Energy minimization on manifolds for docking flexible molecules

PubMed Central

Mirzaei, Hanieh; Zarbafian, Shahrooz; Villar, Elizabeth; Mottarella, Scott; Beglov, Dmitri; Vajda, Sandor; Paschalidis, Ioannis Ch.; Vakili, Pirooz; Kozakov, Dima

2015-01-01

In this paper we extend a recently introduced rigid body minimization algorithm, defined on manifolds, to the problem of minimizing the energy of interacting flexible molecules. The goal is to integrate moving the ligand in six dimensional rotational/translational space with internal rotations around rotatable bonds within the two molecules. We show that adding rotational degrees of freedom to the rigid moves of the ligand results in an overall optimization search space that is a manifold to which our manifold optimization approach can be extended. The effectiveness of the method is shown for three different docking problems of increasing complexity. First we minimize the energy of fragment-size ligands with a single rotatable bond as part of a protein mapping method developed for the identification of binding hot spots. Second, we consider energy minimization for docking a flexible ligand to a rigid protein receptor, an approach frequently used in existing methods. In the third problem we account for flexibility in both the ligand and the receptor. Results show that minimization using the manifold optimization algorithm is substantially more efficient than minimization using a traditional all-atom optimization algorithm while producing solutions of comparable quality. In addition to the specific problems considered, the method is general enough to be used in a large class of applications such as docking multidomain proteins with flexible hinges. The code is available under open source license (at http://cluspro.bu.edu/Code/Code_Rigtree.tar), and with minimal effort can be incorporated into any molecular modeling package. PMID:26478722

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

PubMed Central

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

2016-01-01

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 inter-converting 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. PMID:26691274

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

PubMed

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. © 2015 Wiley Periodicals, Inc.

A web interface for easy flexible protein-protein docking with ATTRACT.

PubMed

de Vries, Sjoerd J; Schindler, Christina E M; Chauvot de Beauchêne, Isaure; Zacharias, Martin

2015-02-03

Protein-protein docking programs can give valuable insights into the structure of protein complexes in the absence of an experimental complex structure. Web interfaces can facilitate the use of docking programs by structural biologists. Here, we present an easy web interface for protein-protein docking with the ATTRACT program. While aimed at nonexpert users, the web interface still covers a considerable range of docking applications. The web interface supports systematic rigid-body protein docking with the ATTRACT coarse-grained force field, as well as various kinds of protein flexibility. The execution of a docking protocol takes up to a few hours on a standard desktop computer. Copyright © 2015 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Lessons in molecular recognition: the effects of ligand and protein flexibility on molecular docking accuracy.

PubMed

Erickson, Jon A; Jalaie, Mehran; Robertson, Daniel H; Lewis, Richard A; Vieth, Michal

2004-01-01

The key to success for computational tools used in structure-based drug design is the ability to accurately place or "dock" a ligand in the binding pocket of the target of interest. In this report we examine the effect of several factors on docking accuracy, including ligand and protein flexibility. To examine ligand flexibility in an unbiased fashion, a test set of 41 ligand-protein cocomplex X-ray structures were assembled that represent a diversity of size, flexibility, and polarity with respect to the ligands. Four docking algorithms, DOCK, FlexX, GOLD, and CDOCKER, were applied to the test set, and the results were examined in terms of the ability to reproduce X-ray ligand positions within 2.0A heavy atom root-mean-square deviation. Overall, each method performed well (>50% accuracy) but for all methods it was found that docking accuracy decreased substantially for ligands with eight or more rotatable bonds. Only CDOCKER was able to accurately dock most of those ligands with eight or more rotatable bonds (71% accuracy rate). A second test set of structures was gathered to examine how protein flexibility influences docking accuracy. CDOCKER was applied to X-ray structures of trypsin, thrombin, and HIV-1-protease, using protein structures bound to several ligands and also the unbound (apo) form. Docking experiments of each ligand to one "average" structure and to the apo form were carried out, and the results were compared to docking each ligand back to its originating structure. The results show that docking accuracy falls off dramatically if one uses an average or apo structure. In fact, it is shown that the drop in docking accuracy mirrors the degree to which the protein moves upon ligand binding.

Docking ligands into flexible and solvated macromolecules. 7. Impact of protein flexibility and water molecules on docking-based virtual screening accuracy.

PubMed

Therrien, Eric; Weill, Nathanael; Tomberg, Anna; Corbeil, Christopher R; Lee, Devin; Moitessier, Nicolas

2014-11-24

The use of predictive computational methods in the drug discovery process is in a state of continual growth. Over the last two decades, an increasingly large number of docking tools have been developed to identify hits or optimize lead molecules through in-silico screening of chemical libraries to proteins. In recent years, the focus has been on implementing protein flexibility and water molecules. Our efforts led to the development of Fitted first reported in 2007 and further developed since then. In this study, we wished to evaluate the impact of protein flexibility and occurrence of water molecules on the accuracy of the Fitted docking program to discriminate active compounds from inactive compounds in virtual screening (VS) campaigns. For this purpose, a total of 171 proteins cocrystallized with small molecules representing 40 unique enzymes and receptors as well as sets of known ligands and decoys were selected from the Protein Data Bank (PDB) and the Directory of Useful Decoys (DUD), respectively. This study revealed that implementing displaceable crystallographic or computationally placed particle water molecules and protein flexibility can improve the enrichment in active compounds. In addition, an informed decision based on library diversity or research objectives (hit discovery vs lead optimization) on which implementation to use may lead to significant improvements.

How to Deal with Low-Resolution Target Structures: Using SAR, Ensemble Docking, Hydropathic Analysis, and 3D-QSAR to Definitively Map the αβ-Tubulin Colchicine Site

PubMed Central

Da, Chenxiao; Mooberry, Susan L.; Gupton, John T.; Kellogg, Glen E.

2013-01-01

αβ-tubulin colchicine site inhibitors (CSIs) from four scaffolds that we previously tested for antiproliferative activity were modeled to better understand their effect on microtubules. Docking models, constructed by exploiting the SAR of a pyrrole subset and HINT scoring, guided ensemble docking of all 59 compounds. This conformation set and two variants having progressively less structure knowledge were subjected to CoMFA, CoMFA+HINT, and CoMSIA 3D-QSAR analyses. The CoMFA+HINT model (docked alignment) showed the best statistics: leave-one-out q2 of 0.616, r2 of 0.949 and r2pred (internal test set) of 0.755. An external (tested in other laboratories) collection of 24 CSIs from eight scaffolds were evaluated with the 3D-QSAR models, which correctly ranked their activity trends in 7/8 scaffolds for CoMFA+HINT (8/8 for CoMFA). The combination of SAR, ensemble docking, hydropathic analysis and 3D-QSAR provides an atomic-scale colchicine site model more consistent with a target structure resolution much higher than the ~3.6 Å available for αβ-tubulin. PMID:23961916

Impact of low-frequency hotspot mutation R282Q on the structure of p53 DNA-binding domain as revealed by crystallography at 1.54 Å resolution

PubMed Central

Tu, Chao; Tan, Yu-Hong; Shaw, Gary; Zhou, Zheng; Bai, Yawen; Luo, Ray; Ji, Xinhua

2008-01-01

Tumor suppressor p53 is a sequence-specific DNA-binding protein and its central DNA-binding domain (DBD) harbors six hotspots (Arg175, Gly245, Arg248, Arg249, Arg273 and Arg282) for human cancers. Here, the crystal structure of a low-frequency hotspot mutant, p53DBD(R282Q), is reported at 1.54 Å resolution together with the results of molecular-dynamics simulations on the basis of the structure. In addition to eliminating a salt bridge, the R282Q mutation has a significant impact on the properties of two DNA-binding loops (L1 and L3). The L1 loop is flexible in the wild type, but it is not flexible in the mutant. The L3 loop of the wild type is not flexible, whereas it assumes two conformations in the mutant. Molecular-dynamics simulations indicated that both conformations of the L3 loop are accessible under biological conditions. It is predicted that the elimination of the salt bridge and the inversion of the flexibility of L1 and L3 are directly or indirectly responsible for deactivating the tumor suppressor p53. PMID:18453682

A flexible docking scheme to explore the binding selectivity of PDZ domains.

PubMed

Gerek, Z Nevin; Ozkan, S Banu

2010-05-01

Modeling of protein binding site flexibility in molecular docking is still a challenging problem due to the large conformational space that needs sampling. Here, we propose a flexible receptor docking scheme: A dihedral restrained replica exchange molecular dynamics (REMD), where we incorporate the normal modes obtained by the Elastic Network Model (ENM) as dihedral restraints to speed up the search towards correct binding site conformations. To our knowledge, this is the first approach that uses ENM modes to bias REMD simulations towards binding induced fluctuations in docking studies. In our docking scheme, we first obtain the deformed structures of the unbound protein as initial conformations by moving along the binding fluctuation mode, and perform REMD using the ENM modes as dihedral restraints. Then, we generate an ensemble of multiple receptor conformations (MRCs) by clustering the lowest replica trajectory. Using ROSETTALIGAND, we dock ligands to the clustered conformations to predict the binding pose and affinity. We apply this method to postsynaptic density-95/Dlg/ZO-1 (PDZ) domains; whose dynamics govern their binding specificity. Our approach produces the lowest energy bound complexes with an average ligand root mean square deviation of 0.36 A. We further test our method on (i) homologs and (ii) mutant structures of PDZ where mutations alter the binding selectivity. In both cases, our approach succeeds to predict the correct pose and the affinity of binding peptides. Overall, with this approach, we generate an ensemble of MRCs that leads to predict the binding poses and specificities of a protein complex accurately.

A flexible docking scheme to explore the binding selectivity of PDZ domains

PubMed Central

Gerek, Z Nevin; Ozkan, S Banu

2010-01-01

Modeling of protein binding site flexibility in molecular docking is still a challenging problem due to the large conformational space that needs sampling. Here, we propose a flexible receptor docking scheme: A dihedral restrained replica exchange molecular dynamics (REMD), where we incorporate the normal modes obtained by the Elastic Network Model (ENM) as dihedral restraints to speed up the search towards correct binding site conformations. To our knowledge, this is the first approach that uses ENM modes to bias REMD simulations towards binding induced fluctuations in docking studies. In our docking scheme, we first obtain the deformed structures of the unbound protein as initial conformations by moving along the binding fluctuation mode, and perform REMD using the ENM modes as dihedral restraints. Then, we generate an ensemble of multiple receptor conformations (MRCs) by clustering the lowest replica trajectory. Using RosettaLigand, we dock ligands to the clustered conformations to predict the binding pose and affinity. We apply this method to postsynaptic density-95/Dlg/ZO-1 (PDZ) domains; whose dynamics govern their binding specificity. Our approach produces the lowest energy bound complexes with an average ligand root mean square deviation of 0.36 Å. We further test our method on (i) homologs and (ii) mutant structures of PDZ where mutations alter the binding selectivity. In both cases, our approach succeeds to predict the correct pose and the affinity of binding peptides. Overall, with this approach, we generate an ensemble of MRCs that leads to predict the binding poses and specificities of a protein complex accurately. PMID:20196074

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

PubMed

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.

Effect of the explicit flexibility of the InhA enzyme from Mycobacterium tuberculosis in molecular docking simulations.

PubMed

Cohen, Elisangela M L; Machado, Karina S; Cohen, Marcelo; de Souza, Osmar Norberto

2011-12-22

Protein/receptor explicit flexibility has recently become an important feature of molecular docking simulations. Taking the flexibility into account brings the docking simulation closer to the receptors' real behaviour in its natural environment. Several approaches have been developed to address this problem. Among them, modelling the full flexibility as an ensemble of snapshots derived from a molecular dynamics simulation (MD) of the receptor has proved very promising. Despite its potential, however, only a few studies have employed this method to probe its effect in molecular docking simulations. We hereby use ensembles of snapshots obtained from three different MD simulations of the InhA enzyme from M. tuberculosis (Mtb), the wild-type (InhA_wt), InhA_I16T, and InhA_I21V mutants to model their explicit flexibility, and to systematically explore their effect in docking simulations with three different InhA inhibitors, namely, ethionamide (ETH), triclosan (TCL), and pentacyano(isoniazid)ferrate(II) (PIF). The use of fully-flexible receptor (FFR) models of InhA_wt, InhA_I16T, and InhA_I21V mutants in docking simulation with the inhibitors ETH, TCL, and PIF revealed significant differences in the way they interact as compared to the rigid, InhA crystal structure (PDB ID: 1ENY). In the latter, only up to five receptor residues interact with the three different ligands. Conversely, in the FFR models this number grows up to an astonishing 80 different residues. The comparison between the rigid crystal structure and the FFR models showed that the inclusion of explicit flexibility, despite the limitations of the FFR models employed in this study, accounts in a substantial manner to the induced fit expected when a protein/receptor and ligand approach each other to interact in the most favourable manner. Protein/receptor explicit flexibility, or FFR models, represented as an ensemble of MD simulation snapshots, can lead to a more realistic representation of the induced fit

FitEM2EM—Tools for Low Resolution Study of Macromolecular Assembly and Dynamics

PubMed Central

Frankenstein, Ziv; Sperling, Joseph; Sperling, Ruth; Eisenstein, Miriam

2008-01-01

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. PMID:18974836

Automated Docking with Protein Flexibility in the Design of Femtomolar “Click Chemistry” Inhibitors of Acetylcholinesterase

PubMed Central

Morris, Garrett M.; Green, Luke G.; Radić, Zoran; Taylor, Palmer; Sharpless, K. Barry; Olson, Arthur J.; Grynszpan, Flavio

2013-01-01

The use of computer-aided structure-based drug design prior to synthesis has proven to be generally valuable in suggesting improved binding analogues of existing ligands.1 Here we describe the application of the program AutoDock2 to the design of a focused library that was used in the “click chemistry in-situ” generation of the most potent non-covalent inhibitor of the enzyme acetylcholinesterase (AChE) yet developed (Kd = ~100 fM).3 AutoDock version 3.0.5 has been widely distributed and successfully used to predict bound conformations of flexible ligands. Here, we also used a version of AutoDock which permits additional conformational flexibility in selected amino acid sidechains of the target protein. PMID:23451944

Recent progress and future directions in protein-protein docking.

PubMed

Ritchie, David W

2008-02-01

This article gives an overview of recent progress in protein-protein docking and it identifies several directions for future research. Recent results from the CAPRI blind docking experiments show that docking algorithms are steadily improving in both reliability and accuracy. Current docking algorithms employ a range of efficient search and scoring strategies, including e.g. fast Fourier transform correlations, geometric hashing, and Monte Carlo techniques. These approaches can often produce a relatively small list of up to a few thousand orientations, amongst which a near-native binding mode is often observed. However, despite the use of improved scoring functions which typically include models of desolvation, hydrophobicity, and electrostatics, current algorithms still have difficulty in identifying the correct solution from the list of false positives, or decoys. Nonetheless, significant progress is being made through better use of bioinformatics, biochemical, and biophysical information such as e.g. sequence conservation analysis, protein interaction databases, alanine scanning, and NMR residual dipolar coupling restraints to help identify key binding residues. Promising new approaches to incorporate models of protein flexibility during docking are being developed, including the use of molecular dynamics snapshots, rotameric and off-rotamer searches, internal coordinate mechanics, and principal component analysis based techniques. Some investigators now use explicit solvent models in their docking protocols. Many of these approaches can be computationally intensive, although new silicon chip technologies such as programmable graphics processor units are beginning to offer competitive alternatives to conventional high performance computer systems. As cryo-EM techniques improve apace, docking NMR and X-ray protein structures into low resolution EM density maps is helping to bridge the resolution gap between these complementary techniques. The use of symmetry and

wFReDoW: A Cloud-Based Web Environment to Handle Molecular Docking Simulations of a Fully Flexible Receptor Model

PubMed Central

De Paris, Renata; Frantz, Fábio A.; Norberto de Souza, Osmar; Ruiz, Duncan D. A.

2013-01-01

Molecular docking simulations of fully flexible protein receptor (FFR) models are coming of age. In our studies, an FFR model is represented by a series of different conformations derived from a molecular dynamic simulation trajectory of the receptor. For each conformation in the FFR model, a docking simulation is executed and analyzed. An important challenge is to perform virtual screening of millions of ligands using an FFR model in a sequential mode since it can become computationally very demanding. In this paper, we propose a cloud-based web environment, called web Flexible Receptor Docking Workflow (wFReDoW), which reduces the CPU time in the molecular docking simulations of FFR models to small molecules. It is based on the new workflow data pattern called self-adaptive multiple instances (P-SaMIs) and on a middleware built on Amazon EC2 instances. P-SaMI reduces the number of molecular docking simulations while the middleware speeds up the docking experiments using a High Performance Computing (HPC) environment on the cloud. The experimental results show a reduction in the total elapsed time of docking experiments and the quality of the new reduced receptor models produced by discarding the nonpromising conformations from an FFR model ruled by the P-SaMI data pattern. PMID:23691504

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

PubMed

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.

Recent advances in flexible low power cholesteric LCDs

NASA Astrophysics Data System (ADS)

Khan, Asad; Shiyanovskaya, Irina; Montbach, Erica; Schneider, Tod; Nicholson, Forrest; Miller, Nick; Marhefka, Duane; Ernst, Todd; Doane, J. W.

2006-05-01

Bistable reflective cholesteric displays are a liquid crystal display technology developed to fill a market need for very low power displays. Their unique look, high reflectivity, bistability, and simple structure make them an ideal flat panel display choice for handheld or other portable devices where small lightweight batteries with long lifetimes are important. Applications ranging from low resolution large signs to ultra high resolution electronic books can utilize cholesteric displays to not only benefit from the numerous features, but also create enabling features that other flat panel display technologies cannot. Flexible displays are the focus of attention of numerous research groups and corporations worldwide. Cholesteric displays have been demonstrated to be highly amenable to flexible substrates. This paper will review recent advances in flexible cholesteric displays including both phase separation and emulsification approaches to encapsulation. Both approaches provide unique benefits to various aspects of manufacturability, processes, flexibility, and conformability.

Metal Ion Dependence, Thermodynamics, and Kinetics for Intramolecular Docking of a GAAA Tetraloop and Receptor Connected by a Flexible Linker†

PubMed Central

Downey, Christopher D.; Fiore, Julie L.; Stoddard, Colby D.; Hodak, Jose H.; Nesbitt, David J.; Pardi, Arthur

2008-01-01

The GAAA tetraloop-receptor is a commonly occurring tertiary interaction motif in RNA. This motif usually occurs in combination with other tertiary interactions in complex RNA structures. Thus, it is difficult to measure directly the contribution that a single GAAA tetraloop-receptor interaction makes to the folding properties of an RNA. To investigate the kinetics and thermodynamics for the isolated interaction, a GAAA tetraloop domain and receptor domain were connected by a single-stranded A7 linker. Fluorescence resonance energy transfer (FRET) experiments were used to probe intramolecular docking of the GAAA tetraloop and receptor. Docking was induced using a variety of metal ions, where the charge of the ion was the most important factor in determining the concentration of the ion required to promote docking ([Co(NH3)63+] ≪ [Ca2+], [Mg2+], [Mn2+] ≪ [Na+], [K+]). Analysis of metal ion cooperativity yielded Hill coefficients of ≈ 2 for Na+- or K+-dependent docking versus ≈ 1 for the divalent ions and Co(NH3)63+. Ensemble stopped-flow FRET kinetic measurements yielded an apparent activation energy of 12.7 kcal/mol for GAAA tetraloop-receptor docking. RNA constructs with U7 and A14 single-stranded linkers were investigated by single-molecule and ensemble FRET techniques to determine how linker length and composition affect docking. These studies showed that the single-stranded region functions primarily as a flexible tether. Inhibition of docking by oligonucleotides complementary to the linker was also investigated. The influence of flexible versus rigid linkers on GAAA tetraloop-receptor docking is discussed. PMID:16533049

WScore: A Flexible and Accurate Treatment of Explicit Water Molecules in Ligand-Receptor Docking.

PubMed

Murphy, Robert B; Repasky, Matthew P; Greenwood, Jeremy R; Tubert-Brohman, Ivan; Jerome, Steven; Annabhimoju, Ramakrishna; Boyles, Nicholas A; Schmitz, Christopher D; Abel, Robert; Farid, Ramy; Friesner, Richard A

2016-05-12

We have developed a new methodology for protein-ligand docking and scoring, WScore, incorporating a flexible description of explicit water molecules. The locations and thermodynamics of the waters are derived from a WaterMap molecular dynamics simulation. The water structure is employed to provide an atomic level description of ligand and protein desolvation. WScore also contains a detailed model for localized ligand and protein strain energy and integrates an MM-GBSA scoring component with these terms to assess delocalized strain of the complex. Ensemble docking is used to take into account induced fit effects on the receptor conformation, and protein reorganization free energies are assigned via fitting to experimental data. The performance of the method is evaluated for pose prediction, rank ordering of self-docked complexes, and enrichment in virtual screening, using a large data set of PDB complexes and compared with the Glide SP and Glide XP models; significant improvements are obtained.

Spacecraft capture and docking system

NASA Technical Reports Server (NTRS)

Kong, Kinyuen (Inventor); Rafeek, Shaheed (Inventor); Myrick, Thomas (Inventor)

2001-01-01

A system for capturing and docking an active craft to a passive craft has a first docking assembly on the active craft with a first contact member and a spike projecting outwardly, a second docking assembly on the passive craft having a second contact member and a flexible net deployed over a target area with an open mesh for capturing the end of the spike of the active craft, and a motorized net drive for reeling in the net and active craft to mate with the passive craft's docking assembly. The spike has extendable tabs to allow it to become engaged with the net. The net's center is coupled to a net spool for reeling in. An alignment funnel has inclined walls to guide the net and captured spike towards the net spool. The passive craft's docking assembly includes circumferentially spaced preload wedges which are driven to lock the wedges against the contact member of the active craft. The active craft's docking assembly includes a rotary table and drive for rotating it to a predetermined angular alignment position, and mating connectors are then engaged with each other. The system may be used for docking spacecraft in zero or low-gravity environments, as well as for docking underwater vehicles, docking of ancillary craft to a mother craft in subsonic flight, in-flight refueling systems, etc.

Semi-automted analysis of high-resolution aerial images to quantify docks in Upper Midwest glacial lakes

USGS Publications Warehouse

Beck, Marcus W.; Vondracek, Bruce C.; Hatch, Lorin K.; Vinje, Jason

2013-01-01

Lake resources can be negatively affected by environmental stressors originating from multiple sources and different spatial scales. Shoreline development, in particular, can negatively affect lake resources through decline in habitat quality, physical disturbance, and impacts on fisheries. The development of remote sensing techniques that efficiently characterize shoreline development in a regional context could greatly improve management approaches for protecting and restoring lake resources. The goal of this study was to develop an approach using high-resolution aerial photographs to quantify and assess docks as indicators of shoreline development. First, we describe a dock analysis workflow that can be used to quantify the spatial extent of docks using aerial images. Our approach incorporates pixel-based classifiers with object-based techniques to effectively analyze high-resolution digital imagery. Second, we apply the analysis workflow to quantify docks for 4261 lakes managed by the Minnesota Department of Natural Resources. Overall accuracy of the analysis results was 98.4% (87.7% based on ) after manual post-processing. The analysis workflow was also 74% more efficient than the time required for manual digitization of docks. These analyses have immediate relevance for resource planning in Minnesota, whereas the dock analysis workflow could be used to quantify shoreline development in other regions with comparable imagery. These data can also be used to better understand the effects of shoreline development on aquatic resources and to evaluate the effects of shoreline development relative to other stressors.

Flexible docking of a ligand peptide to a receptor protein by multicanonical molecular dynamics simulation

NASA Astrophysics Data System (ADS)

Nakajima, Nobuyuki; Higo, Junichi; Kidera, Akinori; Nakamura, Haruki

1997-10-01

A new method for flexible docking by multicanonical molecular dynamics simulation is presented. The method was applied to the binding of a short proline-rich peptide to a Src homology 3 (SH3) domain. The peptide and the side-chains at the ligand binding cleft of SH3 were completely flexible and the large number of possible conformations and dispositions of the peptide were sampled. The reweighted canonical resemble at 300 K resulted in only a few predominant binding modes, one of which was similar to the complex crystal structure. The inverted peptide orientation was also observed in the other binding modes.

Atomic resolution model of the antibody Fc interaction with the complement C1q component.

PubMed

Schneider, Sebastian; Zacharias, Martin

2012-05-01

The globular C1q heterotrimer is a subunit of the C1 complement factor. Binding of the C1q subunit to the constant (Fc) part of antibody molecules is a first step and key event of complement activation. Although three-dimensional structures of C1q and antibody Fc subunits have been determined experimentally no atomic resolution structure of the C1q-Fc complex is known so far. Based on systematic protein-protein docking searches and Molecular Dynamics simulations a structural model of the C1q-IgG1-Fc-binding geometry has been obtained. The structural model is compatible with available experimental data on the interaction between the two partner proteins. It predicts a binding geometry that involves mainly the B-subunit of the C1q-trimer and both subunits of the IgG1-Fc-dimer with small conformational adjustments with respect to the unbound partners to achieve high surface complementarity. In addition to several charge-charge and polar contacts in the rim region of the interface it also involves nonpolar contacts between the two proteins and is compatible with the carbohydrate moiety of the Fc subunit. The model for the complex structure provides a working model for rationalizing available biochemical data on this important interaction and can form the basis for the design of Fc variants with a greater capacity to activate the complement system for example on binding to cancer cells or other target structures. Copyright © 2012 Elsevier Ltd. All rights reserved.

Assessing an ensemble docking-based virtual screening strategy for kinase targets by considering protein flexibility.

PubMed

Tian, Sheng; Sun, Huiyong; Pan, Peichen; Li, Dan; Zhen, Xuechu; Li, Youyong; Hou, Tingjun

2014-10-27

In this study, to accommodate receptor flexibility, based on multiple receptor conformations, a novel ensemble docking protocol was developed by using the naïve Bayesian classification technique, and it was evaluated in terms of the prediction accuracy of docking-based virtual screening (VS) of three important targets in the kinase family: ALK, CDK2, and VEGFR2. First, for each target, the representative crystal structures were selected by structural clustering, and the capability of molecular docking based on each representative structure to discriminate inhibitors from non-inhibitors was examined. Then, for each target, 50 ns molecular dynamics (MD) simulations were carried out to generate an ensemble of the conformations, and multiple representative structures/snapshots were extracted from each MD trajectory by structural clustering. On average, the representative crystal structures outperform the representative structures extracted from MD simulations in terms of the capabilities to separate inhibitors from non-inhibitors. Finally, by using the naïve Bayesian classification technique, an integrated VS strategy was developed to combine the prediction results of molecular docking based on different representative conformations chosen from crystal structures and MD trajectories. It was encouraging to observe that the integrated VS strategy yields better performance than the docking-based VS based on any single rigid conformation. This novel protocol may provide an improvement over existing strategies to search for more diverse and promising active compounds for a target of interest.

Accounting for Intraligand Interactions in Flexible Ligand Docking with a PMF-Based Scoring Function.

PubMed

Lizunov, A Y; Gonchar, A L; Zaitseva, N I; Zosimov, V V

2015-10-26

We analyzed the frequency with which intraligand contacts occurred in a set of 1300 protein-ligand complexes [ Plewczynski et al. J. Comput. Chem. 2011 , 32 , 742 - 755 .]. Our analysis showed that flexible ligands often form intraligand hydrophobic contacts, while intraligand hydrogen bonds are rare. The test set was also thoroughly investigated and classified. We suggest a universal method for enhancement of a scoring function based on a potential of mean force (PMF-based score) by adding a term accounting for intraligand interactions. The method was implemented via in-house developed program, utilizing an Algo_score scoring function [ Ramensky et al. Proteins: Struct., Funct., Genet. 2007 , 69 , 349 - 357 .] based on the Tarasov-Muryshev PMF [ Muryshev et al. J. Comput.-Aided Mol. Des. 2003 , 17 , 597 - 605 .]. The enhancement of the scoring function was shown to significantly improve the docking and scoring quality for flexible ligands in the test set of 1300 protein-ligand complexes [ Plewczynski et al. J. Comput. Chem. 2011 , 32 , 742 - 755 .]. We then investigated the correlation of the docking results with two parameters of intraligand interactions estimation. These parameters are the weight of intraligand interactions and the minimum number of bonds between the ligand atoms required to take their interaction into account.

Efficient method for high-throughput virtual screening based on flexible docking: discovery of novel acetylcholinesterase inhibitors.

PubMed

Mizutani, Miho Yamada; Itai, Akiko

2004-09-23

A method of easily finding ligands, with a variety of core structures, for a given target macromolecule would greatly contribute to the rapid identification of novel lead compounds for drug development. We have developed an efficient method for discovering ligand candidates from a number of flexible compounds included in databases, when the three-dimensional (3D) structure of the drug target is available. The method, named ADAM&EVE, makes use of our automated docking method ADAM, which has already been reported. Like ADAM, ADAM&EVE takes account of the flexibility of each molecule in databases, by exploring the conformational space fully and continuously. Database screening has been made much faster than with ADAM through the tuning of parameters, so that computational screening of several hundred thousand compounds is possible in a practical time. Promising ligand candidates can be selected according to various criteria based on the docking results and characteristics of compounds. Furthermore, we have developed a new tool, EVE-MAKE, for automatically preparing the additional compound data necessary for flexible docking calculation, prior to 3D database screening. Among several successful cases of lead discovery by ADAM&EVE, the finding of novel acetylcholinesterase (AChE) inhibitors is presented here. We performed a virtual screening of about 160 000 commercially available compounds against the X-ray crystallographic structure of AChE. Among 114 compounds that could be purchased and assayed, 35 molecules with various core structures showed inhibitory activities with IC(50) values less than 100 microM. Thirteen compounds had IC(50) values between 0.5 and 10 microM, and almost all their core structures are very different from those of known inhibitors. The results demonstrate the effectiveness and validity of the ADAM&EVE approach and provide a starting point for development of novel drugs to treat Alzheimer's disease.

PTools: an opensource molecular docking library.

PubMed

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.

Surflex-Dock: Docking benchmarks and real-world application

NASA Astrophysics Data System (ADS)

Spitzer, Russell; Jain, Ajay N.

2012-06-01

Benchmarks for molecular docking have historically focused on re-docking the cognate ligand of a well-determined protein-ligand complex to measure geometric pose prediction accuracy, and measurement of virtual screening performance has been focused on increasingly large and diverse sets of target protein structures, cognate ligands, and various types of decoy sets. Here, pose prediction is reported on the Astex Diverse set of 85 protein ligand complexes, and virtual screening performance is reported on the DUD set of 40 protein targets. In both cases, prepared structures of targets and ligands were provided by symposium organizers. The re-prepared data sets yielded results not significantly different than previous reports of Surflex-Dock on the two benchmarks. Minor changes to protein coordinates resulting from complex pre-optimization had large effects on observed performance, highlighting the limitations of cognate ligand re-docking for pose prediction assessment. Docking protocols developed for cross-docking, which address protein flexibility and produce discrete families of predicted poses, produced substantially better performance for pose prediction. Performance on virtual screening performance was shown to benefit by employing and combining multiple screening methods: docking, 2D molecular similarity, and 3D molecular similarity. In addition, use of multiple protein conformations significantly improved screening enrichment.

Fully Flexible Docking of Medium Sized Ligand Libraries with RosettaLigand

PubMed Central

DeLuca, Samuel; Khar, Karen; Meiler, Jens

2015-01-01

RosettaLigand has been successfully used to predict binding poses in protein-small molecule complexes. However, the RosettaLigand docking protocol is comparatively slow in identifying an initial starting pose for the small molecule (ligand) making it unfeasible for use in virtual High Throughput Screening (vHTS). To overcome this limitation, we developed a new sampling approach for placing the ligand in the protein binding site during the initial ‘low-resolution’ docking step. It combines the translational and rotational adjustments to the ligand pose in a single transformation step. The new algorithm is both more accurate and more time-efficient. The docking success rate is improved by 10–15% in a benchmark set of 43 protein/ligand complexes, reducing the number of models that typically need to be generated from 1000 to 150. The average time to generate a model is reduced from 50 seconds to 10 seconds. As a result we observe an effective 30-fold speed increase, making RosettaLigand appropriate for docking medium sized ligand libraries. We demonstrate that this improved initial placement of the ligand is critical for successful prediction of an accurate binding position in the ‘high-resolution’ full atom refinement step. PMID:26207742

PTools: an opensource molecular docking library

PubMed Central

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

2009-01-01

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. PMID:19409097

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

PubMed

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

2011-04-29

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

Rosetta FlexPepDock ab-initio: Simultaneous Folding, Docking and Refinement of Peptides onto Their Receptors

PubMed Central

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

2011-01-01

Flexible peptides that fold upon binding to another protein molecule mediate a large number of regulatory interactions in the living cell and may provide highly specific recognition modules. We present Rosetta FlexPepDock ab-initio, a protocol for simultaneous docking and de-novo folding of peptides, starting from an approximate specification of the peptide binding site. Using the Rosetta fragments library and a coarse-grained structural representation of the peptide and the receptor, FlexPepDock ab-initio samples efficiently and simultaneously the space of possible peptide backbone conformations and rigid-body orientations over the receptor surface of a given binding site. The subsequent all-atom refinement of the coarse-grained models includes full side-chain modeling of both the receptor and the peptide, resulting in high-resolution models in which key side-chain interactions are recapitulated. The protocol was applied to a benchmark in which peptides were modeled over receptors in either their bound backbone conformations or in their free, unbound form. Near-native peptide conformations were identified in 18/26 of the bound cases and 7/14 of the unbound cases. The protocol performs well on peptides from various classes of secondary structures, including coiled peptides with unusual turns and kinks. The results presented here significantly extend the scope of state-of-the-art methods for high-resolution peptide modeling, which can now be applied to a wide variety of peptide-protein interactions where no prior information about the peptide backbone conformation is available, enabling detailed structure-based studies and manipulation of those interactions. PMID:21572516

Encompassing receptor flexibility in virtual screening using ensemble docking-based hybrid QSAR: discovery of novel phytochemicals for BACE1 inhibition.

PubMed

Chakraborty, Sandipan; Ramachandran, Balaji; Basu, Soumalee

2014-10-01

Mimicking receptor flexibility during receptor-ligand binding is a challenging task in computational drug design since it is associated with a large increase in the conformational search space. In the present study, we have devised an in silico design strategy incorporating receptor flexibility in virtual screening to identify potential lead compounds as inhibitors for flexible proteins. We have considered BACE1 (β-secretase), a key target protease from a therapeutic perspective for Alzheimer's disease, as the highly flexible receptor. The protein undergoes significant conformational transitions from open to closed form upon ligand binding, which makes it a difficult target for inhibitor design. We have designed a hybrid structure-activity model containing both ligand based descriptors and energetic descriptors obtained from molecular docking based on a dataset of structurally diverse BACE1 inhibitors. An ensemble of receptor conformations have been used in the docking study, further improving the prediction ability of the model. The designed model that shows significant prediction ability judged by several statistical parameters has been used to screen an in house developed 3-D structural library of 731 phytochemicals. 24 highly potent, novel BACE1 inhibitors with predicted activity (Ki) ≤ 50 nM have been identified. Detailed analysis reveals pharmacophoric features of these novel inhibitors required to inhibit BACE1.

Energy scaling of passively Q-switched lasers In the Mj-range

NASA Astrophysics Data System (ADS)

Neumann, J.; Huss, R.; Kolleck, C.; Kracht, Dietmar

2017-11-01

Q-switched lasers systems with ns pulse duration and energies ranging from 1 to more than 100mJ are utilized for many spaceborne applications such as altimetry of planets and moons. Furthermore, Q-switched lasers can be used for distance measurements during docking and landing manoeuvres. To keep the diameter of the beam small over a large distance and to consequently achieve a good lateral resolution, a good beam propagation factor M² is required. Moreover, Q-switched lasers can be used directly on the planetary surface for exploration by laser-induced breakdown spectroscopy or laser desorption mass spectrometry.

Shape Complementarity of Protein-Protein Complexes at Multiple Resolutions

PubMed Central

Zhang, Qing; Sanner, Michel; Olson, Arthur J.

2010-01-01

structures in their unbound conformation. The histograms calculated for the bound complex structures demonstrate that medium resolution smoothing (blobbyness=−0.9) can reproduce about 88% of the shape complementarity of atomic resolution surfaces. Complexes formed from the free component structures show a partial loss of shape complementarity (more overlaps and gaps) with the atomic resolution surfaces. For surfaces smoothed to low resolution (blobbyness=−0.3), we find more consistency of shape complementarity between the complexed and free cases. To further reduce bad contacts without significantly impacting the good contacts we introduce another blurred surface, in which the Gaussian densities of flexible atoms are reduced. From these results we discuss the use of shape complementarity in protein-protein docking. PMID:18837463

Flexible $$I_{Q}\\!\\!-\\!\\!V$$ Scheme of a DFIG for Rapid Voltage Regulation of a Wind Power Plant

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Jinho; Muljadi, Eduard; Park, Jung -Wook

This paper proposes a flexible reactive current-to-voltage (I Q-V) scheme of a doubly-fed induction generator (DFIG) for the rapid voltage regulation of a wind power plant (WPP). In the proposed scheme, the WPP controller dispatches different voltage set points to the DFIGs depending on their rotor voltage margins. The DFIGs inject different reactive power with the flexible I Q-V schemes implemented in the rotor-side and grid-side converters. The I Q-V characteristic, which consists of the gain and width of a linear band and I Q capability, varies with time depending on the I Q capability of the converters and amore » voltage dip at the point of interconnection (POI). To increase the I Q capability during a fault, the active current is reduced in proportion to a voltage dip. If the I Q capability and/or the POI voltage dip are large, the I Q-V gain is set to be high, thereby providing rapid voltage regulation. To avoid an overvoltage after the fault clearance, a rapid I Q reduction scheme is implemented in the WPP and DFIG controllers. The performance of the proposed flexible scheme was verified under scenarios with various disturbances. In conclusion, the proposed scheme can help increase wind power penetration without jeopardizing voltage stability.« less

Flexible $$I_{Q}\\!\\!-\\!\\!V$$ Scheme of a DFIG for Rapid Voltage Regulation of a Wind Power Plant

DOE PAGES

Kim, Jinho; Muljadi, Eduard; Park, Jung -Wook; ...

2017-04-28

This paper proposes a flexible reactive current-to-voltage (I Q-V) scheme of a doubly-fed induction generator (DFIG) for the rapid voltage regulation of a wind power plant (WPP). In the proposed scheme, the WPP controller dispatches different voltage set points to the DFIGs depending on their rotor voltage margins. The DFIGs inject different reactive power with the flexible I Q-V schemes implemented in the rotor-side and grid-side converters. The I Q-V characteristic, which consists of the gain and width of a linear band and I Q capability, varies with time depending on the I Q capability of the converters and amore » voltage dip at the point of interconnection (POI). To increase the I Q capability during a fault, the active current is reduced in proportion to a voltage dip. If the I Q capability and/or the POI voltage dip are large, the I Q-V gain is set to be high, thereby providing rapid voltage regulation. To avoid an overvoltage after the fault clearance, a rapid I Q reduction scheme is implemented in the WPP and DFIG controllers. The performance of the proposed flexible scheme was verified under scenarios with various disturbances. In conclusion, the proposed scheme can help increase wind power penetration without jeopardizing voltage stability.« less

International Low Impact Docking System (iLIDS) Project Technical Requirements Specification, Revision F

NASA Technical Reports Server (NTRS)

Lewis, James L.

2011-01-01

The NASA Docking System (NDS) is NASA's implementation for the emerging International Docking System Standard (IDSS) using low impact docking technology. The NASA Docking System Project (NDSP) is the International Space Station (ISS) Program's project to produce the NDS, Common Docking Adapter (CDA) and Docking Hub. The NDS design evolved from the Low Impact Docking System (LIDS). The acronym international Low Impact Docking System (iLIDS) is also used to describe this system as well as the Government Furnished Equipment (GFE) project designing the NDS for the NDSP. NDS and iLIDS may be used interchangeability. This document will use the acronym iLIDS. Some of the heritage documentation and implementations (e.g., software command names, requirement identification (ID), figures, etc.) used on NDS will continue to use the LIDS acronym. This specification defines the technical requirements for the iLIDS GFE delivered to the NDSP by the iLIDS project. This document contains requirements for two iLIDS configurations, SEZ29101800-301 and SEZ29101800-302. Requirements with the statement, iLIDS shall, are for all configurations. Examples of requirements that are unique to a single configuration may be identified as iLIDS (-301) shall or iLIDS (-302) shall. Furthermore, to allow a requirement to encompass all configurations with an exception, the requirement may be designated as iLIDS (excluding -302) shall. Verification requirements for the iLIDS project are identified in the Verification Matrix (VM) provided in the iLIDS Verification and Validation Document, JSC-63966. The following definitions differentiate between requirements and other statements: Shall: This is the only verb used for the binding requirements. Should/May: These verbs are used for stating non-mandatory goals. Will: This verb is used for stating facts or declaration of purpose. A Definition of Terms table is provided in Appendix B to define those terms with specific tailored uses in this document.

FlexAID: Revisiting Docking on Non-Native-Complex Structures.

PubMed

Gaudreault, Francis; Najmanovich, Rafael J

2015-07-27

Small-molecule protein docking is an essential tool in drug design and to understand molecular recognition. In the present work we introduce FlexAID, a small-molecule docking algorithm that accounts for target side-chain flexibility and utilizes a soft scoring function, i.e. one that is not highly dependent on specific geometric criteria, based on surface complementarity. The pairwise energy parameters were derived from a large dataset of true positive poses and negative decoys from the PDBbind database through an iterative process using Monte Carlo simulations. The prediction of binding poses is tested using the widely used Astex dataset as well as the HAP2 dataset, while performance in virtual screening is evaluated using a subset of the DUD dataset. We compare FlexAID to AutoDock Vina, FlexX, and rDock in an extensive number of scenarios to understand the strengths and limitations of the different programs as well as to reported results for Glide, GOLD, and DOCK6 where applicable. The most relevant among these scenarios is that of docking on flexible non-native-complex structures where as is the case in reality, the target conformation in the bound form is not known a priori. We demonstrate that FlexAID, unlike other programs, is robust against increasing structural variability. FlexAID obtains equivalent sampling success as GOLD and performs better than AutoDock Vina or FlexX in all scenarios against non-native-complex structures. FlexAID is better than rDock when there is at least one critical side-chain movement required upon ligand binding. In virtual screening, FlexAID results are lower on average than those of AutoDock Vina and rDock. The higher accuracy in flexible targets where critical movements are required, intuitive PyMOL-integrated graphical user interface and free source code as well as precompiled executables for Windows, Linux, and Mac OS make FlexAID a welcome addition to the arsenal of existing small-molecule protein docking methods.

q-Space Upsampling Using x-q Space Regularization.

PubMed

Chen, Geng; Dong, Bin; Zhang, Yong; Shen, Dinggang; Yap, Pew-Thian

2017-09-01

Acquisition time in diffusion MRI increases with the number of diffusion-weighted images that need to be acquired. Particularly in clinical settings, scan time is limited and only a sparse coverage of the vast q -space is possible. In this paper, we show how non-local self-similar information in the x - q space of diffusion MRI data can be harnessed for q -space upsampling. More specifically, we establish the relationships between signal measurements in x - q space using a patch matching mechanism that caters to unstructured data. We then encode these relationships in a graph and use it to regularize an inverse problem associated with recovering a high q -space resolution dataset from its low-resolution counterpart. Experimental results indicate that the high-resolution datasets reconstructed using the proposed method exhibit greater quality, both quantitatively and qualitatively, than those obtained using conventional methods, such as interpolation using spherical radial basis functions (SRBFs).

A Unified Conformational Selection and Induced Fit Approach to Protein-Peptide Docking

PubMed Central

Trellet, Mikael; Melquiond, Adrien S. J.; Bonvin, Alexandre M. J. J.

2013-01-01

Protein-peptide interactions are vital for the cell. They mediate, inhibit or serve as structural components in nearly 40% of all macromolecular interactions, and are often associated with diseases, making them interesting leads for protein drug design. In recent years, large-scale technologies have enabled exhaustive studies on the peptide recognition preferences for a number of peptide-binding domain families. Yet, the paucity of data regarding their molecular binding mechanisms together with their inherent flexibility makes the structural prediction of protein-peptide interactions very challenging. This leaves flexible docking as one of the few amenable computational techniques to model these complexes. We present here an ensemble, flexible protein-peptide docking protocol that combines conformational selection and induced fit mechanisms. Starting from an ensemble of three peptide conformations (extended, a-helix, polyproline-II), flexible docking with HADDOCK generates 79.4% of high quality models for bound/unbound and 69.4% for unbound/unbound docking when tested against the largest protein-peptide complexes benchmark dataset available to date. Conformational selection at the rigid-body docking stage successfully recovers the most relevant conformation for a given protein-peptide complex and the subsequent flexible refinement further improves the interface by up to 4.5 Å interface RMSD. Cluster-based scoring of the models results in a selection of near-native solutions in the top three for ∼75% of the successfully predicted cases. This unified conformational selection and induced fit approach to protein-peptide docking should open the route to the modeling of challenging systems such as disorder-order transitions taking place upon binding, significantly expanding the applicability limit of biomolecular interaction modeling by docking. PMID:23516555

A unified conformational selection and induced fit approach to protein-peptide docking.

PubMed

Trellet, Mikael; Melquiond, Adrien S J; Bonvin, Alexandre M J J

2013-01-01

Protein-peptide interactions are vital for the cell. They mediate, inhibit or serve as structural components in nearly 40% of all macromolecular interactions, and are often associated with diseases, making them interesting leads for protein drug design. In recent years, large-scale technologies have enabled exhaustive studies on the peptide recognition preferences for a number of peptide-binding domain families. Yet, the paucity of data regarding their molecular binding mechanisms together with their inherent flexibility makes the structural prediction of protein-peptide interactions very challenging. This leaves flexible docking as one of the few amenable computational techniques to model these complexes. We present here an ensemble, flexible protein-peptide docking protocol that combines conformational selection and induced fit mechanisms. Starting from an ensemble of three peptide conformations (extended, a-helix, polyproline-II), flexible docking with HADDOCK generates 79.4% of high quality models for bound/unbound and 69.4% for unbound/unbound docking when tested against the largest protein-peptide complexes benchmark dataset available to date. Conformational selection at the rigid-body docking stage successfully recovers the most relevant conformation for a given protein-peptide complex and the subsequent flexible refinement further improves the interface by up to 4.5 Å interface RMSD. Cluster-based scoring of the models results in a selection of near-native solutions in the top three for ∼75% of the successfully predicted cases. This unified conformational selection and induced fit approach to protein-peptide docking should open the route to the modeling of challenging systems such as disorder-order transitions taking place upon binding, significantly expanding the applicability limit of biomolecular interaction modeling by docking.

iATTRACT: simultaneous global and local interface optimization for protein-protein docking refinement.

PubMed

Schindler, Christina E M; de Vries, Sjoerd J; Zacharias, Martin

2015-02-01

Protein-protein interactions are abundant in the cell but to date structural data for a large number of complexes is lacking. Computational docking methods can complement experiments by providing structural models of complexes based on structures of the individual partners. A major caveat for docking success is accounting for protein flexibility. Especially, interface residues undergo significant conformational changes upon binding. This limits the performance of docking methods that keep partner structures rigid or allow limited flexibility. A new docking refinement approach, iATTRACT, has been developed which combines simultaneous full interface flexibility and rigid body optimizations during docking energy minimization. It employs an atomistic molecular mechanics force field for intermolecular interface interactions and a structure-based force field for intramolecular contributions. The approach was systematically evaluated on a large protein-protein docking benchmark, starting from an enriched decoy set of rigidly docked protein-protein complexes deviating by up to 15 Å from the native structure at the interface. Large improvements in sampling and slight but significant improvements in scoring/discrimination of near native docking solutions were observed. Complexes with initial deviations at the interface of up to 5.5 Å were refined to significantly better agreement with the native structure. Improvements in the fraction of native contacts were especially favorable, yielding increases of up to 70%. © 2014 Wiley Periodicals, Inc.

Assessment and Challenges of Ligand Docking into Comparative Models of G-Protein Coupled Receptors

PubMed Central

Frimurer, Thomas M.; Meiler, Jens

2013-01-01

The rapidly increasing number of high-resolution X-ray structures of G-protein coupled receptors (GPCRs) creates a unique opportunity to employ comparative modeling and docking to provide valuable insight into the function and ligand binding determinants of novel receptors, to assist in virtual screening and to design and optimize drug candidates. However, low sequence identity between receptors, conformational flexibility, and chemical diversity of ligands present an enormous challenge to molecular modeling approaches. It is our hypothesis that rapid Monte-Carlo sampling of protein backbone and side-chain conformational space with Rosetta can be leveraged to meet this challenge. This study performs unbiased comparative modeling and docking methodologies using 14 distinct high-resolution GPCRs and proposes knowledge-based filtering methods for improvement of sampling performance and identification of correct ligand-receptor interactions. On average, top ranked receptor models built on template structures over 50% sequence identity are within 2.9 Å of the experimental structure, with an average root mean square deviation (RMSD) of 2.2 Å for the transmembrane region and 5 Å for the second extracellular loop. Furthermore, these models are consistently correlated with low Rosetta energy score. To predict their binding modes, ligand conformers of the 14 ligands co-crystalized with the GPCRs were docked against the top ranked comparative models. In contrast to the comparative models themselves, however, it remains difficult to unambiguously identify correct binding modes by score alone. On average, sampling performance was improved by 103 fold over random using knowledge-based and energy-based filters. In assessing the applicability of experimental constraints, we found that sampling performance is increased by one order of magnitude for every 10 residues known to contact the ligand. Additionally, in the case of DOR, knowledge of a single specific ligand

Wavy Architecture Thin-Film Transistor for Ultrahigh Resolution Flexible Displays.

PubMed

Hanna, Amir Nabil; Kutbee, Arwa Talal; Subedi, Ram Chandra; Ooi, Boon; Hussain, Muhammad Mustafa

2018-01-01

A novel wavy-shaped thin-film-transistor (TFT) architecture, capable of achieving 70% higher drive current per unit chip area when compared with planar conventional TFT architectures, is reported for flexible display application. The transistor, due to its atypical architecture, does not alter the turn-on voltage or the OFF current values, leading to higher performance without compromising static power consumption. The concept behind this architecture is expanding the transistor's width vertically through grooved trenches in a structural layer deposited on a flexible substrate. Operation of zinc oxide (ZnO)-based TFTs is shown down to a bending radius of 5 mm with no degradation in the electrical performance or cracks in the gate stack. Finally, flexible low-power LEDs driven by the respective currents of the novel wavy, and conventional coplanar architectures are demonstrated, where the novel architecture is able to drive the LED at 2 × the output power, 3 versus 1.5 mW, which demonstrates the potential use for ultrahigh resolution displays in an area efficient manner. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Magnetic docking aid for orbiter to ISS docking

NASA Technical Reports Server (NTRS)

Schneider, William C.; Nagy, Kornel; Schliesing, John A.

1996-01-01

The present docking system for the Orbiter uses mechanical capture latches that are actuated by contact forces. The forces are generated when the two approaching masses collide at the docking mechanism. There is always a trade-off between having high enough momentum to effect capture and low enough momentum to avoid structural overload or unacceptable angular displacements. The use of the present docking system includes a contact thrusting maneuver that causes high docking loads to be included into Space Station. A magnetic docking aid has been developed to reduce the load s during docking. The magnetic docking aid is comprised of two extendible booms that are attached adjacent to the docking structure with electromagnets attached on the end of the boom. On the mating vehicle, two steel plates are attached. As the Orbiter approaches Space Station, the booms are extended, and the magnets attach to the actuated (without thrusting), by slowly driving the extendible booms to the stowed position, thus reacting the load into the booms. This results in a docking event that has lower loads induced into Space Station structure. This method also greatly simplifies the Station berthing tasks, since the Shuttle Remote Manipulation System (SRMS) arm need only place the element to be berthed on the magnets (no load required), rather than firing the Reaction Control System (RCS) jets to provide the required force for capture latch actuation. The Magnetic Docking Aid was development testing on a six degree-of-freedom (6 DOF) system at JSC.

Application of Enhanced Sampling Monte Carlo Methods for High-Resolution Protein-Protein Docking in Rosetta

PubMed Central

Zhang, Zhe; Schindler, Christina E. M.; Lange, Oliver F.; Zacharias, Martin

2015-01-01

The high-resolution refinement of docked protein-protein complexes can provide valuable structural and mechanistic insight into protein complex formation complementing experiment. Monte Carlo (MC) based approaches are frequently applied to sample putative interaction geometries of proteins including also possible conformational changes of the binding partners. In order to explore efficiency improvements of the MC sampling, several enhanced sampling techniques, including temperature or Hamiltonian replica exchange and well-tempered ensemble approaches, have been combined with the MC method and were evaluated on 20 protein complexes using unbound partner structures. The well-tempered ensemble method combined with a 2-dimensional temperature and Hamiltonian replica exchange scheme (WTE-H-REMC) was identified as the most efficient search strategy. Comparison with prolonged MC searches indicates that the WTE-H-REMC approach requires approximately 5 times fewer MC steps to identify near native docking geometries compared to conventional MC searches. PMID:26053419

International Docking Standard (IDSS) Interface Definition Document (IDD) . E; Revision

NASA Technical Reports Server (NTRS)

Kelly, Sean M.; Cryan, Scott P.

