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.

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

PubMed Central

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

2015-01-01

Automated docking of drug-like molecules into receptors is an essential tool in structure-based drug design. While modeling receptor flexibility is important for correctly predicting ligand binding, it still remains challenging. This work focuses on an approach in which receptor flexibility is modeled by explicitly specifying a set of receptor side-chains a-priori. The challenges of this approach include the: 1) exponential growth of the search space, demanding more efficient search methods; and 2) increased number of false positives, calling for scoring functions tailored for flexible receptor docking. We present AutoDockFR–AutoDock for Flexible Receptors (ADFR), a new docking engine based on the AutoDock4 scoring function, which addresses the aforementioned challenges with a new Genetic Algorithm (GA) and customized scoring function. We validate ADFR using the Astex Diverse Set, demonstrating an increase in efficiency and reliability of its GA over the one implemented in AutoDock4. We demonstrate greatly increased success rates when cross-docking ligands into apo receptors that require side-chain conformational changes for ligand binding. These cross-docking experiments are based on two datasets: 1) SEQ17 –a receptor diversity set containing 17 pairs of apo-holo structures; and 2) CDK2 –a ligand diversity set composed of one CDK2 apo structure and 52 known bound inhibitors. We show that, when cross-docking ligands into the apo conformation of the receptors with up to 14 flexible side-chains, ADFR reports more correctly cross-docked ligands than AutoDock Vina on both datasets with solutions found for 70.6% vs. 35.3% systems on SEQ17, and 76.9% vs. 61.5% on CDK2. ADFR also outperforms AutoDock Vina in number of top ranking solutions on both datasets. Furthermore, we show that correctly docked CDK2 complexes re-create on average 79.8% of all pairwise atomic interactions between the ligand and moving receptor atoms in the holo complexes. Finally, we show that down-weighting the receptor internal energy improves the ranking of correctly docked poses and that runtime for AutoDockFR scales linearly when side-chain flexibility is added. PMID:26629955

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.

1. Full SW side of dock as viewed from shore ...

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

1. Full SW side of dock as viewed from shore at the Oil/Creosote Unloading Dock. This view formed a panorama with photo WA-131-H-5, which shows the Oil/Creosote Unloading Dock. - Pacific Creosoting Plant, West Dock, 5350 Creosote Place, Northeast, Bremerton, Kitsap County, WA

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.

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.

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

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.

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.

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

PubMed

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

2018-07-01

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

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

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

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.

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.

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.

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/.

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

PubMed Central

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

2015-01-01

Protein–peptide interactions play a key role in cell functions. Their structural characterization, though challenging, is important for the discovery of new drugs. The CABS-dock web server provides an interface for modeling protein–peptide interactions using a highly efficient protocol for the flexible docking of peptides to proteins. While other docking algorithms require pre-defined localization of the binding site, CABS-dock does not require such knowledge. Given a protein receptor structure and a peptide sequence (and starting from random conformations and positions of the peptide), CABS-dock performs simulation search for the binding site allowing for full flexibility of the peptide and small fluctuations of the receptor backbone. This protocol was extensively tested over the largest dataset of non-redundant protein–peptide interactions available to date (including bound and unbound docking cases). For over 80% of bound and unbound dataset cases, we obtained models with high or medium accuracy (sufficient for practical applications). Additionally, as optional features, CABS-dock can exclude user-selected binding modes from docking search or to increase the level of flexibility for chosen receptor fragments. CABS-dock is freely available as a web server at http://biocomp.chem.uw.edu.pl/CABSdock. PMID:25943545

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://www.cs.utexas.edu/~bajaj/cvc/software/f2dock.shtml. Client: http://www.cs.utexas.edu/~bajaj/cvc/software/f2dockclient.shtml. PMID:23483883

AnchorDock: Blind and Flexible Anchor-Driven Peptide Docking.

PubMed

Ben-Shimon, Avraham; Niv, Masha Y

2015-05-05

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

Protein-protein docking with binding site patch prediction and network-based terms enhanced combinatorial scoring.

PubMed

Gong, Xinqi; Wang, Panwen; Yang, Feng; Chang, Shan; Liu, Bin; He, Hongqiu; Cao, Libin; Xu, Xianjin; Li, Chunhua; Chen, Weizu; Wang, Cunxin

2010-11-15

Protein-protein docking has made much progress in recent years, but challenges still exist. Here we present the application of our docking approach HoDock in CAPRI. In this approach, a binding site prediction is implemented to reduce docking sampling space and filter out unreasonable docked structures, and a network-based enhanced combinatorial scoring function HPNCscore is used to evaluate the decoys. The experimental information was combined with the predicted binding site to pick out the most likely key binding site residues. We applied the HoDock method in the recent rounds of the CAPRI experiments, and got good results as predictors on targets 39, 40, and 41. We also got good results as scorers on targets 35, 37, 40, and 41. This indicates that our docking approach can contribute to the progress of protein-protein docking methods and to the understanding of the mechanism of protein-protein interactions. © 2010 Wiley-Liss, Inc.

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

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.

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.

76 FR 27309 - Union Electric Company, dba AmerenUE; Notice of Application for Amendment of License and...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-11

... brief comments up to 6,000 characters, without prior registration, using the eComment system at http... docks, and add 1,330 feet of breakwater. The completed development would have 18 docks (16 boat docks, 1 swim dock, and 1 fishing dock) with 240 boat slips and 156 personal watercraft lifts; boat fueling...

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.

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.

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.

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.

Why are most EU pigs tail docked? Economic and ethical analysis of four pig housing and management scenarios in the light of EU legislation and animal welfare outcomes.

