and MOLA since their utility has been proven by the research community, they are free or affordable, and the programs operate on a range of computer platforms.

  7. Two-dimensional PSD based automatic docking of self-reconfiguration modular exploration robot system

    Institute of Scientific and Technical Information of China (English)

    Zhang Liping; Ma Shugen; Li Bin; Zhang Zheng; Cao Binggang

    2007-01-01

    Based on the design of a docking mechanism, this paper thoroughly investigates the space automatic docking of self-reconfiguration modular exploration robot system (RMERS). The method that leads robot to achieve space docking by using two-dimensional PSD is put forward innovatively for the median size robot system. At the same time, in order to enlarge the detecting extension and the precision of PSD and reduce its dependence on lighting signal, the PSD was remade by increasing the optical device over its light-sensitive surface. The emission board and LED light scheduling were designed according to docking arithmetic, and the operating principle of docking process was analyzed based on these. The simulation experiments were carried out and their results are presented.

  8. DOCK8 Immune Deficiency as a Model for Primary Cytoskeletal Dysfunction

    Directory of Open Access Journals (Sweden)

    Sean A. McGhee

    2010-01-01

    Full Text Available DOCK8 deficiency is a newly described primary immune deficiency resulting in profound susceptibility to cutaneous viral infections, elevated IgE levels, and eosinophilia, but lacking in the skeletal manifestations commonly seen in hyper IgE syndrome, which it otherwise resembles. Although little is known about the DOCK8 protein, it resembles other atypical guanine exchange factors in the DOCK family, and is known to bind to CDC42. This suggests that a likely role for DOCK8 is in modulating signals that trigger cytoskeletal reorganization. As a result, DOCK8 may also be related to other immune deficiencies that involve the cytoskeleton and Rho GTPase signaling pathways, such as Wiskott-Aldrich syndrome and Rac2 deficiency.

  9. ProFit: Bayesian Profile Fitting of Galaxy Images

    CERN Document Server

    Robotham, A S G; Tobar, R; A,; Moffett,; Driver, S P

    2016-01-01

    We present ProFit, a new code for Bayesian two-dimensional photometric galaxy profile modelling. ProFit consists of a low-level C++ library (libprofit), accessible via a command-line interface and documented API, along with high-level R (ProFit) and Python (PyProFit) interfaces (available at github.com/ICRAR/ libprofit, github.com/ICRAR/ProFit, and github.com/ICRAR/pyprofit respectively). R ProFit is also available pre-built from CRAN, however this version will be slightly behind the latest GitHub version. libprofit offers fast and accurate two- dimensional integration for a useful number of profiles, including Sersic, Core-Sersic, broken-exponential, Ferrer, Moffat, empirical King, point-source and sky, with a simple mechanism for adding new profiles. We show detailed comparisons between libprofit and GALFIT. libprofit is both faster and more accurate than GALFIT at integrating the ubiquitous Serrsic profile for the most common values of the Serrsic index n (0.5 < n < 8). The high-level fitting code Pr...

  10. Female Fitness in the Blogosphere

    Directory of Open Access Journals (Sweden)

    Jesper Andreasson

    2013-07-01

    Full Text Available This article analyzes self-portrayals and gender constructions among female personal trainers within an Internet-mediated framework of fitness culture. The empirical material comes from a close examination of three strategically selected blogs. The result shows that some of the blogs clearly build upon what Connell calls emphasized femininity, as a means of legitimizing and constructing appropriate female fitness. In addition, there are also tendencies of sexualization in text and imagery present. As such, these self-representations are framed within a cultural history of body fitness dominated by stereotypical ways of perceiving masculinity and femininity. However, this does not capture the entire presentation of the self among the analyzed fitness bloggers. The blogs also point in the direction of ongoing negotiations and subversions of traditional gender norms. Among other things, they show how irony and humor are used as a means of questioning normative gender constructions while empowering female fitness and bodyliness.

  11. Fitness costs associated with insecticide resistance.

    Science.gov (United States)

    Kliot, Adi; Ghanim, Murad

    2012-11-01

    Insects are exposed to a variety of stress factors in their environment, and, in many cases for insect pests to agriculture, those factors include toxic chemical insecticides. Coping with the toxicity of insecticides can be costly and requires energy and resource allocation for adaptation and survival. Several behavioural, physiological and genetic mechanisms are used by insects to handle toxic insecticides, sometimes leading to resistance by constitutive overexpression of detoxification enzymes or inducing mutations in the target sites. Such actions are costly and may affect reproduction, impair dispersal ability and have several other effects on the insect's fitness. Fitness costs resulting from resistance to insecticides has been reported in many insects from different orders, and several examples are given in this mini-review.