2016-01-01

This International Docking System Standard (IDSS) Interface Definition Document (IDD) is the result of a collaboration by the International Space Station membership to establish a standard docking interface to enable on-orbit crew rescue operations and joint collaborative endeavors utilizing different spacecraft. This IDSS IDD details the physical geometric mating interface and design loads requirements. The physical geometric interface requirements must be strictly followed to ensure physical spacecraft mating compatibility. This includes both defined components and areas that are void of components. The IDD also identifies common design parameters as identified in section 3.0, e.g., docking initial conditions and vehicle mass properties. This information represents a recommended set of design values enveloping a broad set of design reference missions and conditions, which if accommodated in the docking system design, increases the probability of successful docking between different spacecraft. This IDD does not address operational procedures or off-nominal situations, nor does it dictate implementation or design features behind the mating interface. It is the responsibility of the spacecraft developer to perform all hardware verification and validation, and to perform final docking analyses to ensure the needed docking performance and to develop the final certification loads for their application. While there are many other critical requirements needed in the development of a docking system such as fault tolerance, reliability, and environments (e.g. vibration, etc.), it is not the intent of the IDSS IDD to mandate all of these requirements; these requirements must be addressed as part of the specific developer's unique program, spacecraft and mission needs. This approach allows designers the flexibility to design and build docking mechanisms to their unique program needs and requirements. The purpose of the IDSS IDD is to provide basic common design parameters

Ligand Docking to Intermediate and Close-To-Bound Conformers Generated by an Elastic Network Model Based Algorithm for Highly Flexible Proteins

PubMed Central

Kurkcuoglu, Zeynep; Doruker, Pemra

2016-01-01

Incorporating receptor flexibility in small ligand-protein docking still poses a challenge for proteins undergoing large conformational changes. In the absence of bound structures, sampling conformers that are accessible by apo state may facilitate docking and drug design studies. For this aim, we developed an unbiased conformational search algorithm, by integrating global modes from elastic network model, clustering and energy minimization with implicit solvation. Our dataset consists of five diverse proteins with apo to complex RMSDs 4.7–15 Å. Applying this iterative algorithm on apo structures, conformers close to the bound-state (RMSD 1.4–3.8 Å), as well as the intermediate states were generated. Dockings to a sequence of conformers consisting of a closed structure and its “parents” up to the apo were performed to compare binding poses on different states of the receptor. For two periplasmic binding proteins and biotin carboxylase that exhibit hinge-type closure of two dynamics domains, the best pose was obtained for the conformer closest to the bound structure (ligand RMSDs 1.5–2 Å). In contrast, the best pose for adenylate kinase corresponded to an intermediate state with partially closed LID domain and open NMP domain, in line with recent studies (ligand RMSD 2.9 Å). The docking of a helical peptide to calmodulin was the most challenging case due to the complexity of its 15 Å transition, for which a two-stage procedure was necessary. The technique was first applied on the extended calmodulin to generate intermediate conformers; then peptide docking and a second generation stage on the complex were performed, which in turn yielded a final peptide RMSD of 2.9 Å. Our algorithm is effective in producing conformational states based on the apo state. This study underlines the importance of such intermediate states for ligand docking to proteins undergoing large transitions. PMID:27348230

DOT2: Macromolecular Docking With Improved Biophysical Models

PubMed Central

Roberts, Victoria A.; Thompson, Elaine E.; Pique, Michael E.; Perez, Martin S.; Eyck, Lynn Ten

2015-01-01

Computational docking is a useful tool for predicting macromolecular complexes, which are often difficult to determine experimentally. Here we present the DOT2 software suite, an updated version of the DOT intermolecular docking program. DOT2 provides straightforward, automated construction of improved biophysical models based on molecular coordinates, offering checkpoints that guide the user to include critical features. DOT has been updated to run more quickly, allow flexibility in grid size and spacing, and generate a complete list of favorable candidate configu-rations. Output can be filtered by experimental data and rescored by the sum of electrostatic and atomic desolvation energies. We show that this rescoring method improves the ranking of correct complexes for a wide range of macromolecular interactions, and demonstrate that biologically relevant models are essential for biologically relevant results. The flexibility and versatility of DOT2 accommodate realistic models of complex biological systems, improving the likelihood of a successful docking outcome. PMID:23695987

Small-molecule ligand docking into comparative models with Rosetta

PubMed Central

Combs, Steven A; DeLuca, Samuel L; DeLuca, Stephanie H; Lemmon, Gordon H; Nannemann, David P; Nguyen, Elizabeth D; Willis, Jordan R; Sheehan, Jonathan H; Meiler, Jens

2017-01-01

Structure-based drug design is frequently used to accelerate the development of small-molecule therapeutics. Although substantial progress has been made in X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy, the availability of high-resolution structures is limited owing to the frequent inability to crystallize or obtain sufficient NMR restraints for large or flexible proteins. Computational methods can be used to both predict unknown protein structures and model ligand interactions when experimental data are unavailable. This paper describes a comprehensive and detailed protocol using the Rosetta modeling suite to dock small-molecule ligands into comparative models. In the protocol presented here, we review the comparative modeling process, including sequence alignment, threading and loop building. Next, we cover docking a small-molecule ligand into the protein comparative model. In addition, we discuss criteria that can improve ligand docking into comparative models. Finally, and importantly, we present a strategy for assessing model quality. The entire protocol is presented on a single example selected solely for didactic purposes. The results are therefore not representative and do not replace benchmarks published elsewhere. We also provide an additional tutorial so that the user can gain hands-on experience in using Rosetta. The protocol should take 5–7 h, with additional time allocated for computer generation of models. PMID:23744289

Optical resolution photoacoustic microscopy using novel high-repetition-rate passively Q-switched microchip and fiber lasers.

PubMed

Shi, Wei; Kerr, Shaun; Utkin, Ilya; Ranasinghesagara, Janaka; Pan, Lei; Godwal, Yogesh; Zemp, Roger J; Fedosejevs, Robert

2010-01-01

Optical-resolution photoacoustic microscopy (OR-PAM) is a novel imaging technology for visualizing optically absorbing superficial structures in vivo with lateral spatial resolution determined by optical focusing rather than acoustic detection. Since scanning of the illumination spot is required, OR-PAM imaging speed is limited by both scanning speed and laser pulse repetition rate. Unfortunately, lasers with high repetition rates and suitable pulse durations and energies are not widely available and can be cost-prohibitive and bulky. We are developing compact, passively Q-switched fiber and microchip laser sources for this application. The properties of these lasers are discussed, and pulse repetition rates up to 100 kHz are demonstrated. OR-PAM imaging was conducted using a previously developed photoacoustic probe, which enabled flexible scanning of the focused output of the lasers. Phantom studies demonstrate the ability to image with lateral spatial resolution of 7±2 μm with the microchip laser system and 15±5 μm with the fiber laser system. We believe that the high pulse repetition rates and the potentially compact and fiber-coupled nature of these lasers will prove important for clinical imaging applications where real-time imaging performance is essential.

Smart tunnel: Docking mechanism

NASA Technical Reports Server (NTRS)

Schliesing, John A. (Inventor); Edenborough, Kevin L. (Inventor)

1989-01-01

A docking mechanism is presented for the docking of a space vehicle to a space station comprising a flexible tunnel frame structure which is deployable from the space station. The tunnel structure comprises a plurality of series connected frame sections, one end section of which is attached to the space station and the other end attached to a docking module of a configuration adapted for docking in the payload bay of the space vehicle. The docking module is provided with trunnions, adapted for latching engagement with latches installed in the vehicle payload bay and with hatch means connectable to a hatch of the crew cabin of the space vehicle. Each frame section comprises a pair of spaced ring members, interconnected by actuator-attenuator devices which are individually controllable by an automatic control means to impart relative movement of one ring member to the other in six degrees of freedom of motion. The control means includes computer logic responsive to sensor signals of range and attitude information, capture latch condition, structural loads, and actuator stroke for generating commands to the onboard flight control system and the individual actuator-attenuators to deploy the tunnel to effect a coupling with the space vehicle and space station after coupling. A tubular fluid-impervious liner, preferably fabric, is disposed through the frame sections of a size sufficient to accommodate the passage of personnel and cargo.

Automatic design of decision-tree induction algorithms tailored to flexible-receptor docking data.

PubMed

Barros, Rodrigo C; Winck, Ana T; Machado, Karina S; Basgalupp, Márcio P; de Carvalho, André C P L F; Ruiz, Duncan D; de Souza, Osmar Norberto

2012-11-21

This paper addresses the prediction of the free energy of binding of a drug candidate with enzyme InhA associated with Mycobacterium tuberculosis. This problem is found within rational drug design, where interactions between drug candidates and target proteins are verified through molecular docking simulations. In this application, it is important not only to correctly predict the free energy of binding, but also to provide a comprehensible model that could be validated by a domain specialist. Decision-tree induction algorithms have been successfully used in drug-design related applications, specially considering that decision trees are simple to understand, interpret, and validate. There are several decision-tree induction algorithms available for general-use, but each one has a bias that makes it more suitable for a particular data distribution. In this article, we propose and investigate the automatic design of decision-tree induction algorithms tailored to particular drug-enzyme binding data sets. We investigate the performance of our new method for evaluating binding conformations of different drug candidates to InhA, and we analyze our findings with respect to decision tree accuracy, comprehensibility, and biological relevance. The empirical analysis indicates that our method is capable of automatically generating decision-tree induction algorithms that significantly outperform the traditional C4.5 algorithm with respect to both accuracy and comprehensibility. In addition, we provide the biological interpretation of the rules generated by our approach, reinforcing the importance of comprehensible predictive models in this particular bioinformatics application. We conclude that automatically designing a decision-tree algorithm tailored to molecular docking data is a promising alternative for the prediction of the free energy from the binding of a drug candidate with a flexible-receptor.

Androgynous, Reconfigurable Closed Loop Feedback Controlled Low Impact Docking System With Load Sensing Electromagnetic Capture Ring

NASA Technical Reports Server (NTRS)

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.

GalaxyRefineComplex: Refinement of protein-protein complex model structures driven by interface repacking.

PubMed

Heo, Lim; Lee, Hasup; Seok, Chaok

2016-08-18

Protein-protein docking methods have been widely used to gain an atomic-level understanding of protein interactions. However, docking methods that employ low-resolution energy functions are popular because of computational efficiency. Low-resolution docking tends to generate protein complex structures that are not fully optimized. GalaxyRefineComplex takes such low-resolution docking structures and refines them to improve model accuracy in terms of both interface contact and inter-protein orientation. This refinement method allows flexibility at the protein interface and in the overall docking structure to capture conformational changes that occur upon binding. Symmetric refinement is also provided for symmetric homo-complexes. This method was validated by refining models produced by available docking programs, including ZDOCK and M-ZDOCK, and was successfully applied to CAPRI targets in a blind fashion. An example of using the refinement method with an existing docking method for ligand binding mode prediction of a drug target is also presented. A web server that implements the method is freely available at http://galaxy.seoklab.org/refinecomplex.

Estimation of the Mean Axon Diameter and Intra-axonal Space Volume Fraction of the Human Corpus Callosum: Diffusion q-space Imaging with Low q-values.

PubMed

Suzuki, Yuriko; Hori, Masaaki; Kamiya, Kouhei; Fukunaga, Issei; Aoki, Shigeki; VAN Cauteren, Marc

2016-01-01

Q-space imaging (QSI) is a diffusion-weighted imaging (DWI) technique that enables investigation of tissue microstructure. However, for sufficient displacement resolution to measure the microstructure, QSI requires high q-values that are usually difficult to achieve with a clinical scanner. The recently introduced "low q-value method" fits the echo attenuation to only low q-values to extract the root mean square displacement. We investigated the clinical feasibility of the low q-value method for estimating the microstructure of the human corpus callosum using a 3.0-tesla clinical scanner within a clinically feasible scan time. We performed a simulation to explore the acceptable range of maximum q-values for the low q-value method. We simulated echo attenuations caused by restricted diffusion in the intra-axonal space (IAS) and hindered diffusion in the extra-axonal space (EAS) assuming 100,000 cylinders with various diameters, and we estimated mean axon diameter, IAS volume fraction, and EAS diffusivity by fitting echo attenuations with different maximum q-values. Furthermore, we scanned the corpus callosum of 7 healthy volunteers and estimated the mean axon diameter and IAS volume fraction. Good agreement between estimated and defined values in the simulation study with maximum q-values of 700 and 800 cm(-1) suggested that the maximum q-value used in the in vivo experiment, 737 cm(-1), was reasonable. In the in vivo experiment, the mean axon diameter was larger in the body of the corpus callosum and smaller in the genu and splenium, and this anterior-to-posterior trend is consistent with previously reported histology, although our mean axon diameter seems larger in size. On the other hand, we found an opposite anterior-to-posterior trend, with high IAS volume fraction in the genu and splenium and a lower fraction in the body, which is similar to the fiber density reported in the histology study. The low q-value method may provide insights into tissue

Detailed analysis of grid-based molecular docking: A case study of CDOCKER-A CHARMm-based MD docking algorithm.

PubMed

Wu, Guosheng; Robertson, Daniel H; Brooks, Charles L; Vieth, Michal

2003-10-01

The influence of various factors on the accuracy of protein-ligand docking is examined. The factors investigated include the role of a grid representation of protein-ligand interactions, the initial ligand conformation and orientation, the sampling rate of the energy hyper-surface, and the final minimization. A representative docking method is used to study these factors, namely, CDOCKER, a molecular dynamics (MD) simulated-annealing-based algorithm. A major emphasis in these studies is to compare the relative performance and accuracy of various grid-based approximations to explicit all-atom force field calculations. In these docking studies, the protein is kept rigid while the ligands are treated as fully flexible and a final minimization step is used to refine the docked poses. A docking success rate of 74% is observed when an explicit all-atom representation of the protein (full force field) is used, while a lower accuracy of 66-76% is observed for grid-based methods. All docking experiments considered a 41-member protein-ligand validation set. A significant improvement in accuracy (76 vs. 66%) for the grid-based docking is achieved if the explicit all-atom force field is used in a final minimization step to refine the docking poses. Statistical analysis shows that even lower-accuracy grid-based energy representations can be effectively used when followed with full force field minimization. The results of these grid-based protocols are statistically indistinguishable from the detailed atomic dockings and provide up to a sixfold reduction in computation time. For the test case examined here, improving the docking accuracy did not necessarily enhance the ability to estimate binding affinities using the docked structures. Copyright 2003 Wiley Periodicals, Inc.

FDA approved drugs complexed to their targets: evaluating pose prediction accuracy of docking protocols.

PubMed

Bohari, Mohammed H; Sastry, G Narahari

2012-09-01

Efficient drug discovery programs can be designed by utilizing existing pools of knowledge from the already approved drugs. This can be achieved in one way by repositioning of drugs approved for some indications to newer indications. Complex of drug to its target gives fundamental insight into molecular recognition and a clear understanding of putative binding site. Five popular docking protocols, Glide, Gold, FlexX, Cdocker and LigandFit have been evaluated on a dataset of 199 FDA approved drug-target complexes for their accuracy in predicting the experimental pose. Performance for all the protocols is assessed at default settings, with root mean square deviation (RMSD) between the experimental ligand pose and the docked pose of less than 2.0 Å as the success criteria in predicting the pose. Glide (38.7 %) is found to be the most accurate in top ranked pose and Cdocker (58.8 %) in top RMSD pose. Ligand flexibility is a major bottleneck in failure of docking protocols to correctly predict the pose. Resolution of the crystal structure shows an inverse relationship with the performance of docking protocol. All the protocols perform optimally when a balanced type of hydrophilic and hydrophobic interaction or dominant hydrophilic interaction exists. Overall in 16 different target classes, hydrophobic interactions dominate in the binding site and maximum success is achieved for all the docking protocols in nuclear hormone receptor class while performance for the rest of the classes varied based on individual protocol.

SnapDock—template-based docking by Geometric Hashing

PubMed Central

Estrin, Michael; Wolfson, Haim J.

2017-01-01

Abstract Motivation: A highly efficient template-based protein–protein docking algorithm, nicknamed SnapDock, is presented. It employs a Geometric Hashing-based structural alignment scheme to align the target proteins to the interfaces of non-redundant protein–protein interface libraries. Docking of a pair of proteins utilizing the 22 600 interface PIFACE library is performed in < 2 min on the average. A flexible version of the algorithm allowing hinge motion in one of the proteins is presented as well. Results: To evaluate the performance of the algorithm a blind re-modelling of 3547 PDB complexes, which have been uploaded after the PIFACE publication has been performed with success ratio of about 35%. Interestingly, a similar experiment with the template free PatchDock docking algorithm yielded a success rate of about 23% with roughly 1/3 of the solutions different from those of SnapDock. Consequently, the combination of the two methods gave a 42% success ratio. Availability and implementation: A web server of the application is under development. Contact: michaelestrin@gmail.com or wolfson@tau.ac.il PMID:28881968

Molecular Docking Study on Galantamine Derivatives as Cholinesterase Inhibitors.

PubMed

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

2015-06-01

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

Automatic design of decision-tree induction algorithms tailored to flexible-receptor docking data

PubMed Central

2012-01-01

Background This paper addresses the prediction of the free energy of binding of a drug candidate with enzyme InhA associated with Mycobacterium tuberculosis. This problem is found within rational drug design, where interactions between drug candidates and target proteins are verified through molecular docking simulations. In this application, it is important not only to correctly predict the free energy of binding, but also to provide a comprehensible model that could be validated by a domain specialist. Decision-tree induction algorithms have been successfully used in drug-design related applications, specially considering that decision trees are simple to understand, interpret, and validate. There are several decision-tree induction algorithms available for general-use, but each one has a bias that makes it more suitable for a particular data distribution. In this article, we propose and investigate the automatic design of decision-tree induction algorithms tailored to particular drug-enzyme binding data sets. We investigate the performance of our new method for evaluating binding conformations of different drug candidates to InhA, and we analyze our findings with respect to decision tree accuracy, comprehensibility, and biological relevance. Results The empirical analysis indicates that our method is capable of automatically generating decision-tree induction algorithms that significantly outperform the traditional C4.5 algorithm with respect to both accuracy and comprehensibility. In addition, we provide the biological interpretation of the rules generated by our approach, reinforcing the importance of comprehensible predictive models in this particular bioinformatics application. Conclusions We conclude that automatically designing a decision-tree algorithm tailored to molecular docking data is a promising alternative for the prediction of the free energy from the binding of a drug candidate with a flexible-receptor. PMID:23171000

Turning a low Q fiber resonator into a high-sensitivity displacement sensor using slow light concepts

NASA Astrophysics Data System (ADS)

Bravo, Mikel; Angulo-Vinuesa, Xabier; Martin-Lopez, Sonia; Lopez-Amo, Manuel; Gonzalez-Herraez, Miguel

2013-05-01

High-Q resonators have been widely used for sensing purposes. High Q factors normally lead to sharp spectral peaks which accordingly provide a strong sensitivity in spectral interrogation methods. In this work we employ a low-Q ring resonator to develop a high sensitivity sub-micrometric resolution displacement sensor. We use the slow-light effects occurring close to the critical coupling regime to achieve high sensitivity in the device. By tuning the losses in the cavity close to the critical coupling, extremely high group delay variations can be achieved, which in turn introduce strong enhancements of the absorption of the structure. We first validate the concept using an Optical Vector Analyzer (OVA) and then we propose a simple functional scheme for achieving a low-cost interrogation of this kind of sensors.

Enabling Exploration Through Docking Standards

NASA Technical Reports Server (NTRS)

Hatfield, Caris A.

2012-01-01

Human exploration missions beyond low earth orbit will likely require international cooperation in order to leverage limited resources. International standards can help enable cooperative missions by providing well understood, predefined interfaces allowing compatibility between unique spacecraft and systems. The International Space Station (ISS) partnership has developed a publicly available International Docking System Standard (IDSS) that provides a solution to one of these key interfaces by defining a common docking interface. The docking interface provides a way for even dissimilar spacecraft to dock for exchange of crew and cargo, as well as enabling the assembly of large space systems. This paper provides an overview of the key attributes of the IDSS, an overview of the NASA Docking System (NDS), and the plans for updating the ISS with IDSS compatible interfaces. The NDS provides a state of the art, low impact docking system that will initially be made available to commercial crew and cargo providers. The ISS will be used to demonstrate the operational utility of the IDSS interface as a foundational technology for cooperative exploration.

PPI4DOCK: large scale assessment of the use of homology models in free docking over more than 1000 realistic targets.

PubMed

Yu, Jinchao; Guerois, Raphaël

2016-12-15

Protein-protein docking methods are of great importance for understanding interactomes at the structural level. It has become increasingly appealing to use not only experimental structures but also homology models of unbound subunits as input for docking simulations. So far we are missing a large scale assessment of the success of rigid-body free docking methods on homology models. We explored how we could benefit from comparative modelling of unbound subunits to expand docking benchmark datasets. Starting from a collection of 3157 non-redundant, high X-ray resolution heterodimers, we developed the PPI4DOCK benchmark containing 1417 docking targets based on unbound homology models. Rigid-body docking by Zdock showed that for 1208 cases (85.2%), at least one correct decoy was generated, emphasizing the efficiency of rigid-body docking in generating correct assemblies. Overall, the PPI4DOCK benchmark contains a large set of realistic cases and provides new ground for assessing docking and scoring methodologies. Benchmark sets can be downloaded from http://biodev.cea.fr/interevol/ppi4dock/ CONTACT: guerois@cea.frSupplementary information: Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Systematic and efficient side chain optimization for molecular docking using a cheapest-path procedure.

PubMed

Schumann, Marcel; Armen, Roger S

2013-05-30

Molecular docking of small-molecules is an important procedure for computer-aided drug design. Modeling receptor side chain flexibility is often important or even crucial, as it allows the receptor to adopt new conformations as induced by ligand binding. However, the accurate and efficient incorporation of receptor side chain flexibility has proven to be a challenge due to the huge computational complexity required to adequately address this problem. Here we describe a new docking approach with a very fast, graph-based optimization algorithm for assignment of the near-optimal set of residue rotamers. We extensively validate our approach using the 40 DUD target benchmarks commonly used to assess virtual screening performance and demonstrate a large improvement using the developed side chain optimization over rigid receptor docking (average ROC AUC of 0.693 vs. 0.623). Compared to numerous benchmarks, the overall performance is better than nearly all other commonly used procedures. Furthermore, we provide a detailed analysis of the level of receptor flexibility observed in docking results for different classes of residues and elucidate potential avenues for further improvement. Copyright © 2013 Wiley Periodicals, Inc.

Prediction of binding poses to FXR using multi-targeted docking combined with molecular dynamics and enhanced sampling

NASA Astrophysics Data System (ADS)

Bhakat, Soumendranath; Åberg, Emil; Söderhjelm, Pär

2018-01-01

Advanced molecular docking methods often aim at capturing the flexibility of the protein upon binding to the ligand. In this study, we investigate whether instead a simple rigid docking method can be applied, if combined with multiple target structures to model the backbone flexibility and molecular dynamics simulations to model the sidechain and ligand flexibility. The methods are tested for the binding of 35 ligands to FXR as part of the first stage of the Drug Design Data Resource (D3R) Grand Challenge 2 blind challenge. The results show that the multiple-target docking protocol performs surprisingly well, with correct poses found for 21 of the ligands. MD simulations started on the docked structures are remarkably stable, but show almost no tendency of refining the structure closer to the experimentally found binding pose. Reconnaissance metadynamics enhances the exploration of new binding poses, but additional collective variables involving the protein are needed to exploit the full potential of the method.

Prediction of binding poses to FXR using multi-targeted docking combined with molecular dynamics and enhanced sampling.

PubMed

Bhakat, Soumendranath; Åberg, Emil; Söderhjelm, Pär

2018-01-01

Advanced molecular docking methods often aim at capturing the flexibility of the protein upon binding to the ligand. In this study, we investigate whether instead a simple rigid docking method can be applied, if combined with multiple target structures to model the backbone flexibility and molecular dynamics simulations to model the sidechain and ligand flexibility. The methods are tested for the binding of 35 ligands to FXR as part of the first stage of the Drug Design Data Resource (D3R) Grand Challenge 2 blind challenge. The results show that the multiple-target docking protocol performs surprisingly well, with correct poses found for 21 of the ligands. MD simulations started on the docked structures are remarkably stable, but show almost no tendency of refining the structure closer to the experimentally found binding pose. Reconnaissance metadynamics enhances the exploration of new binding poses, but additional collective variables involving the protein are needed to exploit the full potential of the method.

2q37 Deletion syndrome confirmed by high-resolution cytogenetic analysis

PubMed Central

Cho, Eun-Kyung; Kim, Jinsup; Yang, Aram; Jin, Dong-Kyu

2017-01-01

Chromosome 2q37 deletion syndrome is a rare chromosomal disorder characterized by mild to moderate developmental delay, brachydactyly of the third to fifth digits or toes, short stature, obesity, hypotonia, a characteristic facial appearance, and autism spectrum disorder. Here, we report on a patient with 2q37 deletion presenting with dilated cardiomyopathy (DCMP). Congenital heart malformations have been noted in up to 20% of patients with 2q37 deletions. However, DCMP has not been reported in 2q37 deletion patients previously. The patient exhibited the characteristic facial appearance (a flat nasal bridge, deep-set eyes, arched eyebrows, and a thin upper lip), developmental delay, mild mental retardation, peripheral nerve palsy, and Albright hereditary osteodystrophy (AHO)-like phenotypes (short stature and brachydactyly). Conventional chromosomal analysis results were normal; however, microarray-based comparative genomic hybridization revealed terminal deletion at 2q37.1q37.3. In addition, the patient was confirmed to have partial growth hormone (GH) deficiency and had shown a significant increase in growth rate after substitutive GH therapy. Chromosome 2q37 deletion syndrome should be considered in the differential diagnosis of patients presenting with AHO features, especially in the presence of facial dysmorphism. When patients are suspected of having a 2q37 deletion, high-resolution cytogenetic analysis is recommended. PMID:28690993

R102Q mutation shifts the salt-bridge network and reduces the structural flexibility of human neuronal calcium sensor-1 protein.

PubMed

Zhu, Yuzhen; Wu, Ying; Luo, Yin; Zou, Yu; Ma, Buyong; Zhang, Qingwen

2014-11-20

Neuronal calcium sensor-1 (NCS-1) protein has a variety of different neuronal functions and interacts with multiple binding partners mostly through a large solvent-exposed hydrophobic crevice (HC). A single R102Q mutation in human NCS-1 protein was demonstrated to be associated with autism disease. Solution NMR study reported that this R102Q mutant had long-range chemical shift effects on the HC and the C-terminal tail (L3). To understand the influence of the R102Q mutation on the HC and L3 of NCS-1, we have investigated the conformational dynamics and the structural flexibility of wild type (WT) NCS-1 and its R102Q mutant by conducting extensive all-atom molecular dynamics (MD) simulations. On the basis of six independent 450 ns MD simulations, we have found that the R102Q mutation in NCS-1 protein (1) dramatically reduces the flexibility of loops L2 and L3, (2) facilitates L3 in a more extended state to occupy the hydrophobic crevice to a larger extent, (3) significantly affects the intersegment salt bridges, and (4) changes the subspace of the free energy landscape of NCS-1 protein. Analysis of the salt bridge network in both WT and the R102Q variant demonstrates that the R102Q-mutation-induced salt bridge alternations play a critical role on the reduced flexibility of L2 and L3. These results reveal the important role of salt bridges on the structural properties of NCS-1 protein and that R102Q mutation disables the dynamic relocation of C-terminus, which may block the binding of NCS-1 protein to its receptors. This study may provide structural insights into the autistic spectrum disorder associated with R102Q mutation.

Space station full-scale docking/berthing mechanisms development

NASA Technical Reports Server (NTRS)

Burns, Gene C.; Price, Harold A.; Buchanan, David B.

1988-01-01

One of the most critical operational functions for the space station is the orbital docking between the station and the STS orbiter. The program to design, fabricate, and test docking/berthing mechanisms for the space station is described. The design reflects space station overall requirements and consists of two mating docking mechanism halves. One half is designed for use on the shuttle orbiter and incorporates capture and energy attenuation systems using computer controlled electromechanical actuators and/or attenuators. The mating half incorporates a flexible feature to allow two degrees of freedom at the module-to-module interface of the space station pressurized habitat volumes. The design concepts developed for the prototype units may be used for the first space station flight hardware.

Beyond low beta-decay Q values

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mustonen, M. T.; Suhonen, J.

Beta decays with low Q values can be utilized in the quest to determine the neutrino mass scale. This is being realized in two experiments, KATRIN and MARE, using tritium and {sup 187}Re, respectively. The beta-decay of {sup 187}Re had the lowest known Q value until 2005, when the beta decay of {sup 115}In to the first excited state of {sup 115}Sn was discovered in Gran Sasso underground laboratory. Last year two independent ion trap measurements confirmed that this decay breaks the former record by an order of magnitude.Our theoretical study on this tiny decay channel complemented the experimental effortmore » by the JYFLTRAP group in Finland and HADES underground laboratory in Belgium. A significant discrepancy between the experimental and theoretical results was found. This might be explained by various atomic contributions known to grow larger as the Q value decreases. However, the traditional recipes for taking these effects into account break down on this new ultra-low Q value regime, providing new challenges for theorists on the borderline between nuclear and atomic physics.« less

S4MPLE--Sampler for Multiple Protein-Ligand Entities: Methodology and Rigid-Site Docking Benchmarking.

PubMed

Hoffer, Laurent; Chira, Camelia; Marcou, Gilles; Varnek, Alexandre; Horvath, Dragos

2015-05-19

This paper describes the development of the unified conformational sampling and docking tool called Sampler for Multiple Protein-Ligand Entities (S4MPLE). The main novelty in S4MPLE is the unified dealing with intra- and intermolecular degrees of freedom (DoF). While classically programs are either designed for folding or docking, S4MPLE transcends this artificial specialization. It supports folding, docking of a flexible ligand into a flexible site and simultaneous docking of several ligands. The trick behind it is the formal assimilation of inter-molecular to intra-molecular DoF associated to putative inter-molecular contact axes. This is implemented within the genetic operators powering a Lamarckian Genetic Algorithm (GA). Further novelty includes differentiable interaction fingerprints to control population diversity, and fitting a simple continuum solvent model and favorable contact bonus terms to the AMBER/GAFF force field. Novel applications-docking of fragment-like compounds, simultaneous docking of multiple ligands, including free crystallographic waters-were published elsewhere. This paper discusses: (a) methodology, (b) set-up of the force field energy functions and (c) their validation in classical redocking tests. More than 80% success in redocking was achieved (RMSD of top-ranked pose < 2.0 Å).

Protein-ligand docking using fitness learning-based artificial bee colony with proximity stimuli.

PubMed

Uehara, Shota; Fujimoto, Kazuhiro J; Tanaka, Shigenori

2015-07-07

Protein-ligand docking is an optimization problem, which aims to identify the binding pose of a ligand with the lowest energy in the active site of a target protein. In this study, we employed a novel optimization algorithm called fitness learning-based artificial bee colony with proximity stimuli (FlABCps) for docking. Simulation results revealed that FlABCps improved the success rate of docking, compared to four state-of-the-art algorithms. The present results also showed superior docking performance of FlABCps, in particular for dealing with highly flexible ligands and proteins with a wide and shallow binding pocket.

Virtual-system-coupled adaptive umbrella sampling to compute free-energy landscape for flexible molecular docking.

PubMed

Higo, Junichi; Dasgupta, Bhaskar; Mashimo, Tadaaki; Kasahara, Kota; Fukunishi, Yoshifumi; Nakamura, Haruki

2015-07-30

A novel enhanced conformational sampling method, virtual-system-coupled adaptive umbrella sampling (V-AUS), was proposed to compute 300-K free-energy landscape for flexible molecular docking, where a virtual degrees of freedom was introduced to control the sampling. This degree of freedom interacts with the biomolecular system. V-AUS was applied to complex formation of two disordered amyloid-β (Aβ30-35 ) peptides in a periodic box filled by an explicit solvent. An interpeptide distance was defined as the reaction coordinate, along which sampling was enhanced. A uniform conformational distribution was obtained covering a wide interpeptide distance ranging from the bound to unbound states. The 300-K free-energy landscape was characterized by thermodynamically stable basins of antiparallel and parallel β-sheet complexes and some other complex forms. Helices were frequently observed, when the two peptides contacted loosely or fluctuated freely without interpeptide contacts. We observed that V-AUS converged to uniform distribution more effectively than conventional AUS sampling did. © 2015 Wiley Periodicals, Inc.

Low-Impact Mating System for Docking Spacecraft

NASA Technical Reports Server (NTRS)

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

2008-01-01

A document describes a low-impact mating system suitable for both docking (mating of two free-flying spacecraft) and berthing (in which a robot arm in one spacecraft positions an object for mating with either spacecraft). The low-impact mating system is fully androgynous: it mates with a copy of itself, i.e., all spacecraft and other objects to be mated are to be equipped with identical copies of the system. This aspect of the design helps to minimize the number of unique parts and to standardize and facilitate mating operations. The system includes a closed-loop feedback control subsystem that actively accommodates misalignments between mating spacecraft, thereby attenuating spacecraft dynamics and mitigating the need for precise advance positioning of the spacecraft. The operational characteristics of the mating system can be easily configured in software, during operation, to enable mating of spacecraft having various masses, center-of-gravity offsets, and closing velocities. The system design provides multi-fault tolerance for critical operations: for example, to ensure unmating at a critical time, a redundant unlatching mechanism and two independent pyrotechnic release subsystems are included.

PharmDock: a pharmacophore-based docking program

PubMed Central

2014-01-01

Background Protein-based pharmacophore models are enriched with the information of potential interactions between ligands and the protein target. We have shown in a previous study that protein-based pharmacophore models can be applied for ligand pose prediction and pose ranking. In this publication, we present a new pharmacophore-based docking program PharmDock that combines pose sampling and ranking based on optimized protein-based pharmacophore models with local optimization using an empirical scoring function. Results Tests of PharmDock on ligand pose prediction, binding affinity estimation, compound ranking and virtual screening yielded comparable or better performance to existing and widely used docking programs. The docking program comes with an easy-to-use GUI within PyMOL. Two features have been incorporated in the program suite that allow for user-defined guidance of the docking process based on previous experimental data. Docking with those features demonstrated superior performance compared to unbiased docking. Conclusion A protein pharmacophore-based docking program, PharmDock, has been made available with a PyMOL plugin. PharmDock and the PyMOL plugin are freely available from http://people.pharmacy.purdue.edu/~mlill/software/pharmdock. PMID:24739488

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

NASA Technical Reports Server (NTRS)

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

2016-01-01

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

Hi-Q Rotor - Low Wind Speed Technology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Todd E. Mills; Judy Tatum

The project objective was to optimize the performance of the Hi-Q Rotor. Early research funded by the California Energy Commission indicated the design might be advantageous over state-of-the-art turbines for collecting wind energy in low wind conditions. The Hi-Q Rotor is a new kind of rotor targeted for harvesting wind in Class 2, 3, and 4 sites, and has application in areas that are closer to cities, or 'load centers.' An advantage of the Hi-Q Rotor is that the rotor has non-conventional blade tips, producing less turbulence, and is quieter than standard wind turbine blades which is critical to themore » low-wind populated urban sites. Unlike state-of-the-art propeller type blades, the Hi-Q Rotor has six blades connected by end caps. In this phase of the research funded by DOE's Inventions and Innovation Program, the goal was to improve the current design by building a series of theoretical and numeric models, and composite prototypes to determine a best of class device. Development of the rotor was performed by aeronautical engineering and design firm, DARcorporation. From this investigation, an optimized design was determined and an 8-foot diameter, full-scale rotor was built and mounted using a Bergey LX-1 generator and furling system which were adapted to support the rotor. The Hi-Q Rotor was then tested side-by-side against the state-of-the-art Bergey XL-1 at the Alternative Energy Institute's Wind Test Center at West Texas State University for six weeks, and real time measurements of power generated were collected and compared. Early wind tunnel testing showed that the cut-in-speed of the Hi-Q rotor is much lower than a conventional tested HAWT enabling the Hi-Q Wind Turbine to begin collecting energy before a conventional HAWT has started spinning. Also, torque at low wind speeds for the Hi-Q Wind Turbine is higher than the tested conventional HAWT and enabled the wind turbine to generate power at lower wind speeds. Based on the data collected, the

HPOTP low-speed flexible rotor balancing, phase 1

NASA Technical Reports Server (NTRS)

Giordano, J.; Zorzi, E.

1985-01-01

A method was developed that shows promise in overcoming many balancing limitations. This method establishes one or more windows for low speed, out-of-housing balancing of flexible rotors. These windows are regions of speed and support flexibility where two conditions are simultaneously fulfilled. First, the rotor system behaves flexibly; therefore, there is separation among balance planes. Second, the response due to balance weights is large enough to reliably measure. The analytic formulation of the low-speed flexible rotor balancing method is described. The results of proof-of-principle tests conducted under the program are presented. Based on this effort, it is concluded that low speed flexible rotor balancing is a viable technology. In particular, the method can be used to balance a rotor bearing system at low speed which results in smooth operation above more than one bending critical speed. Furthermore, this balancing methodology is applicable to SSME turbopump rotors.

Orbital docking system centerline color television camera system test

NASA Technical Reports Server (NTRS)

Mongan, Philip T.

1993-01-01

A series of tests was run to verify that the design of the centerline color television camera (CTVC) system is adequate optically for the STS-71 Space Shuttle Orbiter docking mission with the Mir space station. In each test, a mockup of the Mir consisting of hatch, docking mechanism, and docking target was positioned above the Johnson Space Center's full fuselage trainer, which simulated the Orbiter with a mockup of the external airlock and docking adapter. Test subjects viewed the docking target through the CTVC under 30 different lighting conditions and evaluated target resolution, field of view, light levels, light placement, and methods of target alignment. Test results indicate that the proposed design will provide adequate visibility through the centerline camera for a successful docking, even with a reasonable number of light failures. It is recommended that the flight deck crew have individual switching capability for docking lights to provide maximum shadow management and that centerline lights be retained to deal with light failures and user preferences. Procedures for light management should be developed and target alignment aids should be selected during simulated docking runs.

A cross docking pipeline for improving pose prediction and virtual screening performance

NASA Astrophysics Data System (ADS)

Kumar, Ashutosh; Zhang, Kam Y. J.

2018-01-01

Pose prediction and virtual screening performance of a molecular docking method depend on the choice of protein structures used for docking. Multiple structures for a target protein are often used to take into account the receptor flexibility and problems associated with a single receptor structure. However, the use of multiple receptor structures is computationally expensive when docking a large library of small molecules. Here, we propose a new cross-docking pipeline suitable to dock a large library of molecules while taking advantage of multiple target protein structures. Our method involves the selection of a suitable receptor for each ligand in a screening library utilizing ligand 3D shape similarity with crystallographic ligands. We have prospectively evaluated our method in D3R Grand Challenge 2 and demonstrated that our cross-docking pipeline can achieve similar or better performance than using either single or multiple-receptor structures. Moreover, our method displayed not only decent pose prediction performance but also better virtual screening performance over several other methods.

3D-QSAR and docking studies on 4-anilinoquinazoline and 4-anilinoquinoline epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors

NASA Astrophysics Data System (ADS)

Assefa, Haregewein; Kamath, Shantaram; Buolamwini, John K.

2003-08-01

The overexpression and/or mutation of the epidermal growth factor receptor (EGFR) tyrosine kinase has been observed in many human solid tumors, and is under intense investigation as a novel anticancer molecular target. Comparative 3D-QSAR analyses using different alignments were undertaken employing comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) for 122 anilinoquinazoline and 50 anilinoquinoline inhibitors of EGFR kinase. The SYBYL multifit alignment rule was applied to three different conformational templates, two obtained from a MacroModel Monte Carlo conformational search, and one from the bound conformation of erlotinib in complex with EGFR in the X-ray crystal structure. In addition, a flexible ligand docking alignment obtained with the GOLD docking program, and a novel flexible receptor-guided consensus dynamics alignment obtained with the DISCOVER program in the INSIGHTII modeling package were also investigated. 3D-QSAR models with q2 values up to 0.70 and r2 values up to 0.97 were obtained. Among the 4-anilinoquinazoline set, the q2 values were similar, but the ability of the different conformational models to predict the activities of an external test set varied considerably. In this regard, the model derived using the X-ray crystallographically determined bioactive conformation of erlotinib afforded the best predictive model. Electrostatic, hydrophobic and H-bond donor descriptors contributed the most to the QSAR models of the 4-anilinoquinazolines, whereas electrostatic, hydrophobic and H-bond acceptor descriptors contributed the most to the 4-anilinoquinoline QSAR, particularly the H-bond acceptor descriptor. A novel receptor-guided consensus dynamics alignment has also been introduced for 3D-QSAR studies. This new alignment method may incorporate to some extent ligand-receptor induced fit effects into 3D-QSAR models.

Rendezvous and Docking for Space Exploration

NASA Technical Reports Server (NTRS)

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

2005-01-01

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

F2Dock: Fast Fourier Protein-Protein Docking

PubMed Central

Bajaj, Chandrajit; Chowdhury, Rezaul; Siddavanahalli, Vinay

2009-01-01

The functions of proteins is often realized through their mutual interactions. Determining a relative transformation for a pair of proteins and their conformations which form a stable complex, reproducible in nature, is known as docking. It is an important step in drug design, structure determination and understanding function and structure relationships. In this paper we extend our non-uniform fast Fourier transform docking algorithm to include an adaptive search phase (both translational and rotational) and thereby speed up its execution. We have also implemented a multithreaded version of the adaptive docking algorithm for even faster execution on multicore machines. We call this protein-protein docking code F2Dock (F2 = Fast Fourier). We have calibrated F2Dock based on an extensive experimental study on a list of benchmark complexes and conclude that F2Dock works very well in practice. Though all docking results reported in this paper use shape complementarity and Coulombic potential based scores only, F2Dock is structured to incorporate Lennard-Jones potential and re-ranking docking solutions based on desolvation energy. PMID:21071796

Ligand-biased ensemble receptor docking (LigBEnD): a hybrid ligand/receptor structure-based approach

NASA Astrophysics Data System (ADS)

Lam, Polo C.-H.; Abagyan, Ruben; Totrov, Maxim

2018-01-01

Ligand docking to flexible protein molecules can be efficiently carried out through ensemble docking to multiple protein conformations, either from experimental X-ray structures or from in silico simulations. The success of ensemble docking often requires the careful selection of complementary protein conformations, through docking and scoring of known co-crystallized ligands. False positives, in which a ligand in a wrong pose achieves a better docking score than that of native pose, arise as additional protein conformations are added. In the current study, we developed a new ligand-biased ensemble receptor docking method and composite scoring function which combine the use of ligand-based atomic property field (APF) method with receptor structure-based docking. This method helps us to correctly dock 30 out of 36 ligands presented by the D3R docking challenge. For the six mis-docked ligands, the cognate receptor structures prove to be too different from the 40 available experimental Pocketome conformations used for docking and could be identified only by receptor sampling beyond experimentally explored conformational subspace.

A Flexible Spatiotemporal Method for Fusing Satellite Images with Different Resolutions

USDA-ARS?s Scientific Manuscript database

Studies of land surface dynamics in heterogeneous landscapes often require remote sensing data with high acquisition frequency and high spatial resolution. However, no single sensor meets this requirement. This study presents a new spatiotemporal data fusion method, the Flexible Spatiotemporal DAta ...

Cosolvent-Based Molecular Dynamics for Ensemble Docking: Practical Method for Generating Druggable Protein Conformations.

PubMed

Uehara, Shota; Tanaka, Shigenori

2017-04-24

Protein flexibility is a major hurdle in current structure-based virtual screening (VS). In spite of the recent advances in high-performance computing, protein-ligand docking methods still demand tremendous computational cost to take into account the full degree of protein flexibility. In this context, ensemble docking has proven its utility and efficiency for VS studies, but it still needs a rational and efficient method to select and/or generate multiple protein conformations. Molecular dynamics (MD) simulations are useful to produce distinct protein conformations without abundant experimental structures. In this study, we present a novel strategy that makes use of cosolvent-based molecular dynamics (CMD) simulations for ensemble docking. By mixing small organic molecules into a solvent, CMD can stimulate dynamic protein motions and induce partial conformational changes of binding pocket residues appropriate for the binding of diverse ligands. The present method has been applied to six diverse target proteins and assessed by VS experiments using many actives and decoys of DEKOIS 2.0. The simulation results have revealed that the CMD is beneficial for ensemble docking. Utilizing cosolvent simulation allows the generation of druggable protein conformations, improving the VS performance compared with the use of a single experimental structure or ensemble docking by standard MD with pure water as the solvent.

NASA Docking System (NDS) Technical Integration Meeting

NASA Technical Reports Server (NTRS)

Lewis, James L.

2010-01-01

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

Re-evaluation of low-resolution crystal structures via interactive molecular-dynamics flexible fitting (iMDFF): a case study in complement C4.

PubMed

Croll, Tristan Ian; Andersen, Gregers Rom

2016-09-01

While the rapid proliferation of high-resolution structures in the Protein Data Bank provides a rich set of templates for starting models, it remains the case that a great many structures both past and present are built at least in part by hand-threading through low-resolution and/or weak electron density. With current model-building tools this task can be challenging, and the de facto standard for acceptable error rates (in the form of atomic clashes and unfavourable backbone and side-chain conformations) in structures based on data with dmax not exceeding 3.5 Å reflects this. When combined with other factors such as model bias, these residual errors can conspire to make more serious errors in the protein fold difficult or impossible to detect. The three recently published 3.6-4.2 Å resolution structures of complement C4 (PDB entries 4fxg, 4fxk and 4xam) rank in the top quartile of structures of comparable resolution both in terms of Rfree and MolProbity score, yet, as shown here, contain register errors in six β-strands. By applying a molecular-dynamics force field that explicitly models interatomic forces and hence excludes most physically impossible conformations, the recently developed interactive molecular-dynamics flexible fitting (iMDFF) approach significantly reduces the complexity of the conformational space to be searched during manual rebuilding. This substantially improves the rate of detection and correction of register errors, and allows user-guided model building in maps with a resolution lower than 3.5 Å to converge to solutions with a stereochemical quality comparable to atomic resolution structures. Here, iMDFF has been used to individually correct and re-refine these three structures to MolProbity scores of <1.7, and strategies for working with such challenging data sets are suggested. Notably, the improved model allowed the resolution for complement C4b to be extended from 4.2 to 3.5 Å as demonstrated by paired refinement.

Engineering Evaluation of International Low Impact Docking System Latch Hooks

NASA Technical Reports Server (NTRS)

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

2013-01-01

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

Molecular docking.

PubMed

Morris, Garrett M; Lim-Wilby, Marguerita

2008-01-01

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

Joint 6D k-q Space Compressed Sensing for Accelerated High Angular Resolution Diffusion MRI.

PubMed

Cheng, Jian; Shen, Dinggang; Basser, Peter J; Yap, Pew-Thian

2015-01-01

High Angular Resolution Diffusion Imaging (HARDI) avoids the Gaussian. diffusion assumption that is inherent in Diffusion Tensor Imaging (DTI), and is capable of characterizing complex white matter micro-structure with greater precision. However, HARDI methods such as Diffusion Spectrum Imaging (DSI) typically require significantly more signal measurements than DTI, resulting in prohibitively long scanning times. One of the goals in HARDI research is therefore to improve estimation of quantities such as the Ensemble Average Propagator (EAP) and the Orientation Distribution Function (ODF) with a limited number of diffusion-weighted measurements. A popular approach to this problem, Compressed Sensing (CS), affords highly accurate signal reconstruction using significantly fewer (sub-Nyquist) data points than required traditionally. Existing approaches to CS diffusion MRI (CS-dMRI) mainly focus on applying CS in the q-space of diffusion signal measurements and fail to take into consideration information redundancy in the k-space. In this paper, we propose a framework, called 6-Dimensional Compressed Sensing diffusion MRI (6D-CS-dMRI), for reconstruction of the diffusion signal and the EAP from data sub-sampled in both 3D k-space and 3D q-space. To our knowledge, 6D-CS-dMRI is the first work that applies compressed sensing in the full 6D k-q space and reconstructs the diffusion signal in the full continuous q-space and the EAP in continuous displacement space. Experimental results on synthetic and real data demonstrate that, compared with full DSI sampling in k-q space, 6D-CS-dMRI yields excellent diffusion signal and EAP reconstruction with low root-mean-square error (RMSE) using 11 times less samples (3-fold reduction in k-space and 3.7-fold reduction in q-space).

Structure and Sequence Search on Aptamer-Protein Docking

NASA Astrophysics Data System (ADS)

Xiao, Jiajie; Bonin, Keith; Guthold, Martin; Salsbury, Freddie

2015-03-01

Interactions between proteins and deoxyribonucleic acid (DNA) play a significant role in the living systems, especially through gene regulation. However, short nucleic acids sequences (aptamers) with specific binding affinity to specific proteins exhibit clinical potential as therapeutics. Our capillary and gel electrophoresis selection experiments show that specific sequences of aptamers can be selected that bind specific proteins. Computationally, given the experimentally-determined structure and sequence of a thrombin-binding aptamer, we can successfully dock the aptamer onto thrombin in agreement with experimental structures of the complex. In order to further study the conformational flexibility of this thrombin-binding aptamer and to potentially develop a predictive computational model of aptamer-binding, we use GPU-enabled molecular dynamics simulations to both examine the conformational flexibility of the aptamer in the absence of binding to thrombin, and to determine our ability to fold an aptamer. This study should help further de-novo predictions of aptamer sequences by enabling the study of structural and sequence-dependent effects on aptamer-protein docking specificity.

Microdome-gooved Gd(2)O(2)S:Tb scintillator for flexible and high resolution digital radiography.

PubMed

Jung, Phill Gu; Lee, Chi Hoon; Bae, Kong Myeong; Lee, Jae Min; Lee, Sang Min; Lim, Chang Hwy; Yun, Seungman; Kim, Ho Kyung; Ko, Jong Soo

2010-07-05

A flexible microdome-grooved Gd(2)O(2)S:Tb scintillator is simulated, fabricated, and characterized for digital radiography applications. According to Monte Carlo simulation results, the dome-grooved structure has a high spatial resolution, which is verified by X-ray image performance of the scintillator. The proposed scintillator has lower X-ray sensitivity than a nonstructured scintillator but almost two times higher spatial resolution at high spatial frequency. Through evaluation of the X-ray performance of the fabricated scintillators, we confirm that the microdome-grooved scintillator can be applied to next-generation flexible digital radiography systems requiring high spatial resolution.

Accelerating and focusing protein-protein docking correlations using multi-dimensional rotational FFT generating functions.

PubMed

Ritchie, David W; Kozakov, Dima; Vajda, Sandor

2008-09-01

Predicting how proteins interact at the molecular level is a computationally intensive task. Many protein docking algorithms begin by using fast Fourier transform (FFT) correlation techniques to find putative rigid body docking orientations. Most such approaches use 3D Cartesian grids and are therefore limited to computing three dimensional (3D) translational correlations. However, translational FFTs can speed up the calculation in only three of the six rigid body degrees of freedom, and they cannot easily incorporate prior knowledge about a complex to focus and hence further accelerate the calculation. Furthemore, several groups have developed multi-term interaction potentials and others use multi-copy approaches to simulate protein flexibility, which both add to the computational cost of FFT-based docking algorithms. Hence there is a need to develop more powerful and more versatile FFT docking techniques. This article presents a closed-form 6D spherical polar Fourier correlation expression from which arbitrary multi-dimensional multi-property multi-resolution FFT correlations may be generated. The approach is demonstrated by calculating 1D, 3D and 5D rotational correlations of 3D shape and electrostatic expansions up to polynomial order L=30 on a 2 GB personal computer. As expected, 3D correlations are found to be considerably faster than 1D correlations but, surprisingly, 5D correlations are often slower than 3D correlations. Nonetheless, we show that 5D correlations will be advantageous when calculating multi-term knowledge-based interaction potentials. When docking the 84 complexes of the Protein Docking Benchmark, blind 3D shape plus electrostatic correlations take around 30 minutes on a contemporary personal computer and find acceptable solutions within the top 20 in 16 cases. Applying a simple angular constraint to focus the calculation around the receptor binding site produces acceptable solutions within the top 20 in 28 cases. Further constraining the

istar: a web platform for large-scale protein-ligand docking.

PubMed

Li, Hongjian; Leung, Kwong-Sak; Ballester, Pedro J; Wong, Man-Hon

2014-01-01

Protein-ligand docking is a key computational method in the design of starting points for the drug discovery process. We are motivated by the desire to automate large-scale docking using our popular docking engine idock and thus have developed a publicly-accessible web platform called istar. Without tedious software installation, users can submit jobs using our website. Our istar website supports 1) filtering ligands by desired molecular properties and previewing the number of ligands to dock, 2) monitoring job progress in real time, and 3) visualizing ligand conformations and outputting free energy and ligand efficiency predicted by idock, binding affinity predicted by RF-Score, putative hydrogen bonds, and supplier information for easy purchase, three useful features commonly lacked on other online docking platforms like DOCK Blaster or iScreen. We have collected 17,224,424 ligands from the All Clean subset of the ZINC database, and revamped our docking engine idock to version 2.0, further improving docking speed and accuracy, and integrating RF-Score as an alternative rescoring function. To compare idock 2.0 with the state-of-the-art AutoDock Vina 1.1.2, we have carried out a rescoring benchmark and a redocking benchmark on the 2,897 and 343 protein-ligand complexes of PDBbind v2012 refined set and CSAR NRC HiQ Set 24Sept2010 respectively, and an execution time benchmark on 12 diverse proteins and 3,000 ligands of different molecular weight. Results show that, under various scenarios, idock achieves comparable success rates while outperforming AutoDock Vina in terms of docking speed by at least 8.69 times and at most 37.51 times. When evaluated on the PDBbind v2012 core set, our istar platform combining with RF-Score manages to reproduce Pearson's correlation coefficient and Spearman's correlation coefficient of as high as 0.855 and 0.859 respectively between the experimental binding affinity and the predicted binding affinity of the docked conformation. istar

A flexible spatiotemporal method for fusing satellite images with different resolutions

Treesearch

Xiaolin Zhu; Eileen H. Helmer; Feng Gao; Desheng Liu; Jin Chen; Michael A. Lefsky

2016-01-01

Studies of land surface dynamics in heterogeneous landscapes often require remote sensing datawith high acquisition frequency and high spatial resolution. However, no single sensor meets this requirement. This study presents a new spatiotemporal data fusion method, the Flexible Spatiotemporal DAta Fusion (FSDAF) method, to generate synthesized frequent high spatial...