PubMed

D'Eath, R B; Niemi, J K; Vosough Ahmadi, B; Rutherford, K M D; Ison, S H; Turner, S P; Anker, H T; Jensen, T; Busch, M E; Jensen, K K; Lawrence, A B; Sandøe, P

2016-04-01

To limit tail biting incidence, most pig producers in Europe tail dock their piglets. This is despite EU Council Directive 2008/120/EC banning routine tail docking and allowing it only as a last resort. The paper aims to understand what it takes to fulfil the intentions of the Directive by examining economic results of four management and housing scenarios, and by discussing their consequences for animal welfare in the light of legal and ethical considerations. The four scenarios compared are: 'Standard Docked', a conventional housing scenario with tail docking meeting the recommendations for Danish production (0.7 m2/pig); 'Standard Undocked', which is the same as 'Standard Docked' but with no tail docking, 'Efficient Undocked' and 'Enhanced Undocked', which have increased solid floor area (0.9 and 1.0 m2/pig, respectively) provision of loose manipulable materials (100 and 200 g/straw per pig per day) and no tail docking. A decision tree model based on data from Danish and Finnish pig production suggests that Standard Docked provides the highest economic gross margin with the least tail biting. Given our assumptions, Enhanced Undocked is the least economic, although Efficient Undocked is better economically and both result in a lower incidence of tail biting than Standard Undocked but higher than Standard Docked. For a pig, being bitten is worse for welfare (repeated pain, risk of infections) than being docked, but to compare welfare consequences at a farm level means considering the number of affected pigs. Because of the high levels of biting in Standard Undocked, it has on average inferior welfare to Standard Docked, whereas the comparison of Standard Docked and Enhanced (or Efficient) Undocked is more difficult. In Enhanced (or Efficient) Undocked, more pigs than in Standard Docked suffer from being tail bitten, whereas all the pigs avoid the acute pain of docking endured by the pigs in Standard Docked. We illustrate and discuss this ethical balance using numbers derived from the above-mentioned data. We discuss our results in the light of the EU Directive and its adoption and enforcement by Member States. Widespread use of tail docking seems to be accepted, mainly because the alternative steps that producers are required to take before resorting to it are not specified in detail. By tail docking, producers are acting in their own best interests. We suggest that for the practice of tail docking to be terminated in a way that benefits animal welfare, changes in the way pigs are housed and managed may first be required.

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.

13. ORE DOCK, LOOKING EAST FROM HULETT NO. 1. WHEN ...

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

13. ORE DOCK, LOOKING EAST FROM HULETT NO. 1. WHEN BUILT IN 1911-1912, THIS WAS THE LARGEST ORE-UNLOADING DOCK ON THE GREAT LAKES. THE DOCK FEATURED FOUR HULETT UNLOADERS, EACH WITH A BUCKET CAPACITY OF 17 TONS; A 15-TON CAPACITY ORE STOCKING AND REHANDLING BRIDGE; AND A ONE-MILLION-TON CAPACITY ORE STORAGE YARD. THE WILLIAM-SEAVER-MORGAN COMPANY OF CLEVELAND BUILT THE DOCK EQUIPMENT. - Pennsylvania Railway Ore Dock, Lake Erie at Whiskey Island, approximately 1.5 miles west of Public Square, Cleveland, Cuyahoga County, OH

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 chance of finding more near-native structures. To the best of our knowledge, this is the first ad hoc effort of applying GPU or GPU clusters to the protein-DNA docking problem. PMID:22759575

Docking of small molecules to farnesoid X receptors using AutoDock Vina with the Convex-PL potential: lessons learned from D3R Grand Challenge 2

NASA Astrophysics Data System (ADS)

Kadukova, Maria; Grudinin, Sergei

2018-01-01

The 2016 D3R Grand Challenge 2 provided an opportunity to test multiple protein-ligand docking protocols on a set of ligands bound to farnesoid X receptor that has many available experimental structures. We participated in the Stage 1 of the Challenge devoted to the docking pose predictions, with the mean RMSD value of our submission poses of 2.9 Å. Here we present a thorough analysis of our docking predictions made with AutoDock Vina and the Convex-PL rescoring potential by reproducing our submission protocol and running a series of additional molecular docking experiments. We conclude that a correct receptor structure, or more precisely, the structure of the binding pocket, plays the crucial role in the success of our docking studies. We have also noticed the important role of a local ligand geometry, which seems to be not well discussed in literature. We succeed to improve our results up to the mean RMSD value of 2.15-2.33 Å dependent on the models of the ligands, if docking these to all available homologous receptors. Overall, for docking of ligands of diverse chemical series we suggest to perform docking of each of the ligands to a set of multiple receptors that are homologous to the target.

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

PubMed

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

2015-07-01

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

STS-74 view of MIR Docking module at Pad 39A

NASA Technical Reports Server (NTRS)

1995-01-01

Workers at Launch Pad 39A are preparing to close the payload bay doors on the Space Shuttle Atlantis for its upcoming launch on Mission STS-74 and the second docking with the Russian Space Station Mir. Uppermost in the payload bay is the Orbiter Docking System (ODS), which also flew on the first docking flight between the Space Shuttle and MIR. Lowermost is the primary payload of STS-74, the Russian-built Docking Module. During the mission, the Docking Module will first be attached to ODS and then to Mir. It will be left attached to Mir to become a permanent extension that will afford adequate clearance between the orbiter and the station during future dockings. At left in the payload bay, looking like a very long pole, is the Canadian-built Remote Manipulator System arm that will be used by the crew to hoist the Docking Module and attach it to the ODS.

The SH2/SH3 adaptor protein dock interacts with the Ste20-like kinase misshapen in controlling growth cone motility.

PubMed

Ruan, W; Pang, P; Rao, Y

1999-11-01

Recent studies suggest that the SH2/SH3 adaptor Dock/Nck transduces tyrosine phosphorylation signals to the actin cytoskeleton in regulating growth cone motility. The signaling cascade linking the action of Dock/Nck to the reorganization of cytoskeleton is poorly understood. We now demonstrate that Dock interacts with the Ste20-like kinase Misshapen (Msn) in the Drosophila photoreceptor (R cell) growth cones. Loss of msn causes a failure of growth cones to stop at the target, a phenotype similar to loss of dock, whereas overexpression of msn induces pretarget growth cone termination. Physical and genetic interactions between Msn and Dock indicate a role for Msn in the Dock signaling pathway. We propose that Msn functions as a key controller of growth cone cytoskeleton in response to Dock-mediated signals.

Comparison of neural histomorphology in tail tips from pigs docked using clippers or cautery iron.