  12. Assessing ligand efficiencies using template-based molecular docking and Tabu-clustering on tetrahydroimidazo-[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and -thione (TIBO) derivatives as HIV-1RT inhibitors

    Indian Academy of Sciences (India)

    Nitin S Sapre; Swagata Gupta; Neelima Sapre

    2008-07-01

    A template-based flexible docking simulation followed by `Tabu-clustering’ was performed on a series of 38 TIBO derivatives as HIV-1 reverse transcriptase (HIV-1 RT) inhibitors. Four different templates of the Cl-TIBO (1-REV) were created and used as reference templates for docking and aligning. On the basis of the optimal conformation of the ligands, when fitting to the template, the respective scoring functions were obtained; different ligand efficiencies were evaluated and analysed. Statistical modelling using artificial neural network (ANN: 2 = 0.922) and multiple linear regression method (MLR: 2 = 0.851) showed good correlation between the biological activity, binding affinity, and different ligand efficiencies of the compounds, which suggest the robustness of the template-based binding conformations of these inhibitors. Our studies suggest that, template-based docking followed by `Tabuclustering' will give a better alignment of inhibitors with respect to the crystal coordinates and enhance the docking efficiency. Also, our study indicates that scoring functions based on 3D symmetry analysis along with heavy atoms count serve as a valuable tool for estimating the efficiency of the ligands. Thus, this is a novel method based on heavy atoms count predicting the binding affinity of the TIBO group of inhibitors, so that their therapeutic utility can be enhanced.

  13. The focal adhesion-associated proteins DOCK5 and GIT2 comprise a rheostat in control of epithelial invasion

    DEFF Research Database (Denmark)

    Frank, Scott R; Köllmann, C P; van Lidth de Jeude, J F

    2017-01-01

    DOCK proteins are guanine nucleotide exchange factors for Rac and Cdc42 GTPases. DOCK1 is the founding member of the family and acts downstream of integrins via the canonical Crk-p130Cas complex to activate Rac GTPases in numerous contexts. In contrast, DOCK5, which possesses the greatest similar......:10.1038/onc.2016.345....

  14. AKLSQF - LEAST SQUARES CURVE FITTING

    Science.gov (United States)

    Kantak, A. V.

    1994-01-01

    The Least Squares Curve Fitting program, AKLSQF, computes the polynomial which will least square fit uniformly spaced data easily and efficiently. The program allows the user to specify the tolerable least squares error in the fitting or allows the user to specify the polynomial degree. In both cases AKLSQF returns the polynomial and the actual least squares fit error incurred in the operation. The data may be supplied to the routine either by direct keyboard entry or via a file. AKLSQF produces the least squares polynomial in two steps. First, the data points are least squares fitted using the orthogonal factorial polynomials. The result is then reduced to a regular polynomial using Sterling numbers of the first kind. If an error tolerance is specified, the program starts with a polynomial of degree 1 and computes the least squares fit error. The degree of the polynomial used for fitting is then increased successively until the error criterion specified by the user is met. At every step the polynomial as well as the least squares fitting error is printed to the screen. In general, the program can produce a curve fitting up to a 100 degree polynomial. All computations in the program are carried out under Double Precision format for real numbers and under long integer format for integers to provide the maximum accuracy possible. AKLSQF was written for an IBM PC X/AT or compatible using Microsoft's Quick Basic compiler. It has been implemented under DOS 3.2.1 using 23K of RAM. AKLSQF was developed in 1989.

  15. FACILE SYNTHESIS, DOCKING STUDIES AND ANTIOXIDANT ACTIVITY OF FGVR

    Directory of Open Access Journals (Sweden)

    Himaja M

    2011-08-01

    Full Text Available A rational designing of linear Tetrapeptide FGVR was done and was synthesized by solution phase peptide synthesis. The docking studies of designed linear tetrapeptide FGVR was carried out by using Schrodinger Software Solutions, USA. Qikprop results show the ligand FGVR mostly act as antihypertensive and anti coagulant properties. The solution phase synthesis of FGVR is carried out by using 1-Ethyl-3-(3-dimethylaminopropyl carbodiimide (EDC as coupling agents and N-Methyl morpholine (NMM as base. Structure of synthesized FGVR was confirmed by FTIR, 1H NMR and Mass spectral data, and evaluated for antioxidant property by using 1,1-diphenyl-2-picryl-hydrazil (DPPH. method and the synthesized peptides FGVR possess moderate antioxidant activity.