Overview of LIDS Docking Seals Development

NASA Technical Reports Server (NTRS)

Dunlap, Pat; Steinetz, Bruce; Daniels, Chris

2008-01-01

NASA is developing a new docking system to support future space exploration missions to low-Earth orbit, the Moon, and Mars. This mechanism, called the Low Impact Docking System (LIDS), is designed to connect pressurized space vehicles and structures including the Crew Exploration Vehicle, International Space Station, and lunar lander. NASA Glenn Research Center (GRC) is playing a key role in developing the main interface seal for this new docking system. These seals will be approximately 147 cm (58 in.) in diameter. GRC is evaluating the performance of candidate seal designs under simulated operating conditions at both sub-scale and full-scale levels. GRC is ultimately responsible for delivering flight hardware seals to NASA Johnson Space Center around 2013 for integration into LIDS flight units.

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

PubMed

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.

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

NASA Astrophysics Data System (ADS)

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.

Molecular dynamics, flexible docking, virtual screening, ADMET predictions, and molecular interaction field studies to design novel potential MAO-B inhibitors.

PubMed

Braun, Glaucia H; Jorge, Daniel M M; Ramos, Henrique P; Alves, Raquel M; da Silva, Vinicius B; Giuliatti, Silvana; Sampaio, Suley Vilela; Taft, Carlton A; Silva, Carlos H T P

2008-02-01

Monoamine oxidase is a flavoenzyme bound to the mitochondrial outer membranes of the cells, which is responsible for the oxidative deamination of neurotransmitter and dietary amines. It has two distinct isozymic forms, designated MAO-A and MAO-B, each displaying different substrate and inhibitor specificities. They are the well-known targets for antidepressant, Parkinson's disease, and neuroprotective drugs. Elucidation of the x-ray crystallographic structure of MAO-B has opened the way for the molecular modeling studies. In this work we have used molecular modeling, density functional theory with correlation, virtual screening, flexible docking, molecular dynamics, ADMET predictions, and molecular interaction field studies in order to design new molecules with potential higher selectivity and enzymatic inhibitory activity over MAO-B.

A measurement of the proton structure function F2( x, Q2) at low x and low Q2 at HERA

NASA Astrophysics Data System (ADS)

Adloff, C.; Aid, S.; Anderson, M.; Andreev, V.; Andrieu, B.; Arkadov, V.; Arndt, C.; Ayyaz, I.; Babaev, A.; Bähr, J.; Bán, J.; Ban, Y.; Baranov, P.; Barrelet, E.; Barschke, R.; Bartel, W.; Bassler, U.; Beck, H. P.; Beck, M.; Behrend, H.-J.; Belousov, A.; Berger, Ch.; Bernardi, G.; Bertrand-Coremans, G.; Beyer, R.; Biddulph, P.; Bispham, P.; Bizot, J. C.; Borras, K.; Botterweck, F.; Boudry, V.; Bourov, S.; Braemer, A.; Braunschweig, W.; Brisson, V.; Brückner, W.; Bruel, P.; Bruncko, D.; Brune, C.; Buchholz, R.; Büngener, L.; Bürger, J.; Büsser, F. W.; Buniatian, A.; Burke, S.; Burton, M. J.; Buschhorn, G.; Calvet, D.; Campbell, A. J.; Carli, T.; Charlet, M.; Clarke, D.; Clerbaux, B.; Cocks, S.; Contreras, J. G.; Cormack, C.; Coughlan, J. A.; Courau, A.; Cousinou, M.-C.; Cox, B. E.; Cozzika, G.; Cussans, D. G.; Cvach, J.; Dagoret, S.; Dainton, J. B.; Dau, W. D.; Daum, K.; David, M.; Davis, C. L.; De Roeck, A.; De Wolf, E. A.; Delcourt, B.; Dirkmann, M.; Dixon, P.; Dlugosz, W.; Dollfus, C.; Donovan, K. T.; Dowell, J. D.; Dreis, H. B.; Droutskoi, A.; Ebert, J.; Ebert, T. R.; Eckerlin, G.; Efremenko, V.; Egli, S.; Eichler, R.; Eisele, F.; Eisenhandler, E.; Elsen, E.; Erdmann, M.; Fahr, A. B.; Favart, L.; Fedotov, A.; Felst, R.; Feltesse, J.; Ferencei, J.; Ferrarotto, F.; Flamm, K.; Fleischer, M.; Flieser, M.; Flügge, G.; Fomenko, A.; Formánek, J.; Foster, J. M.; Franke, G.; Gabathuler, E.; Gabathuler, K.; Gaede, F.; Garvey, J.; Gayler, J.; Gebauer, M.; Genzel, H.; Gerhards, R.; Glazov, A.; Goerlich, L.; Gogitidze, N.; Goldberg, M.; Goldner, D.; Golec-Biernat, K.; Gonzalez-Pineiro, B.; Gorelov, I.; Grab, C.; Grässler, H.; Greenshaw, T.; Griffiths, R. K.; Grindhammer, G.; Gruber, A.; Gruber, C.; Hadig, T.; Haidt, D.; Hajduk, L.; Haller, T.; Hampel, M.; Haynes, W. J.; Heinemann, B.; Heinzelmann, G.; Henderson, R. C. W.; Henschel, H.; Herynek, I.; Hess, M. F.; Hewitt, K.; Hiller, K. H.; Hilton, C. D.; Hladký, J.; Höppner, M.; Hoffmann, D.; Holtom, T.; Horisberger, R.; Hudgson, V. L.; Hütte, M.; Ibbotson, M.; İşsever, Ç.; Itterbeck, H.; Jacholkowska, A.; Jacobsson, C.; Jacquet, M.; Jaffre, M.; Janoth, J.; Jansen, D. M.; Jönsson, L.; Johnson, D. P.; Jung, H.; Kalmus, P. I. P.; Kander, M.; Kant, D.; Kathage, U.; Katzy, J.; Kaufmann, H. H.; Kaufmann, O.; Kausch, M.; Kazarian, S.; Kenyon, I. R.; Kermiche, S.; Keuker, C.; Kiesling, C.; Klein, M.; Kleinwort, C.; Knies, G.; Köhler, T.; Köhne, J. H.; Kolanoski, H.; Kolya, S. D.; Korbel, V.; Kostka, P.; Kotelnikov, S. K.; Krämerkämper, T.; Krasny, M. W.; Krehbiel, H.; Krücker, D.; Küpper, A.; Küster, H.; Kuhlen, M.; Kurča, T.; Kurzhöfer, J.; Laforge, B.; Landon, M. P. J.; Lange, W.; Langenegger, U.; Lebedev, A.; Lehner, F.; Lemaitre, V.; Levonian, S.; Lindstroem, M.; Linsel, F.; Lipinski, J.; List, B.; Lobo, G.; Lomas, J. W.; Lopez, G. C.; Lubimov, V.; Lüke, D.; Lytkin, L.; Magnussen, N.; Mahlke-Krüger, H.; Malinovski, E.; Maraček, R.; Marage, P.; Marks, J.; Marshall, R.; Martens, J.; Martin, G.; Martin, R.; Martyn, H.-U.; Martyniak, J.; Mavroidis, T.; Maxfield, S. J.; McMahon, S. J.; Mehta, A.; Meier, K.; Merkel, P.; Metlica, F.; Meyer, A.; Meyer, A.; Meyer, H.; Meyer, J.; Meyer, P.-O.; Migliori, A.; Mikocki, S.; Milstead, D.; Moeck, J.; Moreau, F.; Morris, J. V.; Mroczko, E.; Müller, D.; Walter, T.; Müller, K.; Murín, P.; Nagovizin, V.; Nahnhauer, R.; Naroska, B.; Naumann, Th.; Négri, I.; Newman, P. R.; Newton, D.; Nguyen, H. K.; Nicholls, T. C.; Niebergall, F.; Niebuhr, C.; Niedzballa, Ch.; Niggli, H.; Nowak, G.; Nunnemann, T.; Nyberg-Werther, M.; Oberlack, H.; Olsson, J. E.; Ozerov, D.; Palmen, P.; Panaro, E.; Panitch, A.; Pascaud, C.; Passaggio, S.; Patel, G. D.; Pawletta, H.; Peppel, E.; Perez, E.; Phillips, J. P.; Pieuchot, A.; Pitzl, D.; Pöschl, R.; Pope, G.; Povh, B.; Prell, S.; Rabbertz, K.; Rädel, G.; Reimer, P.; Rick, H.; Riess, S.; Rizvi, E.; Robmann, P.; Roosen, R.; Rosenbauer, K.; Rostovtsev, A.; Rouse, F.; Royon, C.; Rüter, K.; Rusakov, S.; Rybicki, K.; Sankey, D. P. C.; Schacht, P.; Schiek, S.; Schleif, S.; Schleper, P.; von Schlippe, W.; Schmidt, D.; Schmidt, G.; Schoeffel, L.; Schöning, A.; Schröder, V.; Schuhmann, E.; Schwab, B.; Sefkow, F.; Semenov, A.; Shekelyan, V.; Sheviakov, I.; Shtarkov, L. N.; Siegmon, G.; Siewert, U.; Sirois, Y.; Skillicorn, I. O.; Sloan, T.; Smirnov, P.; Smith, M.; Solochenko, V.; Soloviev, Y.; Specka, A.; Spiekermann, J.; Spielman, S.; Spitzer, H.; Squinabol, F.; Steffen, P.; Steinberg, R.; Steinhart, J.; Stella, B.; Stellberger, A.; Stier, J.; Stiewe, J.; Stöβlein, U.; Stolze, K.; Straumann, U.; Struczinski, W.; Sutton, J. P.; Tapprogge, S.; Taševský, M.; Tchernyshov, V.; Tchetchelnitski, S.; Theissen, J.; Thompson, G.; Thompson, P. D.; Tobien, N.; Todenhagen, R.; Truöl, P.; Tsipolitis, G.; Turnau, J.; Tzamariudaki, E.; Uelkes, P.; Usik, A.; Valkár, S.; Valkárová, A.; Valĺee, C.; Van Esch, P.; Van Mechelen, P.; Vandenplas, D.; Vazdik, Y.; Verrecchia, P.; Villet, G.; Wacker, K.; Wagener, A.; Wagener, M.; Wallny, R.; Waugh, B.; Weber, G.; Weber, M.; Wegener, D.; Wegner, A.; Wengler, T.; Werner, M.; West, L. R.; Wiesand, S.; Wilksen, T.; Willard, S.; Winde, M.; Winter, G.-G.; Wittek, C.; Wobisch, M.; Wollatz, H.; Wünsch, E.; Žáček, J.; Zarbock, D.; Zhang, Z.; Zhokin, A.; Zini, P.; Zomer, F.; Zsembery, J.; zurNedden, M.; H1 Collaboration

1997-02-01

The results of a measurement of the proton structure function F2( x, Q2) and the virtual photon-proton cross section are reported for momentum transfers squared Q2 between 0.35 GeV 2 and 3.5 GeV 2 and for Bjorken- x values down to 6 × 10 -6 using data collected by the HERA experiment H1 in 1995. The data represent an increase in kinematic reach to lower x and Q2 values of about a factor of 5 compared to previous H1 measurements. Including measurements from fixed target experiments the rise of F2 with decreasing x is found to be less steep for the lowest Q2 values measured. Phenomenological models at low Q2 are compared with the data.

A super resolution framework for low resolution document image OCR

NASA Astrophysics Data System (ADS)

Ma, Di; Agam, Gady

2013-01-01

Optical character recognition is widely used for converting document images into digital media. Existing OCR algorithms and tools produce good results from high resolution, good quality, document images. In this paper, we propose a machine learning based super resolution framework for low resolution document image OCR. Two main techniques are used in our proposed approach: a document page segmentation algorithm and a modified K-means clustering algorithm. Using this approach, by exploiting coherence in the document, we reconstruct from a low resolution document image a better resolution image and improve OCR results. Experimental results show substantial gain in low resolution documents such as the ones captured from video.

Flexible Electrostatic Technology for Capture and Handling Project

NASA Technical Reports Server (NTRS)

Keys, Andrew; Bryan, Tom; Horwitz, Chris; Rakoczy, John; Waggoner, Jason

2015-01-01

To NASA unfunded & planned missions: This new capability to sense proximity, flexibly align to, and attractively grip and capture practically any object in space without any pre-designed physical features or added sensors or actuators will enable or enhance many of MSFC's strategic emphasis areas in space transportation, and space systems such as: 1. A Flexible Electrostatic gripper can enable the capture, gripping and releasing of an extraterrestrial sample of different minerals or a sample canister (metallic or composite) without requiring a handle or grapple fixture.(B) 2. Flexible self-aligning in-space capture/soft docking or berthing of ISS resupply vehicles, pressurized modules, or nodes for in-space assembly and shielding, radiator, and solar Array deployment for space habitats (C) 3. The flexible electrostatic gripper when combined with a simple steerable extendible boom can grip, position, and release objects of various shapes and materials with low mass and power without any prior handles or physical accommodations or surface contamination for ISS experiment experiments and in-situ repair.(F)(G) 4. The Dexterous Docking concept previously proposed to allow simple commercial resupply ships to station-keep and capture either ISS or an Exploration vehicle for supply or fluid transfer lacked a self-sensing, compliant, soft capture gripper like FETCH that could retract and attach to a CBM. (I) 5. To enable a soft capture and de-orbit of a piece of orbital debris will require self-aligning gripping and holding an object wherever possible (thermal coverings or shields of various materials, radiators, solar arrays, antenna dishes) with little or no residual power while adding either drag or active low level thrust.(K) 6. With the scalability of the FETCH technology, small satellites can be captured and handled or can incorporate FETCH gripper to dock to and handle other small vehicles and larger objects for de-orbiting or mitigating Orbital debris (L) 7. Many of

Development of robotics facility docking test hardware

NASA Technical Reports Server (NTRS)

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.

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

NASA Astrophysics Data System (ADS)

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.

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

PubMed

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.

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

PubMed

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

2017-11-01

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

High Resolution and Large Dynamic Range Resonant Pressure Sensor Based on Q-Factor Measurement

NASA Technical Reports Server (NTRS)

Gutierrez, Roman C. (Inventor); Stell, Christopher B. (Inventor); Tang, Tony K. (Inventor); Vorperian, Vatche (Inventor); Wilcox, Jaroslava (Inventor); Shcheglov, Kirill (Inventor); Kaiser, William J. (Inventor)

2000-01-01

A pressure sensor has a high degree of accuracy over a wide range of pressures. Using a pressure sensor relying upon resonant oscillations to determine pressure, a driving circuit drives such a pressure sensor at resonance and tracks resonant frequency and amplitude shifts with changes in pressure. Pressure changes affect the Q-factor of the resonating portion of the pressure sensor. Such Q-factor changes are detected by the driving/sensing circuit which in turn tracks the changes in resonant frequency to maintain the pressure sensor at resonance. Changes in the Q-factor are reflected in changes of amplitude of the resonating pressure sensor. In response, upon sensing the changes in the amplitude, the driving circuit changes the force or strength of the electrostatic driving signal to maintain the resonator at constant amplitude. The amplitude of the driving signals become a direct measure of the changes in pressure as the operating characteristics of the resonator give rise to a linear response curve for the amplitude of the driving signal. Pressure change resolution is on the order of 10(exp -6) torr over a range spanning from 7,600 torr to 10(exp -6) torr. No temperature compensation for the pressure sensor of the present invention is foreseen. Power requirements for the pressure sensor are generally minimal due to the low-loss mechanical design of the resonating pressure sensor and the simple control electronics.

Identifying Potential Protein Targets for Toluene Using a Molecular Similarity Search, in Silico Docking and in Vitro Validation

DTIC Science & Technology

2015-01-01

the Protein Data Bank (http://www.rcsb.org/ pdb /). These structures are the most accurate and can be used for molecular docking. Target flexibility is...crystallized with the different ligands. In total, 240 files with the structures of 37 proteins were downloaded from PDB and used for docking...total, 240 files with protein structures were downloaded from the PDB and used for protein–ligand docking. It is widely accepted that ligand binding

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

PubMed

Strecker, Claas; Meyer, Bernd

2018-05-29

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

NASA Docking System (NDS) Interface Definitions Document (IDD). Revision F, Dec. 15, 2011

NASA Technical Reports Server (NTRS)

Lewis, James

2011-01-01

The NASA Docking System (NDS) mating system supports low approach velocity docking and provides a modular and reconfigurable standard interface, supporting crewed and autonomous vehicles during mating and assembly operations. The NDS is NASA s implementation for the International Docking System Standard (IDSS) using low impact docking technology. All NDS configurations can mate with the configuration specified in the IDSS Interface Definition Document (IDD), Revision A, released May 13, 2011. The NDS evolved from the Low Impact Docking System (LIDS). The term (and its associated acronym), international Low Impact Docking System (iLIDS) is also used to describe this system. NDS and iLIDS may be used interchangeability. Some of the heritage documentation and implementations (e.g., software command names) used on the NDS will continue to use the LIDS acronym.

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

PubMed

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.

A flexible, highly sensitive catheter for high resolution manometry based on in-fibre Bragg gratings

NASA Astrophysics Data System (ADS)

Bueley, Christopher; Wild, Peter M.

2013-09-01

This work presents a fibre optic-based flexible catheter for high resolution manometry (HRM), with sensing pods located at a pitch of 10 mm and an overall diameter of 2.8 mm. In-fibre Bragg gratings act as the sensing elements within these sensing pods. Hydrodynamic pressure resolution of 0.2 mmHg is demonstrated in conjunction with insensitivity to occlusion pressure. This result is significant in the context of HRM where independent measurement of hydrodynamic pressure is clinically relevant. The sensing system is compact, robust and flexible. Crosstalk between individual sensors is characterized and a compensation scheme is developed and validated.

Structural analysis of a class III preQ 1 riboswitch reveals an aptamer distant from a ribosome-binding site regulated by fast dynamics

DOE PAGES

Liberman, Joseph A.; Suddala, Krishna C.; Aytenfisu, Asaminew; ...

2015-06-23

PreQ 1-III riboswitches are newly identified RNA elements that control bacterial genes in response to preQ 1 (7-aminomethyl-7-deazaguanine), a precursor to the essential hypermodified tRNA base queuosine. Although numerous riboswitches fold as H-type or HL out-type pseudoknots that integrate ligand-binding and regulatory sequences within a single folded domain, the preQ 1-III riboswitch aptamer forms a HL out-type pseudoknot that does not appear to incorporate its ribosome-binding site (RBS). To understand how this unusual organization confers function, in this paper we determined the crystal structure of the class III preQ 1 riboswitch from Faecalibacterium prausnitzii at 2.75 Å resolution. PreQ 1more » binds tightly (K D,app 6.5 ± 0.5 nM) between helices P1 and P2 of a three-way helical junction wherein the third helix, P4, projects orthogonally from the ligand-binding pocket, exposing its stem-loop to base pair with the 3' RBS. Biochemical analysis, computational modeling, and single-molecule FRET imaging demonstrated that preQ 1 enhances P4 reorientation toward P1–P2, promoting a partially nested, H-type pseudoknot in which the RBS undergoes rapid docking (k dock ~0.6 s -1) and undocking (k undock ~1.1 s -1). Finally, discovery of such dynamic conformational switching provides insight into how a riboswitch with bipartite architecture uses dynamics to modulate expression platform accessibility, thus expanding the known repertoire of gene control strategies used by regulatory RNAs.« less

Flexible high-resolution display systems for the next generation of radiology reading rooms

NASA Astrophysics Data System (ADS)

Caban, Jesus J.; Wood, Bradford J.; Park, Adrian

2007-03-01

A flexible, scalable, high-resolution display system is presented to support the next generation of radiology reading rooms or interventional radiology suites. The project aims to create an environment for radiologists that will simultaneously facilitate image interpretation, analysis, and understanding while lowering visual and cognitive stress. Displays currently in use present radiologists with technical challenges to exploring complex datasets that we seek to address. These include resolution and brightness, display and ambient lighting differences, and degrees of complexity in addition to side-by-side comparison of time-variant and 2D/3D images. We address these issues through a scalable projector-based system that uses our custom-designed geometrical and photometrical calibration process to create a seamless, bright, high-resolution display environment that can reduce the visual fatigue commonly experienced by radiologists. The system we have designed uses an array of casually aligned projectors to cooperatively increase overall resolution and brightness. Images from a set of projectors in their narrowest zoom are combined at a shared projection surface, thus increasing the global "pixels per inch" (PPI) of the display environment. Two primary challenges - geometric calibration and photometric calibration - remained to be resolved before our high-resolution display system could be used in a radiology reading room or procedure suite. In this paper we present a method that accomplishes those calibrations and creates a flexible high-resolution display environment that appears seamless, sharp, and uniform across different devices.

Flexible Electrostatic Technologies for Capture and Handling, Phase 1

NASA Technical Reports Server (NTRS)

Bryan, Thomas

2015-01-01

Fundamental to many of NASA's in-space transportation missions is the capture and handling of various objects and vehicles in various orbits for servicing, debris disposal, sample retrieval, and assembly without the benefit of sufficient grapple fixtures and docking ports. To perform similar material handling tasks on Earth, pincher grippers, suction grippers, or magnetic chucks are used, but are unable to reliably grip aluminum and composite spacecraft, insulation, radiators, solar arrays, or extra-terrestrial objects in the vacuum of outer space without dedicated handles in the right places. The electronic Flexible Electrostatic Technologies for space Capture and Handling (FETCH) will enable reliable and compliant gripping (soft dock) of practically any object in various orbits or surfaces without dedicated mechanical features, very low impact capture, and built-in proximity sensing without any conventional actuators. Originally developed to handle semiconductor and glass wafers during vacuum chamber processing without contamination, the normal rigid wafer handling chucks are replaced with thin metal foil segments laminated in flexible insulation driven by commercial off-the-shelf solid state, high-voltage power supplies. Preliminary testing in NASA Marshall Space Flight Center's (MSFC's) Flat Floor Robotics Lab demonstrated compliant alignment and gripping with a full-sized, 150-lb microsat mockup and translation before a clean release with a flip of a switch. The flexible electrostatic gripper pads can be adapted to various space applications with different sizes, shapes, and foil electrode layouts even with openings through the gripper pads for addition of guidance sensors or injection of permanent adhesives. With gripping forces estimated between 0.5 and 2.5 lb/in2 or 70-300 lb/ft2 of surface contact, the FETCH can turn on and off rapidly and repeatedly to enable sample handling, soft docking, in-space assembly, precision relocation, and surface translation

Hybrid Steered Molecular Dynamics-Docking: An Efficient Solution to the Problem of Ranking Inhibitor Affinities Against a Flexible Drug Target.

PubMed

Whalen, Katie L; Chang, Kevin M; Spies, M Ashley

2011-05-16

Existing techniques which attempt to predict the affinity of protein-ligand interactions have demonstrated a direct relationship between computational cost and prediction accuracy. We present here the first application of a hybrid ensemble docking and steered molecular dynamics scheme (with a minimized computational cost), which achieves a binding affinity rank-ordering of ligands with a Spearman correlation coefficient of 0.79 and an RMS error of 0.7 kcal/mol. The scheme, termed Flexible Enzyme Receptor Method by Steered Molecular Dynamics (FERM-SMD), is applied to an in-house collection of 17 validated ligands of glutamate racemase. The resulting improved accuracy in affinity prediction allows elucidation of the key structural components of a heretofore unreported glutamate racemase inhibitor (K(i) = 9 µM), a promising new lead in the development of antibacterial therapeutics.

Bridging ultrahigh-Q devices and photonic circuits

NASA Astrophysics Data System (ADS)

Yang, Ki Youl; Oh, Dong Yoon; Lee, Seung Hoon; Yang, Qi-Fan; Yi, Xu; Shen, Boqiang; Wang, Heming; Vahala, Kerry

2018-05-01

Optical microresonators are essential to a broad range of technologies and scientific disciplines. However, many of their applications rely on discrete devices to attain challenging combinations of ultra-low-loss performance (ultrahigh Q) and resonator design requirements. This prevents access to scalable fabrication methods for photonic integration and lithographic feature control. Indeed, finding a microfabrication bridge that connects ultrahigh-Q device functions with photonic circuits is a priority of the microcavity field. Here, an integrated resonator having a record Q factor over 200 million is presented. Its ultra-low-loss and flexible cavity design brings performance to integrated systems that has been the exclusive domain of discrete silica and crystalline microcavity devices. Two distinctly different devices are demonstrated: soliton sources with electronic repetition rates and high-coherence/low-threshold Brillouin lasers. This multi-device capability and performance from a single integrated cavity platform represents a critical advance for future photonic circuits and systems.

Message passing interface and multithreading hybrid for parallel molecular docking of large databases on petascale high performance computing machines.

PubMed

Zhang, Xiaohua; Wong, Sergio E; Lightstone, Felice C

2013-04-30

A mixed parallel scheme that combines message passing interface (MPI) and multithreading was implemented in the AutoDock Vina molecular docking program. The resulting program, named VinaLC, was tested on the petascale high performance computing (HPC) machines at Lawrence Livermore National Laboratory. To exploit the typical cluster-type supercomputers, thousands of docking calculations were dispatched by the master process to run simultaneously on thousands of slave processes, where each docking calculation takes one slave process on one node, and within the node each docking calculation runs via multithreading on multiple CPU cores and shared memory. Input and output of the program and the data handling within the program were carefully designed to deal with large databases and ultimately achieve HPC on a large number of CPU cores. Parallel performance analysis of the VinaLC program shows that the code scales up to more than 15K CPUs with a very low overhead cost of 3.94%. One million flexible compound docking calculations took only 1.4 h to finish on about 15K CPUs. The docking accuracy of VinaLC has been validated against the DUD data set by the re-docking of X-ray ligands and an enrichment study, 64.4% of the top scoring poses have RMSD values under 2.0 Å. The program has been demonstrated to have good enrichment performance on 70% of the targets in the DUD data set. An analysis of the enrichment factors calculated at various percentages of the screening database indicates VinaLC has very good early recovery of actives. Copyright © 2013 Wiley Periodicals, Inc.

Super-resolution biomolecular crystallography with low-resolution data.

PubMed

Schröder, Gunnar F; Levitt, Michael; Brunger, Axel T

2010-04-22

X-ray diffraction plays a pivotal role in the understanding of biological systems by revealing atomic structures of proteins, nucleic acids and their complexes, with much recent interest in very large assemblies like the ribosome. As crystals of such large assemblies often diffract weakly (resolution worse than 4 A), we need methods that work at such low resolution. In macromolecular assemblies, some of the components may be known at high resolution, whereas others are unknown: current refinement methods fail as they require a high-resolution starting structure for the entire complex. Determining the structure of such complexes, which are often of key biological importance, should be possible in principle as the number of independent diffraction intensities at a resolution better than 5 A generally exceeds the number of degrees of freedom. Here we introduce a method that adds specific information from known homologous structures but allows global and local deformations of these homology models. Our approach uses the observation that local protein structure tends to be conserved as sequence and function evolve. Cross-validation with R(free) (the free R-factor) determines the optimum deformation and influence of the homology model. For test cases at 3.5-5 A resolution with known structures at high resolution, our method gives significant improvements over conventional refinement in the model as monitored by coordinate accuracy, the definition of secondary structure and the quality of electron density maps. For re-refinements of a representative set of 19 low-resolution crystal structures from the Protein Data Bank, we find similar improvements. Thus, a structure derived from low-resolution diffraction data can have quality similar to a high-resolution structure. Our method is applicable to the study of weakly diffracting crystals using X-ray micro-diffraction as well as data from new X-ray light sources. Use of homology information is not restricted to X

Mapping flexible protein domains at subnanometer resolution with the atomic force microscope.

PubMed

Müller, D J; Fotiadis, D; Engel, A

1998-06-23

The mapping of flexible protein domains with the atomic force microscope is reviewed. Examples discussed are the bacteriorhodopsin from Halobacterium salinarum, the head-tail-connector from phage phi29, and the hexagonally packed intermediate layer from Deinococcus radiodurans which all were recorded in physiological buffer solution. All three proteins undergo reversible structural changes that are reflected in standard deviation maps calculated from aligned topographs of individual protein complexes. Depending on the lateral resolution (up to 0.8 nm) flexible surface regions can ultimately be correlated with individual polypeptide loops. In addition, multivariate statistical classification revealed the major conformations of the protein surface.

Overview of LIDS Docking and Berthing System Seals

NASA Technical Reports Server (NTRS)

Daniels, Christopher C.; Dunlap, Patrick H., Jr.; deGroh, Henry C., III; Steinetz, Bruce M.; Oswald, Jay J.; Smith, Ian

2007-01-01

This viewgraph presentation describes the Low Impact Docking System (LIDS) docking and berthing system seals. The contents include: 1) Description of the Application: Low Impact Docking System (LIDS); 2) LIDS Seal Locations: Vehicle Undocked (Hatch Closed); 3) LIDS Seal Locations: Mechanical Pass Thru; 4) LIDS Seal Locations: Electrical and Pyro Connectors; 5) LIDS Seal Locations: Vehicle Docked (Hatches Open); 6) LIDS Seal Locations: Main Interface Seal; 7) Main Interface Seal Challenges and Specifications; 8) Approach; 9) Seal Concepts Under Development/Evaluation; 10) Elastomer Material Evaluations; 11) Evaluation of Relevant Seal Properties; 12) Medium-Scale (12") Gask-O-Seal Compression Tests; 13) Medium-Scale Compression Results; 14) Adhesion Forces of Elliptical Top Gask-o-seals; 15) Medium-Scale Seals; 16) Medium-Scale Leakage Results: Effect of Configuration; 17) Full Scale LIDS Seal Test Rig Development; 18) Materials International Space Station Experiment (MISSE 6A and 6B); and 19) Schedule.

Attention Modifies Spatial Resolution According to Task Demands.

PubMed

Barbot, Antoine; Carrasco, Marisa

2017-03-01

How does visual attention affect spatial resolution? In texture-segmentation tasks, exogenous (involuntary) attention automatically increases resolution at the attended location, which improves performance where resolution is too low (at the periphery) but impairs performance where resolution is already too high (at central locations). Conversely, endogenous (voluntary) attention improves performance at all eccentricities, which suggests a more flexible mechanism. Here, using selective adaptation to spatial frequency, we investigated the mechanism by which endogenous attention benefits performance in resolution tasks. Participants detected a texture target that could appear at several eccentricities. Adapting to high or low spatial frequencies selectively affected performance in a manner consistent with changes in resolution. Moreover, adapting to high, but not low, frequencies mitigated the attentional benefit at central locations where resolution was too high; this shows that attention can improve performance by decreasing resolution. Altogether, our results indicate that endogenous attention benefits performance by modulating the contribution of high-frequency information in order to flexibly adjust spatial resolution according to task demands.

Hydra Rendezvous and Docking Sensor

NASA Technical Reports Server (NTRS)

Roe, Fred; Carrington, Connie

2007-01-01

sensor hardware trades, to address the needs of future vehicles that may rendezvous and dock with the International Space Station (ISS). It will also discuss approaches for upgrading AVGS to address parts obsolescence, and concepts for modularizing the sensor to provide configuration flexibility for multiple vehicle applications. Options for complementary sensors to be integrated into the multi-head Hydra system will also be presented. Complementary sensor options include ULTOR, a digital image correlator system that could provide relative six-degree-of-freedom information independently from AVGS, and time-of-flight sensors, which determine the range between vehicles by timing pulses that travel from the sensor to the target and back. Common targets and integrated targets, suitable for use with the multi-sensor options in Hydra, will also be addressed.

NASA Docking System (NDS) Interface Definitions Document (IDD). Revision C, Nov. 2010

NASA Technical Reports Server (NTRS)

2010-01-01

The NASA Docking System (NDS) mating system supports low approach velocity docking and provides a modular and reconfigurable standard interface, supporting crewed and autonomous vehicles during mating and assembly operations. The NDS is NASA's implementation for the emerging International Docking System Standard (IDSS) using low impact docking technology. All NDS configurations can mate with the configuration specified in the IDSS Interface Definition Document (IDD) released September 21, 2010. The NDS evolved from the Low Impact Docking System (LIDS). The acronym international Low Impact Docking System (iLIDS) is also used to describe this system. NDS and iLIDS may be used interchangeability. Some of the heritage documentation and implementations (e.g., software command names) used on NDS will continue to use the LIDS acronym. The NDS IDD defines the interface characteristics and performance capability of the NDS, including uses ranging from crewed to autonomous space vehicles and from low earth orbit to deep space exploration. The responsibility for developing space vehicles and for making them technically and operationally compatible with the NDS rests with the vehicle providers. Host vehicle examples include crewed/uncrewed spacecraft, space station modules, elements, etc. Within this document, any docking space vehicle will be referred to as the host vehicle. This document defines the NDS-to-NDS interfaces, as well as the NDS-to-host vehicle interfaces and performance capability.

smiFISH and FISH-quant - a flexible single RNA detection approach with super-resolution capability.

PubMed

Tsanov, Nikolay; Samacoits, Aubin; Chouaib, Racha; Traboulsi, Abdel-Meneem; Gostan, Thierry; Weber, Christian; Zimmer, Christophe; Zibara, Kazem; Walter, Thomas; Peter, Marion; Bertrand, Edouard; Mueller, Florian

2016-12-15

Single molecule FISH (smFISH) allows studying transcription and RNA localization by imaging individual mRNAs in single cells. We present smiFISH (single molecule inexpensive FISH), an easy to use and flexible RNA visualization and quantification approach that uses unlabelled primary probes and a fluorescently labelled secondary detector oligonucleotide. The gene-specific probes are unlabelled and can therefore be synthesized at low cost, thus allowing to use more probes per mRNA resulting in a substantial increase in detection efficiency. smiFISH is also flexible since differently labelled secondary detector probes can be used with the same primary probes. We demonstrate that this flexibility allows multicolor labelling without the need to synthesize new probe sets. We further demonstrate that the use of a specific acrydite detector oligonucleotide allows smiFISH to be combined with expansion microscopy, enabling the resolution of transcripts in 3D below the diffraction limit on a standard microscope. Lastly, we provide improved, fully automated software tools from probe-design to quantitative analysis of smFISH images. In short, we provide a complete workflow to obtain automatically counts of individual RNA molecules in single cells. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Orion Rendezvous, Proximity Operations, and Docking Design and Analysis

NASA Technical Reports Server (NTRS)

D'Souza, Christopher; Hanak, F. Chad; Spehar, Pete; Clark, Fred D.; Jackson, Mark

2007-01-01

The Orion vehicle will be required to perform rendezvous, proximity operations, and docking with the International Space Station (ISS) and the Earth Departure Stage (EDS)/Lunar Landing Vehicle (LLV) stack in Low Earth Orbit (LEO) as well as with the Lunar Landing Vehicle in Low Lunar Orbit (LLO). The RPOD system, which consists of sensors, actuators, and software is being designed to be flexible and robust enough to perform RPOD with different vehicles in different environments. This paper will describe the design and the analysis which has been performed to date to allow the vehicle to perform its mission. Since the RPOD design touches on many areas such as sensors selection and placement, trajectory design, navigation performance, and effector performance, it is inherently a systems design problem. This paper will address each of these issues in order to demonstrate how the Orion RPOD has been designed to accommodate and meet all the requirements levied on the system.

Teleportation of atomic and photonic states in low-Q cavity QED

NASA Astrophysics Data System (ADS)

Peng, Zhao-Hui; Zou, Jian; Liu, Xiao-Juan; Kuang, Le-Man

2012-11-01

We propose two alternative teleportation protocols in low-Q cavity QED. Through the input-output process of photons, we can generate atom-photon entangled states as the quantum channel. Then we propose to teleport single-atom (two-atom entangled) state using coherent photonic states, and to teleport single photonic state with the assistance of three-level atom. The distinct feature of our protocols is that we can teleport both atomic and photonic states via the input-output process of photons in the low-Q cavity. Furthermore, as our protocols work in low-Q cavities and only involve virtual excitation of atoms, they are insensitive to both cavity decay and atomic spontaneous emission, and may be feasible with current technology.

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

PubMed

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/.

Accounting for observed small angle X-ray scattering profile in the protein-protein docking server ClusPro.

PubMed

Xia, Bing; Mamonov, Artem; Leysen, Seppe; Allen, Karen N; Strelkov, Sergei V; Paschalidis, Ioannis Ch; Vajda, Sandor; Kozakov, Dima

2015-07-30

The protein-protein docking server ClusPro is used by thousands of laboratories, and models built by the server have been reported in over 300 publications. Although the structures generated by the docking include near-native ones for many proteins, selecting the best model is difficult due to the uncertainty in scoring. Small angle X-ray scattering (SAXS) is an experimental technique for obtaining low resolution structural information in solution. While not sufficient on its own to uniquely predict complex structures, accounting for SAXS data improves the ranking of models and facilitates the identification of the most accurate structure. Although SAXS profiles are currently available only for a small number of complexes, due to its simplicity the method is becoming increasingly popular. Since combining docking with SAXS experiments will provide a viable strategy for fairly high-throughput determination of protein complex structures, the option of using SAXS restraints is added to the ClusPro server. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

qSR: a quantitative super-resolution analysis tool reveals the cell-cycle dependent organization of RNA Polymerase I in live human cells.

PubMed

Andrews, J O; Conway, W; Cho, W -K; Narayanan, A; Spille, J -H; Jayanth, N; Inoue, T; Mullen, S; Thaler, J; Cissé, I I

2018-05-09

We present qSR, an analytical tool for the quantitative analysis of single molecule based super-resolution data. The software is created as an open-source platform integrating multiple algorithms for rigorous spatial and temporal characterizations of protein clusters in super-resolution data of living cells. First, we illustrate qSR using a sample live cell data of RNA Polymerase II (Pol II) as an example of highly dynamic sub-diffractive clusters. Then we utilize qSR to investigate the organization and dynamics of endogenous RNA Polymerase I (Pol I) in live human cells, throughout the cell cycle. Our analysis reveals a previously uncharacterized transient clustering of Pol I. Both stable and transient populations of Pol I clusters co-exist in individual living cells, and their relative fraction vary during cell cycle, in a manner correlating with global gene expression. Thus, qSR serves to facilitate the study of protein organization and dynamics with very high spatial and temporal resolutions directly in live cell.

Docking and scoring with ICM: the benchmarking results and strategies for improvement

PubMed Central

Neves, Marco A. C.; Totrov, Maxim; Abagyan, Ruben

2012-01-01

Flexible docking and scoring using the Internal Coordinate Mechanics software (ICM) was benchmarked for ligand binding mode prediction against the 85 co-crystal structures in the modified Astex data set. The ICM virtual ligand screening was tested against the 40 DUD target benchmarks and 11-target WOMBAT sets. The self-docking accuracy was evaluated for the top 1 and top 3 scoring poses at each ligand binding site with near native conformations below 2 Å RMSD found in 91% and 95% of the predictions, respectively. The virtual ligand screening using single rigid pocket conformations provided the median area under the ROC curves equal to 69.4 with 22.0% true positives recovered at 2% false positive rate. Significant improvements up to ROC AUC= 82.2 and ROC(2%)= 45.2 were achieved following our best practices for flexible pocket refinement and out-of-pocket binding rescore. The virtual screening can be further improved by considering multiple conformations of the target. PMID:22569591

SAMPL4 & DOCK3.7: lessons for automated docking procedures

NASA Astrophysics Data System (ADS)

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

2014-03-01

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

Characteristics of Low-q(a) Disruptions in the Compact Toroidal Hybrid

NASA Astrophysics Data System (ADS)

Pandya, M. D.; Archmiller, M. C.; Ennis, D. A.; Hartwell, G. J.; Maurer, D. A.

2014-10-01

Tokamak disruptions are dramatic events that lead to a sudden loss of plasma confinement. Disruptions that occur at low edge safety-factor, q (a) , limit the operation of tokamaks to q (a) >= 2 . The Compact Toroidal Hybrid (CTH) is a torsatron-tokamak hybrid with a helical field coil and vertical field coils to establish a stellartor equilibrium, while an ohmic coil induces plasma current. A feature of the CTH device is the ability to adjust the vacuum rotational transform, tvac (t =1/q ), by varying the ratio of current in the helical and toroidal field coils. The value of edge tvac can be varied from about 0.02 to 0.3 (qvac (a) ~ 50 to 3.3). Plasma discharges in CTH are routinely observed to operate with q (a) < 2 , and in some cases as low as q (a) ~ 1 . 1 . In CTH, low-q(a) disruptions are observed with a dominant m/n=3/2 precursor. The disruptivity of plasma discharges is over 80% when tvac (a) < 0 . 04 (qvac (a) < 25) and as tvac (a) is increased further, the disruptivity of the plasma discharges decreases. The disruptions are completely suppressed for tvac (a) > 0 . 07 (qvac (a) ~ 14) . This work is supported by US Department of Energy Grant No. DE-FG02-00ER54610.

Task-parallel message passing interface implementation of Autodock4 for docking of very large databases of compounds using high-performance super-computers.

PubMed

Collignon, Barbara; Schulz, Roland; Smith, Jeremy C; Baudry, Jerome

2011-04-30

A message passing interface (MPI)-based implementation (Autodock4.lga.MPI) of the grid-based docking program Autodock4 has been developed to allow simultaneous and independent docking of multiple compounds on up to thousands of central processing units (CPUs) using the Lamarkian genetic algorithm. The MPI version reads a single binary file containing precalculated grids that represent the protein-ligand interactions, i.e., van der Waals, electrostatic, and desolvation potentials, and needs only two input parameter files for the entire docking run. In comparison, the serial version of Autodock4 reads ASCII grid files and requires one parameter file per compound. The modifications performed result in significantly reduced input/output activity compared with the serial version. Autodock4.lga.MPI scales up to 8192 CPUs with a maximal overhead of 16.3%, of which two thirds is due to input/output operations and one third originates from MPI operations. The optimal docking strategy, which minimizes docking CPU time without lowering the quality of the database enrichments, comprises the docking of ligands preordered from the most to the least flexible and the assignment of the number of energy evaluations as a function of the number of rotatable bounds. In 24 h, on 8192 high-performance computing CPUs, the present MPI version would allow docking to a rigid protein of about 300K small flexible compounds or 11 million rigid compounds.

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

PubMed

Chakraborty, Sandeep

2014-01-01

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

Validation studies of the site-directed docking program LibDock.

PubMed

Rao, Shashidhar N; Head, Martha S; Kulkarni, Amit; LaLonde, Judith M

2007-01-01

The performance of the site-features docking algorithm LibDock has been evaluated across eight GlaxoSmithKline targets as a follow-up to a broad validation study of docking and scoring software (Warren, G. L.; Andrews, W. C.; Capelli, A.; Clarke, B.; Lalonde, J.; Lambert, M. H.; Lindvall, M.; Nevins, N.; Semus, S. F.; Senger, S.; Tedesco, G.; Walls, I. D.; Woolven, J. M.; Peishoff, C. E.; Head, M. S. J. Med. Chem. 2006, 49, 5912-5931). Docking experiments were performed to assess both the accuracy in reproducing the binding mode of the ligand and the retrieval of active compounds in a virtual screening protocol using both the DJD (Diller, D. J.; Merz, K. M., Jr. Proteins 2001, 43, 113-124) and LigScore2 (Krammer, A. K.; Kirchoff, P. D.; Jiang, X.; Venkatachalam, C. M.; Waldman, M. J. Mol. Graphics Modell. 2005, 23, 395-407) scoring functions. This study was conducted using DJD scoring, and poses were rescored using all available scoring functions in the Accelrys LigandFit module, including LigScore2. For six out of eight targets at least 30% of the ligands were docked within a root-mean-square difference (RMSD) of 2.0 A for the crystallographic poses when the LigScore2 scoring function was used. LibDock retrieved at least 20% of active compounds in the top 10% of screened ligands for four of the eight targets in the virtual screening protocol. In both studies the LigScore2 scoring function enhanced the retrieval of crystallographic poses or active compounds in comparison with the results obtained using the DJD scoring function. The results for LibDock accuracy and ligand retrieval in virtual screening are compared to 10 other docking and scoring programs. These studies demonstrate the utility of the LigScore2 scoring function and that LibDock as a feature directed docking method performs as well as docking programs that use genetic/growing and Monte Carlo driven algorithms.

Rational Drug Discovery of HCV Helicase Inhibitor: Improved Docking Accuracy with Multiple Seeding in AutoDock Vina and In Situ Minimization.

PubMed

Lim, See K; Othman, Rozana; Yusof, Rohana; Heh, Choon H

2017-01-01

Hepatitis C is a significant cause for end-stage liver diseases and liver transplantation which affects approximately 3% of the global populations. Despite the current several direct antiviral agents in the treatment of Hepatitis C, the standard treatment for HCV infection is accompanied by several drawbacks, such as adverse side effects, high pricing of medications and the rapid emerging rate of resistant HCV variants. To discover potential inhibitors for HCV helicase through an optimized in silico approach. In this study, a homology model (HCV Genotype 3 helicase) was used as the target and screened through a benzopyran-based virtual library. Multiple-seedings of AutoDock Vina and in situ minimization were to account for the non-deterministic nature of AutoDock Vina search algorithm and binding site flexibility, respectively. ADME/T and interaction analyses were also done on the top hits via FAFDRUG3 web server and Discovery Studio 4.5. This study involved the development of an improved flow for virtual screening via implemention of multiple-seeding screening approach and in situ minimization. With the new docking protocol, the redocked standards have shown better RMSD value in reference to their native conformations. Ten benzopyran-like compounds with satisfactory physicochemical properties were discovered to be potential inhibitors of HCV helicase. ZINC38649350 was identified as the most potential inhibitor. Ten potential HCV helicase inhibitors were discovered via a new docking optimization protocol with better docking accuracy. These findings could contribute to the discovery of novel HCV antivirals and serve as an alternative approach of in silico rational drug discovery. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Attention Modifies Spatial Resolution According to Task Demands

PubMed Central

Barbot, Antoine; Carrasco, Marisa

2017-01-01

How does visual attention affect spatial resolution? In texture-segmentation tasks, exogenous (involuntary) attention automatically increases resolution at the attended location, which improves performance where resolution is too low (at the periphery) but impairs performance where resolution is already too high (at central locations). Conversely, endogenous (voluntary) attention improves performance at all eccentricities, which suggests a more flexible mechanism. Here, using selective adaptation to spatial frequency, we investigated the mechanism by which endogenous attention benefits performance in resolution tasks. Participants detected a texture target that could appear at several eccentricities. Adapting to high or low spatial frequencies selectively affected performance in a manner consistent with changes in resolution. Moreover, adapting to high, but not low, frequencies mitigated the attentional benefit at central locations where resolution was too high; this shows that attention can improve performance by decreasing resolution. Altogether, our results indicate that endogenous attention benefits performance by modulating the contribution of high-frequency information in order to flexibly adjust spatial resolution according to task demands. PMID:28118103

The AVIRIS Low Altitude Option-An Approach to Increase Geometric Resolution and Improve Operational Flexibility Simultaneously

NASA Technical Reports Server (NTRS)

Sarture, Charles M.; Chovit, Christopher J.; Chrien, Thomas G.; Eastwood, Michael L.; Green, Robert O.; Kurzwell, Charles G.

1998-01-01

From 1987 through 1997 the Airborne Visible-InfraRed Imaging Spectrometer has matured into a remote sensing instrument capable of producing prodigious amounts of high quality data. Using the NASA/Ames ER-2 high altitude aircraft platform, flight operations have become very reliable as well. Being exclusively dependent on the ER-2, however, has limitations: the ER-2 has a narrow cruise envelope which fixes the AVIRIS ground pixel at 20 meters; it requires a significant support infrastructure; and it has a very limited number of bases it can operate from. In the coming years, the ER-2 will also become less available for AVIRIS flights as NASA Earth Observing System satellite underflights increase. Adapting AVIRIS to lower altitude, less specialized aircraft will create a much broader envelope for data acquisition, i.e., higher ground geometric resolution while maintaining nearly the ideal spatial sampling. This approach will also greatly enhance flexibility while decreasing the overall cost of flight operations and field support. Successful adaptation is expected to culminate with a one-month period of demonstration flights.

Mathematical model for the simulation of Dynamic Docking Test System (DDST) active table motion

NASA Technical Reports Server (NTRS)

Gates, R. M.; Graves, D. L.

1974-01-01

The mathematical model developed to describe the three-dimensional motion of the dynamic docking test system active table is described. The active table is modeled as a rigid body supported by six flexible hydraulic actuators which produce the commanded table motions.

Dry dock no. 4. Service Building between dry docks 4 ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Dry dock no. 4. Service Building between dry docks 4 and 5. Floor plans (Navy Yard Public Works Office 1941). In files of Cushman & Wakefield, building 501. Philadelphia Naval Business Center. - Naval Base Philadelphia-Philadelphia Naval Shipyard, Service Building, Dry Docks No. 4 & 5, League Island, Philadelphia, Philadelphia County, PA

A modular docking mechanism for in-orbit assembly and spacecraft servicing

NASA Technical Reports Server (NTRS)

Gampe, F.; Priesett, K.; Bentall, R. H.

1985-01-01

A Docking Mechanism concept is described which is suitable for use with autonomous docking systems. The central feature of using simple cylindrical handles on one side and a type of prism seating on the other is offered as a practical method of achieving a standardized structural interface without freezing continued development of the latches, either technically or commercially. The main emphasis in docking mechanism concepts is in two directions: (1) a very simple docking mechanism, involving mainly the latch mechanism to achieve a structural link; and (2) a sophisticated Docking Mechanism, where the latch mechanism is designed for nonrigid spacecraft and the achievement of very low dynamic interactions between spacecraft during the docking process.

HPEPDOCK: a web server for blind peptide-protein docking based on a hierarchical algorithm.

PubMed

Zhou, Pei; Jin, Bowen; Li, Hao; Huang, Sheng-You

2018-05-09

Protein-peptide interactions are crucial in many cellular functions. Therefore, determining the structure of protein-peptide complexes is important for understanding the molecular mechanism of related biological processes and developing peptide drugs. HPEPDOCK is a novel web server for blind protein-peptide docking through a hierarchical algorithm. Instead of running lengthy simulations to refine peptide conformations, HPEPDOCK considers the peptide flexibility through an ensemble of peptide conformations generated by our MODPEP program. For blind global peptide docking, HPEPDOCK obtained a success rate of 33.3% in binding mode prediction on a benchmark of 57 unbound cases when the top 10 models were considered, compared to 21.1% for pepATTRACT server. HPEPDOCK also performed well in docking against homology models and obtained a success rate of 29.8% within top 10 predictions. For local peptide docking, HPEPDOCK achieved a high success rate of 72.6% on a benchmark of 62 unbound cases within top 10 predictions, compared to 45.2% for HADDOCK peptide protocol. Our HPEPDOCK server is computationally efficient and consumed an average of 29.8 mins for a global peptide docking job and 14.2 mins for a local peptide docking job. The HPEPDOCK web server is available at http://huanglab.phys.hust.edu.cn/hpepdock/.

Molecular docking studies on tetrahydroimidazo-[4,5,1-jk][1,4]-benzodiazepinone (TIBO) derivatives as HIV-1 NNRT inhibitors

NASA Astrophysics Data System (ADS)

Sapre, Nitin S.; Gupta, Swagata; Pancholi, Nilanjana; Sapre, Neelima

2008-02-01

At present, chemotherapy seems to be the main weapon in the arsenal of remedies for the ongoing crusade against AIDS. The mode of binding of the TIBO family of inhibitors has been of interest because these compounds do not fit the two-hinged-ring model as generally observed in the NNRTIs. Flexible docking simulations were performed with a series of 53 TIBO derivatives as NNRTIs. Binding preferences as well as the structural and energetic factors associated with them were studied. A good correlation ( r 2 = 0.849, q 2 = 0.843) was observed between the biological activity and binding affinity of the compounds which suggest that the identified binding conformations of these inhibitors are reliable. Further screening of PubChem database yielded novel scaffolds. Our studies suggest that modifications to the TIBO group of inhibitors might enhance their binding efficacy and hence, potentially, their therapeutic utility.

Postprocessing of docked protein-ligand complexes using implicit solvation models.

PubMed

Lindström, Anton; Edvinsson, Lotta; Johansson, Andreas; Andersson, C David; Andersson, Ida E; Raubacher, Florian; Linusson, Anna

2011-02-28

Molecular docking plays an important role in drug discovery as a tool for the structure-based design of small organic ligands for macromolecules. Possible applications of docking are identification of the bioactive conformation of a protein-ligand complex and the ranking of different ligands with respect to their strength of binding to a particular target. We have investigated the effect of implicit water on the postprocessing of binding poses generated by molecular docking using MM-PB/GB-SA (molecular mechanics Poisson-Boltzmann and generalized Born surface area) methodology. The investigation was divided into three parts: geometry optimization, pose selection, and estimation of the relative binding energies of docked protein-ligand complexes. Appropriate geometry optimization afforded more accurate binding poses for 20% of the complexes investigated. The time required for this step was greatly reduced by minimizing the energy of the binding site using GB solvation models rather than minimizing the entire complex using the PB model. By optimizing the geometries of docking poses using the GB(HCT+SA) model then calculating their free energies of binding using the PB implicit solvent model, binding poses similar to those observed in crystal structures were obtained. Rescoring of these poses according to their calculated binding energies resulted in improved correlations with experimental binding data. These correlations could be further improved by applying the postprocessing to several of the most highly ranked poses rather than focusing exclusively on the top-scored pose. The postprocessing protocol was successfully applied to the analysis of a set of Factor Xa inhibitors and a set of glycopeptide ligands for the class II major histocompatibility complex (MHC) A(q) protein. These results indicate that the protocol for the postprocessing of docked protein-ligand complexes developed in this paper may be generally useful for structure-based design in drug discovery.