PubMed

Kells, N J; Beausoleil, N J; Johnson, C B; Sutherland, M A; Morrison, R S; Roe, W

2017-07-01

Tail docking of pigs is commonly performed to reduce the incidence of unwanted tail-biting behaviour. Two docking methods are commonly used: blunt trauma cutting (i.e. using side clippers), or cutting and concurrent cauterisation using a hot cautery iron. A potential consequence of tail amputation is the development of neuromas at the docking site. Neuromas have been linked to neuropathic pain, which can influence the longer-term welfare of affected individuals. To determine whether method of tail docking influences the extent of neuroma formation, 75 pigs were allocated to one of three treatments at birth: tail docked using clippers; tail docked using cautery iron; tail left intact. Tail docking was performed at 2 days of age and pigs were kept under conventional conditions until slaughter at 21 weeks of age. Tails were removed following slaughter and subjected to histological examination. Nerve histomorphology was scored according to the following scale: 1=discrete well-organised nerve bundles; 2=moderate neural proliferation and disorganisation affecting more than half of the circumference of the tail; 3=marked neural proliferation to form almost continuous disorganised bundles or non-continuous enlarged bundles compressing the surrounding connective tissue. Scores of 2 or 3 indicated neuroma formation. Scores were higher in docked pigs than undocked pigs (P<0.001), but did not differ between pigs docked using clippers and those docked using cautery (P=0.23). The results indicate that tail docking using either clippers or cautery results in neuroma formation, thus having the potential to affect long-term pig welfare.

Human and Server Docking Prediction for CAPRI Round 30–35 Using LZerD with Combined Scoring Functions

PubMed Central

Peterson, Lenna X.; Kim, Hyungrae; Esquivel-Rodriguez, Juan; Roy, Amitava; Han, Xusi; Shin, Woong-Hee; Zhang, Jian; Terashi, Genki; Lee, Matt; Kihara, Daisuke

2016-01-01

We report the performance of protein-protein docking predictions by our group for recent rounds of the Critical Assessment of Prediction of Interactions (CAPRI), a community-wide assessment of state-of-the-art docking methods. Our prediction procedure uses a protein-protein docking program named LZerD developed in our group. LZerD represents a protein surface with 3D Zernike descriptors (3DZD), which are based on a mathematical series expansion of a 3D function. The appropriate soft representation of protein surface with 3DZD makes the method more tolerant to conformational change of proteins upon docking, which adds an advantage for unbound docking. Docking was guided by interface residue prediction performed with BindML and cons-PPISP as well as literature information when available. The generated docking models were ranked by a combination of scoring functions, including PRESCO, which evaluates the native-likeness of residues’ spatial environments in structure models. First, we discuss the overall performance of our group in the CAPRI prediction rounds and investigate the reasons for unsuccessful cases. Then, we examine the performance of several knowledge-based scoring functions and their combinations for ranking docking models. It was found that the quality of a pool of docking models generated by LZerD, i.e. whether or not the pool includes near-native models, can be predicted by the correlation of multiple scores. Although the current analysis used docking models generated by LZerD, findings on scoring functions are expected to be universally applicable to other docking methods. PMID:27654025

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.

DockQ: A Quality Measure for Protein-Protein Docking Models

PubMed Central

Basu, Sankar

2016-01-01

The state-of-the-art to assess the structural quality of docking models is currently based on three related yet independent quality measures: Fnat, LRMS, and iRMS as proposed and standardized by CAPRI. These quality measures quantify different aspects of the quality of a particular docking model and need to be viewed together to reveal the true quality, e.g. a model with relatively poor LRMS (>10Å) might still qualify as 'acceptable' with a descent Fnat (>0.50) and iRMS (<3.0Å). This is also the reason why the so called CAPRI criteria for assessing the quality of docking models is defined by applying various ad-hoc cutoffs on these measures to classify a docking model into the four classes: Incorrect, Acceptable, Medium, or High quality. This classification has been useful in CAPRI, but since models are grouped in only four bins it is also rather limiting, making it difficult to rank models, correlate with scoring functions or use it as target function in machine learning algorithms. Here, we present DockQ, a continuous protein-protein docking model quality measure derived by combining Fnat, LRMS, and iRMS to a single score in the range [0, 1] that can be used to assess the quality of protein docking models. By using DockQ on CAPRI models it is possible to almost completely reproduce the original CAPRI classification into Incorrect, Acceptable, Medium and High quality. An average PPV of 94% at 90% Recall demonstrating that there is no need to apply predefined ad-hoc cutoffs to classify docking models. Since DockQ recapitulates the CAPRI classification almost perfectly, it can be viewed as a higher resolution version of the CAPRI classification, making it possible to estimate model quality in a more quantitative way using Z-scores or sum of top ranked models, which has been so valuable for the CASP community. The possibility to directly correlate a quality measure to a scoring function has been crucial for the development of scoring functions for protein structure prediction, and DockQ should be useful in a similar development in the protein docking field. DockQ is available at http://github.com/bjornwallner/DockQ/ PMID:27560519

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.

jMetalCpp: optimizing molecular docking problems with a C++ metaheuristic framework.

PubMed

López-Camacho, Esteban; García Godoy, María Jesús; Nebro, Antonio J; Aldana-Montes, José F

2014-02-01

Molecular docking is a method for structure-based drug design and structural molecular biology, which attempts to predict the position and orientation of a small molecule (ligand) in relation to a protein (receptor) to produce a stable complex with a minimum binding energy. One of the most widely used software packages for this purpose is AutoDock, which incorporates three metaheuristic techniques. We propose the integration of AutoDock with jMetalCpp, an optimization framework, thereby providing both single- and multi-objective algorithms that can be used to effectively solve docking problems. The resulting combination of AutoDock + jMetalCpp allows users of the former to easily use the metaheuristics provided by the latter. In this way, biologists have at their disposal a richer set of optimization techniques than those already provided in AutoDock. Moreover, designers of metaheuristic techniques can use molecular docking for case studies, which can lead to more efficient algorithms oriented to solving the target problems.  jMetalCpp software adapted to AutoDock is freely available as a C++ source code at http://khaos.uma.es/AutodockjMetal/.

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.

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.

Overall view of test set-up in bldg 13 at JSC during docking set-up tests

NASA Image and Video Library

1974-08-04

S74-27049 (4 Aug. 1974) --- Overall view of test set-up in Building 23 at the Johnson Space Center during testing of the docking mechanisms for the joint U.S.-USSR Apollo-Soyuz Test Project. The cinematic check was being made when this picture was taken. The test control room is on the right. The Soviet-developed docking system is atop the USA-NASA developed docking system. Both American and Soviet engineers can be seen taking part in the docking testing. The ASTP docking mission in Earth orbit is scheduled for July 1975.