  16. SYNTHESIS, DOCKING STUDIES AND ANTIOXIDANT ACTIVITY OF TETRAPEPTIDE FGVY

    Directory of Open Access Journals (Sweden)

    Md. Abdulla

    2011-03-01

    Full Text Available A rational designing of linear Tetrapeptide FGVY was done and was synthesized by solution phase peptide synthesis. The docking studies of designed linear tetrapeptide FGVY was carried out by using Schrodinger Software Solutions, USA. Qikprop results show the ligand FGVY mostly act as antihypertensive and anti coagulant properties. The solution phase synthesis of FGVY is carried out by using Dicyclohexyl carbodiimide (DCC as coupling agents and triethyl amine as base. Structure of synthesized FGVY was confirmed by FTIR, 1H NMR and Mass spectral data, and evaluated for antioxidant property by using 1,1-diphenyl-2-picryl-hydrazil (DPPH. method and the synthesized peptides FGVY possess moderate antioxidant activity.

  17. Present Status And Tendencies In Docking Systems’ Development

    Directory of Open Access Journals (Sweden)

    Felski Andrzej

    2014-06-01

    Full Text Available The process of the ships docking, especially very large ships, is an very risky operation in confined and busy port waters. The similar difficult is the task to pass along any channel, river, strait or similar water road. The basic difficulty causes maneuvering with the great mass of the ship in situation of small space to maneuvers, the large inertia of the object and poor maneuvering properties at small speeds occurring in such circumstances. An additional factor, which make this task more difficult is the influence of the wind and the sea current on the hull of the inert ship as well as consequences of the limited visibility. The bad weather can cause the necessity to delay the maneuver. However this joins with heavy costs. An alternative is usage of systems supporting this process.

  18. Synthesis, Evaluation and Docking studies of Cholecalciferol Derivative

    Directory of Open Access Journals (Sweden)

    Sultanat

    2014-09-01

    Full Text Available Improved synthesis of 3b-acetoxy-9, 10-seco-19, 8(8-spiro-5(10, 6-cholestadiene has been reported after reacting cholecalciferol acetate with dimethylbutadiene by incorporating BF3·OEt2, SnCl4, ZnBr2, p-TsOH in toluene under Diels-Alder condition to get better yields. Agarose gel electrophoresis showed the potential in vitro DNA damaging nature while as the comet assay depicted the genotoxic nature by mobilizing the tail of the comet in lymphocytes. The molecular docking depicted the intercalation of steroid derivative with minor groove of the DNA molecule and in this configuration the phosphodiester bond of DNA stabilizes the acetoxy group. The bioactivity score and PASS software analysis confirmed the potential physicochemical features of the compound to act as active drug.

  19. Opas CrossFit -harjoitteluun

    OpenAIRE

    Knaapi, Matti

    2014-01-01

    CrossFit on laji, joka pyrkii edistämään terveyttä ja kuntoa. CrossFit saleja löytyy mailmalta yli 10 000 kappaletta. CrossFit -harjoittelussa pyritään parantamaan ihmisen kuntoa mahdollisimman laajalla skaalalla kehittämällä mm. voimaa, kestävyyttä, tarkkuutta, tasapainoa ja eri aineenvaihduntareittejä samanaikaisesti. Terveyden ja kunnon kehittämiseen kuuluu kuntoilun lisäksi myös muita osa-alueita. Ruokavalio ja kehonhuolto ovat tärkeitä osa-alueita hyvän kunnon saavuttamiseksi. Ruokav...

  20. Opas CrossFit -harjoitteluun

    OpenAIRE

    Knaapi, Matti

    2014-01-01

    CrossFit on laji, joka pyrkii edistämään terveyttä ja kuntoa. CrossFit saleja löytyy mailmalta yli 10 000 kappaletta. CrossFit -harjoittelussa pyritään parantamaan ihmisen kuntoa mahdollisimman laajalla skaalalla kehittämällä mm. voimaa, kestävyyttä, tarkkuutta, tasapainoa ja eri aineenvaihduntareittejä samanaikaisesti. Terveyden ja kunnon kehittämiseen kuuluu kuntoilun lisäksi myös muita osa-alueita. Ruokavalio ja kehonhuolto ovat tärkeitä osa-alueita hyvän kunnon saavuttamiseksi. Ruokav...