Protein-Protein Docking with F2Dock 2.0 and GB-Rerank

PubMed Central

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

High Resolution Image Reconstruction from Projection of Low Resolution Images DIffering in Subpixel Shifts

NASA Technical Reports Server (NTRS)

Mareboyana, Manohar; Le Moigne-Stewart, Jacqueline; Bennett, Jerome

2016-01-01

In this paper, we demonstrate a simple algorithm that projects low resolution (LR) images differing in subpixel shifts on a high resolution (HR) also called super resolution (SR) grid. The algorithm is very effective in accuracy as well as time efficiency. A number of spatial interpolation techniques using nearest neighbor, inverse-distance weighted averages, Radial Basis Functions (RBF) etc. used in projection yield comparable results. For best accuracy of reconstructing SR image by a factor of two requires four LR images differing in four independent subpixel shifts. The algorithm has two steps: i) registration of low resolution images and (ii) shifting the low resolution images to align with reference image and projecting them on high resolution grid based on the shifts of each low resolution image using different interpolation techniques. Experiments are conducted by simulating low resolution images by subpixel shifts and subsampling of original high resolution image and the reconstructing the high resolution images from the simulated low resolution images. The results of accuracy of reconstruction are compared by using mean squared error measure between original high resolution image and reconstructed image. The algorithm was tested on remote sensing images and found to outperform previously proposed techniques such as Iterative Back Projection algorithm (IBP), Maximum Likelihood (ML), and Maximum a posterior (MAP) algorithms. The algorithm is robust and is not overly sensitive to the registration inaccuracies.

Docking system for spacecraft

NASA Technical Reports Server (NTRS)

Kahn, Jon B. (Inventor)

1988-01-01

A mechanism is disclosed for the docking of a spacecraft to a space station where a connection for transfer of personnel and equipment is desired. The invention comprises an active docking structure on a spacecraft and a passive docking structure on the station. The passive structure includes a docking ring mounted on a tunnel structure fixed to the space station. The active structure includes a docking ring carried by an actuator-attenuator devices, each attached at one end to the ring and at its other end in the spacecraft payload bay. The devices respond to command signals for moving the docking ring between a stowed position in the spacecraft to a deployed position suitable for engagement with the docking ring. The devices comprise means responsive to signals of sensed loadings to absorb impact energy and retraction means for drawing the coupled spacecraft and station into final docked configuration and moving the tunnel structure to a berthed position in the spacecraft. Latches couple the spacecraft and space station upon contact of the docking rings and latches establish a structural tie between the spacecraft when retracted.

Boom Rendezvous Alternative Docking Approach

NASA Technical Reports Server (NTRS)

Bonometti, Joseph A.

2006-01-01

Space rendezvous and docking has always been attempted with primarily one philosophic methodology. The slow matching of one vehicle's orbit by a second vehicle and then a final closing sequence that ends in matching the orbits with perfect precision and with near zero relative velocities. The task is time consuming, propellant intensive, risk inherent (plume impingement, collisions, fuel depletion, etc.) and requires substantial hardware mass. The historical background and rationale as to why this approach is used is discussed in terms of the path-not-taken and in light of an alternate methodology. Rendezvous and docking by boom extension is suggested to have inherent advantages that today s technology can readily exploit. Extension from the primary spacecraft, beyond its inherent large inertia, allows low inertia connections to be made rapidly and safely. Plume contamination issues are eliminated as well as the extra propellant mass and risk required for the final thruster (docking) operations. Space vehicle connection hardware can be significantly lightened. Also, docking sensors and controls require less fidelity; allowing them to be more robust and less sensitive. It is the potential safety advantage and mission risk reduction that makes this approach attractive, besides the prospect of nominal time and mass savings.

Development of Low Density, Flexible Carbon Phenolic Ablators

NASA Technical Reports Server (NTRS)

Stackpoole, Mairead; Thornton, Jeremy; Fan, Wendy; Covington, Alan; Doxtad, Evan; Beck, Robin; Gasch, Matt; Arnold, Jim

2012-01-01

Phenolic Impregnated Carbon Ablator (PICA) was the enabling TPS material for the Stardust mission where it was used as a single piece heatshield. PICA has the advantages of low density (approximately 0.27 grams per cubic centimeter) coupled with efficient ablative capability at high heat fluxes. Due to its brittle nature and low strain to failure recent efforts at NASA ARC have focused on alternative architectures to yield flexible and more conformal carbon phenolic materials with comparable densities to PICA. This presentation will discuss flexible alternatives to PICA and include preliminary mechanical and thermal properties as well as recent arc jet and LHMEL screening test results.

PtdIns(4,5)P2 is not required for secretory granule docking.

PubMed

Omar-Hmeadi, Muhmmad; Gandasi, Nikhil R; Barg, Sebastian

2018-06-01

Phosphoinositides (PtdIns) play important roles in exocytosis and are thought to regulate secretory granule docking by co-clustering with the SNARE protein syntaxin to form a docking receptor in the plasma membrane. Here we tested this idea by high-resolution total internal reflection imaging of EGFP-labeled PtdIns markers or syntaxin-1 at secretory granule release sites in live insulin-secreting cells. In intact cells, PtdIns markers distributed evenly across the plasma membrane with no preference for granule docking sites. In contrast, syntaxin-1 was found clustered in the plasma membrane, mostly beneath docked granules. We also observed rapid accumulation of syntaxin-1 at sites where granules arrived to dock. Acute depletion of plasma membrane phosphatidylinositol (4,5) bisphosphate (PtdIns(4,5)P 2 ) by recruitment of a 5'-phosphatase strongly inhibited Ca 2+ -dependent exocytosis, but had no effect on docked granules or the distribution and clustering of syntaxin-1. Cell permeabilization by α-toxin or formaldehyde-fixation caused PtdIns marker to slowly cluster, in part near docked granules. In summary, our data indicate that PtdIns(4,5)P 2 accelerates granule priming, but challenge a role of PtdIns in secretory granule docking or clustering of syntaxin-1 at the release site. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Lessons learned in induced fit docking and metadynamics in the Drug Design Data Resource Grand Challenge 2

NASA Astrophysics Data System (ADS)

Baumgartner, Matthew P.; Evans, David A.

2018-01-01

Two of the major ongoing challenges in computational drug discovery are predicting the binding pose and affinity of a compound to a protein. The Drug Design Data Resource Grand Challenge 2 was developed to address these problems and to drive development of new methods. The challenge provided the 2D structures of compounds for which the organizers help blinded data in the form of 35 X-ray crystal structures and 102 binding affinity measurements and challenged participants to predict the binding pose and affinity of the compounds. We tested a number of pose prediction methods as part of the challenge; we found that docking methods that incorporate protein flexibility (Induced Fit Docking) outperformed methods that treated the protein as rigid. We also found that using binding pose metadynamics, a molecular dynamics based method, to score docked poses provided the best predictions of our methods with an average RMSD of 2.01 Å. We tested both structure-based (e.g. docking) and ligand-based methods (e.g. QSAR) in the affinity prediction portion of the competition. We found that our structure-based methods based on docking with Smina (Spearman ρ = 0.614), performed slightly better than our ligand-based methods (ρ = 0.543), and had equivalent performance with the other top methods in the competition. Despite the overall good performance of our methods in comparison to other participants in the challenge, there exists significant room for improvement especially in cases such as these where protein flexibility plays such a large role.

Low NOx Fuel Flexible Combustor Integration Project Overview

NASA Technical Reports Server (NTRS)

Walton, Joanne C.; Chang, Clarence T.; Lee, Chi-Ming; Kramer, Stephen

2015-01-01

The Integrated Technology Demonstration (ITD) 40A Low NOx Fuel Flexible Combustor Integration development is being conducted as part of the NASA Environmentally Responsible Aviation (ERA) Project. Phase 2 of this effort began in 2012 and will end in 2015. This document describes the ERA goals, how the fuel flexible combustor integration development fulfills the ERA combustor goals, and outlines the work to be conducted during project execution.

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

NASA Astrophysics Data System (ADS)

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.

Docking system for spacecraft

NASA Technical Reports Server (NTRS)

Kahn, Jon B. (Inventor)

1990-01-01

A mechanism for the docking of a space vehicle to a space station where a connection for transfer of personnel and equipment is desired. The invention comprises an active docking structure on a space vehicle 10 and a passive docking structure on a station 11. The passive structure includes a docking ring 50 mounted on a tunnel structure 35 fixed to the space station. The active structure including a docking ring 18 carried by actuator-attenuator devices 20, each attached at one end to the ring 18 and at its other end in the vehicle's payload bay 12. The devices 20 respond to command signals for moving the docking ring 18 between a stowed position in the space vehicle to a deployed position suitable for engagement with the docking ring 50. The devices 20 comprise means responsive to signals of sensed loadings to absorb impact energy and retraction means for drawing the coupled space vehicle and station into final docked configuration and moving the tunnel structure to a berthed position in the space vehicle 10. Latches 60 couple the space vehicle and space station upon contact of docking rings 18 and 50 and latches 41-48 establish a structural tie between the spacecraft when retracted.

Comparing Evolutionary Programs and Evolutionary Pattern Search Algorithms: A Drug Docking Application

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hart, W.E.

1999-02-10

Evolutionary programs (EPs) and evolutionary pattern search algorithms (EPSAS) are two general classes of evolutionary methods for optimizing on continuous domains. The relative performance of these methods has been evaluated on standard global optimization test functions, and these results suggest that EPSAs more robustly converge to near-optimal solutions than EPs. In this paper we evaluate the relative performance of EPSAs and EPs on a real-world application: flexible ligand binding in the Autodock docking software. We compare the performance of these methods on a suite of docking test problems. Our results confirm that EPSAs and EPs have comparable performance, and theymore » suggest that EPSAs may be more robust on larger, more complex problems.« less

Magnetic Microcalorimeters with Ultra-High Energy Resolution (FY17 Q2 report)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Friedrich, S.; Ramos, Chris

We will continue to characterize the Ag:Er MMC in detail to compare it with existing models and understand its limiting performance, both in New Mexico and at LLNL. For best resolution, it will be important to reduce external electromagnetic interference and ensure good thermal coupling to the cryostat. Improved resolution will be important for our presentations at the LTD-17 conference in Japan in Q3. We have also hired Cameron Flynn, a junior in physics at the university of New Hampshire, as a summer student to work on the MMC detector project. If he turns out to be as smart andmore » as strong in the lab as his letters of recommendation and his interview performance suggests, we will try to attract him into one of the bay area universities for his Ph.D. and recruit him to LLNL for his thesis research.« less

DockRank: Ranking docked conformations using partner-specific sequence homology-based protein interface prediction

PubMed Central

Xue, Li C.; Jordan, Rafael A.; EL-Manzalawy, Yasser; Dobbs, Drena; Honavar, Vasant

2015-01-01

Selecting near-native conformations from the immense number of conformations generated by docking programs remains a major challenge in molecular docking. We introduce DockRank, a novel approach to scoring docked conformations based on the degree to which the interface residues of the docked conformation match a set of predicted interface residues. Dock-Rank uses interface residues predicted by partner-specific sequence homology-based protein–protein interface predictor (PS-HomPPI), which predicts the interface residues of a query protein with a specific interaction partner. We compared the performance of DockRank with several state-of-the-art docking scoring functions using Success Rate (the percentage of cases that have at least one near-native conformation among the top m conformations) and Hit Rate (the percentage of near-native conformations that are included among the top m conformations). In cases where it is possible to obtain partner-specific (PS) interface predictions from PS-HomPPI, DockRank consistently outperforms both (i) ZRank and IRAD, two state-of-the-art energy-based scoring functions (improving Success Rate by up to 4-fold); and (ii) Variants of DockRank that use predicted interface residues obtained from several protein interface predictors that do not take into account the binding partner in making interface predictions (improving success rate by up to 39-fold). The latter result underscores the importance of using partner-specific interface residues in scoring docked conformations. We show that DockRank, when used to re-rank the conformations returned by ClusPro, improves upon the original ClusPro rankings in terms of both Success Rate and Hit Rate. DockRank is available as a server at http://einstein.cs.iastate.edu/DockRank/. PMID:23873600

DockRank: ranking docked conformations using partner-specific sequence homology-based protein interface prediction.

PubMed

Xue, Li C; Jordan, Rafael A; El-Manzalawy, Yasser; Dobbs, Drena; Honavar, Vasant

2014-02-01

Selecting near-native conformations from the immense number of conformations generated by docking programs remains a major challenge in molecular docking. We introduce DockRank, a novel approach to scoring docked conformations based on the degree to which the interface residues of the docked conformation match a set of predicted interface residues. DockRank uses interface residues predicted by partner-specific sequence homology-based protein-protein interface predictor (PS-HomPPI), which predicts the interface residues of a query protein with a specific interaction partner. We compared the performance of DockRank with several state-of-the-art docking scoring functions using Success Rate (the percentage of cases that have at least one near-native conformation among the top m conformations) and Hit Rate (the percentage of near-native conformations that are included among the top m conformations). In cases where it is possible to obtain partner-specific (PS) interface predictions from PS-HomPPI, DockRank consistently outperforms both (i) ZRank and IRAD, two state-of-the-art energy-based scoring functions (improving Success Rate by up to 4-fold); and (ii) Variants of DockRank that use predicted interface residues obtained from several protein interface predictors that do not take into account the binding partner in making interface predictions (improving success rate by up to 39-fold). The latter result underscores the importance of using partner-specific interface residues in scoring docked conformations. We show that DockRank, when used to re-rank the conformations returned by ClusPro, improves upon the original ClusPro rankings in terms of both Success Rate and Hit Rate. DockRank is available as a server at http://einstein.cs.iastate.edu/DockRank/. Copyright © 2013 Wiley Periodicals, Inc.

A Comparison of Candidate Seal Designs for Future Docking Systems

NASA Technical Reports Server (NTRS)

Dunlap, Patrick, H., Jr.; Steinetz, Bruce, M.

2012-01-01

NASA is developing a new docking system to support future space exploration missions to low Earth orbit, the Moon, and other destinations. A key component of this system is the seal at the main docking interface which inhibits the loss of cabin air once docking is complete. Depending on the mission, the seal must be able to dock in either a seal-on-flange or seal-on-seal configuration. Seal-on-flange mating would occur when a docking system equipped with a seal docks to a system with a flat metal flange. This would occur when a vehicle docks to a node on the International Space Station. Seal-on-seal mating would occur when two docking systems equipped with seals dock to each other. Two types of seal designs were identified for this application: Gask-O-seals and multi-piece seals. Both types of seals had a pair of seal bulbs to satisfy the redundancy requirement. A series of performance assessments and comparisons were made between the candidate seal designs indicating that they meet the requirements for leak rate and compression and adhesion loads under a range of operating conditions. Other design factors such as part count, integration into the docking system tunnel, seal-on-seal mating, and cost were also considered leading to the selection of the multi-piece seal design for the new docking system. The results of this study can be used by designers of future docking systems and other habitable volumes to select the seal design best-suited for their particular application.

Comparative evaluation of several docking tools for docking small molecule ligands to DC-SIGN.

PubMed

Jug, Gregor; Anderluh, Marko; Tomašič, Tihomir

2015-06-01

Five docking tools, namely AutoDock, FRED, CDOCKER, FlexX and GOLD, have been critically examined, with the aim of selecting those most appropriate for use as docking tools for docking molecules to the lectin dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN). This lectin has been selected for its rather non-druggable binding site, which enables complex interactions that guide the binding of the core monosaccharide. Since optimal orientation is crucial for forming coordination bonds, it was important to assess whether the selected docking tools could reproduce the optimal binding conformation for several oligosaccharides that are known to bind DC-SIGN. Our results show that even widely used docking programs have certain limitations when faced with a rather shallow and featureless binding site, as is the case of DC-SIGN. The FRED docking software (OpenEye Scientific Software, Inc.) was found to score as the best tool for docking ligands to DC-SIGN. The performance of FRED was further assessed on another lectin, Langerin. We have demonstrated that this validated docking protocol could be used for docking to other lectins similar to DC-SIGN.

Microgravity experiments of nano-satellite docking mechanism for final rendezvous approach and docking phase

NASA Astrophysics Data System (ADS)

Ui, Kyoichi; Matunaga, Saburo; Satori, Shin; Ishikawa, Tomohiro

2005-09-01

Laboratory for Space Systems (LSS), Tokyo Institute of Technology (Tokyo Tech) conducted three-dimensional microgravity environment experiments about a docking mechanism for mothership-daughtership (MS-DS) nano-satellite using the facility of Japan Micro Gravity Center (JAMIC) with Hokkaido Institute of Technology (HIT). LSS has studied and developed a docking mechanism for MS-DS nano-satellite system in final rendezvous approach and docking phase since 2000. Consideration of the docking mechanism is to mate a nano-satellite stably while remaining control error of relative velocity and attitude because it is difficult for nano-satellite to have complicated attitude control and mating systems. Objective of the experiments is to verify fundamental grasping function based on our proposed docking methodology. The proposed docking sequence is divided between approach/grasping phase and guiding phase. In the approach/grasping phase, the docking mechanism grasps the nano-satellite even though the nano-satellite has relative position and attitude control errors as well as relative velocity in a docking space. In the guiding function, the docking mechanism guides the nano-satellite to a docking port while adjusting its attitude in order to transfer electrical power and fuel to the nano-satellite. In the paper, we describe the experimental system including the docking mechanism, control system, the daughtership system and the release mechanism, and describe results of microgravity experiments in JAMIC.

Simulations of Low-q Disruptions in the Compact Toroidal Hybrid Experiment

NASA Astrophysics Data System (ADS)

Howell, E. C.; Hanson, J. D.; Ennis, D. A.; Hartwell, G. J.; Maurer, D. A.

2017-10-01

Resistive MHD simulations of low-q disruptions in the Compact Toroidal Hybrid Device (CTH) are performed using the NIMROD code. CTH is a current-carrying stellarator used to study the effects of 3D shaping on MHD stability. Experimentally, it is observed that the application of 3D vacuum fields allows CTH to operate with edge safety factor less than 2.0. However, these low-q discharges often disrupt after peak current if the applied 3D fields are too weak. Nonlinear simulations are initialized using model VMEC equilibria representative of low-q discharges with weak vacuum transform. Initially a series of symmetry preserving island chains are excited at the q=6/5, 7/5, 8/5, and 9/5 rational surfaces. These island chains act as transport barriers preventing stochastic magnetic fields in the edge from penetrating into the core. As the simulation progresses, predominately m/n=3/2 and 4/3 instabilities are destabilized. As these instabilities grow to large amplitude they destroy the symmetry preserving islands leading to large regions of stochastic fields. A current spike and loss of core thermal confinement occurs when the innermost island chain (6/5) is destroyed. Work Supported by US-DOE Grant #DE-FG02-03ER54692.

Rational design of methicillin resistance staphylococcus aureus inhibitors through 3D-QSAR, molecular docking and molecular dynamics simulations.

PubMed

Ballu, Srilata; Itteboina, Ramesh; Sivan, Sree Kanth; Manga, Vijjulatha

2018-04-01

Staphylococcus aureus is a gram positive bacterium. It is the leading cause of skin and respiratory infections, osteomyelitis, Ritter's disease, endocarditis, and bacteraemia in the developed world. We employed combined studies of 3D QSAR, molecular docking which are validated by molecular dynamics simulations and in silico ADME prediction have been performed on Isothiazoloquinolones inhibitors against methicillin resistance Staphylococcus aureus. Three-dimensional quantitative structure-activity relationship (3D-QSAR) study was applied using comparative molecular field analysis (CoMFA) with Q 2 of 0.578, R 2 of 0.988, and comparative molecular similarity indices analysis (CoMSIA) with Q 2 of 0.554, R 2 of 0.975. The predictive ability of these model was determined using a test set of molecules that gave acceptable predictive correlation (r 2 Pred) values 0.55 and 0.57 of CoMFA and CoMSIA respectively. Docking, simulations were employed to position the inhibitors into protein active site to find out the most probable binding mode and most reliable conformations. Developed models and Docking methods provide guidance to design molecules with enhanced activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Design-Based Peptidomimetic Ligand Discovery to Target HIV TAR RNA Using Comparative Analysis of Different Docking Methods.

PubMed

Fu, Junjie; Xia, Amy; Dai, Yao; Qi, Xin

2016-01-01

Discovering molecules capable of binding to HIV trans-activation responsive region (TAR) RNA thereby disrupting its interaction with Tat protein is an attractive strategy for developing novel antiviral drugs. Computational docking is considered as a useful tool for predicting binding affinity and conducting virtual screening. Although great progress in predicting protein-ligand interactions has been achieved in the past few decades, modeling RNA-ligand interactions is still largely unexplored due to the highly flexible nature of RNA. In this work, we performed molecular docking study with HIV TAR RNA using previously identified cyclic peptide L22 and its analogues with varying affinities toward HIV-1 TAR RNA. Furthermore, sarcosine scan was conducted to generate derivatives of CGP64222, a peptide-peptoid hybrid with inhibitory activity on Tat/TAR RNA interaction. Each compound was docked using CDOCKER, Surflex-Dock and FlexiDock to compare the effectiveness of each method. It was found that FlexiDock energy values correlated well with the experimental Kd values and could be used to predict the affinity of the ligands toward HIV-1 TAR RNA with a superior accuracy. Our results based on comparative analysis of different docking methods in RNA-ligand modeling will facilitate the structure-based discovery of HIV TAR RNA ligands for antiviral therapy.

Data-Driven Learning of Q-Matrix

PubMed Central

Liu, Jingchen; Xu, Gongjun; Ying, Zhiliang

2013-01-01

The recent surge of interests in cognitive assessment has led to developments of novel statistical models for diagnostic classification. Central to many such models is the well-known Q-matrix, which specifies the item–attribute relationships. This article proposes a data-driven approach to identification of the Q-matrix and estimation of related model parameters. A key ingredient is a flexible T-matrix that relates the Q-matrix to response patterns. The flexibility of the T-matrix allows the construction of a natural criterion function as well as a computationally amenable algorithm. Simulations results are presented to demonstrate usefulness and applicability of the proposed method. Extension to handling of the Q-matrix with partial information is presented. The proposed method also provides a platform on which important statistical issues, such as hypothesis testing and model selection, may be formally addressed. PMID:23926363

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

DTIC Science & Technology

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...Budget Defense Acquisition Management Information Retrieval (DAMIR) March 8, 2016 11:18:10 UNCLASSIFIED LPD 17 December 2015 SAR March 8, 2016 11:18:10... SAR March 8, 2016 11:18:10 UNCLASSIFIED 3 PB - President’s Budget PE - Program Element PEO - Program Executive Officer PM - Program Manager POE

Light resonances and the low-q2 bin of RK*$$ {R}_{K^{*}} $$

DOE Office of Scientific and Technical Information (OSTI.GOV)

Altmannshofer, Wolfgang; Baker, Michael J.; Gori, Stefania

LHCb has reported hints of lepton-flavor universality violation in the rare decaysmore » $$B \\to K^{(*)} \\ell^+\\ell^-$$, both in high- and low-$q^2$ bins. Although the high-$q^2$ hint may be explained by new short-ranged interactions, the low-$q^2$ one cannot. We thus explore the possibility that the latter is explained by a new light resonance. We find that LHCb's central value of $$R_{K^*}$$ in the low-$q^2$ bin is achievable in a restricted parameter space of new-physics scenarios in which the new, light resonance decays preferentially to electrons and has a mass within approximately $10$ MeV of the di-muon threshold. Interestingly, such an explanation can have a kinematic origin and does not require a source of lepton-flavor universality violation. A model-independent prediction is a narrow peak in the differential $$B \\to K^* e^+e^-$$ rate close to the di-muon threshold. If such a peak is observed, other observables, such as the differential $$B \\to K e^+e^-$$ rate and $$R_K$$, may be employed to distinguish between models. However, if a low-mass resonance is not observed and the low-$q^2$ anomaly increases in significance, then the case for an experimental origin of the lepton-flavor universality violating anomalies would be strengthened. Finally, to further explore this, we also point out that, in analogy to $$J/\\psi$$ decays, $e^+e^-$ and $$\\mu^+\\mu^-$$ decays of $$\\phi$$ mesons can be used as a cross check of lepton-flavor universality by LHCb with $5$ fb$$^{-1}$$ of integrated luminosity.« less

Light resonances and the low-q2 bin of RK*$$ {R}_{K^{*}} $$

DOE PAGES

Altmannshofer, Wolfgang; Baker, Michael J.; Gori, Stefania; ...

2018-03-29

LHCb has reported hints of lepton-flavor universality violation in the rare decaysmore » $$B \\to K^{(*)} \\ell^+\\ell^-$$, both in high- and low-$q^2$ bins. Although the high-$q^2$ hint may be explained by new short-ranged interactions, the low-$q^2$ one cannot. We thus explore the possibility that the latter is explained by a new light resonance. We find that LHCb's central value of $$R_{K^*}$$ in the low-$q^2$ bin is achievable in a restricted parameter space of new-physics scenarios in which the new, light resonance decays preferentially to electrons and has a mass within approximately $10$ MeV of the di-muon threshold. Interestingly, such an explanation can have a kinematic origin and does not require a source of lepton-flavor universality violation. A model-independent prediction is a narrow peak in the differential $$B \\to K^* e^+e^-$$ rate close to the di-muon threshold. If such a peak is observed, other observables, such as the differential $$B \\to K e^+e^-$$ rate and $$R_K$$, may be employed to distinguish between models. However, if a low-mass resonance is not observed and the low-$q^2$ anomaly increases in significance, then the case for an experimental origin of the lepton-flavor universality violating anomalies would be strengthened. Finally, to further explore this, we also point out that, in analogy to $$J/\\psi$$ decays, $e^+e^-$ and $$\\mu^+\\mu^-$$ decays of $$\\phi$$ mesons can be used as a cross check of lepton-flavor universality by LHCb with $5$ fb$$^{-1}$$ of integrated luminosity.« less

Flexible palladium-based H2 sensor with fast response and low leakage detection by nanoimprint lithography.

PubMed

Lim, Su Hui; Radha, Boya; Chan, Jie Yong; Saifullah, Mohammad S M; Kulkarni, Giridhar U; Ho, Ghim Wei

2013-08-14

Flexible palladium-based H2 sensors have a great potential in advanced sensing applications, as they offer advantages such as light weight, space conservation, and mechanical durability. Despite these advantages, the paucity of such sensors is due to the fact that they are difficult to fabricate while maintaining excellent sensing performance. Here, we demonstrate, using direct nanoimprint lithography of palladium, the fabrication of a flexible, durable, and fast responsive H2 sensor that is capable of detecting H2 gas concentration as low as 50 ppm. High resolution and high throughput patterning of palladium gratings over a 2 cm × 1 cm area on a rigid substrate was achieved by heat-treating nanoimprinted palladium benzyl mercaptide at 250 °C for 1 h. The flexible and robust H2 sensing device was fabricated by subsequent transfer nanoimprinting of these gratings into a polycarbonate film at its glass transition temperature. This technique produces flexible H2 sensors with improved durability, sensitivity, and response time in comparison to palladium thin films. At ambient pressure and temperature, the device showed a fast response time of 18 s at a H2 concentration of 3500 ppm. At 50 ppm concentration, the response time was found to be 57 s. The flexibility of the sensor does not appear to compromise its performance.

Selenoglycosides in silico: ab initio-derived reparameterization of MM4, conformational analysis using histo-blood group ABH antigens and lectin docking as indication for potential of bioactivity

NASA Astrophysics Data System (ADS)

Strino, Francesco; Lii, Jenn-Huei; Koppisetty, Chaitanya A. K.; Nyholm, Per-Georg; Gabius, Hans-Joachim

2010-12-01

The identification of glycan epitopes such as the histo-blood group ABH determinants as docking sites for bacterial/viral infections and signals in growth regulation fuels the interest to develop non-hydrolysable mimetics for therapeutic applications. Inevitably, the required substitution of the linkage oxygen atom will alter the derivative's topology. Our study addresses the question of the impact of substitution of oxygen by selenium. In order to characterize spatial parameters and flexibility of selenoglycosides, we first performed ab initio calculations on model compounds to refine the MM4 force field. The following application of the resulting MM4R version appears to reduce the difference to ab initio data when compared to using the MM4 estimator. Systematic conformational searches on the derivatives of histo-blood group ABH antigens revealed increased flexibility with acquisition of additional low-energy conformer(s), akin to the behavior of S-glycosides. Docking analysis using the Glide program for eight test cases indicated potential for bioactivity, giving further experimental investigation a clear direction to testing Se-glycosides as lectin ligands.

DockTrina: docking triangular protein trimers.

PubMed

Popov, Petr; Ritchie, David W; Grudinin, Sergei

2014-01-01

In spite of the abundance of oligomeric proteins within a cell, the structural characterization of protein-protein interactions is still a challenging task. In particular, many of these interactions involve heteromeric complexes, which are relatively difficult to determine experimentally. Hence there is growing interest in using computational techniques to model such complexes. However, assembling large heteromeric complexes computationally is a highly combinatorial problem. Nonetheless the problem can be simplified greatly by considering interactions between protein trimers. After dimers and monomers, triangular trimers (i.e. trimers with pair-wise contacts between all three pairs of proteins) are the most frequently observed quaternary structural motifs according to the three-dimensional (3D) complex database. This article presents DockTrina, a novel protein docking method for modeling the 3D structures of nonsymmetrical triangular trimers. The method takes as input pair-wise contact predictions from a rigid body docking program. It then scans and scores all possible combinations of pairs of monomers using a very fast root mean square deviation test. Finally, it ranks the predictions using a scoring function which combines triples of pair-wise contact terms and a geometric clash penalty term. The overall approach takes less than 2 min per complex on a modern desktop computer. The method is tested and validated using a benchmark set of 220 bound and seven unbound protein trimer structures. DockTrina will be made available at http://nano-d.inrialpes.fr/software/docktrina. Copyright © 2013 Wiley Periodicals, Inc.

Orion Handling Qualities During ISS Rendezvous and Docking

NASA Technical Reports Server (NTRS)

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

CovalentDock Cloud: a web server for automated covalent docking.

PubMed

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

2013-07-01

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

CovalentDock Cloud: a web server for automated covalent docking

PubMed Central

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

2013-01-01

Covalent binding is an important mechanism for many drugs to gain its function. We developed a computational algorithm to model this chemical event and extended it to a web server, the CovalentDock Cloud, to make it accessible directly online without any local installation and configuration. It provides a simple yet user-friendly web interface to perform covalent docking experiments and analysis online. The web server accepts the structures of both the ligand and the receptor uploaded by the user or retrieved from online databases with valid access id. It identifies the potential covalent binding patterns, carries out the covalent docking experiments and provides visualization of the result for user analysis. This web server is free and open to all users at http://docking.sce.ntu.edu.sg/. PMID:23677616

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

NASA Technical Reports Server (NTRS)

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

2015-01-01

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

Low-thrust orbit transfer optimization with refined Q-law and multi-objective genetic algorithm

NASA Technical Reports Server (NTRS)

Lee, Seungwon; Petropoulos, Anastassios E.; von Allmen, Paul

2005-01-01

An optimization method for low-thrust orbit transfers around a central body is developed using the Q-law and a multi-objective genetic algorithm. in the hybrid method, the Q-law generates candidate orbit transfers, and the multi-objective genetic algorithm optimizes the Q-law control parameters in order to simultaneously minimize both the consumed propellant mass and flight time of the orbit tranfer. This paper addresses the problem of finding optimal orbit transfers for low-thrust spacecraft.

Cosmological parameters from a re-analysis of the WMAP 7 year low-resolution maps

NASA Astrophysics Data System (ADS)

Finelli, F.; De Rosa, A.; Gruppuso, A.; Paoletti, D.

2013-06-01

Cosmological parameters from Wilkinson Microwave Anisotropy Probe (WMAP) 7 year data are re-analysed by substituting a pixel-based likelihood estimator to the one delivered publicly by the WMAP team. Our pixel-based estimator handles exactly intensity and polarization in a joint manner, allowing us to use low-resolution maps and noise covariance matrices in T, Q, U at the same resolution, which in this work is 3.6°. We describe the features and the performances of the code implementing our pixel-based likelihood estimator. We perform a battery of tests on the application of our pixel-based likelihood routine to WMAP publicly available low-resolution foreground-cleaned products, in combination with the WMAP high-ℓ likelihood, reporting the differences on cosmological parameters evaluated by the full WMAP likelihood public package. The differences are not only due to the treatment of polarization, but also to the marginalization over monopole and dipole uncertainties present in the WMAP pixel likelihood code for temperature. The credible central value for the cosmological parameters change below the 1σ level with respect to the evaluation by the full WMAP 7 year likelihood code, with the largest difference in a shift to smaller values of the scalar spectral index nS.

Apollo Rendezvous Docking Simulator

NASA Image and Video Library

1964-11-02

Originally the Rendezvous was used by the astronauts preparing for Gemini missions. The Rendezvous Docking Simulator was then modified and used to develop docking techniques for the Apollo program. The pilot is shown maneuvering the LEM into position for docking with a full-scale Apollo Command Module. From A.W. Vogeley, Piloted Space-Flight Simulation at Langley Research Center, Paper presented at the American Society of Mechanical Engineers, 1966 Winter Meeting, New York, NY, November 27 - December 1, 1966. The Rendezvous Docking Simulator and also the Lunar Landing Research Facility are both rather large moving-base simulators. It should be noted, however, that neither was built primarily because of its motion characteristics. The main reason they were built was to provide a realistic visual scene. A secondary reason was that they would provide correct angular motion cues (important in control of vehicle short-period motions) even though the linear acceleration cues would be incorrect. Apollo Rendezvous Docking Simulator: Langley s Rendezvous Docking Simulator was developed by NASA scientists to study the complex task of docking the Lunar Excursion Module with the Command Module in Lunar orbit.

MSAll strategy for comprehensive quantitative analysis of PEGylated-doxorubicin, PEG and doxorubicin by LC-high resolution q-q-TOF mass spectrometry coupled with all window acquisition of all fragment ion spectra.

PubMed

Yin, Lei; Su, Chong; Ren, Tianming; Meng, Xiangjun; Shi, Meiyun; Paul Fawcett, J; Zhang, Mengliang; Hu, Wei; Gu, Jingkai

2017-11-06

The covalent attachment of polyethylene glycol (PEG) to therapeutic compounds (known as PEGylation) is one of the most promising techniques to improve the biological efficacy of small molecular weight drugs. After administration, PEGylated prodrugs can be metabolized into pharmacologically active compounds so that PEGylated drug, free drug and released PEG are present simultaneously in the body. Understanding the pharmacokinetic behavior of these three compounds is needed to guide the development of pegylated theranostic agents. However, PEGs are polydisperse molecules with a wide range of molecular weights, so that the simultaneous quantitation of PEGs and PEGylated molecules in biological matrices is very challenging. This article reports the application of a data-independent acquisition method (MS All ) based on liquid chromatography electrospray ionization quadrupole time-of-flight mass spectrometry (LC-q-q-TOF-MS) in the positive ion mode to the simultaneous determination of methoxyPEG2000-doxorubicin (mPEG2K-Dox) and its breakdown products in rat blood. Using the MS All technique, precursor ions of all molecules are generated in q1, fragmented to product ions in q2 (collision cell), and subjected to TOF separation before precursor and product ions are recorded using low and high collision energies (CE) respectively in different experiments for a single sample injection. In this study, dissociation in q2 generated a series of high resolution PEG-related product ions at m/z 89.0611, 133.0869, 177.1102, 221.1366, 265.1622, 309.1878, and 353.2108 corresponding to fragments containing various numbers of ethylene oxide subunits, Dox-related product ions at m/z 321.0838 and 361.0785, and an mPEG2K-Dox specific product ion at m/z 365.0735. Detection of mPEGs and mPEG2K-Dox was based on high resolution extracted ions of mPEG and the specific compound. The method was successfully applied to a pharmacokinetic study of doxorubicin, mPEG2K (methylated polyethylene glycol

The 3D Structure of the Binding Pocket of the Human Oxytocin Receptor for Benzoxazine Antagonists, Determined by Molecular Docking, Scoring Functions and 3D-QSAR Methods

NASA Astrophysics Data System (ADS)

Jójárt, Balázs; Martinek, Tamás A.; Márki, Árpád

2005-05-01

Molecular docking and 3D-QSAR studies were performed to determine the binding mode for a series of benzoxazine oxytocin antagonists taken from the literature. Structural hypotheses were generated by docking the most active molecule to the rigid receptor by means of AutoDock 3.05. The cluster analysis yielded seven possible binding conformations. These structures were refined by using constrained simulated annealing, and the further ligands were aligned in the refined receptor by molecular docking. A good correlation was found between the estimated Δ G bind and the p K i values for complex F. The Connolly-surface analysis, CoMFA and CoMSIA models q CoMFA 2 = 0.653, q CoMSA 2 = 0.630 and r pred,CoMFA 2 = 0.852 , r pred,CoMSIA 2 = 0.815) confirmed the scoring function results. The structural features of the receptor-ligand complex and the CoMFA and CoMSIA fields are in closely connected. These results suggest that receptor-ligand complex F is the most likely binding hypothesis for the studied benzoxazine analogs.

A solar radio dynamic spectrograph with flexible temporal-spectral resolution

NASA Astrophysics Data System (ADS)

Du, Qing-Fu; Chen, Lei; Zhao, Yue-Chang; Li, Xin; Zhou, Yan; Zhang, Jun-Rui; Yan, Fa-Bao; Feng, Shi-Wei; Li, Chuan-Yang; Chen, Yao

2017-09-01

Observation and research on solar radio emission have unique scientific values in solar and space physics and related space weather forecasting applications, since the observed spectral structures may carry important information about energetic electrons and underlying physical mechanisms. In this study, we present the design of a novel dynamic spectrograph that has been installed at the Chashan Solar Radio Observatory operated by the Laboratory for Radio Technologies, Institute of Space Sciences at Shandong University. The spectrograph is characterized by real-time storage of digitized radio intensity data in the time domain and its capability to perform off-line spectral analysis of the radio spectra. The analog signals received via antennas and amplified with a low-noise amplifier are converted into digital data at a speed reaching up to 32 k data points per millisecond. The digital data are then saved into a high-speed electronic disk for further off-line spectral analysis. Using different word lengths (1-32 k) and time cadences (5 ms-10 s) for off-line fast Fourier transform analysis, we can obtain the dynamic spectrum of a radio burst with different (user-defined) temporal (5 ms-10 s) and spectral (3 kHz˜320 kHz) resolutions. This enables great flexibility and convenience in data analysis of solar radio bursts, especially when some specific fine spectral structures are under study.

Consensus Induced Fit Docking (cIFD): methodology, validation, and application to the discovery of novel Crm1 inhibitors

NASA Astrophysics Data System (ADS)

Kalid, Ori; Toledo Warshaviak, Dora; Shechter, Sharon; Sherman, Woody; Shacham, Sharon

2012-11-01

We present the Consensus Induced Fit Docking (cIFD) approach for adapting a protein binding site to accommodate multiple diverse ligands for virtual screening. This novel approach results in a single binding site structure that can bind diverse chemotypes and is thus highly useful for efficient structure-based virtual screening. We first describe the cIFD method and its validation on three targets that were previously shown to be challenging for docking programs (COX-2, estrogen receptor, and HIV reverse transcriptase). We then demonstrate the application of cIFD to the challenging discovery of irreversible Crm1 inhibitors. We report the identification of 33 novel Crm1 inhibitors, which resulted from the testing of 402 purchased compounds selected from a screening set containing 261,680 compounds. This corresponds to a hit rate of 8.2 %. The novel Crm1 inhibitors reveal diverse chemical structures, validating the utility of the cIFD method in a real-world drug discovery project. This approach offers a pragmatic way to implicitly account for protein flexibility without the additional computational costs of ensemble docking or including full protein flexibility during virtual screening.

Coupling Photonics and Coherent Spintronics for Low-Loss Flexible Optical Logic

DTIC Science & Technology

2015-12-02

AFRL-AFOSR-VA-TR-2016-0055 Coupling photonics and coherent spintronics for low-loss flexible optical logic Jesse Berezovsky CASE WESTERN RESERVE UNIV...2012 - 14/06/2015 4. TITLE AND SUBTITLE Coupling photonics and coherent spintronics for low-loss flexible optical logic 5a. CONTRACT NUMBER 5b...into devices, ranging from macroscopic optical cavities, to arrays of microlens cavities, to quantum dot-impregnated integrated polymer waveguides

Rendezvous Docking Simulator

NASA Image and Video Library

1964-10-29

Originally the Rendezvous was used by the astronauts preparing for Gemini missions. The Rendezvous Docking Simulator was then modified and used to develop docking techniques for the Apollo program. "The LEM pilot's compartment, with overhead window and the docking ring (idealized since the pilot cannot see it during the maneuvers), is shown docked with the full-scale Apollo Command Module." A.W. Vogeley described the simulator as follows: "The Rendezvous Docking Simulator and also the Lunar Landing Research Facility are both rather large moving-base simulators. It should be noted, however, that neither was built primarily because of its motion characteristics. The main reason they were built was to provide a realistic visual scene. A secondary reason was that they would provide correct angular motion cues (important in control of vehicle short-period motions) even though the linear acceleration cues would be incorrect." -- Published in A.W. Vogeley, "Piloted Space-Flight Simulation at Langley Research Center," Paper presented at the American Society of Mechanical Engineers, 1966 Winter Meeting, New York, NY, November 27 - December 1, 1966;

Conformational Flexibility of Metazoan Fatty Acid Synthase Enables Catalysis

PubMed Central

Brignole, Edward J.; Smith, Stuart; Asturias, Francisco J.

2008-01-01

The metazoan cytosolic fatty acid synthase (FAS) contains all of the enzymes required for de novo fatty acid biosynthesis covalently linked around two reaction chambers. While the 3D architecture of FAS has been mostly defined, it is unclear how reaction intermediates can transfer between distant catalytic domains. Using single-particle electron microscopy we have identified a near continuum of conformations consistent with remarkable flexibility of FAS. The distribution of conformations was influenced by the presence of substrates and altered by different catalytic mutations suggesting a direct correlation between conformation and specific enzymatic activities. 3D reconstructions were interpreted by docking high-resolution structures of individual domains and illustrate that the substrate loading and condensation domains dramatically swing and swivel to access substrates within either reaction chamber. Concomitant rearrangement of the β-carbon processing domains synchronizes acyl-chain reduction in one chamber with acyl-chain elongation in the other. PMID:19151726

Myelodysplastic Syndrome with concomitant t(5;21)(q15;q22) and del(5)(q13q33): case report and review of literature

PubMed Central

Weckbaugh, Brandon; Sirridge, Christopher; Woodroof, Janet; Persons, Diane

2016-01-01

Chromosomal abnormalities lead to the development of hematologic malignancies such as Myelodysplastic Syndrome (MDS). Known chromosomal changes causing MDS include deletion of the long arm of chromosome 5, runt-related transcription factor 1 (RUNX1) also known as acute myeloid leukemia 1 protein (AML1), and very rarely fusion genes involving RUNX1 at t(5;21)(q15;q22). We present a case of a 71-year-old female with MDS, refractory anemia with excess blasts, type 1, with a combination of two cytogenetic abnormalities, specifically a concomitant translocation between chromosomes 5q15 and 21q22 and deletion of chromosome 5q13q33. Fluorescence in-situ hybridization (FISH) using a probe for RUNX1 (AML1), localized to 21q22, showed three FISH signals for RUNX1, consistent with rearrangement of RUNX1. Therapy was started with Lenalidomide leading to normal blood counts. Most significantly, repeat cytogenetics revealed normal karyotype and resolution of deletion on the long arm of chromosome 5 and a t(5;21). FISH negative for deletion 5q. The results altogether meet criteria for a complete cytogenetic remission (CR). We report a new case of t(5;21)(q15;q22) involving the RUNX1 gene and del(5)(q13q33) in a MDS patient, a combination of chromosomal abnormalities heretofore not reported in the literature. RUNX1 rearrangement is usually associated with an adverse prognosis in AML and MDS. Deletions of 5q are typically associated with poor prognosis in AML, however it is usually associated with a favorable prognosis in MDS. Our patient responded very well to Lenalidomide therapy with achievement of CR. Lenalidomide is approved for treatment of anemia in low and intermediate risk MDS with del (5q), however based on a search of literature it seems that RUNX1 mutations are also more prominent in patients who have responded to Lenalidomide therapy. MDS is a genomically unstable disease. Hence, it is conceivable that our patient started with a 5q minus syndrome and then acquired the

Avalanche statistics from data with low time resolution

DOE Office of Scientific and Technical Information (OSTI.GOV)

LeBlanc, Michael; Nawano, Aya; Wright, Wendelin J.

Extracting avalanche distributions from experimental microplasticity data can be hampered by limited time resolution. We compute the effects of low time resolution on avalanche size distributions and give quantitative criteria for diagnosing and circumventing problems associated with low time resolution. We show that traditional analysis of data obtained at low acquisition rates can lead to avalanche size distributions with incorrect power-law exponents or no power-law scaling at all. Furthermore, we demonstrate that it can lead to apparent data collapses with incorrect power-law and cutoff exponents. We propose new methods to analyze low-resolution stress-time series that can recover the size distributionmore » of the underlying avalanches even when the resolution is so low that naive analysis methods give incorrect results. We test these methods on both downsampled simulation data from a simple model and downsampled bulk metallic glass compression data and find that the methods recover the correct critical exponents.« less

Avalanche statistics from data with low time resolution

DOE PAGES

LeBlanc, Michael; Nawano, Aya; Wright, Wendelin J.; ...

2016-11-22

Extracting avalanche distributions from experimental microplasticity data can be hampered by limited time resolution. We compute the effects of low time resolution on avalanche size distributions and give quantitative criteria for diagnosing and circumventing problems associated with low time resolution. We show that traditional analysis of data obtained at low acquisition rates can lead to avalanche size distributions with incorrect power-law exponents or no power-law scaling at all. Furthermore, we demonstrate that it can lead to apparent data collapses with incorrect power-law and cutoff exponents. We propose new methods to analyze low-resolution stress-time series that can recover the size distributionmore » of the underlying avalanches even when the resolution is so low that naive analysis methods give incorrect results. We test these methods on both downsampled simulation data from a simple model and downsampled bulk metallic glass compression data and find that the methods recover the correct critical exponents.« less

Electrostatics in protein–protein docking

PubMed Central

Heifetz, Alexander; Katchalski-Katzir, Ephraim; Eisenstein, Miriam

2002-01-01

A novel geometric-electrostatic docking algorithm is presented, which tests and quantifies the electrostatic complementarity of the molecular surfaces together with the shape complementarity. We represent each molecule to be docked as a grid of complex numbers, storing information regarding the shape of the molecule in the real part and information regarding the electrostatic character of the molecule in the imaginary part. The electrostatic descriptors are derived from the electrostatic potential of the molecule. Thus, the electrostatic character of the molecule is represented as patches of positive, neutral, or negative values. The potential for each molecule is calculated only once and stored as potential spheres adequate for exhaustive rotation/translation scans. The geometric-electrostatic docking algorithm is applied to 17 systems, starting form the structures of the unbound molecules. The results—in terms of the complementarity scores of the nearly correct solutions, their ranking in the lists of sorted solutions, and their statistical uniqueness—are compared with those of geometric docking, showing that the inclusion of electrostatic complementarity in docking is very important, in particular in docking of unbound structures. Based on our results, we formulate several "good electrostatic docking rules": The geometric-electrostatic docking procedure is more successful than geometric docking when the potential patches are large and when the potential extends away from the molecular surface and protrudes into the solvent. In contrast, geometric docking is recommended when the electrostatic potential around the molecules to be docked appears homogenous, that is, with a similar sign all around the molecule. PMID:11847280

Review of Full-Scale Docking Seal Testing Capabilities

NASA Technical Reports Server (NTRS)

Dunlap, Patrick H., Jr.; Penney, Nicholas; Wasowski, Janice L.; Daniels, Christopher C.; Steinetz, Bruce M.

2008-01-01

NASA is developing a new docking system to support future space exploration missions to low-Earth orbit, the Moon, and Mars. This mechanism, called the Low Impact Docking System (LIDS), is designed to connect pressurized space vehicles and structures including the Crew Exploration Vehicle, International Space Station, and lunar lander. NASA Glenn Research Center (GRC) is playing a key role in developing the main interface seal for this new docking system. These seals will be approximately 147 cm (58 in.) in diameter. To evaluate the performance of the seals under simulated operating conditions, NASA GRC is developing two new test rigs: a non-actuated version that will be used to measure seal leak rates and an actuated test rig that will be able to measure both seal leak rates and loads. Both test rigs will be able to evaluate the seals under seal-on-seal or seal-on-plate configurations at temperatures from -50 to 50 C (-58 to 122 F) under operational and pre-flight checkout pressure gradients in both aligned and misaligned conditions.

X-ray structure determination at low resolution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brunger, Axel T., E-mail: brunger@stanford.edu; Department of Molecular and Cellular Physiology, Stanford University; Department of Neurology and Neurological Sciences, Stanford University

2009-02-01

Refinement is meaningful even at 4 Å or lower, but with present methodologies it should start from high-resolution crystal structures whenever possible. As an example of structure determination in the 3.5–4.5 Å resolution range, crystal structures of the ATPase p97/VCP, consisting of an N-terminal domain followed by a tandem pair of ATPase domains (D1 and D2), are discussed. The structures were originally solved by molecular replacement with the high-resolution structure of the N-D1 fragment of p97/VCP, whereas the D2 domain was manually built using its homology to the D1 domain as a guide. The structure of the D2 domain alonemore » was subsequently solved at 3 Å resolution. The refined model of D2 and the high-resolution structure of the N-D1 fragment were then used as starting models for re-refinement against the low-resolution diffraction data for full-length p97. The re-refined full-length models showed significant improvement in both secondary structure and R values. The free R values dropped by as much as 5% compared with the original structure refinements, indicating that refinement is meaningful at low resolution and that there is information in the diffraction data even at ∼4 Å resolution that objectively assesses the quality of the model. It is concluded that de novo model building is problematic at low resolution and refinement should start from high-resolution crystal structures whenever possible.« less

Docking and Virtual Screening Strategies for GPCR Drug Discovery.

PubMed

Beuming, Thijs; Lenselink, Bart; Pala, Daniele; McRobb, Fiona; Repasky, Matt; Sherman, Woody

2015-01-01

Progress in structure determination of G protein-coupled receptors (GPCRs) has made it possible to apply structure-based drug design (SBDD) methods to this pharmaceutically important target class. The quality of GPCR structures available for SBDD projects fall on a spectrum ranging from high resolution crystal structures (<2 Å), where all water molecules in the binding pocket are resolved, to lower resolution (>3 Å) where some protein residues are not resolved, and finally to homology models that are built using distantly related templates. Each GPCR project involves a distinct set of opportunities and challenges, and requires different approaches to model the interaction between the receptor and the ligands. In this review we will discuss docking and virtual screening to GPCRs, and highlight several refinement and post-processing steps that can be used to improve the accuracy of these calculations. Several examples are discussed that illustrate specific steps that can be taken to improve upon the docking and virtual screening accuracy. While GPCRs are a unique target class, many of the methods and strategies outlined in this review are general and therefore applicable to other protein families.

ARCADE small-scale docking mechanism for micro-satellites

NASA Astrophysics Data System (ADS)

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.

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

NASA Astrophysics Data System (ADS)

Tsvetkov, Vladimir B.; Serbin, Alexander V.

2014-06-01

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

18q- and 18q+ mosaicism in a mentally retarded boy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ausems, M.G.E.M.; Bhola, S.L.; France, H.F. de

A mentally retarded boy was found to have an unusual chromosomal mosaicism [46,XY,del(18) (q22)/46,XY,iso psu dic(18)(q23)]. The clinical manifestations are compatible with the 18q- syndrome. The chromosome alteration was defined by high resolution banding and fluorescence in situ hybridization (FISH). A mechanism to explain the origin of the two cell lines is presented and discussed. 6 refs., 4 figs., 1 tab.

Chemical system biology based molecular interactions to identify inhibitors against Q151M mutant of HIV-1 reverse transcriptase.

PubMed

Pandey, Rajan Kumar; Sharma, Drista; Ojha, Rupal; Bhatt, Tarun Kumar; Prajapati, Vijay Kumar

2018-05-09

The emergence of mutations leading to drug resistance is the main cause of therapeutic failure in the human HIV infection. Chemical system biology approach has drawn great attention to discover new antiretroviral hits with high efficacy and negligible toxicity, which can be used as a prerequisite for HIV drug resistance global action plan 2017-21. To discover potential hits, we docked 49 antiretroviral analogs (n = 6294) against HIV-1 reverse transcriptase Q151M mutant & its wild-type form and narrow downed their number in three sequential modes of docking using Schrödinger suite. Later on, 80 ligands having better docking score than reference ligands (tenofovir and lamivudine) were screened for ADME, toxicity prediction, and binding energy estimation. Simultaneously, the area under the curve (AUC) was estimated using receiver operating characteristics (ROC) curve analysis to validate docking protocols. Finally, single point energy and molecular dynamics simulation approaches were performed for best two ligands (L3 and L14). This study reveals the antiretroviral efficacy of obtained two best ligands and delivers the hits against HIV-1 reverse transcriptase Q151M mutant. Copyright © 2018 Elsevier B.V. All rights reserved.