Experimental validation of docking and capture using space robotics testbeds

NASA Technical Reports Server (NTRS)

Spofford, John

1991-01-01

Docking concepts include capture, berthing, and docking. The definitions of these terms, consistent with AIAA, are as follows: (1) capture (grasping)--the use of a manipulator to make initial contact and attachment between transfer vehicle and a platform; (2) berthing--positioning of a transfer vehicle or payload into platform restraints using a manipulator; and (3) docking--propulsive mechanical connection between vehicle and platform. The combination of the capture and berthing operations is effectively the same as docking; i.e., capture (grasping) + berthing = docking. These concepts are discussed in terms of Martin Marietta's ability to develop validation methods using robotics testbeds.

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.

TORU OBT

NASA Image and Video Library

2014-07-22

ISS040-E-070857 (22 July 2014) --- Russian cosmonaut Alexander Skvortsov, Expedition 40 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 56 spacecraft. Skvortsov, 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 56 craft is scheduled to complete its automated docking to the Pirs docking compartment at 11:30 p.m. (EDT) on July 23, 2014.

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.

TORU OBT

NASA Image and Video Library

2014-07-22

ISS040-E-070859 (22 July 2014) --- Russian cosmonaut Alexander Skvortsov, Expedition 40 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 56 spacecraft. Skvortsov, 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 56 craft is scheduled to complete its automated docking to the Pirs docking compartment at 11:30 p.m. (EDT) on July 23, 2014.

Monte Carlo replica-exchange based ensemble docking of protein conformations.

PubMed

Zhang, Zhe; Ehmann, Uwe; Zacharias, Martin

2017-05-01

A replica-exchange Monte Carlo (REMC) ensemble docking approach has been developed that allows efficient exploration of protein-protein docking geometries. In addition to Monte Carlo steps in translation and orientation of binding partners, possible conformational changes upon binding are included based on Monte Carlo selection of protein conformations stored as ordered pregenerated conformational ensembles. The conformational ensembles of each binding partner protein were generated by three different approaches starting from the unbound partner protein structure with a range spanning a root mean square deviation of 1-2.5 Å with respect to the unbound structure. Because MC sampling is performed to select appropriate partner conformations on the fly the approach is not limited by the number of conformations in the ensemble compared to ensemble docking of each conformer pair in ensemble cross docking. Although only a fraction of generated conformers was in closer agreement with the bound structure the REMC ensemble docking approach achieved improved docking results compared to REMC docking with only the unbound partner structures or using docking energy minimization methods. The approach has significant potential for further improvement in combination with more realistic structural ensembles and better docking scoring functions. Proteins 2017; 85:924-937. © 2016 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

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/ .

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.

The Drosophila SH2-SH3 adapter protein Dock is expressed in embryonic axons and facilitates synapse formation by the RP3 motoneuron.

PubMed

Desai, C J; Garrity, P A; Keshishian, H; Zipursky, S L; Zinn, K

1999-04-01

The Dock SH2-SH3 domain adapter protein, a homolog of the mammalian Nck oncoprotein, is required for axon guidance and target recognition by photoreceptor axons in Drosophila larvae. Here we show that Dock is widely expressed in neurons and at muscle attachment sites in the embryo, and that this expression pattern has both maternal and zygotic components. In motoneurons, Dock is concentrated in growth cones. Loss of zygotic dock function causes a selective delay in synapse formation by the RP3 motoneuron at the cleft between muscles 7 and 6. These muscles often completely lack innervation in late stage 16 dock mutant embryos. RP3 does form a synapse later in development, however, because muscles 7 and 6 are normally innervated in third-instar mutant larvae. The absence of zygotically expressed Dock also results in subtle defects in a longitudinal axon pathway in the embryonic central nervous system. Concomitant loss of both maternally and zygotically derived Dock dramatically enhances these central nervous system defects, but does not increase the delay in RP3 synaptogenesis. These results indicate that Dock facilitates synapse formation by the RP3 motoneuron and is also required for guidance of some interneuronal axons The involvement of Dock in the conversion of the RP3 growth cone into a presynaptic terminal may reflect a role for Dock-mediated signaling in remodeling of the growth cone's cytoskeleton.

Structural Interface Parameters Are Discriminatory in Recognising Near-Native Poses of Protein-Protein Interactions

PubMed Central

Malhotra, Sony; Sankar, Kannan; Sowdhamini, Ramanathan

2014-01-01

Interactions at the molecular level in the cellular environment play a very crucial role in maintaining the physiological functioning of the cell. These molecular interactions exist at varied levels viz. protein-protein interactions, protein-nucleic acid interactions or protein-small molecules interactions. Presently in the field, these interactions and their mechanisms mark intensively studied areas. Molecular interactions can also be studied computationally using the approach named as Molecular Docking. Molecular docking employs search algorithms to predict the possible conformations for interacting partners and then calculates interaction energies. However, docking proposes number of solutions as different docked poses and hence offers a serious challenge to identify the native (or near native) structures from the pool of these docked poses. Here, we propose a rigorous scoring scheme called DockScore which can be used to rank the docked poses and identify the best docked pose out of many as proposed by docking algorithm employed. The scoring identifies the optimal interactions between the two protein partners utilising various features of the putative interface like area, short contacts, conservation, spatial clustering and the presence of positively charged and hydrophobic residues. DockScore was first trained on a set of 30 protein-protein complexes to determine the weights for different parameters. Subsequently, we tested the scoring scheme on 30 different protein-protein complexes and native or near-native structure were assigned the top rank from a pool of docked poses in 26 of the tested cases. We tested the ability of DockScore to discriminate likely dimer interactions that differ substantially within a homologous family and also demonstrate that DOCKSCORE can distinguish correct pose for all 10 recent CAPRI targets. PMID:24498255

Structural interface parameters are discriminatory in recognising near-native poses of protein-protein interactions.

PubMed

Malhotra, Sony; Sankar, Kannan; Sowdhamini, Ramanathan

2014-01-01

Interactions at the molecular level in the cellular environment play a very crucial role in maintaining the physiological functioning of the cell. These molecular interactions exist at varied levels viz. protein-protein interactions, protein-nucleic acid interactions or protein-small molecules interactions. Presently in the field, these interactions and their mechanisms mark intensively studied areas. Molecular interactions can also be studied computationally using the approach named as Molecular Docking. Molecular docking employs search algorithms to predict the possible conformations for interacting partners and then calculates interaction energies. However, docking proposes number of solutions as different docked poses and hence offers a serious challenge to identify the native (or near native) structures from the pool of these docked poses. Here, we propose a rigorous scoring scheme called DockScore which can be used to rank the docked poses and identify the best docked pose out of many as proposed by docking algorithm employed. The scoring identifies the optimal interactions between the two protein partners utilising various features of the putative interface like area, short contacts, conservation, spatial clustering and the presence of positively charged and hydrophobic residues. DockScore was first trained on a set of 30 protein-protein complexes to determine the weights for different parameters. Subsequently, we tested the scoring scheme on 30 different protein-protein complexes and native or near-native structure were assigned the top rank from a pool of docked poses in 26 of the tested cases. We tested the ability of DockScore to discriminate likely dimer interactions that differ substantially within a homologous family and also demonstrate that DOCKSCORE can distinguish correct pose for all 10 recent CAPRI targets.