Experimental validation of docking and capture using space robotics testbeds

NASA Technical Reports Server (NTRS)

Spofford, John; Schmitz, Eric; Hoff, William

1991-01-01

This presentation describes the application of robotic and computer vision systems to validate docking and capture operations for space cargo transfer vehicles. Three applications are discussed: (1) air bearing systems in two dimensions that yield high quality free-flying, flexible, and contact dynamics; (2) validation of docking mechanisms with misalignment and target dynamics; and (3) computer vision technology for target location and real-time tracking. All the testbeds are supported by a network of engineering workstations for dynamic and controls analyses. Dynamic simulation of multibody rigid and elastic systems are performed with the TREETOPS code. MATRIXx/System-Build and PRO-MATLAB/Simulab are the tools for control design and analysis using classical and modern techniques such as H-infinity and LQG/LTR. SANDY is a general design tool to optimize numerically a multivariable robust compensator with a user-defined structure. Mathematica and Macsyma are used to derive symbolically dynamic and kinematic equations.

Evaluation of protein docking predictions using Hex 3.1 in CAPRI rounds 1 and 2.

PubMed

Ritchie, David W

2003-07-01

This article describes and reviews our efforts using Hex 3.1 to predict the docking modes of the seven target protein-protein complexes presented in the CAPRI (Critical Assessment of Predicted Interactions) blind docking trial. For each target, the structure of at least one of the docking partners was given in its unbound form, and several of the targets involved large multimeric structures (e.g., Lactobacillus HPr kinase, hemagglutinin, bovine rotavirus VP6). Here we describe several enhancements to our original spherical polar Fourier docking correlation algorithm. For example, a novel surface sphere smothering algorithm is introduced to generate multiple local coordinate systems around the surface of a large receptor molecule, which may be used to define a small number of initial ligand-docking orientations distributed over the receptor surface. High-resolution spherical polar docking correlations are performed over the resulting receptor surface patches, and candidate docking solutions are refined by using a novel soft molecular mechanics energy minimization procedure. Overall, this approach identified two good solutions at rank 5 or less for two of the seven CAPRI complexes. Subsequent analysis of our results shows that Hex 3.1 is able to place good solutions within a list of docking predictions can now be made with increasing confidence, even for very large macromolecular complexes. Copyright 2003 Wiley-Liss, Inc.

Highly transparent, low-haze, hybrid cellulose nanopaper as electrodes for flexible electronics

Treesearch

Xuezhu Xu; Jian Zhou; Long Jiang; Gilles Lubineau; Tienkhee Ng; Boon S. Ooi; Hsien-Yu Liao; Chao Shen; Long Chen; Junyong Zhu

2016-01-01

Paper is an excellent candidate to replace plastics as a substrate for flexible electronics due to its low cost, renewability and flexibility. Cellulose nanopaper (CNP), a new type of paper made of nanosized cellulose fibers, is a promising substrate material for transparent and flexible electrodes due to its potentially high transparency and high mechanical strength....

Combined 3D-QSAR modeling and molecular docking study on azacycles CCR5 antagonists

NASA Astrophysics Data System (ADS)

Ji, Yongjun; Shu, Mao; Lin, Yong; Wang, Yuanqiang; Wang, Rui; Hu, Yong; Lin, Zhihua

2013-08-01

The beta chemokine receptor 5 (CCR5) is an attractive target for pharmaceutical industry in the HIV-1, inflammation and cancer therapeutic areas. In this study, we have developed quantitative structure activity relationship (QSAR) models for a series of 41 azacycles CCR5 antagonists using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and Topomer CoMFA methods. The cross-validated coefficient q2 values of 3D-QASR (CoMFA, CoMSIA, and Topomer CoMFA) methods were 0.630, 0.758, and 0.852, respectively, the non-cross-validated R2 values were 0.979, 0.978, and 0.990, respectively. Docking studies were also employed to determine the most probable binding mode. 3D contour maps and docking results suggested that bulky groups and electron-withdrawing groups on the core part would decrease antiviral activity. Furthermore, docking results indicated that H-bonds and π bonds were favorable for antiviral activities. Finally, a set of novel derivatives with predicted activities were designed.

Theoretical modeling of multiprotein complexes by iSPOT: Integration of small-angle X-ray scattering, hydroxyl radical footprinting, and computational docking.

PubMed

Huang, Wei; Ravikumar, Krishnakumar M; Parisien, Marc; Yang, Sichun

2016-12-01

Structural determination of protein-protein complexes such as multidomain nuclear receptors has been challenging for high-resolution structural techniques. Here, we present a combined use of multiple biophysical methods, termed iSPOT, an integration of shape information from small-angle X-ray scattering (SAXS), protection factors probed by hydroxyl radical footprinting, and a large series of computationally docked conformations from rigid-body or molecular dynamics (MD) simulations. Specifically tested on two model systems, the power of iSPOT is demonstrated to accurately predict the structures of a large protein-protein complex (TGFβ-FKBP12) and a multidomain nuclear receptor homodimer (HNF-4α), based on the structures of individual components of the complexes. Although neither SAXS nor footprinting alone can yield an unambiguous picture for each complex, the combination of both, seamlessly integrated in iSPOT, narrows down the best-fit structures that are about 3.2Å and 4.2Å in RMSD from their corresponding crystal structures, respectively. Furthermore, this proof-of-principle study based on the data synthetically derived from available crystal structures shows that the iSPOT-using either rigid-body or MD-based flexible docking-is capable of overcoming the shortcomings of standalone computational methods, especially for HNF-4α. By taking advantage of the integration of SAXS-based shape information and footprinting-based protection/accessibility as well as computational docking, this iSPOT platform is set to be a powerful approach towards accurate integrated modeling of many challenging multiprotein complexes. Copyright © 2016 Elsevier Inc. All rights reserved.

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

PubMed

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.

Spacecraft Docking System

NASA Technical Reports Server (NTRS)

Ghofranian, Siamak (Inventor); Chuang, Li-Ping Christopher (Inventor); Motaghedi, Pejmun (Inventor)

2016-01-01

A method and apparatus for docking a spacecraft. The apparatus comprises elongate members, movement systems, and force management systems. The elongate members are associated with a docking structure for a spacecraft. The movement systems are configured to move the elongate members axially such that the docking structure for the spacecraft moves. Each of the elongate members is configured to move independently. The force management systems connect the movement systems to the elongate members and are configured to limit a force applied by the each of the elongate members to a desired threshold during movement of the elongate members.

Molecular docking performance evaluated on the D3R Grand Challenge 2015 drug-like ligand datasets

NASA Astrophysics Data System (ADS)

Selwa, Edithe; Martiny, Virginie Y.; Iorga, Bogdan I.

2016-09-01

The D3R Grand Challenge 2015 was focused on two protein targets: Heat Shock Protein 90 (HSP90) and Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4). We used a protocol involving a preliminary analysis of the available data in PDB and PubChem BioAssay, and then a docking/scoring step using more computationally demanding parameters that were required to provide more reliable predictions. We could evidence that different docking software and scoring functions can behave differently on individual ligand datasets, and that the flexibility of specific binding site residues is a crucial element to provide good predictions.

Accessible high-throughput virtual screening molecular docking software for students and educators.

PubMed

Jacob, Reed B; Andersen, Tim; McDougal, Owen M

2012-05-01

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.

Super-resolution reconstruction of diffusion parameters from diffusion-weighted images with different slice orientations.

PubMed

Van Steenkiste, Gwendolyn; Jeurissen, Ben; Veraart, Jelle; den Dekker, Arnold J; Parizel, Paul M; Poot, Dirk H J; Sijbers, Jan

2016-01-01

Diffusion MRI is hampered by long acquisition times, low spatial resolution, and a low signal-to-noise ratio. Recently, methods have been proposed to improve the trade-off between spatial resolution, signal-to-noise ratio, and acquisition time of diffusion-weighted images via super-resolution reconstruction (SRR) techniques. However, during the reconstruction, these SRR methods neglect the q-space relation between the different diffusion-weighted images. An SRR method that includes a diffusion model and directly reconstructs high resolution diffusion parameters from a set of low resolution diffusion-weighted images was proposed. Our method allows an arbitrary combination of diffusion gradient directions and slice orientations for the low resolution diffusion-weighted images, optimally samples the q- and k-space, and performs motion correction with b-matrix rotation. Experiments with synthetic data and in vivo human brain data show an increase of spatial resolution of the diffusion parameters, while preserving a high signal-to-noise ratio and low scan time. Moreover, the proposed SRR method outperforms the previous methods in terms of the root-mean-square error. The proposed SRR method substantially increases the spatial resolution of MRI that can be obtained in a clinically feasible scan time. © 2015 Wiley Periodicals, Inc.

Robustness of Flexible Systems With Component-Level Uncertainties

NASA Technical Reports Server (NTRS)

Maghami, Peiman G.

2000-01-01

Robustness of flexible systems in the presence of model uncertainties at the component level is considered. Specifically, an approach for formulating robustness of flexible systems in the presence of frequency and damping uncertainties at the component level is presented. The synthesis of the components is based on a modifications of a controls-based algorithm for component mode synthesis. The formulation deals first with robustness of synthesized flexible systems. It is then extended to deal with global (non-synthesized ) dynamic models with component-level uncertainties by projecting uncertainties from component levels to system level. A numerical example involving a two-dimensional simulated docking problem is worked out to demonstrate the feasibility of the proposed approach.

Multiple grid arrangement improves ligand docking with unknown binding sites: Application to the inverse docking problem.

PubMed

Ban, Tomohiro; Ohue, Masahito; Akiyama, Yutaka

2018-04-01

The identification of comprehensive drug-target interactions is important in drug discovery. Although numerous computational methods have been developed over the years, a gold standard technique has not been established. Computational ligand docking and structure-based drug design allow researchers to predict the binding affinity between a compound and a target protein, and thus, they are often used to virtually screen compound libraries. In addition, docking techniques have also been applied to the virtual screening of target proteins (inverse docking) to predict target proteins of a drug candidate. Nevertheless, a more accurate docking method is currently required. In this study, we proposed a method in which a predicted ligand-binding site is covered by multiple grids, termed multiple grid arrangement. Notably, multiple grid arrangement facilitates the conformational search for a grid-based ligand docking software and can be applied to the state-of-the-art commercial docking software Glide (Schrödinger, LLC). We validated the proposed method by re-docking with the Astex diverse benchmark dataset and blind binding site situations, which improved the correct prediction rate of the top scoring docking pose from 27.1% to 34.1%; however, only a slight improvement in target prediction accuracy was observed with inverse docking scenarios. These findings highlight the limitations and challenges of current scoring functions and the need for more accurate docking methods. The proposed multiple grid arrangement method was implemented in Glide by modifying a cross-docking script for Glide, xglide.py. The script of our method is freely available online at http://www.bi.cs.titech.ac.jp/mga_glide/. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

A flexible and accurate digital volume correlation method applicable to high-resolution volumetric images

NASA Astrophysics Data System (ADS)

Pan, Bing; Wang, Bo

2017-10-01

Digital volume correlation (DVC) is a powerful technique for quantifying interior deformation within solid opaque materials and biological tissues. In the last two decades, great efforts have been made to improve the accuracy and efficiency of the DVC algorithm. However, there is still a lack of a flexible, robust and accurate version that can be efficiently implemented in personal computers with limited RAM. This paper proposes an advanced DVC method that can realize accurate full-field internal deformation measurement applicable to high-resolution volume images with up to billions of voxels. Specifically, a novel layer-wise reliability-guided displacement tracking strategy combined with dynamic data management is presented to guide the DVC computation from slice to slice. The displacements at specified calculation points in each layer are computed using the advanced 3D inverse-compositional Gauss-Newton algorithm with the complete initial guess of the deformation vector accurately predicted from the computed calculation points. Since only limited slices of interest in the reference and deformed volume images rather than the whole volume images are required, the DVC calculation can thus be efficiently implemented on personal computers. The flexibility, accuracy and efficiency of the presented DVC approach are demonstrated by analyzing computer-simulated and experimentally obtained high-resolution volume images.

Orbiter Docking System Installation

NASA Technical Reports Server (NTRS)

1995-01-01

Workers in Orbiter Processing Facility Bay 3 are installing the Orbiter Docking System (ODS) in the payload bay of the orbiter Atlantis (OV-104). The ODS includes an airlock, a supporting truss structure, a docking base, and a Russian-built docking mechanism (uppermost). The ODS is nearly 15 feet (4.6 meters) wide, 6.5 feet (2 meters) long, 13.5 feet (4.1 meters high), and weighs more than 3,500 pounds (1,588 kilograms). It is being installed near the forward end of the orbiter's payload bay and will be connected by a short tunnel to the existing airlock inside the orbiter's pressurized crew cabin.The installation will take about two hours to complete. Later this week, the Spacelab module also will be installed in OV-104's payload bay; it will connect to the ODS via a tunnel. During the first docking between the Space Shuttle Atlantis and the Russian Space Station Mir, the Russian-built docking mechanism on the ODS will be mated to a similar interface on the Krystall module docking port on Mir, allowing crew members to pass back and forth between the two spacecraft. That Shuttle mission, STS-71, is scheduled for liftoff in early June.

Application of a post-docking procedure based on MM-PBSA and MM-GBSA on single and multiple protein conformations.

PubMed

Sgobba, Miriam; Caporuscio, Fabiana; Anighoro, Andrew; Portioli, Corinne; Rastelli, Giulio

2012-12-01

In the last decades, molecular docking has emerged as an increasingly useful tool in the modern drug discovery process, but it still needs to overcome many hurdles and limitations such as how to account for protein flexibility and poor scoring function performance. For this reason, it has been recognized that in many cases docking results need to be post-processed to achieve a significant agreement with experimental activities. In this study, we have evaluated the performance of MM-PBSA and MM-GBSA scoring functions, implemented in our post-docking procedure BEAR, in rescoring docking solutions. For the first time, the performance of this post-docking procedure has been evaluated on six different biological targets (namely estrogen receptor, thymidine kinase, factor Xa, adenosine deaminase, aldose reductase, and enoyl ACP reductase) by using i) both a single and a multiple protein conformation approach, and ii) two different software, namely AutoDock and LibDock. The assessment has been based on two of the most important criteria for the evaluation of docking methods, i.e., the ability of known ligands to enrich the top positions of a ranked database with respect to molecular decoys, and the consistency of the docking poses with crystallographic binding modes. We found that, in many cases, MM-PBSA and MM-GBSA are able to yield higher enrichment factors compared to those obtained with the docking scoring functions alone. However, for only a minority of the cases, the enrichment factors obtained by using multiple protein conformations were higher than those obtained by using only one protein conformation. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Optical Docking Aid Containing Fresnel Lenses

NASA Technical Reports Server (NTRS)

Pierce, Cole J.

1995-01-01

Proposed device provides self-contained visual cues to aid in docking. Similar to devices used to guide pilots in landing on aircraft carriers. Positions and directions of beams of light give observer visual cues of position relative to docking target point. Optical assemblies generate directed, diverging beams of light that, together, mark approach path to docking point. Conceived for use in docking spacecraft at Space Station Freedom, device adapted to numerous industrial docking and alignment applications.

Synergistic use of compound properties and docking scores in neural network modeling of CYP2D6 binding: predicting affinity and conformational sampling.

PubMed

Bazeley, Peter S; Prithivi, Sridevi; Struble, Craig A; Povinelli, Richard J; Sem, Daniel S

2006-01-01

Cytochrome P450 2D6 (CYP2D6) is used to develop an approach for predicting affinity and relevant binding conformation(s) for highly flexible binding sites. The approach combines the use of docking scores and compound properties as attributes in building a neural network (NN) model. It begins by identifying segments of CYP2D6 that are important for binding specificity, based on structural variability among diverse CYP enzymes. A family of distinct, low-energy conformations of CYP2D6 are generated using simulated annealing (SA) and a collection of 82 compounds with known CYP2D6 affinities are docked. Interestingly, docking poses are observed on the backside of the heme as well as in the known active site. Docking scores for the active site binders, along with compound-specific attributes, are used to train a neural network model to properly bin compounds as strong binders, moderate binders, or nonbinders. Attribute selection is used to preselect the most important scores and compound-specific attributes for the model. A prediction accuracy of 85+/-6% is achieved. Dominant attributes include docking scores for three of the 20 conformations in the ensemble as well as the compound's formal charge, number of aromatic rings, and AlogP. Although compound properties were highly predictive attributes (12% improvement over baseline) in the NN-based prediction of CYP2D6 binders, their combined use with docking score attributes is synergistic (net increase of 23% above baseline). Beyond prediction of affinity, attribute selection provides a way to identify the most relevant protein conformation(s), in terms of binding competence. In the case of CYP2D6, three out of the ensemble of 20 SA-generated structures are found to be the most predictive for binding.

Multibody dynamical modeling for spacecraft docking process with spring-damper buffering device: A new validation approach

NASA Astrophysics Data System (ADS)

Daneshjou, Kamran; Alibakhshi, Reza

2018-01-01

In the current manuscript, the process of spacecraft docking, as one of the main risky operations in an on-orbit servicing mission, is modeled based on unconstrained multibody dynamics. The spring-damper buffering device is utilized here in the docking probe-cone system for micro-satellites. Owing to the impact occurs inevitably during docking process and the motion characteristics of multibody systems are remarkably affected by this phenomenon, a continuous contact force model needs to be considered. Spring-damper buffering device, keeping the spacecraft stable in an orbit when impact occurs, connects a base (cylinder) inserted in the chaser satellite and the end of docking probe. Furthermore, by considering a revolute joint equipped with torsional shock absorber, between base and chaser satellite, the docking probe can experience both translational and rotational motions simultaneously. Although spacecraft docking process accompanied by the buffering mechanisms may be modeled by constrained multibody dynamics, this paper deals with a simple and efficient formulation to eliminate the surplus generalized coordinates and solve the impact docking problem based on unconstrained Lagrangian mechanics. By an example problem, first, model verification is accomplished by comparing the computed results with those recently reported in the literature. Second, according to a new alternative validation approach, which is based on constrained multibody problem, the accuracy of presented model can be also evaluated. This proposed verification approach can be applied to indirectly solve the constrained multibody problems by minimum required effort. The time history of impact force, the influence of system flexibility and physical interaction between shock absorber and penetration depth caused by impact are the issues followed in this paper. Third, the MATLAB/SIMULINK multibody dynamic analysis software will be applied to build impact docking model to validate computed results and

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

NASA Astrophysics Data System (ADS)

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.

qPCR-High resolution melt analysis for drug susceptibility testing of Mycobacterium leprae directly from clinical specimens of leprosy patients.

PubMed

Araujo, Sergio; Goulart, Luiz Ricardo; Truman, Richard W; Goulart, Isabela Maria B; Vissa, Varalakshmi; Li, Wei; Matsuoka, Masanori; Suffys, Philip; Fontes, Amanda B; Rosa, Patricia S; Scollard, David M; Williams, Diana L

2017-06-01

Real-Time PCR-High Resolution Melting (qPCR-HRM) analysis has been recently described for rapid drug susceptibility testing (DST) of Mycobacterium leprae. The purpose of the current study was to further evaluate the validity, reliability, and accuracy of this assay for M. leprae DST in clinical specimens. The specificity and sensitivity for determining the presence and susceptibility of M. leprae to dapsone based on the folP1 drug resistance determining region (DRDR), rifampin (rpoB DRDR) and ofloxacin (gyrA DRDR) was evaluated using 211 clinical specimens from leprosy patients, including 156 multibacillary (MB) and 55 paucibacillary (PB) cases. When comparing the results of qPCR-HRM DST and PCR/direct DNA sequencing, 100% concordance was obtained. The effects of in-house phenol/chloroform extraction versus column-based DNA purification protocols, and that of storage and fixation protocols of specimens for qPCR-HRM DST, were also evaluated. qPCR-HRM results for all DRDR gene assays (folP1, rpoB, and gyrA) were obtained from both MB (154/156; 98.7%) and PB (35/55; 63.3%) patients. All PCR negative specimens were from patients with low numbers of bacilli enumerated by an M. leprae-specific qPCR. We observed that frozen and formalin-fixed paraffin embedded (FFPE) tissues or archival Fite's stained slides were suitable for HRM analysis. Among 20 mycobacterial and other skin bacterial species tested, only M. lepromatosis, highly related to M. leprae, generated amplicons in the qPCR-HRM DST assay for folP1 and rpoB DRDR targets. Both DNA purification protocols tested were efficient in recovering DNA suitable for HRM analysis. However, 3% of clinical specimens purified using the phenol/chloroform DNA purification protocol gave false drug resistant data. DNA obtained from freshly frozen (n = 172), formalin-fixed paraffin embedded (FFPE) tissues (n = 36) or archival Fite's stained slides (n = 3) were suitable for qPCR-HRM DST analysis. The HRM-based assay was also able to

qPCR-High resolution melt analysis for drug susceptibility testing of Mycobacterium leprae directly from clinical specimens of leprosy patients

PubMed Central

Goulart, Luiz Ricardo; Truman, Richard W.; Goulart, Isabela Maria B.; Vissa, Varalakshmi; Li, Wei; Matsuoka, Masanori; Suffys, Philip; Fontes, Amanda B.; Rosa, Patricia S.; Scollard, David M.; Williams, Diana L.

2017-01-01

Background Real-Time PCR-High Resolution Melting (qPCR-HRM) analysis has been recently described for rapid drug susceptibility testing (DST) of Mycobacterium leprae. The purpose of the current study was to further evaluate the validity, reliability, and accuracy of this assay for M. leprae DST in clinical specimens. Methodology/Principal findings The specificity and sensitivity for determining the presence and susceptibility of M. leprae to dapsone based on the folP1 drug resistance determining region (DRDR), rifampin (rpoB DRDR) and ofloxacin (gyrA DRDR) was evaluated using 211 clinical specimens from leprosy patients, including 156 multibacillary (MB) and 55 paucibacillary (PB) cases. When comparing the results of qPCR-HRM DST and PCR/direct DNA sequencing, 100% concordance was obtained. The effects of in-house phenol/chloroform extraction versus column-based DNA purification protocols, and that of storage and fixation protocols of specimens for qPCR-HRM DST, were also evaluated. qPCR-HRM results for all DRDR gene assays (folP1, rpoB, and gyrA) were obtained from both MB (154/156; 98.7%) and PB (35/55; 63.3%) patients. All PCR negative specimens were from patients with low numbers of bacilli enumerated by an M. leprae-specific qPCR. We observed that frozen and formalin-fixed paraffin embedded (FFPE) tissues or archival Fite’s stained slides were suitable for HRM analysis. Among 20 mycobacterial and other skin bacterial species tested, only M. lepromatosis, highly related to M. leprae, generated amplicons in the qPCR-HRM DST assay for folP1 and rpoB DRDR targets. Both DNA purification protocols tested were efficient in recovering DNA suitable for HRM analysis. However, 3% of clinical specimens purified using the phenol/chloroform DNA purification protocol gave false drug resistant data. DNA obtained from freshly frozen (n = 172), formalin-fixed paraffin embedded (FFPE) tissues (n = 36) or archival Fite’s stained slides (n = 3) were suitable for qPCR-HRM DST

InterEvDock: a docking server to predict the structure of protein–protein interactions using evolutionary information

PubMed Central

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

2016-01-01

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/. PMID:27131368

A Hadoop-based Molecular Docking System

NASA Astrophysics Data System (ADS)

Dong, Yueli; Guo, Quan; Sun, Bin

2017-10-01

Molecular docking always faces the challenge of managing tens of TB datasets. It is necessary to improve the efficiency of the storage and docking. We proposed the molecular docking platform based on Hadoop for virtual screening, it provides the preprocessing of ligand datasets and the analysis function of the docking results. A molecular cloud database that supports mass data management is constructed. Through this platform, the docking time is reduced, the data storage is efficient, and the management of the ligand datasets is convenient.

Low-resolution structure of Drosophila translin

PubMed Central

Kumar, Vinay; Gupta, Gagan D.

2012-01-01

Crystals of native Drosophila melanogaster translin diffracted to 7 Å resolution. Reductive methylation of the protein improved crystal quality. The native and methylated proteins showed similar profiles in size-exclusion chromatography analyses but the methylated protein displayed reduced DNA-binding activity. Crystals of the methylated protein diffracted to 4.2 Å resolution at BM14 of the ESRF synchrotron. Crystals with 49% solvent content belonged to monoclinic space group P21 with eight protomers in the asymmetric unit. Only 2% of low-resolution structures with similar low percentage solvent content were found in the PDB. The crystal structure, solved by molecular replacement method, refined to Rwork (Rfree) of 0.24 (0.29) with excellent stereochemistry. The crystal structure clearly shows that drosophila protein exists as an octamer, and not as a decamer as expected from gel-filtration elution profiles. The similar octameric quaternary fold in translin orthologs and in translin–TRAX complexes suggests an up-down dimer as the basic structural subunit of translin-like proteins. The drosophila oligomer displays asymmetric assembly and increased radius of gyration that accounts for the observed differences between the elution profiles of human and drosophila proteins on gel-filtration columns. This study demonstrates clearly that low-resolution X-ray structure can be useful in understanding complex biological oligomers. PMID:23650579

FlexPepDock lessons from CAPRI peptide-protein rounds and suggested new criteria for assessment of model quality and utility.

PubMed

Marcu, Orly; Dodson, Emma-Joy; Alam, Nawsad; Sperber, Michal; Kozakov, Dima; Lensink, Marc F; Schueler-Furman, Ora

2017-03-01

CAPRI rounds 28 and 29 included, for the first time, peptide-receptor targets of three different systems, reflecting increased appreciation of the importance of peptide-protein interactions. The CAPRI rounds allowed us to objectively assess the performance of Rosetta FlexPepDock, one of the first protocols to explicitly include peptide flexibility in docking, accounting for peptide conformational changes upon binding. We discuss here successes and challenges in modeling these targets: we obtain top-performing, high-resolution models of the peptide motif for cases with known binding sites but there is a need for better modeling of flanking regions, as well as better selection criteria, in particular for unknown binding sites. These rounds have also provided us the opportunity to reassess the success criteria, to better reflect the quality of a peptide-protein complex model. Using all models submitted to CAPRI, we analyze the correlation between current classification criteria and the ability to retrieve critical interface features, such as hydrogen bonds and hotspots. We find that loosening the backbone (and ligand) RMSD threshold, together with a restriction on the side chain RMSD measure, allows us to improve the selection of high-accuracy models. We also suggest a new measure to assess interface hydrogen bond recovery, which is not assessed by the current CAPRI criteria. Finally, we find that surprisingly much can be learned from rather inaccurate models about binding hotspots, suggesting that the current status of peptide-protein docking methods, as reflected by the submitted CAPRI models, can already have a significant impact on our understanding of protein interactions. Proteins 2017; 85:445-462. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Design of Novel Chemotherapeutic Agents Targeting Checkpoint Kinase 1 Using 3D-QSAR Modeling and Molecular Docking Methods.

PubMed

Balupuri, Anand; Balasubramanian, Pavithra K; Cho, Seung J

2016-01-01

Checkpoint kinase 1 (Chk1) has emerged as a potential therapeutic target for design and development of novel anticancer drugs. Herein, we have performed three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular docking analyses on a series of diazacarbazoles to design potent Chk1 inhibitors. 3D-QSAR models were developed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. Docking studies were performed using AutoDock. The best CoMFA and CoMSIA models exhibited cross-validated correlation coefficient (q2) values of 0.631 and 0.585, and non-cross-validated correlation coefficient (r2) values of 0.933 and 0.900, respectively. CoMFA and CoMSIA models showed reasonable external predictabilities (r2 pred) of 0.672 and 0.513, respectively. A satisfactory performance in the various internal and external validation techniques indicated the reliability and robustness of the best model. Docking studies were performed to explore the binding mode of inhibitors inside the active site of Chk1. Molecular docking revealed that hydrogen bond interactions with Lys38, Glu85 and Cys87 are essential for Chk1 inhibitory activity. The binding interaction patterns observed during docking studies were complementary to 3D-QSAR results. Information obtained from the contour map analysis was utilized to design novel potent Chk1 inhibitors. Their activities and binding affinities were predicted using the derived model and docking studies. Designed inhibitors were proposed as potential candidates for experimental synthesis.

Recent progress of flexible AMOLED displays

NASA Astrophysics Data System (ADS)

Pang, Huiqing; Rajan, Kamala; Silvernail, Jeff; Mandlik, Prashant; Ma, Ruiqing; Hack, Mike; Brown, Julie J.; Yoo, Juhn S.; Jung, Sang-Hoon; Kim, Yong-Cheol; Byun, Seung-Chan; Kim, Jong-Moo; Yoon, Soo-Young; Kim, Chang-Dong; Hwang, Yong-Kee; Chung, In-Jae; Fletcher, Mark; Green, Derek; Pangle, Mike; McIntyre, Jim; Smith, Randal D.

2011-03-01

Significant progress has been made in recent years in flexible AMOLED displays and numerous prototypes have been demonstrated. Replacing rigid glass with flexible substrates and thin-film encapsulation makes displays thinner, lighter, and non-breakable - all attractive features for portable applications. Flexible AMOLEDs equipped with phosphorescent OLEDs are considered one of the best candidates for low-power, rugged, full-color video applications. Recently, we have demonstrated a portable communication display device, built upon a full-color 4.3-inch HVGA foil display with a resolution of 134 dpi using an all-phosphorescent OLED frontplane. The prototype is shaped into a thin and rugged housing that will fit over a user's wrist, providing situational awareness and enabling the wearer to see real-time video and graphics information.

pyDockWEB: a web server for rigid-body protein-protein docking using electrostatics and desolvation scoring.

PubMed

Jiménez-García, Brian; Pons, Carles; Fernández-Recio, Juan

2013-07-01

pyDockWEB is a web server for the rigid-body docking prediction of protein-protein complex structures using a new version of the pyDock scoring algorithm. We use here a new custom parallel FTDock implementation, with adjusted grid size for optimal FFT calculations, and a new version of pyDock, which dramatically speeds up calculations while keeping the same predictive accuracy. Given the 3D coordinates of two interacting proteins, pyDockWEB returns the best docking orientations as scored mainly by electrostatics and desolvation energy. The server does not require registration by the user and is freely accessible for academics at http://life.bsc.es/servlet/pydock. Supplementary data are available at Bioinformatics online.

Transparent, Flexible, Low Noise Graphene Electrodes for Simultaneous Electrophysiology and Neuroimaging

PubMed Central

Kuzum, Duygu; Takano, Hajime; Shim, Euijae; Reed, Jason C; Juul, Halvor; Richardson, Andrew G.; de Vries, Julius; Bink, Hank; Dichter, Marc A.; Lucas, Timothy H.; Coulter, Douglas A.; Cubukcu, Ertugrul; Litt, Brian

2014-01-01

Calcium imaging is a versatile experimental approach capable of resolving single neurons with single-cell spatial resolution in the brain. Electrophysiological recordings provide high temporal, but limited spatial resolution, due to the geometrical inaccessibility of the brain. An approach that integrates the advantages of both techniques could provide new insights into functions of neural circuits. Here, we report a transparent, flexible neural electrode technology based on graphene, which enables simultaneous optical imaging and electrophysiological recording. We demonstrate that hippocampal slices can be imaged through transparent graphene electrodes by both confocal and two-photon microscopy without causing any light-induced artifacts in the electrical recordings. Graphene electrodes record high frequency bursting activity and slow synaptic potentials that are hard to resolve by multi-cellular calcium imaging. This transparent electrode technology may pave the way for high spatio-temporal resolution electrooptic mapping of the dynamic neuronal activity. PMID:25327632

Gemini rendezvous docking simulator

NASA Image and Video Library

1963-11-04

Multiple exposure of Gemini rendezvous docking simulator. Francis B. Smith wrote in his paper "Simulators for Manned Space Research," "The rendezvous and docking operation of the Gemini spacecraft with the Agena and of the Apollo Command Module with the Lunar Excursion Module have been the subject of simulator studies for several years. [This figure] illustrates the Gemini-Agena rendezvous docking simulator at Langley. The Gemini spacecraft was supported in a gimbal system by an overhead crane and gantry arrangement which provided 6 degrees of freedom - roll, pitch, yaw, and translation in any direction - all controllable by the astronaut in the spacecraft. Here again the controls fed into a computer which in turn provided an input to the servos driving the spacecraft so that it responded to control motions in a manner which accurately simulated the Gemini spacecraft." A.W. Vogeley further described the simulator in his paper "Discussion of Existing and Planned Simulators For Space Research," "Docking operations are considered to start when the pilot first can discern vehicle target size and aspect and terminate, of course, when soft contact is made. ... This facility enables simulation of the docking operation from a distance of 200 feet to actual contact with the target. A full-scale mock-up of the target vehicle is suspended near one end of the track. ... On [the Agena target] we have mounted the actual Agena docking mechanism and also various types of visual aids. We have been able to devise visual aids which have made it possible to accomplish nighttime docking with as much success as daytime docking." -- Published in Barton C. Hacker and James M. Grimwood, On the Shoulders of Titans: A History of Project Gemini, NASA SP-4203; Francis B. Smith, "Simulators for Manned Space Research," Paper presented at the 1966 IEEE International convention, March 21-25, 1966; A.W. Vogeley, "Discussion of Existing and Planned Simulators For Space Research," Paper presented at

Russian Docking Module is lowered

NASA Technical Reports Server (NTRS)

1995-01-01

The Russian-built Docking Module (DM) is lowered for installation into the payload bay of the Space Shuttle Orbiter Atlantis while the spaceplane is in Orbiter Processing Facility bay 2. The module will fly as a primary payload on the second Space Shuttle/Mir space station docking mission, STS-74, which is now scheduled for liftoff in the fall of 1995. During the mission, the module will first be attached with the orbiter's robot arm to the Orbiter Docking System (ODS) in the payload bay of the orbiter Atlantis and then be docked with the Mir. When Atlantis undocks from the Mir, it will leave the new docking module permanently attached to the space station for use during future Shuttle Mir docking missions. The new module will simplify future Shuttle linkups with Mir by improving orbiter clearances when it serves as a bridge between the two space vehicles. The white structures attached to the module's sides are solar panels that will be attached to the Mir after the conclusion of the STS-74 mission.

Automated Rendezvous and Docking Sensor Testing at the Flight Robotics Laboratory

NASA Technical Reports Server (NTRS)

Mitchell, J.; Johnston, A.; Howard, R.; Williamson, M.; Brewster, L.; Strack, D.; Cryan, S.

2007-01-01

The Exploration Systems Architecture defines missions that require rendezvous, proximity operations, and docking (RPOD) of two spacecraft both in Low Earth Orbit (LEO) and in Low Lunar Orbit (LLO). Uncrewed spacecraft must perform automated and/or autonomous rendezvous, proximity operations and docking operations (commonly known as Automated Rendezvous and Docking, AR&D). The crewed versions may also perform AR&D, possibly with a different level of automation and/or autonomy, and must also provide the crew with relative navigation information for manual piloting. The capabilities of the RPOD sensors are critical to the success of the Exploration Program. NASA has the responsibility to determine whether the Crew Exploration Vehicle (CEV) contractor-proposed relative navigation sensor suite will meet the CEV requirements. The relatively low technology readiness of relative navigation sensors for AR&D has been carried as one of the CEV Projects top risks. The AR&D Sensor Technology Project seeks to reduce this risk by increasing technology maturation of selected relative navigation sensor technologies through testing and simulation, and to allow the CEV Project to assess the relative navigation sensors.

Achieving flexible low-scattering metasurface based on randomly distribution of meta-elements.

PubMed

Zhao, Junming; Sima, Boyu; Jia, Nan; Wang, Cheng; Zhu, Bo; Jiang, Tian; Feng, Yijun

2016-11-28

In the paper, a flexible low-scattering metasurface is proposed and realized. The layout is composed of similar "#" shaped elements with variable sizes which are randomly distributed along the surface. The various dimensions of the meta-elements lead to different reflection phases for the meta-elements with respect to the incident plane wave, resulting a diffuse reflection surface and exhibiting a broadband backward low-scattering property. In consideration of the flexibility, metasurfaces composed of printed metallic element films attaching with flexible substrate are designed, fabricated and measured in microwave domain. The measurement results show that 10dB radar cross section (RCS) reduction is obtained across the X-band by coating them to either metallic plates or metallic cylinders with only 1/8 working wavelength thickness. We think that the proposed flexible metasurface is applicable to other frequency bands and can be applied in EM stealth technology.

Q-switch-pumped supercontinuum for ultra-high resolution optical coherence tomography.

PubMed

Maria, Michael; Bravo Gonzalo, Ivan; Feuchter, Thomas; Denninger, Mark; Moselund, Peter M; Leick, Lasse; Bang, Ole; Podoleanu, Adrian

2017-11-15

In this Letter, we investigate the possibility of using a commercially available Q-switch-pumped supercontinuum (QS-SC) source, operating in the kilohertz regime, for ultra-high resolution optical coherence tomography (UHR-OCT) in the 1300 nm region. The QS-SC source proves to be more intrinsically stable from pulse to pulse than a mode-locked-based SC (ML-SC) source while, at the same time, is less expensive. However, its pumping rate is lower than that used in ML-SC sources. Therefore, we investigate here specific conditions to make such a source usable for OCT. We compare images acquired with the QS-SC source and with a current state-of-the-art SC source used for imaging. We show that comparable visual contrast obtained with the two technologies is achievable by increasing the readout time of the camera to include a sufficient number of QS-SC pulses.

Building macromolecular assemblies by information-driven docking: introducing the HADDOCK multibody docking server.

PubMed

Karaca, Ezgi; Melquiond, Adrien S J; de Vries, Sjoerd J; Kastritis, Panagiotis L; Bonvin, Alexandre M J J

2010-08-01

Over the last years, large scale proteomics studies have generated a wealth of information of biomolecular complexes. Adding the structural dimension to the resulting interactomes represents a major challenge that classical structural experimental methods alone will have difficulties to confront. To meet this challenge, complementary modeling techniques such as docking are thus needed. Among the current docking methods, HADDOCK (High Ambiguity-Driven DOCKing) distinguishes itself from others by the use of experimental and/or bioinformatics data to drive the modeling process and has shown a strong performance in the critical assessment of prediction of interactions (CAPRI), a blind experiment for the prediction of interactions. Although most docking programs are limited to binary complexes, HADDOCK can deal with multiple molecules (up to six), a capability that will be required to build large macromolecular assemblies. We present here a novel web interface of HADDOCK that allows the user to dock up to six biomolecules simultaneously. This interface allows the inclusion of a large variety of both experimental and/or bioinformatics data and supports several types of cyclic and dihedral symmetries in the docking of multibody assemblies. The server was tested on a benchmark of six cases, containing five symmetric homo-oligomeric protein complexes and one symmetric protein-DNA complex. Our results reveal that, in the presence of either bioinformatics and/or experimental data, HADDOCK shows an excellent performance: in all cases, HADDOCK was able to generate good to high quality solutions and ranked them at the top, demonstrating its ability to model symmetric multicomponent assemblies. Docking methods can thus play an important role in adding the structural dimension to interactomes. However, although the current docking methodologies were successful for a vast range of cases, considering the variety and complexity of macromolecular assemblies, inclusion of some kind of

Investigations of FAK inhibitors: a combination of 3D-QSAR, docking, and molecular dynamics simulations studies.

PubMed

Cheng, Peng; Li, Jiaojiao; Wang, Juan; Zhang, Xiaoyun; Zhai, Honglin

2018-05-01

Focal adhesion kinase (FAK) is one kind of tyrosine kinases that modulates integrin and growth factor signaling pathways, which is a promising therapeutic target because of involving in cancer cell migration, proliferation, and survival. To investigate the mechanism between FAK and triazinic inhibitors and design high activity inhibitors, a molecular modeling integrated with 3D-QSAR, molecular docking, molecular dynamics simulations, and binding free energy calculations was performed. The optimum CoMFA and CoMSIA models showed good reliability and satisfactory predictability (with Q 2  = 0.663, R 2  = 0.987, [Formula: see text] = 0.921 and Q 2  = 0.670, R 2  = 0.981, [Formula: see text] = 0.953). Its contour maps could provide structural features to improve inhibitory activity. Furthermore, a good consistency between contour maps, docking, and molecular dynamics simulations strongly demonstrates that the molecular modeling is reliable. Based on it, we designed several new compounds and their inhibitory activities were validated by the molecular models. We expect our studies could bring new ideas to promote the development of novel inhibitors with higher inhibitory activity for FAK.

Docking and scoring protein complexes: CAPRI 3rd Edition.

PubMed

Lensink, Marc F; Méndez, Raúl; Wodak, Shoshana J

2007-12-01

The performance of methods for predicting protein-protein interactions at the atomic scale is assessed by evaluating blind predictions performed during 2005-2007 as part of Rounds 6-12 of the community-wide experiment on Critical Assessment of PRedicted Interactions (CAPRI). These Rounds also included a new scoring experiment, where a larger set of models contributed by the predictors was made available to groups developing scoring functions. These groups scored the uploaded set and submitted their own best models for assessment. The structures of nine protein complexes including one homodimer were used as targets. These targets represent biologically relevant interactions involved in gene expression, signal transduction, RNA, or protein processing and membrane maintenance. For all the targets except one, predictions started from the experimentally determined structures of the free (unbound) components or from models derived by homology, making it mandatory for docking methods to model the conformational changes that often accompany association. In total, 63 groups and eight automatic servers, a substantial increase from previous years, submitted docking predictions, of which 1994 were evaluated here. Fifteen groups submitted 305 models for five targets in the scoring experiment. Assessment of the predictions reveals that 31 different groups produced models of acceptable and medium accuracy-but only one high accuracy submission-for all the targets, except the homodimer. In the latter, none of the docking procedures reproduced the large conformational adjustment required for correct assembly, underscoring yet again that handling protein flexibility remains a major challenge. In the scoring experiment, a large fraction of the groups attained the set goal of singling out the correct association modes from incorrect solutions in the limited ensembles of contributed models. But in general they seemed unable to identify the best models, indicating that current scoring

Binding site and affinity prediction of general anesthetics to protein targets using docking.

PubMed

Liu, Renyu; Perez-Aguilar, Jose Manuel; Liang, David; Saven, Jeffery G

2012-05-01

The protein targets for general anesthetics remain unclear. A tool to predict anesthetic binding for potential binding targets is needed. In this study, we explored whether a computational method, AutoDock, could serve as such a tool. High-resolution crystal data of water-soluble proteins (cytochrome C, apoferritin, and human serum albumin), and a membrane protein (a pentameric ligand-gated ion channel from Gloeobacter violaceus [GLIC]) were used. Isothermal titration calorimetry (ITC) experiments were performed to determine anesthetic affinity in solution conditions for apoferritin. Docking calculations were performed using DockingServer with the Lamarckian genetic algorithm and the Solis and Wets local search method (http://www.dockingserver.com/web). Twenty general anesthetics were docked into apoferritin. The predicted binding constants were compared with those obtained from ITC experiments for potential correlations. In the case of apoferritin, details of the binding site and their interactions were compared with recent cocrystallization data. Docking calculations for 6 general anesthetics currently used in clinical settings (isoflurane, sevoflurane, desflurane, halothane, propofol, and etomidate) with known 50% effective concentration (EC(50)) values were also performed in all tested proteins. The binding constants derived from docking experiments were compared with known EC(50) values and octanol/water partition coefficients for the 6 general anesthetics. All 20 general anesthetics docked unambiguously into the anesthetic binding site identified in the crystal structure of apoferritin. The binding constants for 20 anesthetics obtained from the docking calculations correlate significantly with those obtained from ITC experiments (P = 0.04). In the case of GLIC, the identified anesthetic binding sites in the crystal structure are among the docking predicted binding sites, but not the top ranked site. Docking calculations suggest a most probable binding site

Expedition 23 Docking

NASA Image and Video Library

2010-04-03

View from the balcony of the Russian Mission Control Center in Korolev, Russia as the Soyuz TMA-18 docks to the International Space Station on Sunday, April 4, 2010. The Soyuz TMA-18 docked to the International Space Station carrying Expedition 23 Soyuz Commander Alexander Skvortsov, Flight Engineer Mikhail Kornienko and NASA Flight Engineer Tracy Caldwell Dyson. Photo Credit: (NASA/Carla Cioffi)

Protein docking prediction using predicted protein-protein interface.

PubMed

Li, Bin; Kihara, Daisuke

2012-01-10

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

Nanoparticle Selective Laser Processing for a Flexible Display Fabrication

NASA Astrophysics Data System (ADS)

Seung Hwan Ko,; Heng Pan,; Daeho Lee,; Costas P. Grigoropoulos,; Hee K. Park,

2010-05-01

To demonstrate a first step for a novel fabrication method of a flexible display, nanomaterial based laser processing schemes to demonstrate organic light emitting diode (OLED) pixel transfer and organic field effect transistor (OFET) fabrication on a polymer substrate without using any conventional vacuum or photolithography processes were developed. The unique properties of nanomaterials allow laser induced forward transfer of organic light emitting material at low laser energy while maintaining good fluorescence and also allow high resolution transistor electrode patterning at plastic compatible low temperature. These novel processes enable an environmentally friendly and cost effective process as well as a low temperature manufacturing sequence to realize inexpensive, large area, flexible electronics on polymer substrates.

Structural insights into transient receptor potential vanilloid type 1 (TRPV1) from homology modeling, flexible docking, and mutational studies.

PubMed

Lee, Jin Hee; Lee, Yoonji; Ryu, HyungChul; Kang, Dong Wook; Lee, Jeewoo; Lazar, Jozsef; Pearce, Larry V; Pavlyukovets, Vladimir A; Blumberg, Peter M; Choi, Sun

2011-04-01

The transient receptor potential vanilloid subtype 1 (TRPV1) is a non-selective cation channel composed of four monomers with six transmembrane helices (TM1-TM6). TRPV1 is found in the central and peripheral nervous system, and it is an important therapeutic target for pain relief. We describe here the construction of a tetrameric homology model of rat TRPV1 (rTRPV1). We experimentally evaluated by mutational analysis the contribution of residues of rTRPV1 contributing to ligand binding by the prototypical TRPV1 agonists, capsaicin and resiniferatoxin (RTX). We then performed docking analysis using our homology model. The docking results with capsaicin and RTX showed that our homology model was reliable, affording good agreement with our mutation data. Additionally, the binding mode of a simplified RTX (sRTX) ligand as predicted by the modeling agreed well with those of capsaicin and RTX, accounting for the high binding affinity of the sRTX ligand for TRPV1. Through the homology modeling, docking and mutational studies, we obtained important insights into the ligand-receptor interactions at the molecular level which should prove of value in the design of novel TRPV1 ligands.

Structural insights into transient receptor potential vanilloid type 1 (TRPV1) from homology modeling, flexible docking, and mutational studies

NASA Astrophysics Data System (ADS)

Lee, Jin Hee; Lee, Yoonji; Ryu, HyungChul; Kang, Dong Wook; Lee, Jeewoo; Lazar, Jozsef; Pearce, Larry V.; Pavlyukovets, Vladimir A.; Blumberg, Peter M.; Choi, Sun

2011-04-01

The transient receptor potential vanilloid subtype 1 (TRPV1) is a non-selective cation channel composed of four monomers with six transmembrane helices (TM1-TM6). TRPV1 is found in the central and peripheral nervous system, and it is an important therapeutic target for pain relief. We describe here the construction of a tetrameric homology model of rat TRPV1 (rTRPV1). We experimentally evaluated by mutational analysis the contribution of residues of rTRPV1 contributing to ligand binding by the prototypical TRPV1 agonists, capsaicin and resiniferatoxin (RTX). We then performed docking analysis using our homology model. The docking results with capsaicin and RTX showed that our homology model was reliable, affording good agreement with our mutation data. Additionally, the binding mode of a simplified RTX (sRTX) ligand as predicted by the modeling agreed well with those of capsaicin and RTX, accounting for the high binding affinity of the sRTX ligand for TRPV1. Through the homology modeling, docking and mutational studies, we obtained important insights into the ligand-receptor interactions at the molecular level which should prove of value in the design of novel TRPV1 ligands.

Flexible and low-voltage integrated circuits constructed from high-performance nanocrystal transistors.

PubMed

Kim, David K; Lai, Yuming; Diroll, Benjamin T; Murray, Christopher B; Kagan, Cherie R

2012-01-01

Colloidal semiconductor nanocrystals are emerging as a new class of solution-processable materials for low-cost, flexible, thin-film electronics. Although these colloidal inks have been shown to form single, thin-film field-effect transistors with impressive characteristics, the use of multiple high-performance nanocrystal field-effect transistors in large-area integrated circuits has not been shown. This is needed to understand and demonstrate the applicability of these discrete nanocrystal field-effect transistors for advanced electronic technologies. Here we report solution-deposited nanocrystal integrated circuits, showing nanocrystal integrated circuit inverters, amplifiers and ring oscillators, constructed from high-performance, low-voltage, low-hysteresis CdSe nanocrystal field-effect transistors with electron mobilities of up to 22 cm(2) V(-1) s(-1), current modulation >10(6) and subthreshold swing of 0.28 V dec(-1). We fabricated the nanocrystal field-effect transistors and nanocrystal integrated circuits from colloidal inks on flexible plastic substrates and scaled the devices to operate at low voltages. We demonstrate that colloidal nanocrystal field-effect transistors can be used as building blocks to construct complex integrated circuits, promising a viable material for low-cost, flexible, large-area electronics.

Prediction of the binding sites of huperzine A in acetylcholinesterase by docking studies

NASA Astrophysics Data System (ADS)

Pang, Yuan-Ping; Kozikowski, Alan P.

1994-12-01

We have performed docking studies with the SYSDOC program on acetylcholinesterase (AChE) to predict the binding sites in AChE of huperzine A (HA), which is a potent and selective, reversible inhibitor of AChE. The unique aspects of our docking studies include the following: (i) Molecular flexibility of the guest and the host is taken into account, which permits both to change their conformations upon binding. (ii) The binding energy is evaluated by a sum of energies of steric, electrostatic and hydrogen bonding interactions. In the energy calculation no grid approximation is used, and all hydrogen atoms of the system are treated explicitly. (iii) The energy of cation-π interactions between the guest and the host, which is important in the binding of AChE, is included in the calculated binding energy. (iv) Docking is performed in all regions of the host's binding cavity. Based on our docking studies and the pharmacological results reported for HA and its analogs, we predict that HA binds to the bottom of the binding cavity of AChE (the gorge) with its ammonium group interacting with Trp84, Phe330, Glu199 and Asp72 (catalytic site). At the the opening of the gorge with its ammonium group partially interacting with Trp279 (peripheral site). At the catalytic site, three partially overlapping subsites of HA were identified which might provide a dynamic view of binding of HA to the catalytic site.

Siblings with opposite chromosome constitutions, dup(2q)/del(7q) and del(2q)/dup(7q).

PubMed

Shim, Sung Han; Shim, Jae Sun; Min, Kyunghoon; Lee, Hee Song; Park, Ji Eun; Park, Sang Hee; Hwang, Euna; Kim, Minyoung

2014-01-15

Chromosome 7q36 microdeletion syndrome is a rare genomic disorder characterized by underdevelopment of the brain, microcephaly, anomalies of the sex organs, and language problems. Developmental delay, intellectual disability, autistic spectrum disorders, BDMR syndrome, and unusual facial morphology are the key features of the chromosome 2q37 microdeletion syndrome. A genetic screening for two brothers with global developmental delay using high-resolution chromosomal analysis and subtelomeric multiplex ligation-dependent probe amplification revealed subtelomeric rearrangements on the same sites of 2q37.2 and 7q35, with reversed deletion and duplication. Both of them showed dysmorphic facial features, severe disability of physical and intellectual development, and abnormal genitalia with differential abnormalities in their phenotypes. The family did not have abnormal genetic phenotypes. According to the genetic analysis of their parents, adjacent-1 segregation from their mother's was suggested as a mechanism of their gene mutation. By comparing the phenotypes of our patients with previous reports on similar patients, we tried to obtain the information of related genes and their chromosomal locations. © 2013.

Expedition 27 Docking

NASA Image and Video Library

2011-04-06

Top officials from the Russian Federal Space Agency and NASA hold a Soyuz post-docking press conference at the Russian Mission Control Center in Korolev, Russia on Thursday, April 7, 2011. The Soyuz TMA-21 docked to the International Space Station carrying Expedition 27 Soyuz Commander Alexander Samokutyaev, NASA Flight Engineer Ron Garan and Russian Flight Engineer Andrey Borisenko. Photo Credit: (NASA/Carla Cioffi)

Expedition 23 Docking

NASA Image and Video Library

2010-04-03

Kirk Shireman, NASA's deputy ISS program manager, answers reporter’s questions during a Soyuz post-docking press conference at the Russian Mission Control Center in Korolev, Russia on Sunday, April 4, 2010. The Soyuz TMA-18 docked to the International Space Station carrying Expedition 23 Soyuz Commander Alexander Skvortsov, Flight Engineer Mikhail Kornienko and NASA Flight Engineer Tracy Caldwell Dyson. Photo Credit: (NASA/Carla Cioffi)

Expedition 23 Docking

NASA Image and Video Library

2010-04-03

Kirk Shireman, right, NASA's deputy ISS program manager, answers reporter’s questions during a Soyuz post-docking press conference at the Russian Mission Control Center in Korolev, Russia on Sunday, April 4, 2010. The Soyuz TMA-18 docked to the International Space Station carrying Expedition 23 Soyuz Commander Alexander Skvortsov, Flight Engineer Mikhail Kornienko and NASA Flight Engineer Tracy Caldwell Dyson. Photo Credit: (NASA/Carla Cioffi)

FOLD-EM: automated fold recognition in medium- and low-resolution (4-15 Å) electron density maps.

PubMed

Saha, Mitul; Morais, Marc C

2012-12-15

Owing to the size and complexity of large multi-component biological assemblies, the most tractable approach to determining their atomic structure is often to fit high-resolution radiographic or nuclear magnetic resonance structures of isolated components into lower resolution electron density maps of the larger assembly obtained using cryo-electron microscopy (cryo-EM). This hybrid approach to structure determination requires that an atomic resolution structure of each component, or a suitable homolog, is available. If neither is available, then the amount of structural information regarding that component is limited by the resolution of the cryo-EM map. However, even if a suitable homolog cannot be identified using sequence analysis, a search for structural homologs should still be performed because structural homology often persists throughout evolution even when sequence homology is undetectable, As macromolecules can often be described as a collection of independently folded domains, one way of searching for structural homologs would be to systematically fit representative domain structures from a protein domain database into the medium/low resolution cryo-EM map and return the best fits. Taken together, the best fitting non-overlapping structures would constitute a 'mosaic' backbone model of the assembly that could aid map interpretation and illuminate biological function. Using the computational principles of the Scale-Invariant Feature Transform (SIFT), we have developed FOLD-EM-a computational tool that can identify folded macromolecular domains in medium to low resolution (4-15 Å) electron density maps and return a model of the constituent polypeptides in a fully automated fashion. As a by-product, FOLD-EM can also do flexible multi-domain fitting that may provide insight into conformational changes that occur in macromolecular assemblies.

InterEvDock2: an expanded server for protein docking using evolutionary and biological information from homology models and multimeric inputs.

PubMed

Quignot, Chloé; Rey, Julien; Yu, Jinchao; Tufféry, Pierre; Guerois, Raphaël; Andreani, Jessica

2018-05-08

Computational protein docking is a powerful strategy to predict structures of protein-protein interactions and provides crucial insights for the functional characterization of macromolecular cross-talks. We previously developed InterEvDock, a server for ab initio protein docking based on rigid-body sampling followed by consensus scoring using physics-based and statistical potentials, including the InterEvScore function specifically developed to incorporate co-evolutionary information in docking. InterEvDock2 is a major evolution of InterEvDock which allows users to submit input sequences - not only structures - and multimeric inputs and to specify constraints for the pairwise docking process based on previous knowledge about the interaction. For this purpose, we added modules in InterEvDock2 for automatic template search and comparative modeling of the input proteins. The InterEvDock2 pipeline was benchmarked on 812 complexes for which unbound homology models of the two partners and co-evolutionary information are available in the PPI4DOCK database. InterEvDock2 identified a correct model among the top 10 consensus in 29% of these cases (compared to 15-24% for individual scoring functions) and at least one correct interface residue among 10 predicted in 91% of these cases. InterEvDock2 is thus a unique protein docking server, designed to be useful for the experimental biology community. The InterEvDock2 web interface is available at http://bioserv.rpbs.univ-paris-diderot.fr/services/InterEvDock2/.

Coenzyme Q10-Loaded Fish Oil-Based Bigel System: Probing the Delivery Across Porcine Skin and Possible Interaction with Fish Oil Fatty Acids.

PubMed

Zulfakar, Mohd Hanif; Chan, Lee Mei; Rehman, Khurram; Wai, Lam Kok; Heard, Charles M

2018-04-01

Coenzyme Q10 (CoQ10) is a vitamin-like oil-soluble molecule that has anti-oxidant and anti-ageing effects. To determine the most optimal CoQ10 delivery vehicle, CoQ10 was solubilised in both water and fish oil, and formulated into hydrogel, oleogel and bigel. Permeability of CoQ10 from each formulation across porcine ear skin was then evaluated. Furthermore, the effects of the omega-3 fatty eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids from fish oil on skin permeation were investigated by means of nuclear magnetic resonance (NMR) and computerised molecular modelling docking experiments. The highest drug permeation was achieved with the bigel formulation that proved to be the most effective vehicle in delivering CoQ10 across the skin membrane due to a combination of its adhesive, viscous and lipophilic properties. Furthermore, the interactions between CoQ10 and fatty acids revealed by NMR and molecular modelling experiments likely accounted for skin permeability of CoQ10. NMR data showed dose-dependent changes in proton chemical shifts in EPA and DHA. Molecular modelling revealed complex formation and large binding energies between fatty acids and CoQ10. This study advances the knowledge about bigels as drug delivery vehicles and highlights the use of NMR and molecular docking studies for the prediction of the influence of drug-excipient relationships at the molecular level.

Multilevel Parallelization of AutoDock 4.2.

PubMed

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.

Highly transparent, low-haze, hybrid cellulose nanopaper as electrodes for flexible electronics.

PubMed

Xu, Xuezhu; Zhou, Jian; Jiang, Long; Lubineau, Gilles; Ng, Tienkhee; Ooi, Boon S; Liao, Hsien-Yu; Shen, Chao; Chen, Long; Zhu, J Y

2016-06-16

Paper is an excellent candidate to replace plastics as a substrate for flexible electronics due to its low cost, renewability and flexibility. Cellulose nanopaper (CNP), a new type of paper made of nanosized cellulose fibers, is a promising substrate material for transparent and flexible electrodes due to its potentially high transparency and high mechanical strength. Although CNP substrates can achieve high transparency, they are still characterized by high diffuse transmittance and small direct transmittance, resulting in high optical haze of the substrates. In this study, we proposed a simple methodology for large-scale production of high-transparency, low-haze CNP comprising both long cellulose nanofibrils (CNFs) and short cellulose nanocrystals (CNCs). By varying the CNC/CNF ratio in the hybrid CNP, we could tailor its total transmittance, direct transmittance and diffuse transmittance. By increasing the CNC content, the optical haze of the hybrid CNP could be decreased and its transparency could be increased. The direct transmittance and optical haze of the CNP were 75.1% and 10.0%, respectively, greatly improved from the values of previously reported CNP (31.1% and 62.0%, respectively). Transparent, flexible electrodes were fabricated by coating the hybrid CNP with silver nanowires (AgNWs). The electrodes showed a low sheet resistance (minimum 1.2 Ω sq(-1)) and a high total transmittance (maximum of 82.5%). The electrodes were used to make a light emitting diode (LED) assembly to demonstrate their potential use in flexible displays.

Comparing high-resolution microscopy techniques for potential intraoperative use in guiding low-grade glioma resections.

PubMed

Meza, Daphne; Wang, Danni; Wang, Yu; Borwege, Sabine; Sanai, Nader; Liu, Jonathan T C

2015-04-01

Fluorescence image-guided surgery (FIGS), with contrast provided by 5-ALA-induced PpIX, has been shown to enable a higher extent of resection of high-grade gliomas. However, conventional FIGS with low-power microscopy lacks the sensitivity to aid in low-grade glioma (LGG) resection because PpIX signal is weak and sparse in such tissues. Intraoperative high-resolution microscopy of PpIX fluorescence has been proposed as a method to guide LGG resection, where sub-cellular resolution allows for the visualization of sparse and punctate mitochondrial PpIX production in tumor cells. Here, we assess the performance of three potentially portable high-resolution microscopy techniques that may be used for the intraoperative imaging of human LGG tissue samples with PpIX contrast: high-resolution fiber-optic microscopy (HRFM), high-resolution wide-field microscopy (WFM), and dual-axis confocal (DAC) microscopy. Thick unsectioned human LGG tissue samples (n = 7) with 5-ALA-induced PpIX contrast were imaged using three imaging techniques (HRFM, WFM, DAC). The average signal-to-background ratio (SBR) was then calculated for each imaging modality (5 images per tissue, per modality). HRFM provides the ease of use and portability of a flexible fiber bundle, and is simple and inexpensive to build. However, in most cases (6/7), HRFM is not capable of detecting PpIX signal from LGGs due to high autofluorescence, generated by the fiber bundle under laser illumination at 405 nm, which overwhelms the PpIX signal and impedes its visualization. WFM is a camera-based method possessing high lateral resolution but poor axial resolution, resulting in sub-optimal image contrast. Consistent successful detection of PpIX signal throughout our human LGG tissue samples (n = 7), with an acceptable image contrast (SBR >2), was only achieved using DAC microscopy, which offers superior image resolution and contrast that is comparable to histology, but requires a laser-scanning mechanism to

Engineering Low-Dimensional Nanostructures Towards Flexible Electronics

NASA Astrophysics Data System (ADS)

Byrley, Peter Samuel

Flexible electronics have been proposed as the next generation of electronic devices. They have advantages over traditional electronics in that they use less material, are more durable and have greater versatility in their proposed applications. However, there are a variety of types of devices being developed that have specific engineering challenges. This dissertation addresses two of those challenges. The first challenge involves lowering contact resistance in MoS2 based flexible thin film transistor devices using a photochemical phase change method while the second addresses using silver nanowire networks as a replacement flexible electrode for indium tin oxide in flexible electronics. In this dissertation, a scalable method was developed for making monolayer MoS2 using ambient pressure chemical vapor deposition. These films were then characterized using spectroscopic techniques and atomic force microscopy. A photochemical phase change mechanism was then proposed to improve contact resistance in MoS2 based devices. The central hypothesis is that the controllable partial transition from a semiconducting 2H to metallic 1T phase can be realized in monolayer TMDs through photo-reduction in the presence of hole scavenging chemicals. Phase-engineering in monolayer TMDs would enable the fabrication of high-quality heterophase structures with the potential to improve carrier mobility and contact. Phase change as a result of the proposed photochemical method was confirmed using Raman spectroscopy, photoluminescence measurements, X-Ray photoelectron spectroscopy and other supporting data. Gold coated silver nanowires were then created to serve as flexible nanowire based electrodes by overcoming galvanic replacement in solution. This was confirmed using various forms of electron microscopy. The central hypothesis is that a thin gold coating will enable silver nanowire meshes to remain electrically stable in atmosphere and retain necessary low resistance values and

Subtle trisomy 12q24.3 and subtle monosomy 22q13.3: three new cases and review.

PubMed

Rodríguez, Laura; Martínez Guardia, Nieves; Herens, Christian; Jamar, Mauricette; Verloes, Alain; López, Fermina; Santos Muñoz, José; Martínez-Frías, María Luisa

2003-10-01

The high resolution G-bands (850 bands) karyotype have made it possible to identify small chromosome anomalies (5 megabases) which are now microscopically visible. New techniques have been improved, such as the Fluorescent in situ hybridization (FISH) with subtelomeric probes, which can be employed to detect cryptic chromosome alterations not visible microscopically. We present three cases which had been remitted for a high resolution karyotype. The high resolution G-band karyotype and the FISH techniques led us to conclude that the three cases were carriers of a similar subtle chromosomal alteration. Case I is a new born female with developmental and psychomotor delay, hypotonia, and long limbs with arachnodactily. A high resolution G-band karyotype showed an abnormal chromosome 22. FISH techniques confirmed a der(22)t(12;22)(q24.31;q13.3). Case II is a 12-year-old girl, with growth retardation, long shaped face with thick eyebrows, smooth philtrum, and thin upper lip with severe mental retardation (still no language), with a phenotype very similar to that of his sister: long shaped face, thick eyebrows, smooth philtrum, and thin upper lip. A high resolution G-band karyotype also showed in Case II and III an abnormal chromosome 22, studied by FISH techniques which confirmed a der(22)t(12;22)(q24.3;q13.3) in both cases. Copyright 2003 Wiley-Liss, Inc.

Binding Site and Affinity Prediction of General Anesthetics to Protein Targets Using Docking

PubMed Central

Liu, Renyu; Perez-Aguilar, Jose Manuel; Liang, David; Saven, Jeffery G.

2012-01-01

Background The protein targets for general anesthetics remain unclear. A tool to predict anesthetic binding for potential binding targets is needed. In this study, we explore whether a computational method, AutoDock, could serve as such a tool. Methods High-resolution crystal data of water soluble proteins (cytochrome C, apoferritin and human serum albumin), and a membrane protein (a pentameric ligand-gated ion channel from Gloeobacter violaceus, GLIC) were used. Isothermal titration calorimetry (ITC) experiments were performed to determine anesthetic affinity in solution conditions for apoferritin. Docking calculations were performed using DockingServer with the Lamarckian genetic algorithm and the Solis and Wets local search method (https://www.dockingserver.com/web). Twenty general anesthetics were docked into apoferritin. The predicted binding constants are compared with those obtained from ITC experiments for potential correlations. In the case of apoferritin, details of the binding site and their interactions were compared with recent co-crystallization data. Docking calculations for six general anesthetics currently used in clinical settings (isoflurane, sevoflurane, desflurane, halothane, propofol, and etomidate) with known EC50 were also performed in all tested proteins. The binding constants derived from docking experiments were compared with known EC50s and octanol/water partition coefficients for the six general anesthetics. Results All 20 general anesthetics docked unambiguously into the anesthetic binding site identified in the crystal structure of apoferritin. The binding constants for 20 anesthetics obtained from the docking calculations correlate significantly with those obtained from ITC experiments (p=0.04). In the case of GLIC, the identified anesthetic binding sites in the crystal structure are among the docking predicted binding sites, but not the top ranked site. Docking calculations suggest a most probable binding site located in the

Expedition 28 Docking

NASA Image and Video Library

2011-06-10

Top officials from the Russian Federal Space Agency and NASA hold a Soyuz post-docking press conference at the Russian Mission Control Center in Korolev, Russia on Friday, June 10, 2011. The Soyuz TMA-02M docked to the International Space Station carrying Expedition 28 Soyuz Commander Sergei Volkov, NASA Flight Engineer Mike Fossum and JAXA (Japanase Aerospace Exploration Agency) Flight Engineer Satoshi Furukawa. Photo Credit: (NASA/Carla Cioffi)

Expedition 23 Docking

NASA Image and Video Library

2010-04-03

Alexei Krasnov, Director of Manned Space Programs Department, Roscosmos, listens to reporter’s questions during a Soyuz post-docking press conference at the Russian mission Control Center in Korolev, Russia on Sunday, April 4, 2010. The Soyuz TMA-18 docked to the International Space Station carrying Expedition 23 Soyuz Commander Alexander Skvortsov, Flight Engineer Mikhail Kornienko and NASA Flight Engineer Tracy Caldwell Dyson. Photo Credit: (NASA/Carla Cioffi)

Automated Rendezvous and Docking Sensor Testing at the Flight Robotics Laboratory

NASA Technical Reports Server (NTRS)

Howard, Richard T.; Williamson, Marlin L.; Johnston, Albert S.; Brewster, Linda L.; Mitchell, Jennifer D.; Cryan, Scott P.; Strack, David; Key, Kevin

2007-01-01

The Exploration Systems Architecture defines missions that require rendezvous, proximity operations, and docking (RPOD) of two spacecraft both in Low Earth Orbit (LEO) and in Low Lunar Orbit (LLO). Uncrewed spacecraft must perform automated and/or autonomous rendezvous, proximity operations and docking operations (commonly known as Automated Rendezvous and Docking, (AR&D).) The crewed versions of the spacecraft may also perform AR&D, possibly with a different level of automation and/or autonomy, and must also provide the crew with relative navigation information for manual piloting. The capabilities of the RPOD sensors are critical to the success of the Exploration Program. NASA has the responsibility to determine whether the Crew Exploration Vehicle (CEV) contractor-proposed relative navigation sensor suite will meet the CEV requirements. The relatively low technology readiness of relative navigation sensors for AR&D has been carried as one of the CEV Projects top risks. The AR&D Sensor Technology Project seeks to reduce this risk by increasing technology maturation of selected relative navigation sensor technologies through testing and simulation, and to allow the CEV Project to assess the relative navigation sensors.

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

PubMed

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.

Satellite Docking Simulator with Generic Contact Dynamics Capabilities

NASA Astrophysics Data System (ADS)

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

Addressing recent docking challenges: A hybrid strategy to integrate template-based and free protein-protein docking.

PubMed

Yan, Yumeng; Wen, Zeyu; Wang, Xinxiang; Huang, Sheng-You

2017-03-01

Protein-protein docking is an important computational tool for predicting protein-protein interactions. With the rapid development of proteomics projects, more and more experimental binding information ranging from mutagenesis data to three-dimensional structures of protein complexes are becoming available. Therefore, how to appropriately incorporate the biological information into traditional ab initio docking has been an important issue and challenge in the field of protein-protein docking. To address these challenges, we have developed a Hybrid DOCKing protocol of template-based and template-free approaches, referred to as HDOCK. The basic procedure of HDOCK is to model the structures of individual components based on the template complex by a template-based method if a template is available; otherwise, the component structures will be modeled based on monomer proteins by regular homology modeling. Then, the complex structure of the component models is predicted by traditional protein-protein docking. With the HDOCK protocol, we have participated in the CPARI experiment for rounds 28-35. Out of the 25 CASP-CAPRI targets for oligomer modeling, our HDOCK protocol predicted correct models for 16 targets, ranking one of the top algorithms in this challenge. Our docking method also made correct predictions on other CAPRI challenges such as protein-peptide binding for 6 out of 8 targets and water predictions for 2 out of 2 targets. The advantage of our hybrid docking approach over pure template-based docking was further confirmed by a comparative evaluation on 20 CASP-CAPRI targets. Proteins 2017; 85:497-512. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Low-resolution simulations of vesicle suspensions in 2D

NASA Astrophysics Data System (ADS)

Kabacaoğlu, Gökberk; Quaife, Bryan; Biros, George

2018-03-01

Vesicle suspensions appear in many biological and industrial applications. These suspensions are characterized by rich and complex dynamics of vesicles due to their interaction with the bulk fluid, and their large deformations and nonlinear elastic properties. Many existing state-of-the-art numerical schemes can resolve such complex vesicle flows. However, even when using provably optimal algorithms, these simulations can be computationally expensive, especially for suspensions with a large number of vesicles. These high computational costs can limit the use of simulations for parameter exploration, optimization, or uncertainty quantification. One way to reduce the cost is to use low-resolution discretizations in space and time. However, it is well-known that simply reducing the resolution results in vesicle collisions, numerical instabilities, and often in erroneous results. In this paper, we investigate the effect of a number of algorithmic empirical fixes (which are commonly used by many groups) in an attempt to make low-resolution simulations more stable and more predictive. Based on our empirical studies for a number of flow configurations, we propose a scheme that attempts to integrate these fixes in a systematic way. This low-resolution scheme is an extension of our previous work [51,53]. Our low-resolution correction algorithms (LRCA) include anti-aliasing and membrane reparametrization for avoiding spurious oscillations in vesicles' membranes, adaptive time stepping and a repulsion force for handling vesicle collisions and, correction of vesicles' area and arc-length for maintaining physical vesicle shapes. We perform a systematic error analysis by comparing the low-resolution simulations of dilute and dense suspensions with their high-fidelity, fully resolved, counterparts. We observe that the LRCA enables both efficient and statistically accurate low-resolution simulations of vesicle suspensions, while it can be 10× to 100× faster.

Advances in the treatment of explicit water molecules in docking and binding free energy calculations.

PubMed

Hu, Xiao; Maffucci, Irene; Contini, Alessandro

2018-05-13

The inclusion of direct effects mediated by water during the ligand-receptor recognition is a hot-topic of modern computational chemistry applied to drug discovery and development. Docking or virtual screening with explicit hydration is still debatable, despite the successful cases that have been presented in the last years. Indeed, how to select the water molecules that will be included in the docking process or how the included waters should be treated remain open questions. In this review, we will discuss some of the most recent methods that can be used in computational drug discovery and drug development when the effect of a single water, or of a small network of interacting waters, needs to be explicitly considered. Here, we analyse software to aid the selection, or to predict the position, of water molecules that are going to be explicitly considered in later docking studies. We also present software and protocols able to efficiently treat flexible water molecules during docking, including examples of applications. Finally, we discuss methods based on molecular dynamics simulations that can be used to integrate docking studies or to reliably and efficiently compute binding energies of ligands in presence of interfacial or bridging water molecules. Software applications aiding the design of new drugs that exploit water molecules, either as displaceable residues or as bridges to the receptor, are constantly being developed. Although further validation is needed, workflows that explicitly consider water will probably become a standard for computational drug discovery soon. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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

NASA Astrophysics Data System (ADS)

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

2009-07-01

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

High-resolution land cover classification using low resolution global data

NASA Astrophysics Data System (ADS)

Carlotto, Mark J.

2013-05-01

A fusion approach is described that combines texture features from high-resolution panchromatic imagery with land cover statistics derived from co-registered low-resolution global databases to obtain high-resolution land cover maps. The method does not require training data or any human intervention. We use an MxN Gabor filter bank consisting of M=16 oriented bandpass filters (0-180°) at N resolutions (3-24 meters/pixel). The size range of these spatial filters is consistent with the typical scale of manmade objects and patterns of cultural activity in imagery. Clustering reduces the complexity of the data by combining pixels that have similar texture into clusters (regions). Texture classification assigns a vector of class likelihoods to each cluster based on its textural properties. Classification is unsupervised and accomplished using a bank of texture anomaly detectors. Class likelihoods are modulated by land cover statistics derived from lower resolution global data over the scene. Preliminary results from a number of Quickbird scenes show our approach is able to classify general land cover features such as roads, built up area, forests, open areas, and bodies of water over a wide range of scenes.

Portable wireless electrocorticography system with a flexible microelectrodes array for epilepsy treatment.

PubMed

Xie, Kejun; Zhang, Shaomin; Dong, Shurong; Li, Shijian; Yu, Chaonan; Xu, Kedi; Chen, Wanke; Guo, Wei; Luo, Jikui; Wu, Zhaohui

2017-08-10

In this paper, we present a portable wireless electrocorticography (ECoG) system. It uses a high resolution 32-channel flexible ECoG electrodes array to collect electrical signals of brain activities and to stimulate the lesions. Electronic circuits are designed for signal acquisition, processing and transmission using Bluetooth Low Energy 4 (LTE4) for wireless communication with cell phone. In-vivo experiments on a rat show that the flexible ECoG system can accurately record electrical signals of brain activities and transmit them to cell phone with a maximal sampling rate of 30 ksampling/s per channel. It demonstrates that the epilepsy lesions can be detected, located and treated through the ECoG system. The wireless ECoG system has low energy consumption and high brain spatial resolution, thus has great prospects for future application.

Expedition 28 Docking

NASA Image and Video Library

2011-06-10

Vladimir Popovkin, Head of the Russian Federal Space Agency (ROSCOSMOS) answers a reporter’s question during a Soyuz post-docking press conference at the Russian Mission Control Center in Korolev, Russia on Friday, June 10, 2011. The Soyuz TMA-02M docked to the International Space Station carrying Expedition 28 Soyuz Commander Sergei Volkov, NASA Flight Engineer Mike Fossum and JAXA (Japanase Aerospace Exploration Agency) Flight Engineer Satoshi Furukawa. Photo Credit: (NASA/Carla Cioffi)

Expedition 28 Docking

NASA Image and Video Library

2011-06-10

William Gerstenmaier, Associate Administrator for Space Operations, is interviewed by Russian Federal Space Agency (ROSCOSMOS) TV following a Soyuz post-docking press conference at the Russian Mission Control Center in Korolev, Russia on Friday, June 10, 2011. The Soyuz TMA-02M docked to the International Space Station carrying Expedition 28 Soyuz Commander Sergei Volkov, NASA Flight Engineer Mike Fossum and JAXA (Japanase Aerospace Exploration Agency) Flight Engineer Satoshi Furukawa. Photo Credit: (NASA/Carla Cioffi)

Expedition 27 Docking

NASA Image and Video Library

2011-04-06

Russian Federal Space Agency Director of Human Space Flight, Alexey Krasnov, third from right, answers reporter’s questions during a Soyuz post-docking press conference at the Russian Mission Control Center in Korolev, Russia on Thursday, April 7, 2011. The Soyuz TMA-21 docked to the International Space Station carrying Expedition 27 Soyuz Commander Alexander Samokutyaev, NASA Flight Engineer Ron Garan and Russian Flight Engineer Andrey Borisenko. Photo Credit: (NASA/Carla Cioffi)

Expedition 26 Docking

NASA Image and Video Library

2010-12-18

Vitaly Davyidov, second from right, Deputy Head of the Russian Federal Space Agency, answers reporter’s questions during a Soyuz post-docking press conference at the Russian Mission Control Center in Korolev, Russia on Saturday, Dec. 18, 2010. The Soyuz TMA-20 docked to the International Space Station carrying Expedition 26 Soyuz Commander Dmitry Kondratyev, Flight Engineer Catherine Coleman and European Space Agency Flight Engineer Paolo Nespoli. Photo Credit: (NASA/Carla Cioffi)

Homology modeling, active site prediction, and targeting the anti hypertension activity through molecular docking on endothelin – B receptor domain

PubMed Central

Rayalu, Daddam Jayasimha; Selvaraj, Chandrabose; Singh, Sanjeev Kumar; Ganeshan, Ramakrishan; Kumar, Nagapatla Udaya; Seshapani, Panthangi

2012-01-01

In cardiovascular system, activation of Endothelin receptors causes vasoconstriction which leads to Pulmonary Arterial Hypertension (PAH). Endothelin receptor antagonism has emerged as an important therapeutic strategy in pulmonary arterial hypertension. Bosentan is intended to affect vasoconstriction, hypertrophic and fibrotic effects by blocking the actions of receptors ETA and ETB. In this study we identified the action of Bosentan on endothelin B receptor using docking studies with homology modeled endothelin B receptor. Through the modeled protein, the flexible Docking study was performed with Bosentan and its derivatives with theoretically predicted active sites. The results indicated that amino acid ARG82, ARG84 and HIS197 present in endothelin B receptor are core important for binding activities and these residues are having strong hydrogen bond interactions with Bosentan. We have investigated the Bosentan and its derivatives interactions and scoring parameters using gold docking package. Among the docked compounds, one of the Bosentan derivatives BD6 shows better interaction than Bosentan with endothelin B receptor. Our results may be helpful for further investigations in both in vivo and in vitro conditions. PMID:22359440

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

PubMed

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.

Miniature Low-Noise G-Band I-Q Receiver

NASA Technical Reports Server (NTRS)

Kangaslahti, Pekka P.; Pukala, David M.; Gaier, Todd C.; Tanner, Alan B.; O'Dwyer, Ian J.; Lambrigtsen, Bjom H.; Soria, Mary M.; Owen, Heather R.; Lai, Richard; Mei, Xiaobing

2010-01-01

Weather forecasting, hurricane tracking, and atmospheric science applications depend on humidity sounding of atmosphere. Current instruments provide these measurements from groundbased, airborne, and low Earth orbit (LEO) satellites by measuring radiometric temperature on the flanks of the 183-GHz water vapor line. Miniature, low-noise receivers have been designed that will enable these measurements from a geostationary, thinned array sounder, which is based on hundreds of low-noise receivers that convert the 180-GHz signal directly to baseband in-phase and in-quadrature signals for digitization and correlation. The developed receivers provide a noise temperature of 450 K from 165 to 183 GHz (NF = 4.1 dB), and have a mass of 3 g while consuming 24 mW of power. These are the most sensitive broadband I-Q receivers at this frequency range that operate at room temperature, and are significantly lower in mass and power consumption than previously reported receivers.

The ClusPro web server for protein-protein docking

PubMed Central

Kozakov, Dima; Hall, David R.; Xia, Bing; Porter, Kathryn A.; Padhorny, Dzmitry; Yueh, Christine; Beglov, Dmitri; Vajda, Sandor

2017-01-01

The ClusPro server (https://cluspro.org) is a widely used tool for protein-protein docking. The server provides a simple home page for basic use, requiring only two files in Protein Data Bank format. However, ClusPro also offers a number of advanced options to modify the search that include the removal of unstructured protein regions, applying attraction or repulsion, accounting for pairwise distance restraints, constructing homo-multimers, considering small angle X-ray scattering (SAXS) data, and finding heparin binding sites. Six different energy functions can be used depending on the type of proteins. Docking with each energy parameter set results in ten models defined by centers of highly populated clusters of low energy docked structures. This protocol describes the use of the various options, the construction of auxiliary restraints files, the selection of the energy parameters, and the analysis of the results. Although the server is heavily used, runs are generally completed in < 4 hours. PMID:28079879

Flexible low-power RF nanoelectronics in the GHz regime using CVD MoS2

NASA Astrophysics Data System (ADS)

Yogeesh, Maruthi

Two-dimensional (2D) materials have attracted substantial interest for flexible nanoelectronics due to the overall device mechanical flexibility and thickness scalability for high mechanical performance and low operating power. In this work, we demonstrate the first MoS2 RF transistors on flexible substrates based on CVD-grown monolayers, featuring record GHz cutoff frequency (5.6 GHz) and saturation velocity (~1.8×106 cm/s), which is significantly superior to contemporary organic and metal oxide thin-film transistors. Furthermore, multicycle three-point bending results demonstrated the electrical robustness of our flexible MoS2 transistors after 10,000 cycles of mechanical bending. Additionally, basic RF communication circuit blocks such as amplifier, mixer and wireless AM receiver have been demonstrated. These collective results indicate that MoS2 is an ideal advanced semiconducting material for low-power, RF devices for large-area flexible nanoelectronics and smart nanosystems owing to its unique combination of large bandgap, high saturation velocity and high mechanical strength.

Self-Powered, Flexible, and Solution-Processable Perovskite Photodetector Based on Low-Cost Carbon Cloth.

PubMed

Sun, Haoxuan; Lei, Tianyu; Tian, Wei; Cao, Fengren; Xiong, Jie; Li, Liang

2017-07-01

Flexible perovskite photodetectors are usually constructed on indium-tin-oxide-coated polymer substrates, which are expensive, fragile, and not resistant to high temperature. Herein, for the first time, a high-performance flexible perovskite photodetector is fabricated based on low-cost carbon cloth via a facile solution processable strategy. In this device, perovskite microcrystal and Spiro-OMeTAD (hole transporting material) blended film act as active materials for light detection, and carbon cloth serves as both a flexible substrate and a conductive electrode. The as-fabricated photodetector shows a broad spectrum response from ultraviolet to near-infrared light, high responsivity, fast response speed, long-term stability, and self-powered capability. Flexible devices show negligible degradation after several tens of bending cycles and at the extremely bending angle of 180°. This work promises a new technique to construct flexible, high-performance photodetectors with low cost and self-powered capability. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

High-resolution coded-aperture design for compressive X-ray tomography using low resolution detectors

NASA Astrophysics Data System (ADS)

Mojica, Edson; Pertuz, Said; Arguello, Henry

2017-12-01

One of the main challenges in Computed Tomography (CT) is obtaining accurate reconstructions of the imaged object while keeping a low radiation dose in the acquisition process. In order to solve this problem, several researchers have proposed the use of compressed sensing for reducing the amount of measurements required to perform CT. This paper tackles the problem of designing high-resolution coded apertures for compressed sensing computed tomography. In contrast to previous approaches, we aim at designing apertures to be used with low-resolution detectors in order to achieve super-resolution. The proposed method iteratively improves random coded apertures using a gradient descent algorithm subject to constraints in the coherence and homogeneity of the compressive sensing matrix induced by the coded aperture. Experiments with different test sets show consistent results for different transmittances, number of shots and super-resolution factors.

Resolution of G(s)alpha and G(q)alpha/G(11)alpha proteins in membrane domains by two-dimensional electrophoresis: the effect of long-term agonist stimulation.

PubMed

Matousek, P; Novotný, J; Svoboda, P

2004-01-01

Low-density membrane-domain fractions were prepared from S49 lymphoma cells and clone e2m11 of HEK293 cells expressing a large number of thyrotropin-releasing hormone receptor (TRH-R) and G(11)alpha by flotation on sucrose density gradients. The intact cell structure was broken by detergent-extraction, alkaline-treatment or drastic homogenization. Three types of low-density membranes were resolved by two-dimensional electrophoresis and analyzed for G(s)alpha (S49) or G(q)alpha/G11) (e2m11) content. Four individual immunoblot signals of Gsalpha protein were identified in S49 lymphoma cells indicating complete resolution of the long G(s)alpha L+/-ser and short G(s)alpha S+/-ser variants of G(s)alpha. All these were diminished by prolonged agonist (isoprenaline) stimulation. In e2m11-HEK cells, five different immunoblot signals were detected indicating post-translational modification of G proteins of G(q)alpha/G(11)alpha family. The two major spots corresponding to exogenously (over)expressed G(11)alpha and endogenous G(q)alpha were reduced; the minor spots diminished by hormonal stimulation. Parallel analysis by silver staining of the total protein content indicated that no major changes in protein composition occurred under these conditions. Our data thus indicate that agonist-stimulation of target cells results in down-regulation of all different members of G(s) and G(q)/G(11) families. This agonist-specific effect may be demonstrated in crude membrane as well as domain/raft preparations and it is not accompanied by changes in overall protein composition.

Dry dock gate stability modelling

NASA Astrophysics Data System (ADS)

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

2018-03-01

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

De novo interstitial tandem duplication of chromosome 4(q21-q28)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Navarro, E.G.; Ramon, F.J.H.; Jimenez, R.D.

1996-03-29

We describe a girl with a previously unreported de novo duplication of chromosome 4q involving segment q21-q28. Clinical manifestations included growth and psychomotor retardation, facial asymmetry, hypotelorism, epicanthic folds, mongoloid slant of palpebral fissures, apparently low-set auricles, high nasal bridge, long philtrum, small mouth, short neck, low-set thumbs, and bilateral club foot. This phenotype is compared with that of previously reported cases of duplication 4q. 12 refs., 3 figs., 1 tab.

Multi-Conformer Ensemble Docking to Difficult Protein Targets

DOE PAGES

Ellingson, Sally R.; Miao, Yinglong; Baudry, Jerome; ...

2014-09-08

We investigate large-scale ensemble docking using five proteins from the Directory of Useful Decoys (DUD, dud.docking.org) for which docking to crystal structures has proven difficult. Molecular dynamics trajectories are produced for each protein and an ensemble of representative conformational structures extracted from the trajectories. Docking calculations are performed on these selected simulation structures and ensemble-based enrichment factors compared with those obtained using docking in crystal structures of the same protein targets or random selection of compounds. We also found simulation-derived snapshots with improved enrichment factors that increased the chemical diversity of docking hits for four of the five selected proteins.more » A combination of all the docking results obtained from molecular dynamics simulation followed by selection of top-ranking compounds appears to be an effective strategy for increasing the number and diversity of hits when using docking to screen large libraries of chemicals against difficult protein targets.« less

3D-QSAR and docking studies of flavonoids as potent Escherichia coli inhibitors

PubMed Central

Fang, Yajing; Lu, Yulin; Zang, Xixi; Wu, Ting; Qi, XiaoJuan; Pan, Siyi; Xu, Xiaoyun

2016-01-01

Flavonoids are potential antibacterial agents. However, key substituents and mechanism for their antibacterial activity have not been fully investigated. The quantitative structure-activity relationship (QSAR) and molecular docking of flavonoids relating to potent anti-Escherichia coli agents were investigated. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were developed by using the pIC50 values of flavonoids. The cross-validated coefficient (q2) values for CoMFA (0.743) and for CoMSIA (0.708) were achieved, illustrating high predictive capabilities. Selected descriptors for the CoMFA model were ClogP (logarithm of the octanol/water partition coefficient), steric and electrostatic fields, while, ClogP, electrostatic and hydrogen bond donor fields were used for the CoMSIA model. Molecular docking results confirmed that half of the tested flavonoids inhibited DNA gyrase B (GyrB) by interacting with adenosine-triphosphate (ATP) pocket in a same orientation. Polymethoxyl flavones, flavonoid glycosides, isoflavonoids changed their orientation, resulting in a decrease of inhibitory activity. Moreover, docking results showed that 3-hydroxyl, 5-hydroxyl, 7-hydroxyl and 4-carbonyl groups were found to be crucial active substituents of flavonoids by interacting with key residues of GyrB, which were in agreement with the QSAR study results. These results provide valuable information for structure requirements of flavonoids as antibacterial agents. PMID:27049530

Automated Docking Screens: A Feasibility Study

PubMed Central

2009-01-01

Molecular docking is the most practical approach to leverage protein structure for ligand discovery, but the technique retains important liabilities that make it challenging to deploy on a large scale. We have therefore created an expert system, DOCK Blaster, to investigate the feasibility of full automation. The method requires a PDB code, sometimes with a ligand structure, and from that alone can launch a full screen of large libraries. A critical feature is self-assessment, which estimates the anticipated reliability of the automated screening results using pose fidelity and enrichment. Against common benchmarks, DOCK Blaster recapitulates the crystal ligand pose within 2 Å rmsd 50−60% of the time; inferior to an expert, but respectrable. Half the time the ligand also ranked among the top 5% of 100 physically matched decoys chosen on the fly. Further tests were undertaken culminating in a study of 7755 eligible PDB structures. In 1398 cases, the redocked ligand ranked in the top 5% of 100 property-matched decoys while also posing within 2 Å rmsd, suggesting that unsupervised prospective docking is viable. DOCK Blaster is available at http://blaster.docking.org. PMID:19719084

Automated docking screens: a feasibility study.

PubMed

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

2009-09-24

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

Structural analysis of a class III preQ1 riboswitch reveals an aptamer distant from a ribosome-binding site regulated by fast dynamics

PubMed Central

Liberman, Joseph A.; Suddala, Krishna C.; Aytenfisu, Asaminew; Chan, Dalen; Belashov, Ivan A.; Salim, Mohammad; Mathews, David H.; Spitale, Robert C.; Walter, Nils G.; Wedekind, Joseph E.

2015-01-01

PreQ1-III riboswitches are newly identified RNA elements that control bacterial genes in response to preQ1 (7-aminomethyl-7-deazaguanine), a precursor to the essential hypermodified tRNA base queuosine. Although numerous riboswitches fold as H-type or HLout-type pseudoknots that integrate ligand-binding and regulatory sequences within a single folded domain, the preQ1-III riboswitch aptamer forms a HLout-type pseudoknot that does not appear to incorporate its ribosome-binding site (RBS). To understand how this unusual organization confers function, we determined the crystal structure of the class III preQ1 riboswitch from Faecalibacterium prausnitzii at 2.75 Å resolution. PreQ1 binds tightly (KD,app 6.5 ± 0.5 nM) between helices P1 and P2 of a three-way helical junction wherein the third helix, P4, projects orthogonally from the ligand-binding pocket, exposing its stem-loop to base pair with the 3′ RBS. Biochemical analysis, computational modeling, and single-molecule FRET imaging demonstrated that preQ1 enhances P4 reorientation toward P1–P2, promoting a partially nested, H-type pseudoknot in which the RBS undergoes rapid docking (kdock ∼0.6 s−1) and undocking (kundock ∼1.1 s−1). Discovery of such dynamic conformational switching provides insight into how a riboswitch with bipartite architecture uses dynamics to modulate expression platform accessibility, thus expanding the known repertoire of gene control strategies used by regulatory RNAs. PMID:26106162

The Mechanical Performance of Subscale Candidate Elastomer Docking Seals

NASA Technical Reports Server (NTRS)

Bastrzyk, Marta B.; Daniels, Christopher C.

2010-01-01

The National Aeronautics and Space Administration is developing a Low Impact Docking System (LIDS) for future exploration missions. The mechanism is a new state-of-the-art device for in-space assembly of structures and rendezvous of vehicles. At the interface between two pressurized modules, each with a version of the LIDS attached, a composite elastomer-metal seal assembly prevents the breathable air from escaping into the vacuum of space. Attached to the active LIDS, this seal mates against the passive LIDS during docking operation. The main interface seal assembly must exhibit low leak and outgas values, must be able to withstand various harsh space environments, must remain operational over a range of temperatures from -50 C to 75 C, and perform after numerous docking cycles. This paper presents results from a comprehensive study of the mechanical performance of four candidate subscale seal assembly designs at -50, 23, 50, and 75 C test temperatures. In particular, the force required to fully compress the seal during docking, and that which is required for separation during the undocking operation were measured. The height of subscale main interface seal bulbs, as well as the test temperature, were shown to have a significant effect on the forces the main interface seal of the LIDS may experience during docking and undocking operations. The average force values required to fully compress each of the seal assemblies were shown to increase with test temperature by approximately 50% from -50 to 75 C. Also, the required compression forces were shown to increase as the height of the seal bulb was increased. The seal design with the tallest elastomer seal bulb, which was 31% taller than that with the shortest bulb, required force values approximately 45% higher than those for the shortest bulb, independent of the test temperature. The force required to separate the seal was shown to increase with decreasing temperature after 15 hours of simulated docking. No adhesion

Quantitative EEG and low resolution electromagnetic tomography (LORETA) imaging of patients with persistent auditory hallucinations.

PubMed

Lee, Seung-Hwan; Wynn, Jonathan K; Green, Michael F; Kim, Hyun; Lee, Kang-Joon; Nam, Min; Park, Joong-Kyu; Chung, Young-Cho

2006-04-01

Electrophysiological studies have demonstrated gamma and beta frequency oscillations in response to auditory stimuli. The purpose of this study was to test whether auditory hallucinations (AH) in schizophrenia patients reflect abnormalities in gamma and beta frequency oscillations and to investigate source generators of these abnormalities. This theory was tested using quantitative electroencephalography (qEEG) and low-resolution electromagnetic tomography (LORETA) source imaging. Twenty-five schizophrenia patients with treatment refractory AH, lasting for at least 2 years, and 23 schizophrenia patients with non-AH (N-AH) in the past 2 years were recruited for the study. Spectral analysis of the qEEG and source imaging of frequency bands of artifact-free 30 s epochs were examined during rest. AH patients showed significantly increased beta 1 and beta 2 frequency amplitude compared with N-AH patients. Gamma and beta (2 and 3) frequencies were significantly correlated in AH but not in N-AH patients. Source imaging revealed significantly increased beta (1 and 2) activity in the left inferior parietal lobule and the left medial frontal gyrus in AH versus N-AH patients. These results imply that AH is reflecting increased beta frequency oscillations with neural generators localized in speech-related areas.

Ultrastable, highly luminescent quantum dot composites based on advanced surface manipulation strategy for flexible lighting-emitting.

PubMed

Kong, Lingqing; Zhang, Lin; Meng, Zhaohui; Xu, Chuan; Lin, Naibo; Liu, Xiang-Yang

2018-08-03

Although quantum dots (QDs) have remarkable potential application in flexible light emitting diodes (LED), the loss of solvent-protected QDs leads to low quantum yield (QY) and poor stability, severely restricting the development. Flexible QD LEDs (Q-LEDs) with three primary colors were fabricated by mixing CdS/ZnS, CdSe@ZnS/ZnS, and CdSe/CdS QDs with polydimethylsiloxane (PDMS) by in situ hydrosilylation based surface manipulation strategy, which endows the device with highly ultrastable and luminescent performance. The surface manipulation strategy mainly includes the control of solvent dosage, purification times of QDs, concentration of QDs in PDMS, and oxidation on the preparation process of the QDs and PDMS composites. The highest QY of CdSe@ZnS/ZnS-PDMS composite is 82.03%, higher than the QY (80%) of the QD solution. After UV bleaching, organic solvents (acetone, ethanol and water), and heating treatment, the QYs of the QDs and PDMS maintain a high value, manifesting their good stability. Q-LED hybrid light-emitting devices were further fabricated by a molding technique demonstrating satisfied current and thermal stability. Flexible Q-LEDs can be expended to other shapes, such as fibers and blocks, indicating the huge potential of QD-polymer composites for light sources and displays etc.

Ambient atomic resolution atomic force microscopy with qPlus sensors: Part 1.

PubMed

Wastl, Daniel S

2017-01-01

Atomic force microscopy (AFM) is an enormous tool to observe nature in highest resolution and understand fundamental processes like friction and tribology on the nanoscale. Atomic resolution in highest quality was possible only in well-controlled environments like ultrahigh vacuum (UHV) or controlled buffer environments (liquid conditions) and more specified for long-term high-resolution analysis at low temperatures (∼4 K) in UHV where drift is nearly completely absent. Atomic resolution in these environments is possible and is widely used. However, in uncontrolled environments like air, with all its pollutants and aerosols, unspecified thin liquid films as thin as a single molecular water-layer of 200 pm or thicker condensation films with thicknesses up to hundred nanometer, have been a problem for highest resolution since the invention of the AFM. The goal of true atomic resolution on hydrophilic as well as hydrophobic samples was reached recently. In this manuscript we want to review the concept of ambient AFM with atomic resolution. The reader will be introduced to the phenomenology in ambient conditions and the problems will be explained and analyzed while a method for scan parameter optimization will be explained. Recently developed concepts and techniques how to reach atomic resolution in air and ultra-thin liquid films will be shown and explained in detail, using several examples. Microsc. Res. Tech. 80:50-65, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

A measurement of the proton’s spin structure function g2 at low Q2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, Pengjia

2015-10-21

JLab E08-027, a measurement of g2p and the longitudinal-transverse (LT) spin polarizability, successfully collected data from March to May, 2012. Nucleon spin structure study has been an active research area, which has attracted a very large effort from both experimentalists and theorists. The spin structure study for the last 2 decades has provided us with many exciting and often surprising results. Recently, new precision results in the low-to-intermediate momentum transfer Q2 region from JLab have provided extensive information on the nucleon structure in the confinement region and the transition region between asymptotic free to confinement. In particular, the extensive comparisonsmore » of experimental results with Chiral Perturbation Theory (the effective theory of QCD at low energy) calculations show general good agreements, but strong disagreement in the case of the neutron LT spin polarizability. This experiment completed the measurements of gp2 and the LT spin polarizability on the proton in the low-to-intermediate Q2 region. The experiment used a polarized proton (NH3) target for the first time in Hall A. Scattered electrons were detected by a pair of Hall A high resolution spectrometer (HRS) with a pair of septum magnets. To avoid too much depolarization of the target, beam current was limited to 50-100 nA during the experiment. Since the existing beam current monitors (BCMs), beam position monitors (BPMs) and calibration methods did not work at such a low current range, new BPM and BCM receivers were designed and used for current condition. A pair of super-harps and a tungsten calorimeter were installed to calibrate the BPMs and BCMs. To compensate for the effect of the 2.5/5T transverse magnet field, two chicane dipole magnets were installed. A pair of slow rasters were installed for the first time in Hall A, combining with a pair of fast raster. The standard Hall A DAQ system and the improved high resolution DAQ system were used to record the

Expedition 39 Docking

NASA Image and Video Library

2014-03-28

A view of the Russian Mission Control Center in Korolev, Russia on Friday, March 28, 2014 prior to the docking of Soyuz TMA-12M. The Soyuz TMA-12M spacecraft docked to the International Space Station at 7:53 p.m. EDT bringing Expedition 39 Soyuz Commander Alexander Skvortsov of the Russian Federal Space Agency, Roscosmos, Flight Engineer Steve Swanson of NASA and Flight Engineer Oleg Artemyev of Roscosmos to the ISS for their six month stay aboard the orbiting labratory. Photo Credit: (NASA/Joel Kowsky)

Ground Demonstration on the Autonomous Docking of Two 3U CubeSats Using a Novel Permanent-Magnet Docking Mechanism

NASA Technical Reports Server (NTRS)

Pei, Jing; Murchison, Luke; BenShabat, Adam; Stewart, Victor; Rosenthal, James; Follman, Jacob; Branchy, Mark; Sellers, Drew; Elandt, Ryan; Elliott, Sawyer;

Magnet-Based System for Docking of Miniature Spacecraft

NASA Technical Reports Server (NTRS)

Howard, Nathan; Nguyen, Hai D.

2007-01-01

A prototype system for docking a miniature spacecraft with a larger spacecraft has been developed by engineers at the Johnson Space Center. Engineers working on Mini AERCam, a free-flying robotic camera, needed to find a way to successfully dock and undock their miniature spacecraft to refuel the propulsion and recharge the batteries. The subsystems developed (see figure) include (1) a docking port, designed for the larger spacecraft, which contains an electromagnet, a ball lock mechanism, and a service probe; and (2) a docking cluster, designed for the smaller spacecraft, which contains either a permanent magnet or an electromagnet. A typical docking operation begins with the docking spacecraft maneuvering into position near the docking port on the parent vehicle. The electromagnet( s) are then turned on, and, if necessary, the docking spacecraft is then maneuvered within the capture envelope of the docking port. The capture envelope for this system is approximated by a 5-in. (12.7-cm) cube centered on the front of the docking-port electromagnet and within an angular misalignment of <30 . Thereafter, the magnetic forces draw the smaller spacecraft toward the larger one and this brings the spacecraft into approximate alignment prior to contact. Mechanical alignment guides provide the final rotational alignment into one of 12 positions. Once the docking vehicle has been captured magnetically in the docking port, the ball-lock mechanism is activated, which locks the two spacecraft together. At this point the electromagnet( s) are turned off, and the service probe extended if recharge and refueling are to be performed. Additionally, during undocking, the polarity of one electromagnet can be reversed to provide a gentle push to separate the two spacecraft. This system is currently being incorporated into the design of Mini AERCam vehicle.

Structure Refinement of Protein Low Resolution Models Using the GNEIMO Constrained Dynamics Method

PubMed Central

Park, In-Hee; Gangupomu, Vamshi; Wagner, Jeffrey; Jain, Abhinandan; Vaidehi, Nagara-jan

2012-01-01

The challenge in protein structure prediction using homology modeling is the lack of reliable methods to refine the low resolution homology models. Unconstrained all-atom molecular dynamics (MD) does not serve well for structure refinement due to its limited conformational search. We have developed and tested the constrained MD method, based on the Generalized Newton-Euler Inverse Mass Operator (GNEIMO) algorithm for protein structure refinement. In this method, the high-frequency degrees of freedom are replaced with hard holonomic constraints and a protein is modeled as a collection of rigid body clusters connected by flexible torsional hinges. This allows larger integration time steps and enhances the conformational search space. In this work, we have demonstrated the use of a constraint free GNEIMO method for protein structure refinement that starts from low-resolution decoy sets derived from homology methods. In the eight proteins with three decoys for each, we observed an improvement of ~2 Å in the RMSD to the known experimental structures of these proteins. The GNEIMO method also showed enrichment in the population density of native-like conformations. In addition, we demonstrated structural refinement using a “Freeze and Thaw” clustering scheme with the GNEIMO framework as a viable tool for enhancing localized conformational search. We have derived a robust protocol based on the GNEIMO replica exchange method for protein structure refinement that can be readily extended to other proteins and possibly applicable for high throughput protein structure refinement. PMID:22260550

Suitlock Docking Mechanism

NASA Technical Reports Server (NTRS)

Culbertson, Philip, Jr. (Inventor)

1997-01-01

An environmental protective suit used for hazardous clean-up or space applications includes a suitlock docking mechanism that allows for easy egress and ingress of a crew member between a sealed vessel and a possibly contaminated environment. The suitlock docking mechanism comprises a single actuator that controls latches which, in turn, respectfully control rack and pinion assemblies that allow for easy removal and attachment of a life support equipment enclosure shell to the environmental protective suit or to the vehicle from which the operator performs his/her duties.

The flex track: flexible partitioning between low- and high-acuity areas of an emergency department.

PubMed

Laker, Lauren F; Froehle, Craig M; Lindsell, Christopher J; Ward, Michael J

2014-12-01

Emergency departments (EDs) with both low- and high-acuity treatment areas often have fixed allocation of resources, regardless of demand. We demonstrate the utility of discrete-event simulation to evaluate flexible partitioning between low- and high-acuity ED areas to identify the best operational strategy for subsequent implementation. A discrete-event simulation was used to model patient flow through a 50-bed, urban, teaching ED that handles 85,000 patient visits annually. The ED has historically allocated 10 beds to a fast track for low-acuity patients. We estimated the effect of a flex track policy, which involved switching up to 5 of these fast track beds to serving both low- and high-acuity patients, on patient waiting times. When the high-acuity beds were not at capacity, low-acuity patients were given priority access to flexible beds. Otherwise, high-acuity patients were given priority access to flexible beds. Wait times were estimated for patients by disposition and Emergency Severity Index score. A flex track policy using 3 flexible beds produced the lowest mean patient waiting time of 30.9 minutes (95% confidence interval [CI] 30.6 to 31.2 minutes). The typical fast track approach of rigidly separating high- and low-acuity beds produced a mean patient wait time of 40.6 minutes (95% CI 40.2 to 50.0 minutes), 31% higher than that of the 3-bed flex track. A completely flexible ED, in which all beds can accommodate any patient, produced mean wait times of 35.1 minutes (95% CI 34.8 to 35.4 minutes). The results from the 3-bed flex track scenario were robust, performing well across a range of scenarios involving higher and lower patient volumes and care durations. Using discrete-event simulation, we have shown that adding some flexibility into bed allocation between low and high acuity can provide substantial reductions in overall patient waiting and a more efficient ED. Copyright © 2014 American College of Emergency Physicians. Published by Elsevier Inc

Radial q-space sampling for DSI

PubMed Central

Baete, Steven H.; Yutzy, Stephen; Boada, Fernando, E.

2015-01-01

Purpose Diffusion Spectrum Imaging (DSI) has been shown to be an effective tool for non-invasively depicting the anatomical details of brain microstructure. Existing implementations of DSI sample the diffusion encoding space using a rectangular grid. Here we present a different implementation of DSI whereby a radially symmetric q-space sampling scheme for DSI (RDSI) is used to improve the angular resolution and accuracy of the reconstructed Orientation Distribution Functions (ODF). Methods Q-space is sampled by acquiring several q-space samples along a number of radial lines. Each of these radial lines in q-space is analytically connected to a value of the ODF at the same angular location by the Fourier slice theorem. Results Computer simulations and in vivo brain results demonstrate that RDSI correctly estimates the ODF when moderately high b-values (4000 s/mm2) and number of q-space samples (236) are used. Conclusion The nominal angular resolution of RDSI depends on the number of radial lines used in the sampling scheme, and only weakly on the maximum b-value. In addition, the radial analytical reconstruction reduces truncation artifacts which affect Cartesian reconstructions. Hence, a radial acquisition of q-space can be favorable for DSI. PMID:26363002

Flexible retrospective selection of temporal resolution in real-time speech MRI using a golden-ratio spiral view order.

PubMed

Kim, Yoon-Chul; Narayanan, Shrikanth S; Nayak, Krishna S

2011-05-01

In speech production research using real-time magnetic resonance imaging (MRI), the analysis of articulatory dynamics is performed retrospectively. A flexible selection of temporal resolution is highly desirable because of natural variations in speech rate and variations in the speed of different articulators. The purpose of the study is to demonstrate a first application of golden-ratio spiral temporal view order to real-time speech MRI and investigate its performance by comparison with conventional bit-reversed temporal view order. Golden-ratio view order proved to be more effective at capturing the dynamics of rapid tongue tip motion. A method for automated blockwise selection of temporal resolution is presented that enables the synthesis of a single video from multiple temporal resolution videos and potentially facilitates subsequent vocal tract shape analysis. Copyright © 2010 Wiley-Liss, Inc.