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.

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;

Human and server docking prediction for CAPRI round 30-35 using LZerD with combined scoring functions.

PubMed

Peterson, Lenna X; Kim, Hyungrae; Esquivel-Rodriguez, Juan; Roy, Amitava; Han, Xusi; Shin, Woong-Hee; Zhang, Jian; Terashi, Genki; Lee, Matt; Kihara, Daisuke

2017-03-01

We report the performance of protein-protein docking predictions by our group for recent rounds of the Critical Assessment of Prediction of Interactions (CAPRI), a community-wide assessment of state-of-the-art docking methods. Our prediction procedure uses a protein-protein docking program named LZerD developed in our group. LZerD represents a protein surface with 3D Zernike descriptors (3DZD), which are based on a mathematical series expansion of a 3D function. The appropriate soft representation of protein surface with 3DZD makes the method more tolerant to conformational change of proteins upon docking, which adds an advantage for unbound docking. Docking was guided by interface residue prediction performed with BindML and cons-PPISP as well as literature information when available. The generated docking models were ranked by a combination of scoring functions, including PRESCO, which evaluates the native-likeness of residues' spatial environments in structure models. First, we discuss the overall performance of our group in the CAPRI prediction rounds and investigate the reasons for unsuccessful cases. Then, we examine the performance of several knowledge-based scoring functions and their combinations for ranking docking models. It was found that the quality of a pool of docking models generated by LZerD, that is whether or not the pool includes near-native models, can be predicted by the correlation of multiple scores. Although the current analysis used docking models generated by LZerD, findings on scoring functions are expected to be universally applicable to other docking methods. Proteins 2017; 85:513-527. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

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.

Protein-protein docking using region-based 3D Zernike descriptors

PubMed Central

2009-01-01

Background Protein-protein interactions are a pivotal component of many biological processes and mediate a variety of functions. Knowing the tertiary structure of a protein complex is therefore essential for understanding the interaction mechanism. However, experimental techniques to solve the structure of the complex are often found to be difficult. To this end, computational protein-protein docking approaches can provide a useful alternative to address this issue. Prediction of docking conformations relies on methods that effectively capture shape features of the participating proteins while giving due consideration to conformational changes that may occur. Results We present a novel protein docking algorithm based on the use of 3D Zernike descriptors as regional features of molecular shape. The key motivation of using these descriptors is their invariance to transformation, in addition to a compact representation of local surface shape characteristics. Docking decoys are generated using geometric hashing, which are then ranked by a scoring function that incorporates a buried surface area and a novel geometric complementarity term based on normals associated with the 3D Zernike shape description. Our docking algorithm was tested on both bound and unbound cases in the ZDOCK benchmark 2.0 dataset. In 74% of the bound docking predictions, our method was able to find a near-native solution (interface C-αRMSD ≤ 2.5 Å) within the top 1000 ranks. For unbound docking, among the 60 complexes for which our algorithm returned at least one hit, 60% of the cases were ranked within the top 2000. Comparison with existing shape-based docking algorithms shows that our method has a better performance than the others in unbound docking while remaining competitive for bound docking cases. Conclusion We show for the first time that the 3D Zernike descriptors are adept in capturing shape complementarity at the protein-protein interface and useful for protein docking prediction. Rigorous benchmark studies show that our docking approach has a superior performance compared to existing methods. PMID:20003235

Protein-protein docking using region-based 3D Zernike descriptors.

PubMed

Venkatraman, Vishwesh; Yang, Yifeng D; Sael, Lee; Kihara, Daisuke

2009-12-09

Protein-protein interactions are a pivotal component of many biological processes and mediate a variety of functions. Knowing the tertiary structure of a protein complex is therefore essential for understanding the interaction mechanism. However, experimental techniques to solve the structure of the complex are often found to be difficult. To this end, computational protein-protein docking approaches can provide a useful alternative to address this issue. Prediction of docking conformations relies on methods that effectively capture shape features of the participating proteins while giving due consideration to conformational changes that may occur. We present a novel protein docking algorithm based on the use of 3D Zernike descriptors as regional features of molecular shape. The key motivation of using these descriptors is their invariance to transformation, in addition to a compact representation of local surface shape characteristics. Docking decoys are generated using geometric hashing, which are then ranked by a scoring function that incorporates a buried surface area and a novel geometric complementarity term based on normals associated with the 3D Zernike shape description. Our docking algorithm was tested on both bound and unbound cases in the ZDOCK benchmark 2.0 dataset. In 74% of the bound docking predictions, our method was able to find a near-native solution (interface C-alphaRMSD < or = 2.5 A) within the top 1000 ranks. For unbound docking, among the 60 complexes for which our algorithm returned at least one hit, 60% of the cases were ranked within the top 2000. Comparison with existing shape-based docking algorithms shows that our method has a better performance than the others in unbound docking while remaining competitive for bound docking cases. We show for the first time that the 3D Zernike descriptors are adept in capturing shape complementarity at the protein-protein interface and useful for protein docking prediction. Rigorous benchmark studies show that our docking approach has a superior performance compared to existing methods.

6. Looking west showing top of dock: steaming frozen ore ...

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

6. Looking west showing top of dock: steaming frozen ore which had been put in pockets in December 1959, May 6, 1990. Photographer: unknown - Marquette Ore Dock No. 6, Ore Dock, On pilings in Marquette City Lower Harbor, Marquette, Marquette County, MI

Fast and accurate grid representations for atom-based docking with partner flexibility.