Meteoroid and Orbital Debris Threats to NASA's Docking Seals: Initial Assessment and Methodology

NASA Technical Reports Server (NTRS)

deGroh, Henry C., III; Nahra, Henry K.

2009-01-01

The Crew Exploration Vehicle (CEV) will be exposed to the Micrometeoroid Orbital Debris (MMOD) environment in Low Earth Orbit (LEO) during missions to the International Space Station (ISS) and to the micrometeoroid environment during lunar missions. The CEV will be equipped with a docking system which enables it to connect to ISS and the lunar module known as Altair; this docking system includes a hatch that opens so crew and supplies can pass between the spacecrafts. This docking system is known as the Low Impact Docking System (LIDS) and uses a silicone rubber seal to seal in cabin air. The rubber seal on LIDS presses against a metal flange on ISS (or Altair). All of these mating surfaces are exposed to the space environment prior to docking. The effects of atomic oxygen, ultraviolet and ionizing radiation, and MMOD have been estimated using ground based facilities. This work presents an initial methodology to predict meteoroid and orbital debris threats to candidate docking seals being considered for LIDS. The methodology integrates the results of ground based hypervelocity impacts on silicone rubber seals and aluminum sheets, risk assessments of the MMOD environment for a variety of mission scenarios, and candidate failure criteria. The experimental effort that addressed the effects of projectile incidence angle, speed, mass, and density, relations between projectile size and resulting crater size, and relations between crater size and the leak rate of candidate seals has culminated in a definition of the seal/flange failure criteria. The risk assessment performed with the BUMPER code used the failure criteria to determine the probability of failure of the seal/flange system and compared the risk to the allotted risk dictated by NASA's program requirements.

Meteoroid and Orbital Debris Threats to NASA's Docking Seals: Initial Assessment and Methodology

NASA Technical Reports Server (NTRS)

deGroh, Henry C., III; Gallo, Christopher A.; Nahra, Henry K.

2009-01-01

The Crew Exploration Vehicle (CEV) will be exposed to the Micrometeoroid Orbital Debris (MMOD) environment in Low Earth Orbit (LEO) during missions to the International Space Station (ISS) and to the micrometeoroid environment during lunar missions. The CEV will be equipped with a docking system which enables it to connect to ISS and the lunar module known as Altair; this docking system includes a hatch that opens so crew and supplies can pass between the spacecrafts. This docking system is known as the Low Impact Docking System (LIDS) and uses a silicone rubber seal to seal in cabin air. The rubber seal on LIDS presses against a metal flange on ISS (or Altair). All of these mating surfaces are exposed to the space environment prior to docking. The effects of atomic oxygen, ultraviolet and ionizing radiation, and MMOD have been estimated using ground based facilities. This work presents an initial methodology to predict meteoroid and orbital debris threats to candidate docking seals being considered for LIDS. The methodology integrates the results of ground based hypervelocity impacts on silicone rubber seals and aluminum sheets, risk assessments of the MMOD environment for a variety of mission scenarios, and candidate failure criteria. The experimental effort that addressed the effects of projectile incidence angle, speed, mass, and density, relations between projectile size and resulting crater size, and relations between crater size and the leak rate of candidate seals has culminated in a definition of the seal/flange failure criteria. The risk assessment performed with the BUMPER code used the failure criteria to determine the probability of failure of the seal/flange system and compared the risk to the allotted risk dictated by NASA s program requirements.

CHARGE association in a child with de novo inv dup (14)(q22{yields}q24.3)

DOE Office of Scientific and Technical Information (OSTI.GOV)

North, K.; Wu, B.L.; Whiteman, D.

1994-09-01

The CHARGE association is an increasingly recognized complex of multiple malformations, that include Coloboma, Heart defect, choanal Atresia, Retardation of mental and somatic development, hypoplastic Genitalia, and Ear abnormalities or deafness. It has been postulated that many of the defects result from abnormalities in the development, migration or interaction of cells of the cephalic neural crest. The majority of cases are sporadic. We report a case of an inverted duplication (14)(q22{yields}q24.3) associated with CHARGE association. The patient was a 4 {1/2}-year-old female and was the product of a normal pregnancy. Family history was unremarkable. The clinical manifestations included the combinationmore » of congenital anomalies (coloboma, ventricular septal defect, severe developmental delay and growth retardation, genital hypoplasia and sensorineural deafness) in association with soft tissue choanal atresia, dysphagia, and minor dysmorphic features (low set ears, upslanting palpebral fissures). High resolution cytogenetic studies revealed that the child has 46,XX,inv dup(14)(q22{yields}q24.3) and parents have normal chromosomes. FISH with a chromosome 14 paint probe confirmed that the duplicated region is entirely derived from chromosome 14. FISH with D22S75 probe for region 22q11.2 detected no deletion for this locus. Several duplications or deletions involving different chromosomes have been reported for patients with conditions resembling CHARGE association. This indicates that CHARGE is possible genetically heterogenous, parallelling the phenotypic heterogeneity of the disorder. Two published cases with unbalanced rearrengements involving 14q22 have some comparable features with our case, which suggests that the locus for a gene causing some of the features of CHARGE association may reside at 14q22 or 14q24.3.« less

Low-Resolution Raman-Spectroscopy Combustion Thermometry

NASA Technical Reports Server (NTRS)

Nguyen, Quang-Viet; Kojima, Jun

2008-01-01

A method of optical thermometry, now undergoing development, involves low-resolution measurement of the spectrum of spontaneous Raman scattering (SRS) from N2 and O2 molecules. The method is especially suitable for measuring temperatures in high pressure combustion environments that contain N2, O2, or N2/O2 mixtures (including air). Methods based on SRS (in which scattered light is shifted in wavelength by amounts that depend on vibrational and rotational energy levels of laser-illuminated molecules) have been popular means of probing flames because they are almost the only methods that provide spatially and temporally resolved concentrations and temperatures of multiple molecular species in turbulent combustion. The present SRS-based method differs from prior SRS-based methods that have various drawbacks, a description of which would exceed the scope of this article. Two main differences between this and prior SRS-based methods are that it involves analysis in the frequency (equivalently, wavelength) domain, in contradistinction to analysis in the intensity domain in prior methods; and it involves low-resolution measurement of what amounts to predominantly the rotational Raman spectra of N2 and O2, in contradistinction to higher-resolution measurement of the vibrational Raman spectrum of N2 only in prior methods.

Voss with docking probe in Service module

NASA Image and Video Library

2001-05-30

ISS002-E-6478 (30 May 2001) --- James S. Voss, Expedition Two flight engineer, handles a spacecraft docking probe in the Service Module. The docking probe assists with the docking of the Soyuz and Progress vehicles to the International Space Station. The image was taken with a digital still camera.

Design for low-power and reliable flexible electronics

NASA Astrophysics Data System (ADS)

Huang, Tsung-Ching (Jim)

Flexible electronics are emerging as an alternative to conventional Si electronics for large-area low-cost applications such as e-paper, smart sensors, and disposable RFID tags. By utilizing inexpensive manufacturing methods such as ink-jet printing and roll-to-roll imprinting, flexible electronics can be made on low-cost plastics just like printing a newspaper. However, the key elements of exible electronics, thin-film transistors (TFTs), have slower operating speeds and less reliability than their Si electronics counterparts. Furthermore, depending on the material property, TFTs are usually mono-type -- either p- or n-type -- devices. Making air-stable complementary TFT circuits is very challenging and not applicable to most TFT technologies. Existing design methodologies for Si electronics, therefore, cannot be directly applied to exible electronics. Other inhibiting factors such as high supply voltage, large process variation, and lack of trustworthy device modeling also make designing larger-scale and robust TFT circuits a significant challenge. The major goal of this dissertation is to provide a viable solution for robust circuit design in exible electronics. I will first introduce a reliability simulation framework that can predict the degraded TFT circuits' performance under bias-stress. This framework has been validated using the amorphous-silicon (a-Si) TFT scan driver for TFT-LCD displays. To reuse the existing CMOS design ow for exible electronics, I propose a Pseudo-CMOS cell library that can make TFT circuits operable under low supply voltage and which has post-fabrication tunability for reliability and performance enhancement. This cell library has been validated using 2V self-assembly-monolayer (SAM) organic TFTs with a low-cost shadow-mask deposition process. I will also demonstrate a 3-bit 1.25KS/s Flash ADC in a-Si TFTs, which is based on the proposed Pseudo-CMOS cell library, and explore more possibilities in display, energy, and sensing

Low-cost flexible thin-film detector for medical dosimetry applications.

PubMed

Zygmanski, P; Abkai, C; Han, Z; Shulevich, Y; Menichelli, D; Hesser, J

2014-03-06

The purpose of this study is to characterize dosimetric properties of thin film photovoltaic sensors as a platform for development of prototype dose verification equipment in radiotherapy. Towards this goal, flexible thin-film sensors of dose with embedded data acquisition electronics and wireless data transmission are prototyped and tested in kV and MV photon beams. Fundamental dosimetric properties are determined in view of a specific application to dose verification in multiple planes or curved surfaces inside a phantom. Uniqueness of the new thin-film sensors consists in their mechanical properties, low-power operation, and low-cost. They are thinner and more flexible than dosimetric films. In principle, each thin-film sensor can be fabricated in any size (mm² - cm² areas) and shape. Individual sensors can be put together in an array of sensors spreading over large areas and yet being light. Photovoltaic mode of charge collection (of electrons and holes) does not require external electric field applied to the sensor, and this implies simplicity of data acquisition electronics and low power operation. The prototype device used for testing consists of several thin film dose sensors, each of about 1.5 cm × 5 cm area, connected to simple readout electronics. Sensitivity of the sensors is determined per unit area and compared to EPID sensitivity, as well as other standard photodiodes. Each sensor independently measures dose and is based on commercially available flexible thin-film aSi photodiodes. Readout electronics consists of an ultra low-power microcontroller, radio frequency transmitter, and a low-noise amplification circuit implemented on a flexible printed circuit board. Detector output is digitized and transmitted wirelessly to an external host computer where it is integrated and processed. A megavoltage medical linear accelerator (Varian Tx) equipped with kilovoltage online imaging system and a Cobalt source are used to irradiate different thin

Integrated Docking Simulation and Testing with the Johnson Space Center Six-Degree of Freedom Dynamic Test System

NASA Technical Reports Server (NTRS)

Mitchell, Jennifer D.; Cryan, Scott P.; Baker, Kenneth; Martin, Toby; Goode, Robert; Key, Kevin W.; Manning, Thomas; Chien, Chiun-Hong

2008-01-01

The Exploration Systems Architecture defines missions that require rendezvous, proximity operations, and docking (RPOD) of two spacecraft both in Low Earth Orbit (LEO) and in Low Lunar Orbit (LLO). Uncrewed spacecraft must perform automated and/or autonomous rendezvous, proximity operations and docking operations (commonly known as Automated Rendezvous and Docking, AR&D). The crewed versions may also perform AR&D, possibly with a different level of automation and/or autonomy, and must also provide the crew with relative navigation information for manual piloting. The capabilities of the RPOD sensors are critical to the success of the Constellation Program; this is carried as one of the CEV Project top risks. The Exploration Technology Development Program (ETDP) AR&D Sensor Technology Project seeks to reduce this risk by increasing technology maturation of selected relative navigation sensor technologies through testing and simulation. One of the project activities is a series of "pathfinder" testing and simulation activities to integrate relative navigation sensors with the Johnson Space Center Six-Degree-of-Freedom Test System (SDTS). The SDTS will be the primary testing location for the Orion spacecraft s Low Impact Docking System (LIDS). Project team members have integrated the Orion simulation with the SDTS computer system so that real-time closed loop testing can be performed with relative navigation sensors and the docking system in the loop during docking and undocking scenarios. Two relative navigation sensors are being used as part of a "pathfinder" activity in order to pave the way for future testing with the actual Orion sensors. This paper describes the test configuration and test results.

IRAS low resolution spectra of 26 symbiotic stars

NASA Technical Reports Server (NTRS)

Stencel, Robert E.; Brugel, Edward W.; Goodwill, Michael E.

1990-01-01

Data related to the spectral scans for 26 symbiotic stars are described which were extracted from the IRAS low resolution database. Data from the 8-15- and 15-23-micron bands are merged in a program that scales the longer wavelength and produces a weighted average of the spectral scans for each source. The survey shows that active dust producers can probably be isolated and some theories related to the presence of dust emission features are discussed in terms of source variability for measurements made with low resolution spectra.

Performance of Subscale Docking Seals Under Simulated Temperature Conditions

NASA Technical Reports Server (NTRS)

Smith, Ian M.; Daniels, Christopher C.

2008-01-01

A universal docking system is being developed by the National Aeronautics and Space Administration (NASA) to support future space exploration missions to low Earth orbit (LEO), to the moon, and to Mars. The candidate docking seals for the system are a composite design consisting of elastomer seal bulbs molded into the front and rear sides of a metal ring. The test specimens were subscale seals with two different elastomer cross-sections and a 12-in. outside diameter. The seal assemblies were mated in elastomer seal-on-metal plate and elastomer seal-on-elastomer seal configurations. The seals were manufactured from S0383-70 silicone elastomer compound. Nominal and off-nominal joint configurations were examined. Both the compression load required to mate the seals and the leak rate observed were recorded while the assemblies were subjected to representative docking system operating temperatures of -58, 73, and 122 F (-50, 23, and 50 C). Both the loads required to fully compress the seals and their leak rates were directly proportional to the test temperature.

Docking Based 3D-QSAR Study of Tricyclic Guanidine Analogues of Batzelladine K as anti-malarial agents

NASA Astrophysics Data System (ADS)

Ahmed, Nafees; Anwar, Sirajudheen; Thet Htar, Thet

2017-06-01

The Plasmodium falciparum Lactate Dehydrogenase enzyme (PfLDH) catalyzes inter-conversion of pyruvate to lactate during glycolysis producing the energy required for parasitic growth. The PfLDH has been studied as a potential molecular target for development of anti-malarial agents. In an attempt to find the potent inhibitor of PfLDH, we have used Discovery studio to perform molecular docking in the active binding pocket of PfLDH by CDOCKER, followed by three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of tricyclic guanidine batzelladine compounds, which were previously synthesized in our laboratory. Docking studies showed that there is a very strong correlation between in silico and in vitro results. Based on docking results, a highly predictive 3D-QSAR model was developed with q2 of 0.516. The model has predicted r2 of 0.91 showing that predicted IC50 values are in good agreement with experimental IC50 values. The results obtained from this study revealed the developed model can be used to design new anti-malarial compounds based on tricyclic guanidine derivatives and to predict activities of new inhibitors.

Docking Based 3D-QSAR Study of Tricyclic Guanidine Analogues of Batzelladine K As Anti-Malarial Agents.

PubMed

Ahmed, Nafees; Anwar, Sirajudheen; Thet Htar, Thet

2017-01-01

The Plasmodium falciparum Lactate Dehydrogenase enzyme ( Pf LDH) catalyzes inter-conversion of pyruvate to lactate during glycolysis producing the energy required for parasitic growth. The Pf LDH has been studied as a potential molecular target for development of anti-malarial agents. In an attempt to find the potent inhibitor of Pf LDH, we have used Discovery studio to perform molecular docking in the active binding pocket of Pf LDH by CDOCKER, followed by three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of tricyclic guanidine batzelladine compounds, which were previously synthesized in our laboratory. Docking studies showed that there is a very strong correlation between in silico and in vitro results. Based on docking results, a highly predictive 3D-QSAR model was developed with q 2 of 0.516. The model has predicted r 2 of 0.91 showing that predicted IC 50 values are in good agreement with experimental IC 50 values. The results obtained from this study revealed the developed model can be used to design new anti-malarial compounds based on tricyclic guanidine derivatives and to predict activities of new inhibitors.

Docking Based 3D-QSAR Study of Tricyclic Guanidine Analogues of Batzelladine K As Anti-Malarial Agents

PubMed Central

Ahmed, Nafees; Anwar, Sirajudheen; Thet Htar, Thet

2017-01-01

The Plasmodium falciparum Lactate Dehydrogenase enzyme (PfLDH) catalyzes inter-conversion of pyruvate to lactate during glycolysis producing the energy required for parasitic growth. The PfLDH has been studied as a potential molecular target for development of anti-malarial agents. In an attempt to find the potent inhibitor of PfLDH, we have used Discovery studio to perform molecular docking in the active binding pocket of PfLDH by CDOCKER, followed by three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of tricyclic guanidine batzelladine compounds, which were previously synthesized in our laboratory. Docking studies showed that there is a very strong correlation between in silico and in vitro results. Based on docking results, a highly predictive 3D-QSAR model was developed with q2 of 0.516. The model has predicted r2 of 0.91 showing that predicted IC50 values are in good agreement with experimental IC50 values. The results obtained from this study revealed the developed model can be used to design new anti-malarial compounds based on tricyclic guanidine derivatives and to predict activities of new inhibitors. PMID:28664157

Protein Models Docking Benchmark 2

PubMed Central

Anishchenko, Ivan; Kundrotas, Petras J.; Tuzikov, Alexander V.; Vakser, Ilya A.

2015-01-01

Structural characterization of protein-protein interactions is essential for our ability to understand life processes. However, only a fraction of known proteins have experimentally determined structures. Such structures provide templates for modeling of a large part of the proteome, where individual proteins can be docked by template-free or template-based techniques. Still, the sensitivity of the docking methods to the inherent inaccuracies of protein models, as opposed to the experimentally determined high-resolution structures, remains largely untested, primarily due to the absence of appropriate benchmark set(s). Structures in such a set should have pre-defined inaccuracy levels and, at the same time, resemble actual protein models in terms of structural motifs/packing. The set should also be large enough to ensure statistical reliability of the benchmarking results. We present a major update of the previously developed benchmark set of protein models. For each interactor, six models were generated with the model-to-native Cα RMSD in the 1 to 6 Å range. The models in the set were generated by a new approach, which corresponds to the actual modeling of new protein structures in the “real case scenario,” as opposed to the previous set, where a significant number of structures were model-like only. In addition, the larger number of complexes (165 vs. 63 in the previous set) increases the statistical reliability of the benchmarking. We estimated the highest accuracy of the predicted complexes (according to CAPRI criteria), which can be attained using the benchmark structures. The set is available at http://dockground.bioinformatics.ku.edu. PMID:25712716

Tunable Q-factor silicon microring resonators for ultra-low power parametric processes.

PubMed

Strain, Michael J; Lacava, Cosimo; Meriggi, Laura; Cristiani, Ilaria; Sorel, Marc

2015-04-01

A compact silicon ring resonator is demonstrated that allows simple electrical tuning of the ring coupling coefficient and Q-factor and therefore the resonant enhancement of on-chip nonlinear optical processes. Fabrication-induced variation in designed coupling fraction, crucial in the resonator performance, can be overcome using this post-fabrication trimming technique. Tuning of the microring resonator across the critical coupling point is demonstrated, exhibiting a Q-factor tunable between 9000 and 96,000. Consequently, resonantly enhanced four-wave mixing shows tunable efficiency between -40 and -16.3  dB at an ultra-low on-chip pump power of 0.7 mW.

Low-Q structure related to partially saturated pores within the reservoir beneath The Geysers area in the northern California

NASA Astrophysics Data System (ADS)

Matsubara, M.

2011-12-01

A large reservoir is located beneath The Geysers geothermal area, northern California. Seismic tomography revealed high-velocity (high-V) and low-Vp/Vs zones in the reservoir (Julian et al., 1996) and a decrease of Vp/Vs from 1991 to 1998 (Guasekera et al., 2003) owing to withdrawal of steam from the reservoir. I perform attenuation tomography in this region to investigate the state of vapor and liquid within the reservoir. The target region, 38.5-39.0°N and 122.5-123°W, covers The Geysers area. I use seismograms of 1,231 events whose focal mechanism are determined among 65,810 events recorded by the Northern California Earthquake Data Center from 2002 to 2008 in the target region. The band-pass filtered seismograms are analyzed for collecting the maximum amplitude data. There are 26 stations that have a three-component seismometer among 47 seismic stations. I use the P- and S-wave maximum amplitudes during the two seconds after the arrival of those waves in order to avoid coda effects. A total of 8,545 P- and 1,168 S-wave amplitude data for 949 earthquakes recorded at 47 stations are available for the analysis using the attenuation tomographic method derived from the velocity tomographic method (Matsubara et al., 2005, 2008) in which spatial velocity correlation and station corrections are introduced to the original code of Zhao et al. (1992). I use 3-D velocity structure obtained by Thurber et al. (2009). The initial Q value is set to 150, corresponding to the average Q of the northern California (Ford et al., 2010). At sea level, low-Q zones are found extending from the middle of the steam reservoir within the main greywacke to the south part of the reservoir. At a depth of 1 km below sea level, a low-Q zone is located solely in the southern part of the reservoir. However, at a depth of 2 km a low-Q zone is located beneath the northern part of the reservoir. At depths of 1 to 3 km a felsite batholith in the deeper portions of the reservoir, and it corresponds

Advanced Docking System With Magnetic Initial Capture

NASA Technical Reports Server (NTRS)

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.

Time-domain self-consistent theory of frequency-locking regimes in gyrotrons with low-Q resonators

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ginzburg, N. S., E-mail: ginzburg@appl.sci-nnov.ru; Nizhny Novgorod State University, 603950, gagarin av., 23, Nizhny Novgorod; Sergeev, A. S.

2015-03-15

A time-domain theory of frequency-locking gyrotron oscillators with low-Q resonators has been developed. The presented theory is based on the description of wave propagation by a parabolic equation taking into account the external signal by modification of boundary conditions. We show that the developed model can be effectively used for simulations of both single- and multi-mode operation regimes in gyrotrons driven by an external signal. For the case of low-Q resonators typical for powerful gyrotrons, the external signal can influence the axial field profile inside the interaction space significantly and, correspondingly, the value of the electron orbital efficiency.

Arik-Coon q-oscillator cat states on the noncommutative complex plane ℂq-1 and their nonclassical properties

NASA Astrophysics Data System (ADS)

Fakhri, H.; Sayyah-Fard, M.

The normalized even and odd q-cat states corresponding to Arik-Coon q-oscillator on the noncommutative complex plane ℂq-1 are constructed as the eigenstates of the lowering operator of a q-deformed su(1, 1) algebra with the left eigenvalues. We present the appropriate noncommutative measures in order to realize the resolution of the identity condition by the even and odd q-cat states. Then, we obtain the q-Bargmann-Fock realizations of the Fock representation of the q-deformed su(1, 1) algebra as well as the inner products of standard states in the q-Bargmann representations of the even and odd subspaces. Also, the Euler’s formula of the q-factorial and the Gaussian integrals based on the noncommutative q-integration are obtained. Violation of the uncertainty relation, photon antibunching effect and sub-Poissonian photon statistics by the even and odd q-cat states are considered in the cases 0 < q < 1 and q > 1.

Resolution enhancement of low-quality videos using a high-resolution frame

NASA Astrophysics Data System (ADS)

Pham, Tuan Q.; van Vliet, Lucas J.; Schutte, Klamer

2006-01-01

This paper proposes an example-based Super-Resolution (SR) algorithm of compressed videos in the Discrete Cosine Transform (DCT) domain. Input to the system is a Low-Resolution (LR) compressed video together with a High-Resolution (HR) still image of similar content. Using a training set of corresponding LR-HR pairs of image patches from the HR still image, high-frequency details are transferred from the HR source to the LR video. The DCT-domain algorithm is much faster than example-based SR in spatial domain 6 because of a reduction in search dimensionality, which is a direct result of the compact and uncorrelated DCT representation. Fast searching techniques like tree-structure vector quantization 16 and coherence search1 are also key to the improved efficiency. Preliminary results on MJPEG sequence show promising result of the DCT-domain SR synthesis approach.

The Flex Track: Flexible Partitioning between Low- and High-Acuity Areas of an Emergency Department

PubMed Central

Laker, Lauren F.; Froehle, Craig M.; Lindsell, Christopher J.; Ward, Michael J.

2014-01-01

Study Objective EDs with both low- and high-acuity treatment areas often have fixed allocation of resources, regardless of demand. We demonstrate the utility of discrete-event simulation to evaluate flexible partitioning between low- and high-acuity ED areas to identify the best operational strategy for subsequent implementation. Methods A discrete-event simulation was used to model patient flow through a 50-bed, urban, teaching ED that handles 85,000 patient visits annually. The ED has historically allocated ten beds to a Fast Track for low-acuity patients. We estimated the effect of a Flex Track policy, which involved switching up to five of these Fast Track beds to serving both low- and high-acuity patients, on patient waiting times. When the high-acuity beds were not at capacity, low-acuity patients were given priority access to flexible beds. Otherwise, high-acuity patients were given priority access to flexible beds. Wait times were estimated for patients by disposition and emergency severity index (ESI) score. Results A Flex Track policy using three flexible beds produced the lowest mean patient waiting of 30.9 (95% CI 30.6–31.2) minutes. The typical Fast Track approach of rigidly separating high- and low–acuity beds produced a mean patient wait time of 40.6 (95% CI 40.2–50.0) minutes, 31% higher than the three-bed Flex Track. A completely flexible ED, where all beds can accommodate any patient, produced mean wait times of 35.1 (95% CI 34.8–35.4) minutes. The results from the three-bed Flex Track scenario were robust, performing well across a range of scenarios involving higher and lower patient volumes and care durations. Conclusion Using discrete-event simulation, we have shown that adding some flexibility into bed allocation between low- and high-acuity can provide substantial reductions in overall patient waiting and a more efficient ED. PMID:24954578

The Caenorhabditis elegans Q neuroblasts: A powerful system to study cell migration at single-cell resolution in vivo.

PubMed

Rella, Lorenzo; Fernandes Póvoa, Euclides E; Korswagen, Hendrik C

2016-04-01

During development, cell migration plays a central role in the formation of tissues and organs. Understanding the molecular mechanisms that drive and control these migrations is a key challenge in developmental biology that will provide important insights into disease processes, including cancer cell metastasis. In this article, we discuss the Caenorhabditis elegans Q neuroblasts and their descendants as a tool to study cell migration at single-cell resolution in vivo. The highly stereotypical migration of these cells provides a powerful system to study the dynamic cytoskeletal processes that drive migration as well as the evolutionarily conserved signaling pathways (including different Wnt signaling cascades) that guide the cells along their specific trajectories. Here, we provide an overview of what is currently known about Q neuroblast migration and highlight the live-cell imaging, genome editing, and quantitative gene expression techniques that have been developed to study this process. © 2016 Wiley Periodicals, Inc.

POSE Algorithms for Automated Docking

NASA Technical Reports Server (NTRS)

Heaton, Andrew F.; Howard, Richard T.

2011-01-01

POSE (relative position and attitude) can be computed in many different ways. Given a sensor that measures bearing to a finite number of spots corresponding to known features (such as a target) of a spacecraft, a number of different algorithms can be used to compute the POSE. NASA has sponsored the development of a flash LIDAR proximity sensor called the Vision Navigation Sensor (VNS) for use by the Orion capsule in future docking missions. This sensor generates data that can be used by a variety of algorithms to compute POSE solutions inside of 15 meters, including at the critical docking range of approximately 1-2 meters. Previously NASA participated in a DARPA program called Orbital Express that achieved the first automated docking for the American space program. During this mission a large set of high quality mated sensor data was obtained at what is essentially the docking distance. This data set is perhaps the most accurate truth data in existence for docking proximity sensors in orbit. In this paper, the flight data from Orbital Express is used to test POSE algorithms at 1.22 meters range. Two different POSE algorithms are tested for two different Fields-of-View (FOVs) and two different pixel noise levels. The results of the analysis are used to predict future performance of the POSE algorithms with VNS data.

Proximity Operations and Docking Sensor Development

NASA Technical Reports Server (NTRS)

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

2009-01-01

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

Molecular dynamics and docking simulations as a proof of high flexibility in E. coli FabH and its relevance for accurate inhibitor modeling

NASA Astrophysics Data System (ADS)

Pérez-Castillo, Yunierkis; Froeyen, Matheus; Cabrera-Pérez, Miguel Ángel; Nowé, Ann

2011-04-01

Bacterial β-ketoacyl-acyl carrier protein synthase III (FabH) has become an attractive target for the development of new antibacterial agents which can overcome the increased resistance of these pathogens to antibiotics in clinical use. Despite several efforts have been dedicated to find inhibitors for this enzyme, it is not a straightforward task, mainly due its high flexibility which makes difficult the structure-based design of FabH inhibitors. Here, we present for the first time a Molecular Dynamics (MD) study of the E. colil FabH enzyme to explore its conformational space. We compare the flexibility of this enzyme for the unliganded protein and an enzyme-inhibitor complex and find a correspondence between our modeling results and the experimental evidence previously reported for this enzyme. Furthermore, through a 100 ns MD simulation of the unliganded enzyme we extract useful information related to the concerted motions that take place along the principal components of displacement. We also establish a relation between the presence of water molecules in the oxyanion hole with the conformational stability of structural important loops. Representative conformations of the binding pocket along the whole trajectory of the unliganded protein are selected through cluster analysis and we find that they contain a conformational diversity which is not provided by the X-ray structures of ecFabH. As a proof of this last hypothesis, we use a set of 10 FabH inhibitors and show that they cannot be correctly modeled in any available X-ray structure, while by using our set of conformations extracted from the MD simulations, this task can be accomplish. Finally, we show the ability of short MD simulations for the refinement of the docking binding poses and for MM-PBSA calculations to predict stable protein-inhibitor complexes in this enzyme.

Small molecule inhibitors of mesotrypsin from a structure-based docking screen

DOE PAGES

Kayode, Olumide; Huang, Zunnan; Soares, Alexei S.; ...

2017-05-02

PRSS3/mesotrypsin is an atypical isoform of trypsin, the upregulation of which has been implicated in promoting tumor progression. To date there are no mesotrypsin-selective pharmacological inhibitors which could serve as tools for deciphering the pathological role of this enzyme, and could potentially form the basis for novel therapeutic strategies targeting mesotrypsin. A virtual screen of the Natural Product Database (NPD) and Food and Drug Administration (FDA) approved Drug Database was conducted by high-throughput molecular docking utilizing crystal structures of mesotrypsin. Twelve high-scoring compounds were selected for testing based on lowest free energy docking scores, interaction with key mesotrypsin active sitemore » residues, and commercial availability. Diminazene (C1D22956468), along with two similar compounds presenting the bis-benzamidine substructure, was validated as a competitive inhibitor of mesotrypsin and other human trypsin isoforms. Diminazene is the most potent small molecule inhibitor of mesotrypsin reported to date with an inhibitory constant (K i) of 3.6±0.3 pM. Diminazene was subsequently co-crystalized with mesotrypsin and the crystal structure was solved and refined to 1.25 Å resolution. This high resolution crystal structure can now offer a foundation for structure-guided efforts to develop novel and potentially more selective mesotrypsin inhibitors based on similar molecular substructures.« less

Small molecule inhibitors of mesotrypsin from a structure-based docking screen

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kayode, Olumide; Huang, Zunnan; Soares, Alexei S.

PRSS3/mesotrypsin is an atypical isoform of trypsin, the upregulation of which has been implicated in promoting tumor progression. To date there are no mesotrypsin-selective pharmacological inhibitors which could serve as tools for deciphering the pathological role of this enzyme, and could potentially form the basis for novel therapeutic strategies targeting mesotrypsin. A virtual screen of the Natural Product Database (NPD) and Food and Drug Administration (FDA) approved Drug Database was conducted by high-throughput molecular docking utilizing crystal structures of mesotrypsin. Twelve high-scoring compounds were selected for testing based on lowest free energy docking scores, interaction with key mesotrypsin active sitemore » residues, and commercial availability. Diminazene (C1D22956468), along with two similar compounds presenting the bis-benzamidine substructure, was validated as a competitive inhibitor of mesotrypsin and other human trypsin isoforms. Diminazene is the most potent small molecule inhibitor of mesotrypsin reported to date with an inhibitory constant (K i) of 3.6±0.3 pM. Diminazene was subsequently co-crystalized with mesotrypsin and the crystal structure was solved and refined to 1.25 Å resolution. This high resolution crystal structure can now offer a foundation for structure-guided efforts to develop novel and potentially more selective mesotrypsin inhibitors based on similar molecular substructures.« less

Potential mosquito repellent compounds of Ocimum species against 3N7H and 3Q8I of Anopheles gambiae.

PubMed

Gaddaguti, Venugopal; Venkateswara Rao, Talluri; Prasada Rao, Allu

2016-06-01

Mosquitoes are exceptionally efficient in detecting their hosts for blood meal using odorant binding proteins, viz. 3N7H and 3Q8I and spread several dreadful diseases. DEET is a synthetic mosquito repellent widely used all over world for protection against mosquito bite. Reports reveal that, synthetic mosquito repellents may pose health problems in considerably large population. In view of the above fact, we made an attempt to discover efficient and novel natural mosquito repellent compounds with least impact on human health. Methanolic leaf extracts of Ocimum basilicum Linn. var. pilosum (willd.)-Benth and Ocimum tenuiflorum var. CIM-AYU were subjected to GC-MS analysis and obtained 35 phytochemical constituents. Repellent potentiality of the Ocimum compounds was assessed against 3Q8I and 3N7H of Anopheles gambiae. PDB structures of mosquito odorant binding proteins were downloaded, processed and docking studies were performed along with reference ligand DEET using Schrodinger MAESTRO 9.2 software. Molecular docking results reveal that phenol, 2-methoxy-3-(2-propenyl)-, licopersin, gamma sitosterol and benzene, 1,2-dimethoxy-4-(2-propenyl)- from O. tenuiflorum var. CIM-AYU are strongly bound with 3N7H. Whereas, 4h-1-benzopyran-4-one, 5-hydroxy-6,7-dimethoxy-2-(4-methoxyphenyl)-, catechol and monoacetin from O. basilicum Linn. var. pilosum (willd.)-Benth. show high binding affinity with odorant binding protein 3Q8I. All natural compounds tested in the present study display better docking scores than DEET. The results further substantiate that the 12 out of 35 compounds of the two Ocimum species found to be ideal candidates for design and development of potential mosquito repellents. ADME properties of the tested compounds further confirm that bioactive compounds of Ocimum species were found to be in acceptable range. Synchronized application of at least two different natural compounds (with best docking scores) which target 3N7H and 3Q8I (Odorant Binding Proteins

Demonstration of a switchable damping system to allow low-noise operation of high-Q low-mass suspension systems

NASA Astrophysics Data System (ADS)

Hennig, Jan-Simon; Barr, Bryan W.; Bell, Angus S.; Cunningham, William; Danilishin, Stefan L.; Dupej, Peter; Gräf, Christian; Hough, James; Huttner, Sabina H.; Jones, Russell; Leavey, Sean S.; Pascucci, Daniela; Sinclair, Martin; Sorazu, Borja; Spencer, Andrew; Steinlechner, Sebastian; Strain, Kenneth A.; Wright, Jennifer; Zhang, Teng; Hild, Stefan

2017-12-01

Low-mass suspension systems with high-Q pendulum stages are used to enable quantum radiation pressure noise limited experiments. Utilizing multiple pendulum stages with vertical blade springs and materials with high-quality factors provides attenuation of seismic and thermal noise; however, damping of these high-Q pendulum systems in multiple degrees of freedom is essential for practical implementation. Viscous damping such as eddy-current damping can be employed, but it introduces displacement noise from force noise due to thermal fluctuations in the damping system. In this paper we demonstrate a passive damping system with adjustable damping strength as a solution for this problem that can be used for low-mass suspension systems without adding additional displacement noise in science mode. We show a reduction of the damping factor by a factor of 8 on a test suspension and provide a general optimization for this system.

Study on propellant dynamics during docking

NASA Technical Reports Server (NTRS)

Feng, G. C.; Robertson, S. J.

1972-01-01

The marker-and-cell numerical technique was applied to the study of axisymmetric and two-dimensional flow of liquid in containers under low gravity conditions. The purpose of the study was to provide the capability for numerically simulating liquid propellant motion in partially filled containers during a docking maneuver in orbit. A computer program to provide this capability for axisymmetric and two-dimensional flow was completed and computations were made for a number of hypothetical flow conditions.

Flexible Ablators

NASA Technical Reports Server (NTRS)

Stackpoole, Margaret M. (Inventor); Ghandehari, Ehson M. (Inventor); Thornton, Jeremy J. (Inventor); Covington, Melmoth Alan (Inventor)

2017-01-01

A low-density article comprising a flexible substrate and a pyrolizable material impregnated therein, methods of preparing, and devices using the article are disclosed. The pyrolizable material pyrolizes above 350 C and does not flow at temperatures below the pyrolysis temperature. The low-density article remains flexible after impregnation and continues to remain flexible when the pyrolizable material is fully pyrolized.

High-Sensitivity and Low-Power Flexible Schottky Hydrogen Sensor Based on Silicon Nanomembrane.

PubMed

Cho, Minkyu; Yun, Jeonghoon; Kwon, Donguk; Kim, Kyuyoung; Park, Inkyu

2018-04-18

High-performance and low-power flexible Schottky diode-based hydrogen sensor was developed. The sensor was fabricated by releasing Si nanomembrane (SiNM) and transferring onto a plastic substrate. After the transfer, palladium (Pd) and aluminum (Al) were selectively deposited as a sensing material and an electrode, respectively. The top-down fabrication process of flexible Pd/SiNM diode H 2 sensor is facile compared to other existing bottom-up fabricated flexible gas sensors while showing excellent H 2 sensitivity (Δ I/ I 0 > 700-0.5% H 2 concentrations) and fast response time (τ 10-90 = 22 s) at room temperature. In addition, selectivity, humidity, and mechanical tests verify that the sensor has excellent reliability and robustness under various environments. The operating power consumption of the sensor is only in the nanowatt range, which indicates its potential applications in low-power portable and wearable electronics.

Solution Processable Electrochemiluminescent Ion Gels for Flexible, Low Voltage, Emissive Displays on Plastic

NASA Astrophysics Data System (ADS)

Moon, Hong Chul; Lodge, Timothy P.; Frisbie, C. Daniel

2014-03-01

We have expanded the functionality of ion gels and successfully demonstrated low voltage, flexible electrochemiluminescent (ECL) devices using patterned ECL gels. An ECL device composed of only an emissive gel and two electrodes was fabricated on an ITO-coated substrate by solution casting the ECL gel and brush-painting the top silver electrode. The device turned on at an AC voltage as low as 2.6 V (-1.3 V ~ +1.3 V) and showed a relatively rapid response (sub-ms). Also, we varied the mechanical properties of the ECL gel simply by substituting polystyrene-block-poly(methyl methacrylate)-block-polystyrene (SMS) with commercially available poly(vinylidene fluoride-co-hexafluoropropylene) (P(VDF-co-HFP)), enabling the fabrication of flexible ECL devices on any target substrate by the ``cut-and-stick'' strategy. This simple, rubbery ECL gel should be attractive for flexible electronics applications such as displays on packaging.

Genetics Home Reference: distal 18q deletion syndrome

MedlinePlus

... Veltman JA, van Ravenswaaij-Arts CM. Genotype-phenotype mapping of chromosome 18q deletions by high-resolution array ... L, Pihko H. 18q deletions: clinical, molecular, and brain MRI findings of 14 individuals. Am J Med ...

Extending RosettaDock with water, sugar, and pH for prediction of complex structures and affinities for CAPRI rounds 20-27.

PubMed

Kilambi, Krishna Praneeth; Pacella, Michael S; Xu, Jianqing; Labonte, Jason W; Porter, Justin R; Muthu, Pravin; Drew, Kevin; Kuroda, Daisuke; Schueler-Furman, Ora; Bonneau, Richard; Gray, Jeffrey J

2013-12-01

Rounds 20-27 of the Critical Assessment of PRotein Interactions (CAPRI) provided a testing platform for computational methods designed to address a wide range of challenges. The diverse targets drove the creation of and new combinations of computational tools. In this study, RosettaDock and other novel Rosetta protocols were used to successfully predict four of the 10 blind targets. For example, for DNase domain of Colicin E2-Im2 immunity protein, RosettaDock and RosettaLigand were used to predict the positions of water molecules at the interface, recovering 46% of the native water-mediated contacts. For α-repeat Rep4-Rep2 and g-type lysozyme-PliG inhibitor complexes, homology models were built and standard and pH-sensitive docking algorithms were used to generate structures with interface RMSD values of 3.3 Å and 2.0 Å, respectively. A novel flexible sugar-protein docking protocol was also developed and used for structure prediction of the BT4661-heparin-like saccharide complex, recovering 71% of the native contacts. Challenges remain in the generation of accurate homology models for protein mutants and sampling during global docking. On proteins designed to bind influenza hemagglutinin, only about half of the mutations were identified that affect binding (T55: 54%; T56: 48%). The prediction of the structure of the xylanase complex involving homology modeling and multidomain docking pushed the limits of global conformational sampling and did not result in any successful prediction. The diversity of problems at hand requires computational algorithms to be versatile; the recent additions to the Rosetta suite expand the capabilities to encompass more biologically realistic docking problems. Copyright © 2013 Wiley Periodicals, Inc.

High-resolution low-dose scanning transmission electron microscopy.

PubMed

Buban, James P; Ramasse, Quentin; Gipson, Bryant; Browning, Nigel D; Stahlberg, Henning

2010-01-01

During the past two decades instrumentation in scanning transmission electron microscopy (STEM) has pushed toward higher intensity electron probes to increase the signal-to-noise ratio of recorded images. While this is suitable for robust specimens, biological specimens require a much reduced electron dose for high-resolution imaging. We describe here protocols for low-dose STEM image recording with a conventional field-emission gun STEM, while maintaining the high-resolution capability of the instrument. Our findings show that a combination of reduced pixel dwell time and reduced gun current can achieve radiation doses comparable to low-dose TEM.

Radial q-space sampling for DSI.

PubMed

Baete, Steven H; Yutzy, Stephen; Boada, Fernando E

2016-09-01

Diffusion spectrum imaging (DSI) has been shown to be an effective tool for noninvasively depicting the anatomical details of brain microstructure. Existing implementations of DSI sample the diffusion encoding space using a rectangular grid. Here we present a different implementation of DSI whereby a radially symmetric q-space sampling scheme for DSI is used to improve the angular resolution and accuracy of the reconstructed orientation distribution functions. Q-space is sampled by acquiring several q-space samples along a number of radial lines. Each of these radial lines in q-space is analytically connected to a value of the orientation distribution functions at the same angular location by the Fourier slice theorem. Computer simulations and in vivo brain results demonstrate that radial diffusion spectrum imaging correctly estimates the orientation distribution functions when moderately high b-values (4000 s/mm2) and number of q-space samples (236) are used. The nominal angular resolution of radial diffusion spectrum imaging depends on the number of radial lines used in the sampling scheme, and only weakly on the maximum b-value. In addition, the radial analytical reconstruction reduces truncation artifacts which affect Cartesian reconstructions. Hence, a radial acquisition of q-space can be favorable for DSI. Magn Reson Med 76:769-780, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Text Mining for Protein Docking

PubMed Central

Badal, Varsha D.; Kundrotas, Petras J.; Vakser, Ilya A.

2015-01-01

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 benchmark set

ATV 2 Johannes Kepler docked

NASA Image and Video Library

2011-02-24

ISS026-E-029294 (24 Feb. 2011) --- Backdropped by the blackness of space, the European Space Agency's "Johannes Kepler" Automated Transfer Vehicle-2 (ATV-2) docks to the aft end of the International Space Station's Zvezda Service Module. Docking of the two spacecraft occurred at 10:59 a.m. (EST) on Feb. 24, 2011.

Pharmacophore Based 3D-QSAR, Virtual Screening and Docking Studies on Novel Series of HDAC Inhibitors with Thiophen Linker as Anticancer Agents.

PubMed

Patel, Preeti; Singh, Avineesh; Patel, Vijay K; Jain, Deepak K; Veerasamy, Ravichandran; Rajak, Harish

2016-01-01

Histone deacetylase (HDAC) inhibitors can reactivate gene expression and inhibit the growth and survival of cancer cells. To identify the important pharmacophoric features and correlate 3Dchemical structure with biological activity using 3D-QSAR and Pharmacophore modeling studies. The pharmacophore hypotheses were developed using e-pharmacophore script and phase module. Pharmacophore hypothesis represents the 3D arrangement of molecular features necessary for activity. A series of 55 compounds with wellassigned HDAC inhibitory activity were used for 3D-QSAR model development. Best 3D-QSAR model, which is a five partial least square (PLS) factor model with good statistics and predictive ability, acquired Q2 (0.7293), R2 (0.9811), cross-validated coefficient rcv 2=0.9807 and R2 pred=0.7147 with low standard deviation (0.0952). Additionally, the selected pharmacophore model DDRRR.419 was used as a 3D query for virtual screening against the ZINC database. In the virtual screening workflow, docking studies (HTVS, SP and XP) were carried out by selecting multiple receptors (PDB ID: 1T69, 1T64, 4LXZ, 4LY1, 3MAX, 2VQQ, 3C10, 1W22). Finally, six compounds were obtained based on high scoring function (dock score -11.2278-10.2222 kcal/mol) and diverse structures. The structure activity correlation was established using virtual screening, docking, energetic based pharmacophore modelling, pharmacophore, atom based 3D QSAR models and their validation. The outcomes of these studies could be further employed for the design of novel HDAC inhibitors for anticancer activity.

AM OLED using a-Si TFT backplane on flexible plastic substrate

NASA Astrophysics Data System (ADS)

Sarma, Kalluri R.; Schmidt, John; Roush, Jerry; Chanley, Charles; Dodd, Sonia R.

2004-09-01

Amorphous silicon TFT technology continues to show promise for fabricating large area high resolution flexible AM OLED displays. This paper describes the recent progress in the flexible AM OLED development efforts at Honeywell since our publication in this conference's proceedings in 2003, describing the feasibility of fabricating a 64x64 pixel AM OLED on a flexible plastic substrate. In this paper we describe the design, and fabrication of a 160x160(x3) pixel AM OLED on a flexible plastic substrate with an equivalent 80cgpi resolution. Flexibility characteristics of the fabricated displays are discussed. Further advances and improvements required for extending the size and resolution of flexible AM OLED displays are discussed.

Autonomous docking ground demonstration

NASA Technical Reports Server (NTRS)

Lamkin, Steve L.; Le, Thomas Quan; Othon, L. T.; Prather, Joseph L.; Eick, Richard E.; Baxter, Jim M.; Boyd, M. G.; Clark, Fred D.; Spehar, Peter T.; Teters, Rebecca T.

1991-01-01

The Autonomous Docking Ground Demonstration is an evaluation of the laser sensor system to support the docking phase (12 ft to contact) when operated in conjunction with the guidance, navigation, and control (GN&C) software. The docking mechanism being used was developed for the Apollo/Soyuz Test Program. This demonstration will be conducted using the 6-DOF Dynamic Test System (DTS). The DTS simulates the Space Station Freedom as the stationary or target vehicle and the Orbiter as the active or chase vehicle. For this demonstration, the laser sensor will be mounted on the target vehicle and the retroflectors will be on the chase vehicle. This arrangement was chosen to prevent potential damage to the laser. The laser sensor system, GN&C, and 6-DOF DTS will be operated closed-loop. Initial conditions to simulate vehicle misalignments, translational and rotational, will be introduced within the constraints of the systems involved.

Human Mobility Monitoring in Very Low Resolution Visual Sensor Network

PubMed Central

Bo Bo, Nyan; Deboeverie, Francis; Eldib, Mohamed; Guan, Junzhi; Xie, Xingzhe; Niño, Jorge; Van Haerenborgh, Dirk; Slembrouck, Maarten; Van de Velde, Samuel; Steendam, Heidi; Veelaert, Peter; Kleihorst, Richard; Aghajan, Hamid; Philips, Wilfried

2014-01-01

This paper proposes an automated system for monitoring mobility patterns using a network of very low resolution visual sensors (30 × 30 pixels). The use of very low resolution sensors reduces privacy concern, cost, computation requirement and power consumption. The core of our proposed system is a robust people tracker that uses low resolution videos provided by the visual sensor network. The distributed processing architecture of our tracking system allows all image processing tasks to be done on the digital signal controller in each visual sensor. In this paper, we experimentally show that reliable tracking of people is possible using very low resolution imagery. We also compare the performance of our tracker against a state-of-the-art tracking method and show that our method outperforms. Moreover, the mobility statistics of tracks such as total distance traveled and average speed derived from trajectories are compared with those derived from ground truth given by Ultra-Wide Band sensors. The results of this comparison show that the trajectories from our system are accurate enough to obtain useful mobility statistics. PMID:25375754

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

NASA Astrophysics Data System (ADS)

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

2018-01-01

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

Validation of the GerdQ questionnaire for the diagnosis of gastro-oesophageal reflux disease.

PubMed

Jonasson, C; Wernersson, B; Hoff, D A L; Hatlebakk, J G

2013-03-01

The diagnosis of gastro-oesophageal reflux disease (GERD) remains a challenge as both invasive methods and symptom-based strategies have limitations. The symptom-based management of GERD in primary care may be further optimised with the use of a questionnaire. To assess the diagnostic validity of the GerdQ questionnaire in patients with symptoms suggestive of GERD. Patients with symptoms suggestive of GERD without alarm features, underwent upper endoscopy, and if normal, pH-metry. Patients were followed for 4 weeks and GerdQ was completed blinded to the investigator at both visits. Reflux oesophagitis or pathological acid exposure was used as diagnostic references for GERD. The diagnostic accuracy for GERD on symptom response to proton pump inhibitor (PPI) was assessed. Among the 169 patients, a GerdQ cutoff ≥9 gave the best balance with regard to sensitivity, 66% (95% CI: 58-74), and specificity, 64% (95% CI: 41-83), for GERD. The high prevalence of reflux oesophagitis (81%) resulted in a high proportion of true positives, but at the same time a high proportion of false-negatives. Consequently, GerdQ had a high positive predictive value, 92% (95% CI: 86-97), but a low negative predictive value, 22% (95% CI: 13-34), for GERD. Symptom resolution on PPI therapy had high sensitivity, 76% (95% CI: 66-84), but low specificity, 33% (95% CI: 17-53), for GERD. GerdQ is a useful complementary tool for the diagnosis of gastro-oesophageal reflux disease in primary care. The implementation of GerdQ could reduce the need for upper endoscopy and improve resource utilisation. Symptom resolution on proton pump inhibitor did not predict gastro-oesophageal reflux disease. © 2013 Blackwell Publishing Ltd.