PubMed

de Vries, Sjoerd J; Zacharias, Martin

2017-06-30

Macromolecular docking methods can broadly be divided into geometric and atom-based methods. Geometric methods use fast algorithms that operate on simplified, grid-like molecular representations, while atom-based methods are more realistic and flexible, but far less efficient. Here, a hybrid approach of grid-based and atom-based docking is presented, combining precalculated grid potentials with neighbor lists for fast and accurate calculation of atom-based intermolecular energies and forces. The grid representation is compatible with simultaneous multibody docking and can tolerate considerable protein flexibility. When implemented in our docking method ATTRACT, grid-based docking was found to be ∼35x faster. With the OPLSX forcefield instead of the ATTRACT coarse-grained forcefield, the average speed improvement was >100x. Grid-based representations may allow atom-based docking methods to explore large conformational spaces with many degrees of freedom, such as multiple macromolecules including flexibility. This increases the domain of biological problems to which docking methods can be applied. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

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.

Extracellular domains play different roles in gap junction formation and docking compatibility.

PubMed

Bai, Donglin; Wang, Ao Hong

2014-02-15

GJ (gap junction) channels mediate direct intercellular communication and play an important role in many physiological processes. Six connexins oligomerize to form a hemichannel and two hemichannels dock together end-to-end to form a GJ channel. Connexin extracellular domains (E1 and E2) have been shown to be important for the docking, but the molecular mechanisms behind the docking and formation of GJ channels are not clear. Recent developments in atomic GJ structure and functional studies on a series of connexin mutants revealed that E1 and E2 are likely to play different roles in the docking. Non-covalent interactions at the docking interface, including hydrogen bonds, are predicted to form between interdocked extracellular domains. Protein sequence alignment analysis on the docking compatible/incompatible connexins indicate that the E1 domain is important for the formation of the GJ channel and the E2 domain is important in the docking compatibility in heterotypic channels. Interestingly, the hydrogen-bond forming or equivalent residues in both E1 and E2 domains are mutational hot spots for connexin-linked human diseases. Understanding the molecular mechanisms of GJ docking can assist us to develop novel strategies in rescuing the disease-linked connexin mutants.

DOCK2 regulates cell proliferation through Rac and ERK activation in B cell lymphoma

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

Wang, Lei; Nishihara, Hiroshi, E-mail: nisihara@patho2.med.hokudai.ac.jp; Kimura, Taichi

2010-04-23

DOCK2; a member of the CDM protein family, regulates cell motility and cytokine production through the activation of Rac in mammalian hematopoietic cells and plays a pivotal role in the modulation of the immune system. Here we demonstrated the alternative function of DOCK2 in hematopoietic tumor cells, especially in terms of its association with the tumor progression. Immunostaining for DOCK2 in 20 cases of human B cell lymphoma tissue specimens including diffuse large B cell lymphoma and follicular lymphoma revealed the prominent expression of DOCK2 in all of the lymphoma cells. DOCK2-knockdown (KD) of the B cell lymphoma cell lines,more » Ramos and Raji, using the lentiviral shRNA system presented decreased cell proliferation compared to the control cells. Furthermore, the tumor formation of DOCK2-KD Ramos cell in nude mice was significantly abrogated. Western blotting analysis and pull-down assay using GST-PAK-RBD kimeric protein suggested the presence of DOCK2-Rac-ERK pathway regulating the cell proliferation of these lymphoma cells. This is the first report to clarify the prominent role of DOCK2 in hematopoietic malignancy.« less

In Silico Screening for Biothreat Countermeasures

DTIC Science & Technology

2006-02-03

drug candidates to each kinase structure using the well-known docking algorithm LibDock . This population of 1200 ligands includes ~400 ligands with...mentioned previously, each of the known p38 inhibitors in the population was docked to its target using the LibDock application. This method resulted

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.

HDOCK: a web server for protein–protein and protein–DNA/RNA docking based on a hybrid strategy

PubMed Central

Yan, Yumeng; Zhang, Di; Zhou, Pei; Li, Botong

2017-01-01

Abstract Protein–protein and protein–DNA/RNA interactions play a fundamental role in a variety of biological processes. Determining the complex structures of these interactions is valuable, in which molecular docking has played an important role. To automatically make use of the binding information from the PDB in docking, here we have presented HDOCK, a novel web server of our hybrid docking algorithm of template-based modeling and free docking, in which cases with misleading templates can be rescued by the free docking protocol. The server supports protein–protein and protein–DNA/RNA docking and accepts both sequence and structure inputs for proteins. The docking process is fast and consumes about 10–20 min for a docking run. Tested on the cases with weakly homologous complexes of <30% sequence identity from five docking benchmarks, the HDOCK pipeline tied with template-based modeling on the protein–protein and protein–DNA benchmarks and performed better than template-based modeling on the three protein–RNA benchmarks when the top 10 predictions were considered. The performance of HDOCK became better when more predictions were considered. Combining the results of HDOCK and template-based modeling by ranking first of the template-based model further improved the predictive power of the server. The HDOCK web server is available at http://hdock.phys.hust.edu.cn/. PMID:28521030

Calculating an optimal box size for ligand docking and virtual screening against experimental and predicted binding pockets.

PubMed

Feinstein, Wei P; Brylinski, Michal

2015-01-01

Computational approaches have emerged as an instrumental methodology in modern research. For example, virtual screening by molecular docking is routinely used in computer-aided drug discovery. One of the critical parameters for ligand docking is the size of a search space used to identify low-energy binding poses of drug candidates. Currently available docking packages often come with a default protocol for calculating the box size, however, many of these procedures have not been systematically evaluated. In this study, we investigate how the docking accuracy of AutoDock Vina is affected by the selection of a search space. We propose a new procedure for calculating the optimal docking box size that maximizes the accuracy of binding pose prediction against a non-redundant and representative dataset of 3,659 protein-ligand complexes selected from the Protein Data Bank. Subsequently, we use the Directory of Useful Decoys, Enhanced to demonstrate that the optimized docking box size also yields an improved ranking in virtual screening. Binding pockets in both datasets are derived from the experimental complex structures and, additionally, predicted by eFindSite. A systematic analysis of ligand binding poses generated by AutoDock Vina shows that the highest accuracy is achieved when the dimensions of the search space are 2.9 times larger than the radius of gyration of a docking compound. Subsequent virtual screening benchmarks demonstrate that this optimized docking box size also improves compound ranking. For instance, using predicted ligand binding sites, the average enrichment factor calculated for the top 1 % (10 %) of the screening library is 8.20 (3.28) for the optimized protocol, compared to 7.67 (3.19) for the default procedure. Depending on the evaluation metric, the optimal docking box size gives better ranking in virtual screening for about two-thirds of target proteins. This fully automated procedure can be used to optimize docking protocols in order to improve the ranking accuracy in production virtual screening simulations. Importantly, the optimized search space systematically yields better results than the default method not only for experimental pockets, but also for those predicted from protein structures. A script for calculating the optimal docking box size is freely available at www.brylinski.org/content/docking-box-size. Graphical AbstractWe developed a procedure to optimize the box size in molecular docking calculations. Left panel shows the predicted binding pose of NADP (green sticks) compared to the experimental complex structure of human aldose reductase (blue sticks) using a default protocol. Right panel shows the docking accuracy using an optimized box size.