Measurement of the proton structure function F2 and σγ*ptot at low Q2 and very low x at HERA

NASA Astrophysics Data System (ADS)

Breitweg, J.; Derrick, M.; Krakauer, D.; Magill, S.; Mikunas, D.; Musgrave, B.; Repond, J.; Stanek, R.; Talaga, R. L.; Yoshida, R.; Zhang, H.; Mattingly, M. C. K.; Anselmo, F.; Antonioli, P.; Bari, G.; Basile, M.; Bellagamba, L.; Boscherini, D.; Bruni, A.; Bruni, G.; Romeo, G. Cara; Castellini, G.; Cifarelli, L.; Cindolo, F.; Contin, A.; Corradi, M.; de Pasquale, S.; Gialas, I.; Giusti, P.; Iacobucci, G.; Laurenti, G.; Levi, G.; Margotti, A.; Massam, T.; Nania, R.; Palmonari, F.; Pesci, A.; Polini, A.; Ricci, F.; Sartorelli, G.; Garcia, Y. Zamora; Zichichi, A.; Amelung, C.; Bornheim, A.; Brock, I.; Coböken, K.; Crittenden, J.; Deffner, R.; Eckert, M.; Grothe, M.; Hartmann, H.; Heinloth, K.; Heinz, L.; Hilger, E.; Jakob, H.-P.; Katz, U. F.; Kerger, R.; Paul, E.; Pfeiffer, M.; Rembser, Ch.; Stamm, J.; Wedemeyer, R.; Wieber, H.; Bailey, D. S.; Campbell-Robson, S.; Cottingham, W. N.; Foster, B.; Hall-Wilton, R.; Hayes, M. E.; Heath, G. P.; Heath, H. F.; Piccioni, D.; Roff, D. G.; Tapper, R. J.; Arneodo, M.; Ayad, R.; Capua, M.; Garfagnini, A.; Iannotti, L.; Schioppa, M.; Susinno, G.; Kim, J. Y.; Lee, J. H.; Lim, I. T.; Pac, M. Y.; Caldwell, A.; Cartiglia, N.; Jing, Z.; Liu, W.; Mellado, B.; Parsons, J. A.; Ritz, S.; Sampson, S.; Sciulli, F.; Straub, P. B.; Zhu, Q.; Borzemski, P.; Chwastowski, J.; Eskreys, A.; Jakubowski, Z.; Przybycień, M. B.; Zachara, M.; Zawiejski, L.; Adamczyk, L.; Bednarek, B.; Jeleń, J.; Kisielewska, D.; Kowalski, T.; Przybycień, M.; Rulikowska-Zarȩbska, E.; Suszycki, L.; Zajac, J.; Duliński, Z.; Kotański, A.; Abbiendi, G.; Bauerdick, L. A. T.; Behrens, U.; Beier, H.; Bienlein, J. K.; Cases, G.; Deppe, O.; Desler, K.; Drews, G.; Fricke, U.; Gilkinson, D. J.; Glasman, C.; Göttlicher, P.; Große-Knetter, J.; Haas, T.; Hain, W.; Hasell, D.; Johnson, K. F.; Kasemann, M.; Koch, W.; Kötz, U.; Kowalski, H.; Labs, J.; Lindemann, L.; Löhr, B.; Löwe, M.; Mańczak, O.; Milewski, J.; Monteiro, T.; Ng, J. S. T.; Notz, D.; Ohrenberg, K.; Park, I. H.; Pellegrino, A.; Pelucchi, F.; Piotrzkowski, K.; Roco, M.; Rohde, M.; Roldán, J.; Ryan, J. J.; Savin, A. A.; Schneekloth, U.; Selonke, F.; Surrow, B.; Tassi, E.; Voß, T.; Westphal, D.; Wolf, G.; Wollmer, U.; Youngman, C.; Żarnecki, A. F.; Zeuner, W.; Burow, B. D.; Grabosch, H. J.; Meyer, A.; Schlenstedt, S.; Barbagli, G.; Gallo, E.; Pelfer, P.; Maccarrone, G.; Votano, L.; Bamberger, A.; Eisenhardt, S.; Markun, P.; Trefzger, T.; Wölfle, S.; Bromley, J. T.; Brook, N. H.; Bussey, P. J.; Doyle, A. T.; Saxon, D. H.; Sinclair, L. E.; Strickland, E.; Utley, M. L.; Waugh, R.; Wilson, A. S.; Bohnet, I.; Gendner, N.; Holm, U.; Meyer-Larsen, A.; Salehi, H.; Wick, K.; Gladilin, L. K.; Horstmann, D.; Kçira, D.; Klanner, R.; Lohrmann, E.; Poelz, G.; Schott, W.; Zetsche, F.; Bacon, T. C.; Butterworth, I.; Cole, J. E.; Harris, V. L.; Howell, G.; Hung, B. H. Y.; Lamberti, L.; Long, K. R.; Miller, D. B.; Pavel, N.; Prinias, A.; Sedgbeer, J. K.; Sideris, D.; Whitfield, A. F.; Mallik, U.; Wang, S. M.; Wu, J. T.; Cloth, P.; Filges, D.; Fleck, J. I.; Ishii, T.; Kuze, M.; Nakao, M.; Tokushuku, K.; Yamada, S.; Yamazaki, Y.; An, S. H.; Lee, S. B.; Nam, S. W.; Park, H. S.; Park, S. K.; Barreiro, F.; Fernández, J. P.; García, G.; Graciani, R.; Hernández, J. M.; Hervás, L.; Labarga, L.; Martínez, M.; del Peso, J.; Puga, J.; Terrón, J.; de Trocóniz, J. F.; Corriveau, F.; Hanna, D. S.; Hartmann, J.; Hung, L. W.; Lim, J. N.; Murray, W. N.; Ochs, A.; Riveline, M.; Stairs, D. G.; St-Laurent, M.; Ullmann, R.; Tsurugai, T.; Bashkirov, V.; Dolgoshein, B. A.; Stifutkin, A.; Bashindzhagyan, G. L.; Ermolov, P. F.; Golubkov, Yu. A.; Khein, L. A.; Korotkova, N. A.; Korzhavina, I. A.; Kuzmin, V. A.; Lukina, O. Yu.; Proskuryakov, A. S.; Shcheglova, L. M.; Solomin, A. N.; Zotkin, S. A.; Bokel, C.; Botje, M.; Brümmer, N.; Chlebana, F.; Engelen, J.; Kooijman, P.; van Sighem, A.; Tiecke, H.; Tuning, N.; Verkerke, W.; Vossebeld, J.; Vreeswijk, M.; Wiggers, L.; de Wolf, E.; Acosta, D.; Bylsma, B.; Durkin, L. S.; Gilmore, J.; Ginsburg, C. M.; Kim, C. L.; Ling, T. Y.; Nylander, P.; Romanowski, T. A.; Blaikley, H. E.; Cashmore, R. J.; Cooper-Sarkar, A. M.; Devenish, R. C. E.; Edmonds, J. K.; Harnew, N.; Lancaster, M.; McFall, J. D.; Nath, C.; Noyes, V. A.; Quadt, A.; Ruske, O.; Tickner, J. R.; Uijterwaal, H.; Walczak, R.; Waters, D. S.; Bertolin, A.; Brugnera, R.; Carlin, R.; dal Corso, F.; Dosselli, U.; Limentani, S.; Morandin, M.; Posocco, M.; Stanco, L.; Stroili, R.; Voci, C.; Bulmahn, J.; Feild, R. G.; Oh, B. Y.; Okrasiński, J. R.; Whitmore, J. J.; Iga, Y.; D'Agostini, G.; Marini, G.; Nigro, A.; Raso, M.; Hart, J. C.; McCubbin, N. A.; Shah, T. P.; Epperson, D.; Heusch, C.; Rahn, J. T.; Sadrozinski, H. F.-W.; Seiden, A.; Williams, D. C.; Schwarzer, O.; Walenta, A. H.; Abramowicz, H.; Briskin, G.; Dagan, S.; Doeker, T.; Kananov, S.; Levy, A.; Abe, T.; Fusayasu, T.; Inuzuka, M.; Nagano, K.; Suzuki, I.; Umemori, K.; Yamashita, T.; Hamatsu, R.; Hirose, T.; Homma, K.; Kitamura, S.; Matsushita, T.; Yamauchi, K.; Cirio, R.; Costa, M.; Ferrero, M. I.; Maselli, S.; Monaco, V.; Peroni, C.; Petrucci, M. C.; Sacchi, R.; Solano, A.; Staiano, A.; Dardo, M.; Bailey, D. C.; Brkic, M.; Fagerstroem, C.-P.; Hartner, G. F.; Joo, K. K.; Levman, G. M.; Martin, J. F.; Orr, R. S.; Polenz, S.; Sampson, C. R.; Simmons, D.; Teuscher, R. J.; Butterworth, J. M.; Catterall, C. D.; Jones, T. W.; Kaziewicz, P. B.; Lane, J. B.; Saunders, R. L.; Shulman, J.; Sutton, M. R.; Lu, B.; Mo, L. W.; Ciborowski, J.; Grzelak, G.; Kasprzak, M.; Muchorowski, K.; Nowak, R. J.; Pawlak, J. M.; Pawlak, R.; Tymieniecka, T.; Wróblewski, A. K.; Zakrzewski, J. A.; Adamus, M.; Coldewey, C.; Eisenberg, Y.; Hochman, D.; Karshon, U.; Revel, D.; Badgett, W. F.; Chapin, D.; Cross, R.; Dasu, S.; Foudas, C.; Loveless, R. J.; Mattingly, S.; Reeder, D. D.; Smith, W. H.; Vaiciulis, A.; Wodarczyk, M.; Bhadra, S.; Frisken, W. R.; Khakzad, M.; Schmidke, W. B.

1997-02-01

A small electromagnetic sampling calorimeter, installed in the ZEUS experiment in 1995, significantly enhanced the acceptance for very low x and low Q2 inelastic neutral current scattering, e+p -> e+X, at HERA. A measurement of the proton structure function F2 and the total virtual photon-proton (γ*p) cross-section is presented for 0.11 <= Q2 <= 0.65 GeV2 and 2 × 10-6 <= x <= 6 × 10-5, corresponding to a range in the γ*p c.m. energy of 100 <= W <= 230 GeV. Comparisons with various models are also presented.

Scheduling the future NASA Space Network: Experiences with a flexible scheduling prototype

NASA Technical Reports Server (NTRS)

Happell, Nadine; Moe, Karen L.; Minnix, Jay

1993-01-01

NASA's Space Network (SN) provides telecommunications and tracking services to low earth orbiting spacecraft. One proposal for improving resource allocation and automating conflict resolution for the SN is the concept of flexible scheduling. In this concept, each Payload Operations Control Center (POCC) will possess a Space Network User POCC Interface (SNUPI) to support the development and management of flexible requests. Flexible requests express the flexibility, constraints, and repetitious nature of the user's communications requirements. Flexible scheduling is expected to improve SN resource utilization and user satisfaction, as well as reduce the effort to produce and maintain a schedule. A prototype testbed has been developed to better understand flexible scheduling as it applies to the SN. This testbed consists of a SNUPI workstation, an SN scheduler, and a flexible request language that conveys information between the two systems. All three are being evaluated by operations personnel. Benchmark testing is being conducted on the scheduler to quantify the productivity improvements achieved with flexible requests.

Expedition 19 Docks to ISS

NASA Image and Video Library

2009-03-27

Russian Orthodox Priest, Vladyka Feofan speaks during a Soyuz post-docking press conference at the Russian mission Control Center in Korolev, Russia on Saturday March 28, 2009. The Soyuz TMA-14 docked to the International Space Station carrying Expedition 19 Commander Gennady I. Padalka, Flight Engineer Michael R. Barratt and Spaceflight Participant Charles Simonyi. Photo Credit: (NASA/Bill Ingalls)

Intuitive, but not simple: including explicit water molecules in protein-protein docking simulations improves model quality.

PubMed

Parikh, Hardik I; Kellogg, Glen E

2014-06-01

Characterizing the nature of interaction between proteins that have not been experimentally cocrystallized requires a computational docking approach that can successfully predict the spatial conformation adopted in the complex. In this work, the Hydropathic INTeractions (HINT) force field model was used for scoring docked models in a data set of 30 high-resolution crystallographically characterized "dry" protein-protein complexes and was shown to reliably identify native-like models. However, most current protein-protein docking algorithms fail to explicitly account for water molecules involved in bridging interactions that mediate and stabilize the association of the protein partners, so we used HINT to illuminate the physical and chemical properties of bridging waters and account for their energetic stabilizing contributions. The HINT water Relevance metric identified the "truly" bridging waters at the 30 protein-protein interfaces and we utilized them in "solvated" docking by manually inserting them into the input files for the rigid body ZDOCK program. By accounting for these interfacial waters, a statistically significant improvement of ∼24% in the average hit-count within the top-10 predictions the protein-protein dataset was seen, compared to standard "dry" docking. The results also show scoring improvement, with medium and high accuracy models ranking much better than incorrect ones. These improvements can be attributed to the physical presence of water molecules that alter surface properties and better represent native shape and hydropathic complementarity between interacting partners, with concomitantly more accurate native-like structure predictions. © 2013 Wiley Periodicals, Inc.

Molecular docking and 3D-QSAR studies on triazolinone and pyridazinone, non-nucleoside inhibitor of HIV-1 reverse transcriptase.

PubMed

Sivan, Sree Kanth; Manga, Vijjulatha

2010-06-01

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are allosteric inhibitors of the HIV-1 reverse transcriptase. Recently a series of Triazolinone and Pyridazinone were reported as potent inhibitors of HIV-1 wild type reverse transcriptase. In the present study, docking and 3D quantitative structure activity relationship (3D QSAR) studies involving comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on 31 molecules. Ligands were built and minimized using Tripos force field and applying Gasteiger-Hückel charges. These ligands were docked into protein active site using GLIDE 4.0. The docked poses were analyzed; the best docked poses were selected and aligned. CoMFA and CoMSIA fields were calculated using SYBYL6.9. The molecules were divided into training set and test set, a PLS analysis was performed and QSAR models were generated. The model showed good statistical reliability which is evident from the r2 nv, q2 loo and r2 pred values. The CoMFA model provides the most significant correlation of steric and electrostatic fields with biological activities. The CoMSIA model provides a correlation of steric, electrostatic, acceptor and hydrophobic fields with biological activities. The information rendered by 3D QSAR model initiated us to optimize the lead and design new potential inhibitors.

Design of low surface roughness-low residual stress-high optoelectronic merit a-IZO thin films for flexible OLEDs

DOE PAGES

Kumar, Naveen; Wilkinson, Taylor M.; Packard, Corinne E.; ...

2016-06-08

The development of efficient and reliable large-area flexible optoelectronic devices demands low surface roughness-low residual stress-high optoelectronic merit transparent conducting oxide (TCO) thin films. Here, we correlate surface roughness-residual stress-optoelectronic properties of sputtered amorphous indium zinc oxide (a-IZO) thin films using a statistical design of experiment (DOE) approach and find a common growth space to achieve a smooth surface in a stress-free and high optoelectronic merit a-IZO thin film. The sputtering power, growth pressure, oxygen partial pressure, and RF/(RF+DC) are varied in a two-level system with a full factorial design, and results are used to deconvolve the complex growth space,more » identifying significant control growth parameters and their possible interactions. The surface roughness of a-IZO thin film varies over 0.19 nm to 3.97 nm, which is not in line with the general assumption of low surface roughness in a-IZO thin films. The initial regression model and analysis of variance reveal no single optimum growth sub-space to achieve low surface roughness (=0.5 nm), low residual stress (-1 to 0 GPa), and industrially acceptable electrical conductivity (>1000 S/cm) for a-IZO thin films. The extrapolation of growth parameters in light of the current results and previous knowledge leads to a new sub-space, resulting in a low residual stress of -0.52 +/- 0.04 GPa, a low surface roughness of 0.55 +/- 0.03 nm, and moderate electrical conductivity of 1962 +/- 3.84 S/cm in a-IZO thin films. Lastly, these results demonstrate the utility of the DOE approach to multi-parameter optimization, which provides an important tool for the development of flexible TCOs for the next-generation flexible organic light emitting diodes applications.« less

Design of low surface roughness-low residual stress-high optoelectronic merit a-IZO thin films for flexible OLEDs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kumar, Naveen; Kumar, Mukesh, E-mail: mkumar@iitrpr.ac.in, E-mail: cpackard@mines.edu; Wilkinson, Taylor M.

2016-06-14

The development of efficient and reliable large-area flexible optoelectronic devices demands low surface roughness-low residual stress-high optoelectronic merit transparent conducting oxide (TCO) thin films. Here, we correlate surface roughness-residual stress-optoelectronic properties of sputtered amorphous indium zinc oxide (a-IZO) thin films using a statistical design of experiment (DOE) approach and find a common growth space to achieve a smooth surface in a stress-free and high optoelectronic merit a-IZO thin film. The sputtering power, growth pressure, oxygen partial pressure, and RF/(RF+DC) are varied in a two-level system with a full factorial design, and results are used to deconvolve the complex growth space,more » identifying significant control growth parameters and their possible interactions. The surface roughness of a-IZO thin film varies over 0.19 nm to 3.97 nm, which is not in line with the general assumption of low surface roughness in a-IZO thin films. The initial regression model and analysis of variance reveal no single optimum growth sub-space to achieve low surface roughness (≤0.5 nm), low residual stress (−1 to 0 GPa), and industrially acceptable electrical conductivity (>1000 S/cm) for a-IZO thin films. The extrapolation of growth parameters in light of the current results and previous knowledge leads to a new sub-space, resulting in a low residual stress of −0.52±0.04 GPa, a low surface roughness of 0.55±0.03 nm, and moderate electrical conductivity of 1962±3.84 S/cm in a-IZO thin films. These results demonstrate the utility of the DOE approach to multi-parameter optimization, which provides an important tool for the development of flexible TCOs for the next-generation flexible organic light emitting diodes applications.« less

Study of and proposals for the correction of errors in a radar ranging device designed to facilitate docking of a teleoperator maneuvering system

NASA Technical Reports Server (NTRS)

Mcdonald, M. W.

1982-01-01

A frequency modulated continuous wave radar system was developed. The system operates in the 35 gigahertz frequency range and provides millimeter accuracy range and range rate measurements. This level of range resolution allows soft docking for the proposed teleoperator maneuvering system (TMS) or other autonomous or robotic space vehicles. Sources of error in the operation of the system which tend to limit its range resolution capabilities are identified. Alternative signal processing techniques are explored with emphasis on determination of the effects of inserting various signal filtering circuits in the system. The identification and elimination of an extraneous low frequency signal component created as a result of zero range immediate reflection of radar energy from the surface of the antenna dish back into the mixer of the system is described.

Interface electronic structures of reversible double-docking self-assembled monolayers on an Au(111) surface

PubMed Central

Zhang, Tian; Ma, Zhongyun; Wang, Linjun; Xi, Jinyang; Shuai, Zhigang

2014-01-01

Double-docking self-assembled monolayers (DDSAMs), namely self-assembled monolayers (SAMs) formed by molecules possessing two docking groups, provide great flexibility to tune the work function of metal electrodes and the tunnelling barrier between metal electrodes and the SAMs, and thus offer promising applications in both organic and molecular electronics. Based on the dispersion-corrected density functional theory (DFT) in comparison with conventional DFT, we carry out a systematic investigation on the dual configurations of a series of DDSAMs on an Au(111) surface. Through analysing the interface electronic structures, we obtain the relationship between single molecular properties and the SAM-induced work-function modification as well as the level alignment between the metal Fermi level and molecular frontier states. The two possible conformations of one type of DDSAM on a metal surface reveal a strong difference in the work-function modification and the electron/hole tunnelling barriers. Fermi-level pinning is found to be a key factor to understand the interface electronic properties. PMID:24615153

Absorption band Q model for the Earth

NASA Technical Reports Server (NTRS)

Anderson, D. L.; Given, J. W.

1981-01-01

Attenuation in solids and liquids, as measured by the quality factor Q, is typically frequency dependent. In seismology, however, Q is usually assumed to be independent of frequency. Body wave, surface wave, and normal mode data are used to place constraints on the frequency dependence of Q in the mantle. Specific features of the absorption band model are: low-Q in the seismic band at both the top and the base of the mantle, low-Q for long-period body waves in the outer core, an inner core Q sub s that increases with period, and low Q sub p/Q sub s at short periods in the middle mantle.

Comprehensive Mechanistic Analysis of Hits from High-Throughput and Docking Screens against β-Lactamase

PubMed Central

Babaoglu, Kerim; Simeonov, Anton; Irwin, John J.; Nelson, Michael E.; Feng, Brian; Thomas, Craig J.; Cancian, Laura; Costi, M. Paola; Maltby, David A.; Jadhav, Ajit; Inglese, James; Austin, Christopher P.; Shoichet, Brian K.

2009-01-01

High-throughput screening (HTS) is widely used in drug discovery. Especially for screens of unbiased libraries, false positives can dominate “hit lists”; their origins are much debated. Here we determine the mechanism of every active hit from a screen of 70,563 unbiased molecules against β-lactamase using quantitative HTS (qHTS). Of the 1274 initial inhibitors, 95% were detergent-sensitive and were classified as aggregators. Among the 70 remaining were 25 potent, covalent-acting β-lactams. Mass spectra, counter-screens, and crystallography identified 12 as promiscuous covalent inhibitors. The remaining 33 were either aggregators or irreproducible. No specific reversible inhibitors were found. We turned to molecular docking to prioritize molecules from the same library for testing at higher concentrations. Of 16 tested, 2 were modest inhibitors. Subsequent X-ray structures corresponded to the docking prediction. Analog synthesis improved affinity to 8 µM. These results suggest that it may be the physical behavior of organic molecules, not their reactivity, that accounts for most screening artifacts. Structure-based methods may prioritize weak-but-novel chemotypes in unbiased library screens. PMID:18333608

Deep Coverage Proteomics Identifies More Low-Abundance Missing Proteins in Human Testis Tissue with Q-Exactive HF Mass Spectrometer.

PubMed

Wei, Wei; Luo, Weijia; Wu, Feilin; Peng, Xuehui; Zhang, Yao; Zhang, Manli; Zhao, Yan; Su, Na; Qi, YingZi; Chen, Lingsheng; Zhang, Yangjun; Wen, Bo; He, Fuchu; Xu, Ping

2016-11-04

Since 2012, missing proteins (MPs) investigation has been one of the critical missions of Chromosome-Centric Human Proteome Project (C-HPP) through various biochemical strategies. On the basis of our previous testis MPs study, faster scanning and higher resolution mass-spectrometry-based proteomics might be conducive to MPs exploration, especially for low-abundance proteins. In this study, Q-Exactive HF (HF) was used to survey proteins from the same testis tissues separated by two separating methods (tricine- and glycine-SDS-PAGE), as previously described. A total of 8526 proteins were identified, of which more low-abundance proteins were uniquely detected in HF data but not in our previous LTQ Orbitrap Velos (Velos) reanalysis data. Further transcriptomics analysis showed that these uniquely identified proteins by HF also had lower expression at the mRNA level. Of the 81 total identified MPs, 74 and 39 proteins were listed as MPs in HF and Velos data sets, respectively. Among the above MPs, 47 proteins (43 neXtProt PE2 and 4 PE3) were ranked as confirmed MPs after verifying with the stringent spectra match and isobaric and single amino acid variants filtering. Functional investigation of these 47 MPs revealed that 11 MPs were testis-specific proteins and 7 MPs were involved in spermatogenesis process. Therefore, we concluded that higher scanning speed and resolution of HF might be factors for improving the low-abundance MP identification in future C-HPP studies. All mass-spectrometry data from this study have been deposited in the ProteomeXchange with identifier PXD004092.

High performance transcription factor-DNA docking with GPU computing

PubMed Central

2012-01-01

Background Protein-DNA docking is a very challenging problem in structural bioinformatics and has important implications in a number of applications, such as structure-based prediction of transcription factor binding sites and rational drug design. Protein-DNA docking is very computational demanding due to the high cost of energy calculation and the statistical nature of conformational sampling algorithms. More importantly, experiments show that the docking quality depends on the coverage of the conformational sampling space. It is therefore desirable to accelerate the computation of the docking algorithm, not only to reduce computing time, but also to improve docking quality. Methods In an attempt to accelerate the sampling process and to improve the docking performance, we developed a graphics processing unit (GPU)-based protein-DNA docking algorithm. The algorithm employs a potential-based energy function to describe the binding affinity of a protein-DNA pair, and integrates Monte-Carlo simulation and a simulated annealing method to search through the conformational space. Algorithmic techniques were developed to improve the computation efficiency and scalability on GPU-based high performance computing systems. Results The effectiveness of our approach is tested on a non-redundant set of 75 TF-DNA complexes and a newly developed TF-DNA docking benchmark. We demonstrated that the GPU-based docking algorithm can significantly accelerate the simulation process and thereby improving the chance of finding near-native TF-DNA complex structures. This study also suggests that further improvement in protein-DNA docking research would require efforts from two integral aspects: improvement in computation efficiency and energy function design. Conclusions We present a high performance computing approach for improving the prediction accuracy of protein-DNA docking. The GPU-based docking algorithm accelerates the search of the conformational space and thus increases the

Ligand- and receptor-based docking with LiBELa

NASA Astrophysics Data System (ADS)

dos Santos Muniz, Heloisa; Nascimento, Alessandro S.

2015-08-01

Methodologies on molecular docking are constantly improving. The problem consists on finding an optimal interplay between the computational cost and a satisfactory physical description of ligand-receptor interaction. In pursuit of an advance in current methods we developed a mixed docking approach combining ligand- and receptor-based strategies in a docking engine, where tridimensional descriptors for shape and charge distribution of a reference ligand guide the initial placement of the docking molecule and an interaction energy-based global minimization follows. This hybrid docking was evaluated with soft-core and force field potentials taking into account ligand pose and scoring. Our approach was found to be competitive to a purely receptor-based dock resulting in improved logAUC values when evaluated with DUD and DUD-E. Furthermore, the smoothed potential as evaluated here, was not advantageous when ligand binding poses were compared to experimentally determined conformations. In conclusion we show that a combination of ligand- and receptor-based strategy docking with a force field energy model results in good reproduction of binding poses and enrichment of active molecules against decoys. This strategy is implemented in our tool, LiBELa, available to the scientific community.

American & Soviet engineers examine ASTP docking set-up following tests

NASA Image and Video Library

1974-07-10

S74-25394 (10 July 1974) --- A group of American and Soviet engineers of the Apollo-Soyuz Test Project working group three examines an ASTP docking set-up following a docking mechanism fitness test conducted in Building 13 at the Johnson Space Center. Working Group No. 3 is concerned with ASTP docking problems and techniques. The joint U.S.-USSR ASTP docking mission in Earth orbit is scheduled for the summer of 1975. The Apollo docking mechanism is atop the Soyuz docking mechanism.

Maximizing propulsive thrust of a driven filament at low Reynolds number via variable flexibility.

PubMed

Peng, Zhiwei; Elfring, Gwynn J; Pak, On Shun

2017-03-22

At low Reynolds numbers the locomotive capability of a body can be dramatically hindered by the absence of inertia. In this work, we show how propulsive performance in this regime can be significantly enhanced by employing spatially varying flexibility. As a prototypical example, we consider the propulsive thrust generated by a filament periodically driven at one end. The rigid case leads to zero propulsion, as so constrained by Purcell's scallop theorem, while for uniform filaments there exists a bending stiffness maximizing the propulsive force at a given frequency; here we demonstrate explicitly how considerable further improvement can be achieved by simply varying the stiffness along the filament. The optimal flexibility distribution is strongly configuration-dependent: while increasing the flexibility towards the tail-end enhances the propulsion of a clamped filament, for a hinged filament decreasing the flexibility towards the tail-end is instead favorable. The results reveal new design principles for maximizing propulsion at low Reynolds numbers, potentially useful for developing synthetic micro-swimmers requiring large propulsive force for various biomedical applications.

Lessons in molecular recognition. 2. Assessing and improving cross-docking accuracy.

PubMed

Sutherland, Jeffrey J; Nandigam, Ravi K; Erickson, Jon A; Vieth, Michal

2007-01-01

Docking methods are used to predict the manner in which a ligand binds to a protein receptor. Many studies have assessed the success rate of programs in self-docking tests, whereby a ligand is docked into the protein structure from which it was extracted. Cross-docking, or using a protein structure from a complex containing a different ligand, provides a more realistic assessment of a docking program's ability to reproduce X-ray results. In this work, cross-docking was performed with CDocker, Fred, and Rocs using multiple X-ray structures for eight proteins (two kinases, one nuclear hormone receptor, one serine protease, two metalloproteases, and two phosphodiesterases). While average cross-docking accuracy is not encouraging, it is shown that using the protein structure from the complex that contains the bound ligand most similar to the docked ligand increases docking accuracy for all methods ("similarity selection"). Identifying the most successful protein conformer ("best selection") and similarity selection substantially reduce the difference between self-docking and average cross-docking accuracy. We identify universal predictors of docking accuracy (i.e., showing consistent behavior across most protein-method combinations), and show that models for predicting docking accuracy built using these parameters can be used to select the most appropriate docking method.

Application of molecular docking for the degradation of organic pollutants in the environmental remediation: A review.

PubMed

Liu, Zhifeng; Liu, Yujie; Zeng, Guangming; Shao, Binbin; Chen, Ming; Li, Zhigang; Jiang, Yilin; Liu, Yang; Zhang, Yu; Zhong, Hua

2018-07-01

The molecular docking has been employed successfully to study the mechanism of biodegradation in the environmental remediation in the past few years, although medical science and biology are the main application areas for it. Molecular docking is a very convenient and low cost method to understand the reaction mechanism of proteins or enzymes with ligands with a high accuracy. This paper mainly provides a review for the application of molecular docking between organic pollutants and enzymes. It summarizes the fundamental knowledge of molecular docking, such as its theory, available softwares and main databases. Moreover, five types of pollutants, including phenols, BTEX (benzene, toluene, ethylbenzene, and xylenes), nitrile, polycyclic aromatic hydrocarbons (PAHs), and high polymer (e.g., lignin and cellulose), are discussed from molecular level. Different removal mechanisms are also explained in detail via docking technology. Even though this method shows promising application in the research of biodegradation, further studies are still needed to relate with actual condition. Copyright © 2018 Elsevier Ltd. All rights reserved.

Deformable complex network for refining low-resolution X-ray structures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Chong; Wang, Qinghua; Ma, Jianpeng, E-mail: jpma@bcm.edu

2015-10-27

A new refinement algorithm called the deformable complex network that combines a novel angular network-based restraint with a deformable elastic network model in the target function has been developed to aid in structural refinement in macromolecular X-ray crystallography. In macromolecular X-ray crystallography, building more accurate atomic models based on lower resolution experimental diffraction data remains a great challenge. Previous studies have used a deformable elastic network (DEN) model to aid in low-resolution structural refinement. In this study, the development of a new refinement algorithm called the deformable complex network (DCN) is reported that combines a novel angular network-based restraint withmore » the DEN model in the target function. Testing of DCN on a wide range of low-resolution structures demonstrated that it constantly leads to significantly improved structural models as judged by multiple refinement criteria, thus representing a new effective refinement tool for low-resolution structural determination.« less

Discovery of binding proteins for a protein target using protein-protein docking-based virtual screening.

PubMed

Zhang, Changsheng; Tang, Bo; Wang, Qian; Lai, Luhua

2014-10-01

Target structure-based virtual screening, which employs protein-small molecule docking to identify potential ligands, has been widely used in small-molecule drug discovery. In the present study, we used a protein-protein docking program to identify proteins that bind to a specific target protein. In the testing phase, an all-to-all protein-protein docking run on a large dataset was performed. The three-dimensional rigid docking program SDOCK was used to examine protein-protein docking on all protein pairs in the dataset. Both the binding affinity and features of the binding energy landscape were considered in the scoring function in order to distinguish positive binding pairs from negative binding pairs. Thus, the lowest docking score, the average Z-score, and convergency of the low-score solutions were incorporated in the analysis. The hybrid scoring function was optimized in the all-to-all docking test. The docking method and the hybrid scoring function were then used to screen for proteins that bind to tumor necrosis factor-α (TNFα), which is a well-known therapeutic target for rheumatoid arthritis and other autoimmune diseases. A protein library containing 677 proteins was used for the screen. Proteins with scores among the top 20% were further examined. Sixteen proteins from the top-ranking 67 proteins were selected for experimental study. Two of these proteins showed significant binding to TNFα in an in vitro binding study. The results of the present study demonstrate the power and potential application of protein-protein docking for the discovery of novel binding proteins for specific protein targets. © 2014 Wiley Periodicals, Inc.

Flexible low-voltage organic transistors with high thermal stability at 250 °C.

PubMed

Yokota, Tomoyuki; Kuribara, Kazunori; Tokuhara, Takeyoshi; Zschieschang, Ute; Klauk, Hagen; Takimiya, Kazuo; Sadamitsu, Yuji; Hamada, Masahiro; Sekitani, Tsuyoshi; Someya, Takao

2013-07-19

Low-operating-voltage flexible organic thin-film transistors with high thermal stability using DPh-DNTT and SAM gate dielectrics are reported. The mobility of the transistors are decreased by 23% after heating to 250 °C for 30 min. Furthermore, flexible organic pseudo-CMOS inverter circuits, which are functional after heating to 200 °C, are demonstrated. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Expedition 19 Docks to ISS

NASA Image and Video Library

2009-03-27

Vladimir Solovyov, Chief Flight Director, MCC-M, answers reporters questions during a Soyuz post-docking press conference at the Russian mission Control Center in Korolev, Russia on Saturday March 28, 2009. The Soyuz TMA-14 docked to the International Space Station carrying Expedition 19 Commander Gennady I. Padalka, Flight Engineer Michael R. Barratt and Spaceflight Participant Charles Simonyi. Photo Credit: (NASA/Bill Ingalls)

Expedition 19 Docks to ISS

NASA Image and Video Library

2009-03-27

Vitaly Lopota, President, General Designer, RSC-Energia, answers reporters questions during a Soyuz post-docking press conference at the Russian mission Control Center in Korolev, Russia on Saturday March 28, 2009. The Soyuz TMA-14 docked to the International Space Station carrying Expedition 19 Commander Gennady I. Padalka, Flight Engineer Michael R. Barratt and Spaceflight Participant Charles Simonyi. Photo Credit: (NASA/Bill Ingalls)

High resolution chromosome 3p, 8p, 9q and 22q allelotyping analysis in the pathogenesis of gallbladder carcinoma

PubMed Central

Wistuba, I I; Maitra, A; Carrasco, R; Tang, M; Troncoso, P; Minna, J D; Gazdar, A F

2002-01-01

Our recent genome-wide allelotyping analysis of gallbladder carcinoma identified 3p, 8p, 9q and 22q as chromosomal regions with frequent loss of heterozygosity. The present study was undertaken to more precisely identify the presence and location of regions of frequent allele loss involving those chromosomes in gallbladder carcinoma. Microdissected tissue from 24 gallbladder carcinoma were analysed for PCR-based loss of heterozygosity using 81 microsatellite markers spanning chromosome 3p (n=26), 8p (n=14), 9q (n=29) and 22q (n=12) regions. We also studied the role of those allele losses in gallbladder carcinoma pathogenesis by examining 45 microdissected normal and dysplastic gallbladder epithelia accompanying gallbladder carcinoma, using 17 microsatellite markers. Overall frequencies of loss of heterozygosity at 3p (100%), 8p (100%), 9q (88%), and 22q (92%) sites were very high in gallbladder carcinoma, and we identified 13 distinct regions undergoing frequent loss of heterozygosity in tumours. Allele losses were frequently detected in normal and dysplastic gallbladder epithelia. There was a progressive increase of the overall loss of heterozygosity frequency with increasing severity of histopathological changes. Allele losses were not random and followed a sequence. This study refines several distinct chromosome 3p, 8p, 9q and 22q regions undergoing frequent allele loss in gallbladder carcinoma that will aid in the positional identification of tumour suppressor genes involved in gallbladder carcinoma pathogenesis. British Journal of Cancer (2002) 87, 432–440. doi:10.1038/sj.bjc.6600490 www.bjcancer.com © 2002 Cancer Research UK PMID:12177780

Low authority-threshold control for large flexible structures

NASA Technical Reports Server (NTRS)

Zimmerman, D. C.; Inman, D. J.; Juang, J.-N.

1988-01-01

An improved active control strategy for the vibration control of large flexible structures is presented. A minimum force, low authority-threshold controller is developed to bring a system with or without known external disturbances back into an 'allowable' state manifold over a finite time interval. The concept of a constrained, or allowable feedback form of the controller is introduced that reflects practical hardware implementation concerns. The robustness properties of the control strategy are then assessed. Finally, examples are presented which highlight the key points made within the paper.

Effects of a three-month therapeutic exercise programme on flexibility in subjects with low back pain.

PubMed

Kuukkanen, T; Mälkiä, E

2000-01-01

Spinal and muscle flexibility have been studied intensively and used clinically as outcome measurements in the rehabilitation of subjects with low back pain. The results of previous studies are contradictory and there is a lack of longitudinal data on the effects of long term therapeutic exercise on flexibility. A controlled experimental study was conducted to determine the effects of progressive therapeutic exercise on spinal and muscle flexibility. Eighty-six chronic low back pain subjects fulfilled the inclusion criteria and were divided into three study groups: (1) intensive training group, (2) home exercise group and (3) control group. The intervention period lasted three months and measurements were performed at both the beginning of the study and immediately after intervention. Follow-up measurements were carried out six and 12 months after baseline. Spinal flexibility was measured with lumbar flexion, extension, spinal lateral flexion and rotation, and muscle flexibility was measured with measurements of erector spinae, hamstring and iliopsoas muscles. Also self-reported outcomes of the Oswestry Index and Borg Scale--Back Pain Intensity were used. Associations between change (pre- to post-treatment) were determined for the dependent variables. The results showed no correlation between flexibility, the Oswestry Index or back pain intensity. After the first three-month period lumbar flexion, extension and spinal rotation decreased among all subjects. Spinal rotation and erector spinae muscle flexibility improved significantly with intensive training. At the nine-month follow-up, erector spine flexibility was still greater than at baseline. Hamstring flexibility increased among the intensive training and home exercise groups from pre- to post-intervention. However, the degree of hamstring flexibility gained during training was subsequently lost following the period without programmed exercise in both training groups. Self-reported outcome variables showed

Open-flavor charm and bottom s q q ¯ Q ¯ and q q q ¯ Q ¯ tetraquark states

NASA Astrophysics Data System (ADS)

Chen, Wei; Chen, Hua-Xing; Liu, Xiang; Steele, T. G.; Zhu, Shi-Lin

2017-06-01

We provide comprehensive investigations for the mass spectrum of exotic open-flavor charmed/bottom s q q ¯ c ¯ , q q q ¯ c ¯ , s q q ¯ b ¯ , q q q ¯ b ¯ tetraquark states with various spin-parity assignments JP=0+,1+,2+ and 0- , 1- in the framework of QCD sum rules. In the diquark configuration, we construct the diquark-antidiquark interpolating tetraquark currents using the color-antisymmetric scalar and axial-vector diquark fields. The stable mass sum rules are established in reasonable parameter working ranges, which are used to give reliable mass predictions for these tetraquark states. We obtain the mass spectra for the open-flavor charmed/bottom s q q ¯c ¯, q q q ¯c ¯, s q q ¯b ¯, q q q ¯b ¯ tetraquark states with various spin-parity quantum numbers. In addition, we suggest searching for exotic doubly-charged tetraquarks, such as [s d ][u ¯ c ¯ ]→Ds(*)-π- in future experiments at facilities such as BESIII, BelleII, PANDA, LHCb, and CMS, etc.

Investigation of MM-PBSA rescoring of docking poses.

PubMed

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.

Flexible docking-based molecular dynamics/steered molecular dynamics calculations of protein-protein contacts in a complex of cytochrome P450 1A2 with cytochrome b5.

PubMed

Jeřábek, Petr; Florián, Jan; Stiborová, Marie; Martínek, Václav

2014-10-28

Formation of transient complexes of cytochrome P450 (P450) with another protein of the endoplasmic reticulum membrane, cytochrome b5 (cyt b5), dictates the catalytic activities of several P450s. Therefore, we examined formation and binding modes of the complex of human P450 1A2 with cyt b5. Docking of soluble domains of these proteins was performed using an information-driven flexible docking approach implemented in HADDOCK. Stabilities of the five unique binding modes of the P450 1A2-cyt b5 complex yielded by HADDOCK were evaluated using explicit 10 ns molecular dynamics (MD) simulations in aqueous solution. Further, steered MD was used to compare the stability of the individual P450 1A2-cyt b5 binding modes. The best binding mode was characterized by a T-shaped mutual orientation of the porphyrin rings and a 10.7 Å distance between the two redox centers, thus satisfying the condition for a fast electron transfer. Mutagenesis studies and chemical cross-linking, which, in the absence of crystal structures, were previously used to deduce specific P450-cyt b5 interactions, indicated that the negatively charged convex surface of cyt b5 binds to the positively charged concave surface of P450. Our simulations further elaborate structural details of this interface, including nine ion pairs between R95, R100, R138, R362, K442, K455, and K465 side chains of P450 1A2 and E42, E43, E49, D65, D71, and heme propionates of cyt b5. The universal heme-centric system of internal coordinates was proposed to facilitate consistent classification of the orientation of the two porphyrins in any protein complex.

CircDOCK1 suppresses cell apoptosis via inhibition of miR-196a-5p by targeting BIRC3 in OSCC

PubMed Central

Wang, Liping; Wei, Yongxiang; Yan, Yongyong; Wang, Haiyan; Yang, Jiantin; Zheng, Zhichao; Zha, Jun; Bo, Peng; Tang, Yinghua; Guo, Xueqi; Chen, Weihong; Zhu, Xinxin; Ge, Linhu

2018-01-01

Oral squamous cell carcinoma (OSCC) is the most frequent oral cancer in the world, accounting for more than 90% of all oral cancer diagnosis. Circular RNAs (circRNAs) are large types of non-coding RNAs, demonstrating a great capacity of regulating the expression of genes. However, most of the functions of circRNAs are still unknown. Recent research revealed that circRNAs could serve as a miRNA-sponge, consequently regulating the expression of target genes indirectly, including oncogenes. In this study, we built an apoptotic model with TNF-α, and then we confirmed a circRNA associated with the apoptosis of OSCC cells, circDOCK1 by comparing the expression profile of circRNAs in an apoptotic model with that in untreated OSCC cells. We ascertained the presence of circDOCK1 with qRT-PCR and circRNA sequencing. The knockdown of the expression of circDOCK1 led to the increase of apoptosis. Utilizing multiple bioinformatics methods, we predicted the interactions among circRNAs, miRNAs and genes, and built the circDOCK1/miR-196a-5p/BIRC3 axis. Both the silencing of circDOCK1 with small interfering RNA and the upregulation of the expression of miR-196a-5p with mimics led OSCC cells to increase apoptosis and decrease BIRC3 formation. We further confirmed this outcome by comparing the expression of circDOCK1, miR-196a-5p and BIRC3 in oral squamous carcinoma tissue with those in para-carcinoma tissue, and examining the expression profile of circRNAs in oral squamous carcinoma tissue and para-carcinoma tissue with microarray. Our results demonstrated that circDOCK1 regulated BIRC3 expression by functioning as a competing endogenous RNA (ceRNA) and participated in the process of OSCC apoptosis. Thus, we propose that circDOCK1 could represent a novel potential biomarker and therapeutic target of OSCC. PMID:29286141

Coumarin derivatives bearing benzoheterocycle moiety: synthesis, cholinesterase inhibitory, and docking simulation study

PubMed Central

Hirbod, Kimia; Jalili-baleh, Leili; Nadri, Hamid; ebrahimi, Seyed esmaeil Sadat; Moradi, Alireza; Pakseresht, Bahar; Foroumadi, Alireza; Shafiee, Abbas; Khoobi, Mehdi

2017-01-01

Objective(s): To investigate the efficiency of a novel series of coumarin derivatives bearing benzoheterocycle moiety as novel cholinesterase inhibitors. Materials and Methods: Different 7-hydroxycoumarin derivatives were synthesized via Pechmann or Knoevenagel condensation and conjugated to different benzoheterocycle (8-hydroxyquinoline, 2-mercaptobenzoxazole or 2-mercaptobenzimidazole) using dibromoalkanes 3a-m: Final compounds were evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) by Ellman’s method. Kinetic study of AChE inhibition and ligand-protein docking simulation were also carried out for the most potent compound 3b. Results: Some of the compounds revealed potent and selective activity against AChE. Compound 3b containing the quinoline group showed the best activity with an IC50 value of 8.80 μM against AChE. Kinetic study of AChE inhibition revealed the mixed-type inhibition of the enzyme by compound 3b. Ligand-protein docking simulation also showed that the flexibility of the hydrophobic five carbons linker allows the quinoline ring to form π-π interaction with Trp279 in the PAS. Conclusion: We suggest these synthesized compounds could become potential leads for AChE inhibition and prevention of AD symptoms. PMID:28868119

Construction of pixel-level resolution DEMs from monocular images by shape and albedo from shading constrained with low-resolution DEM

NASA Astrophysics Data System (ADS)

Wu, Bo; Liu, Wai Chung; Grumpe, Arne; Wöhler, Christian

2018-06-01

Lunar Digital Elevation Model (DEM) is important for lunar successful landing and exploration missions. Lunar DEMs are typically generated by photogrammetry or laser altimetry approaches. Photogrammetric methods require multiple stereo images of the region of interest and it may not be applicable in cases where stereo coverage is not available. In contrast, reflectance based shape reconstruction techniques, such as shape from shading (SfS) and shape and albedo from shading (SAfS), apply monocular images to generate DEMs with pixel-level resolution. We present a novel hierarchical SAfS method that refines a lower-resolution DEM to pixel-level resolution given a monocular image with known light source. We also estimate the corresponding pixel-wise albedo map in the process and based on that to regularize the shape reconstruction with pixel-level resolution based on the low-resolution DEM. In this study, a Lunar-Lambertian reflectance model is applied to estimate the albedo map. Experiments were carried out using monocular images from the Lunar Reconnaissance Orbiter Narrow Angle Camera (LRO NAC), with spatial resolution of 0.5-1.5 m per pixel, constrained by the Selenological and Engineering Explorer and LRO Elevation Model (SLDEM), with spatial resolution of 60 m. The results indicate that local details are well recovered by the proposed algorithm with plausible albedo estimation. The low-frequency topographic consistency depends on the quality of low-resolution DEM and the resolution difference between the image and the low-resolution DEM.

Kotov in SM during Progress 37P Docking

NASA Image and Video Library

2010-05-01

ISS023-E-031743 (1 May 2010) --- Russian cosmonaut Oleg Kotov, Expedition 23 commander, is pictured at the manual TORU docking system controls in the Zvezda Service Module of the International Space Station just before conducting a manual control docking of the Progress 37 due to a jet failure on the Progress that forced a shutdown of the Kurs automated rendezvous system. Progress 37 docked to the Pirs Docking Compartment at 2:30 p.m. (EDT) on May 1, 2010, after a three-day flight from the Baikonur Cosmodrome in Kazakhstan.

DOCKSCORE: a webserver for ranking protein-protein docked poses.

PubMed

Malhotra, Sony; Mathew, Oommen K; Sowdhamini, Ramanathan

2015-04-24

Proteins interact with a variety of other molecules such as nucleic acids, small molecules and other proteins inside the cell. Structure-determination of protein-protein complexes is challenging due to several reasons such as the large molecular weights of these macromolecular complexes, their dynamic nature, difficulty in purification and sample preparation. Computational docking permits an early understanding of the feasibility and mode of protein-protein interactions. However, docking algorithms propose a number of solutions and it is a challenging task to select the native or near native pose(s) from this pool. DockScore is an objective scoring scheme that can be used to rank protein-protein docked poses. It considers several interface parameters, namely, surface area, evolutionary conservation, hydrophobicity, short contacts and spatial clustering at the interface for scoring. We have implemented DockScore in form of a webserver for its use by the scientific community. DockScore webserver can be employed, subsequent to docking, to perform scoring of the docked solutions, starting from multiple poses as inputs. The results, on scores and ranks for all the poses, can be downloaded as a csv file and graphical view of the interface of best ranking poses is possible. The webserver for DockScore is made freely available for the scientific community at: http://caps.ncbs.res.in/dockscore/ .

Expedition 19 Docks to ISS

NASA Image and Video Library

2009-03-27

Alexei Krasnov, Director of Manned Space Programs Department, Roscosmos, answers reporters questions during a Soyuz post-docking press conference at the Russian mission Control Center in Korolev, Russia on Saturday March 28, 2009. The Soyuz TMA-14 docked to the International Space Station carrying Expedition 19 Commander Gennady I. Padalka, Flight Engineer Michael R. Barratt and Spaceflight Participant Charles Simonyi. Photo Credit: (NASA/Bill Ingalls)

Expedition 19 Docks to ISS

NASA Image and Video Library

2009-03-27

Managers from NASA, Roscosmos, RSC-Energia and other related agencies answer reporters questions during a Soyuz post-docking press conference at the Russian mission Control Center in Korolev, Russia on Saturday March 28, 2009. The Soyuz TMA-14 docked to the International Space Station carrying Expedition 19 Commander Gennady I. Padalka, Flight Engineer Michael R. Barratt and Spaceflight Participant Charles Simonyi. Photo Credit: (NASA/Bill Ingalls)

Low-Resolution Structure of the Full-Length Barley (Hordeum vulgare) SGT1 Protein in Solution, Obtained Using Small-Angle X-Ray Scattering

PubMed Central

Taube, Michał; Pieńkowska, Joanna R.; Jarmołowski, Artur; Kozak, Maciej

2014-01-01

SGT1 is an evolutionarily conserved eukaryotic protein involved in many important cellular processes. In plants, SGT1 is involved in resistance to disease. In a low ionic strength environment, the SGT1 protein tends to form dimers. The protein consists of three structurally independent domains (the tetratricopeptide repeats domain (TPR), the CHORD- and SGT1-containing domain (CS), and the SGT1-specific domain (SGS)), and two less conserved variable regions (VR1 and VR2). In the present study, we provide the low-resolution structure of the barley (Hordeum vulgare) SGT1 protein in solution and its dimer/monomer equilibrium using small-angle scattering of synchrotron radiation, ab-initio modeling and circular dichroism spectroscopy. The multivariate curve resolution least-square method (MCR-ALS) was applied to separate the scattering data of the monomeric and dimeric species from a complex mixture. The models of the barley SGT1 dimer and monomer were formulated using rigid body modeling with ab-initio structure prediction. Both oligomeric forms of barley SGT1 have elongated shapes with unfolded inter-domain regions. Circular dichroism spectroscopy confirmed that the barley SGT1 protein had a modular architecture, with an α-helical TPR domain, a β-sheet sandwich CS domain, and a disordered SGS domain separated by VR1 and VR2 regions. Using molecular docking and ab-initio protein structure prediction, a model of dimerization of the TPR domains was proposed. PMID:24714665

Molecular modeling-driven approach for identification of Janus kinase 1 inhibitors through 3D-QSAR, docking and molecular dynamics simulations.

PubMed

Itteboina, Ramesh; Ballu, Srilata; Sivan, Sree Kanth; Manga, Vijjulatha

2017-10-01

Janus kinase 1 (JAK 1) belongs to the JAK family of intracellular nonreceptor tyrosine kinase. JAK-signal transducer and activator of transcription (JAK-STAT) pathway mediate signaling by cytokines, which control survival, proliferation and differentiation of a variety of cells. Three-dimensional quantitative structure activity relationship (3 D-QSAR), molecular docking and molecular dynamics (MD) methods was carried out on a dataset of Janus kinase 1(JAK 1) inhibitors. Ligands were constructed and docked into the active site of protein using GLIDE 5.6. Best docked poses were selected after analysis for further 3 D-QSAR analysis using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methodology. Employing 60 molecules in the training set, 3 D-QSAR models were generate that showed good statistical reliability, which is clearly observed in terms of r 2 ncv and q 2 loo values. The predictive ability of these models was determined using a test set of 25 molecules that gave acceptable predictive correlation (r 2 Pred ) values. The key amino acid residues were identified by means of molecular docking, and the stability and rationality of the derived molecular conformations were also validated by MD simulation. The good consonance between the docking results and CoMFA/CoMSIA contour maps provides helpful clues about the reasonable modification of molecules in order to design more efficient JAK 1 inhibitors. The developed models are expected to provide some directives for further synthesis of highly effective JAK 1 inhibitors.

Kotov practices the manual docking techniques with the TORU

NASA Image and Video Library

2013-11-22

ISS038-E-006656 (22 Nov. 2013) --- Russian cosmonaut Oleg Kotov, Expedition 38 commander, practices manual docking techniques with the TORU, or telerobotically operated rendezvous system, in the Zvezda Service Module of the International Space Station in preparation for the docking of the Progress 53 spacecraft. Kotov, using the Simvol-TS screen and hand controllers, could manually dock the Progress to the station in the event of a failure of the Kurs automated docking system. The Progress 53 craft is scheduled to complete its automated docking to the aft port of Zvezda at 5:28 p.m. (EST) on Nov. 29.

Tyurin practices the manual docking techniques with the TORU

NASA Image and Video Library

2013-11-22

ISS038-E-006663 (22 Nov. 2013) --- Russian cosmonaut Mikhail Tyurin, Expedition 38 flight engineer, practices manual docking techniques with the TORU, or telerobotically operated rendezvous system, in the Zvezda Service Module of the International Space Station in preparation for the docking of the Progress 53 spacecraft. Tyurin, using the Simvol-TS screen and hand controllers, could manually dock the Progress to the station in the event of a failure of the Kurs automated docking system. The Progress 53 craft is scheduled to complete its automated docking to the aft port of Zvezda at 5:28 p.m. (EST) on Nov. 29.

Dynamic Responses of Flexible Cylinders with Low Mass Ratio

NASA Astrophysics Data System (ADS)

Olaoye, Abiodun; Wang, Zhicheng; Triantafyllou, Michael

2017-11-01

Flexible cylinders with low mass ratios such as composite risers are attractive in the offshore industry because they require lower top tension and are less likely to buckle under self-weight compared to steel risers. However, their relatively low stiffness characteristics make them more vulnerable to vortex induced vibrations. Additionally, numerical investigation of the dynamic responses of such structures based on realistic conditions is limited by high Reynolds number, complex sheared flow profile, large aspect ratio and low mass ratio challenges. In the framework of Fourier spectral/hp element method, the current technique employs entropy-viscosity method (EVM) based large-eddy simulation approach for flow solver and fictitious added mass method for structure solver. The combination of both methods can handle fluid-structure interaction problems at high Reynolds number with low mass ratio. A validation of the numerical approach is provided by comparison with experiments.

High Spatiotemporal Resolution ECoG Recording of Somatosensory Evoked Potentials with Flexible Micro-Electrode Arrays.

PubMed

Kaiju, Taro; Doi, Keiichi; Yokota, Masashi; Watanabe, Kei; Inoue, Masato; Ando, Hiroshi; Takahashi, Kazutaka; Yoshida, Fumiaki; Hirata, Masayuki; Suzuki, Takafumi

2017-01-01

Electrocorticogram (ECoG) has great potential as a source signal, especially for clinical BMI. Until recently, ECoG electrodes were commonly used for identifying epileptogenic foci in clinical situations, and such electrodes were low-density and large. Increasing the number and density of recording channels could enable the collection of richer motor/sensory information, and may enhance the precision of decoding and increase opportunities for controlling external devices. Several reports have aimed to increase the number and density of channels. However, few studies have discussed the actual validity of high-density ECoG arrays. In this study, we developed novel high-density flexible ECoG arrays and conducted decoding analyses with monkey somatosensory evoked potentials (SEPs). Using MEMS technology, we made 96-channel Parylene electrode arrays with an inter-electrode distance of 700 μm and recording site area of 350 μm 2 . The arrays were mainly placed onto the finger representation area in the somatosensory cortex of the macaque, and partially inserted into the central sulcus. With electrical finger stimulation, we successfully recorded and visualized finger SEPs with a high spatiotemporal resolution. We conducted offline analyses in which the stimulated fingers and intensity were predicted from recorded SEPs using a support vector machine. We obtained the following results: (1) Very high accuracy (~98%) was achieved with just a short segment of data (~15 ms from stimulus onset). (2) High accuracy (~96%) was achieved even when only a single channel was used. This result indicated placement optimality for decoding. (3) Higher channel counts generally improved prediction accuracy, but the efficacy was small for predictions with feature vectors that included time-series information. These results suggest that ECoG signals with high spatiotemporal resolution could enable greater decoding precision or external device control.

High Spatiotemporal Resolution ECoG Recording of Somatosensory Evoked Potentials with Flexible Micro-Electrode Arrays

PubMed Central

Kaiju, Taro; Doi, Keiichi; Yokota, Masashi; Watanabe, Kei; Inoue, Masato; Ando, Hiroshi; Takahashi, Kazutaka; Yoshida, Fumiaki; Hirata, Masayuki; Suzuki, Takafumi