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.

Stimulation of insulin release by glucose is associated with an increase in the number of docked granules in the beta-cells of rat pancreatic islets.

PubMed

Straub, Susanne G; Shanmugam, Geetha; Sharp, Geoffrey W G

2004-12-01

Electron microscopy and quantitative stereological techniques were used to study the dynamics of the docked granule pool in the rat pancreatic beta-cell. The mean number of granules per beta-cell was 11,136. After equilibration in RPMI containing 5.6 mmol/l glucose, 6.4% of the granules (approximately 700) were docked at the plasma membrane (also measured as [means +/- SE] 4.3 +/- 0.6 docked granules per 10 microm of plasma membrane at the perimeter of the cell sections). After a 40-min exposure to 16.7 mmol/l glucose, 10.2% of the granules (approximately 1,060) were docked (6.4 +/- 0.8 granules per 10 microm of plasma membrane). Thus, the docked pool increased by 50% during stimulation with glucose. Islets were also exposed to 16.7 mmol/l glucose in the absence or presence of 10 micromol/l nitrendipine. In the absence and presence of nitrendipine, there were 6.1 +/- 0.7 and 6.3 +/- 0.6 granules per 10 microm of membrane, respectively. Thus, glucose increased granule docking independently of increased [Ca2+]i and exocytosis. The data suggest a limit to the number of docking sites. As the rate of docking exceeded the rate of exocytosis, docking is not rate limiting for insulin release. Only with extremely high release rates, glucose stimulation after a 4-h incubation with a high concentration of fatty acid-free BSA, was the docked granule pool reduced in size.

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.

Tyurin packs the docking probe in Node 1 during Expedition Three

NASA Image and Video Library

2001-09-17

ISS003-E-5634 (17 September 2001) --- Cosmonaut Mikhail Tyurin, Expedition Three flight engineer, packs the docking probe in a stowage bag in Unity. The docking probe successfully guided the arrival of the Russian-built Pirs docking compartment to the International Space Station (ISS). Tyurin represents Rosaviakosmos.

9 CFR 355.15 - Inedible material operating and storage rooms; outer premises, docks, driveways, etc.; fly...

Code of Federal Regulations, 2012 CFR

2012-01-01

... storage rooms; outer premises, docks, driveways, etc.; fly-breeding material; nuisances. 355.15 Section....15 Inedible material operating and storage rooms; outer premises, docks, driveways, etc.; fly... departments where certified products are prepared, handled, or stored. Docks and areas where cars and vehicles...

9 CFR 355.15 - Inedible material operating and storage rooms; outer premises, docks, driveways, etc.; fly...

Code of Federal Regulations, 2014 CFR

2014-01-01

... storage rooms; outer premises, docks, driveways, etc.; fly-breeding material; nuisances. 355.15 Section....15 Inedible material operating and storage rooms; outer premises, docks, driveways, etc.; fly... departments where certified products are prepared, handled, or stored. Docks and areas where cars and vehicles...

9 CFR 355.15 - Inedible material operating and storage rooms; outer premises, docks, driveways, etc.; fly...

Code of Federal Regulations, 2013 CFR

2013-01-01

... storage rooms; outer premises, docks, driveways, etc.; fly-breeding material; nuisances. 355.15 Section....15 Inedible material operating and storage rooms; outer premises, docks, driveways, etc.; fly... departments where certified products are prepared, handled, or stored. Docks and areas where cars and vehicles...

17. ORE DOCK, LOOKING EAST FROM HULETT NO. 1. WHEN ...

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

17. ORE DOCK, LOOKING EAST FROM HULETT NO. 1. WHEN BUILT IN 1911-1912, THIS WAS THE LARGEST ORE-UNLOADING DOCK ON THE GREAT LAKES. - Pennsylvania Railway Ore Dock, Lake Erie at Whiskey Island, approximately 1.5 miles west of Public Square, Cleveland, Cuyahoga County, OH

Vinogradov practices docking procedures of the Progress 21 in the SM during Expedition 13

NASA Image and Video Library

2006-04-26

ISS013-E-10225 (26 April 2006) --- Cosmonaut Pavel V. Vinogradov, Expedition 13 commander representing Russia's Federal Space Agency, practices docking procedures with the TORU teleoperated control system in the Zvezda Service Module of the International Space Station in preparation for the docking of the Progress 21 spacecraft. Vinogradov, 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.

Safety in earth orbit study. Volume 2: Analysis of hazardous payloads, docking, on-board survivability

NASA Technical Reports Server (NTRS)

1972-01-01

Detailed and supporting analyses are presented of the hazardous payloads, docking, and on-board survivability aspects connected with earth orbital operations of the space shuttle program. The hazards resulting from delivery, deployment, and retrieval of hazardous payloads, and from handling and transport of cargo between orbiter, sortie modules, and space station are identified and analyzed. The safety aspects of shuttle orbiter to modular space station docking includes docking for assembly of space station, normal resupply docking, and emergency docking. Personnel traffic patterns, escape routes, and on-board survivability are analyzed for orbiter with crew and passenger, sortie modules, and modular space station, under normal, emergency, and EVA and IVA operations.

Ensemble-based docking: From hit discovery to metabolism and toxicity predictions.

PubMed

Evangelista, Wilfredo; Weir, Rebecca L; Ellingson, Sally R; Harris, Jason B; Kapoor, Karan; Smith, Jeremy C; Baudry, Jerome

2016-10-15

This paper describes and illustrates the use of ensemble-based docking, i.e., using a collection of protein structures in docking calculations for hit discovery, the exploration of biochemical pathways and toxicity prediction of drug candidates. We describe the computational engineering work necessary to enable large ensemble docking campaigns on supercomputers. We show examples where ensemble-based docking has significantly increased the number and the diversity of validated drug candidates. Finally, we illustrate how ensemble-based docking can be extended beyond hit discovery and toward providing a structural basis for the prediction of metabolism and off-target binding relevant to pre-clinical and clinical trials. Copyright © 2016 Elsevier Ltd. All rights reserved.

Drosophila photoreceptor axon guidance and targeting requires the dreadlocks SH2/SH3 adapter protein.

PubMed

Garrity, P A; Rao, Y; Salecker, I; McGlade, J; Pawson, T; Zipursky, S L

1996-05-31

Mutations in the Drosophila gene dreadlocks (dock) disrupt photoreceptor cell (R cell) axon guidance and targeting. Genetic mosaic analysis and cell-type-specific expression of dock transgenes demonstrate dock is required in R cells for proper innervation. Dock protein contains one SH2 and three SH3 domains, implicating it in tyrosine kinase signaling, and is highly related to the human proto-oncogene Nck. Dock expression is detected in R cell growth cones in the target region. We propose Dock transmits signals in the growth cone in response to guidance and targeting cues. These findings provide an important step for dissection of signaling pathways regulating growth cone motility.

Naringenin and quercetin--potential anti-HCV agents for NS2 protease targets.

PubMed

Lulu, S Sajitha; Thabitha, A; Vino, S; Priya, A Mohana; Rout, Madhusmita

2016-01-01

Nonstructural proteins of hepatitis C virus had drawn much attention for the scientific fraternity in drug discovery due to its important role in the disease. 3D structure of the protein was predicted using molecular modelling protocol. Docking studies of 10 medicinal plant compounds and three drugs available in the market (control) with NS2 protease were employed by using rigid docking approach of AutoDock 4.2. Among the molecules tested for docking study, naringenin and quercetin revealed minimum binding energy of - 7.97 and - 7.95 kcal/mol with NS2 protease. All the ligands were docked deeply within the binding pocket region of the protein. The docking study results showed that these compounds are potential inhibitors of the target; and also all these docked compounds have good inhibition constant, vdW+Hbond+desolv energy with best RMSD value.

STS-74 view of ODS from Payload Changout Room

NASA Technical Reports Server (NTRS)

1995-01-01

Workers at Launch Pad 39A are preparing to close the payload bay doors on the Space Shuttle Atlantis for its upcoming launch on Mission STS-74 and the second docking with the Russian Space Station Mir. Uppermost in the payload bay is the Orbiter Docking System (ODS), which also flew on the first docking flight between the Space Shuttle and MIR. Lowermost is the primary payload of STS-74, the Russian-built Docking Module. During the mission, the Docking Module will first be attached to ODS and then to Mir. It will be left attached to Mir to become a permanent extension that will afford adequate clearance between the orbiter and the station during future dockings. At left in the payload bay, looking like a very long pole, is the Canadian-built Remote Manipulator System arm that will be used by the crew to hoist the Docking Module and attach it to the ODS.

Pak functions downstream of Dock to regulate photoreceptor axon guidance in Drosophila.

PubMed

Hing, H; Xiao, J; Harden, N; Lim, L; Zipursky, S L

1999-06-25

The SH2/SH3 adaptor protein Dock has been proposed to transduce signals from guidance receptors to the actin cytoskeleton in Drosophila photoreceptor (R cell) growth cones. Here, we demonstrate that Drosophila p21-activated kinase (Pak) is required in a Dock pathway regulating R cell axon guidance and targeting. Dock and Pak colocalize to R cell axons and growth cones, physically interact, and their loss-of-function phenotypes are indistinguishable. Normal patterns of R cell connectivity require Pak's kinase activity and binding sites for both Dock and Cdc42/Rac. A membrane-tethered form of Pak (Pak(myr) acts as a dominant gain-of-function protein. Retinal expression of Pak(myr) rescues the R cell connectivity phenotype in dock mutants. These data establish Pak as a critical regulator of axon guidance and a downstream effector of Dock in vivo.

Post processing of protein-compound docking for fragment-based drug discovery (FBDD): in-silico structure-based drug screening and ligand-binding pose prediction.

PubMed

Fukunishi, Yoshifumi

2010-01-01

For fragment-based drug development, both hit (active) compound prediction and docking-pose (protein-ligand complex structure) prediction of the hit compound are important, since chemical modification (fragment linking, fragment evolution) subsequent to the hit discovery must be performed based on the protein-ligand complex structure. However, the naïve protein-compound docking calculation shows poor accuracy in terms of docking-pose prediction. Thus, post-processing of the protein-compound docking is necessary. Recently, several methods for the post-processing of protein-compound docking have been proposed. In FBDD, the compounds are smaller than those for conventional drug screening. This makes it difficult to perform the protein-compound docking calculation. A method to avoid this problem has been reported. Protein-ligand binding free energy estimation is useful to reduce the procedures involved in the chemical modification of the hit fragment. Several prediction methods have been proposed for high-accuracy estimation of protein-ligand binding free energy. This paper summarizes the various computational methods proposed for docking-pose prediction and their usefulness in FBDD.

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.

Commercial Fishing Port Development in North Florida. [Escambia, Bay, Gulf, Franklin, Wakulla, Nassau, and Duval Counties

NASA Technical Reports Server (NTRS)

Mathis, K. (Principal Investigator); Cato, J. C.; Degner, P. D.; Landrum, P. D.; Prochaska, F. J.

1978-01-01

The author has identified the following significant results. Seven major counties were examined: Escambia, Bay, Gulf, Franklin, Wakulla, Nassau, and Duval. Population and economic activity were reviewed, along with commercial fishing and port facilities. Recommendations for five northwest Florida counties were based on interpretation of aerial photographs, satellite imagery, an aerial survey site visit, and published data. Major needs in Pensacola included docking, ice supply, and net and engine repair services. Costs for additional docks, an ice plant, and gear storage were estimated at $3,658,600. Port users in Panama City identified additional docking and gear storage as primary needs, along with gear repair and a marine railway. Estimated costs for dock and gear storage were $2,860,000. Added docking, gear storage, and ice supply, as well as gear electronics and diesel repair were needed in Port St. Joe. Costs were calculated at $1,231,500. Franklin County has three ports (Apalachicola - $1,107,000 for docks and gear storage, Eastpoint - $420,000 for additional docks, and Carrabella - $2,824,100 for docks, gear storage, and ice plant).

Fragment-based docking: development of the CHARMMing Web user interface as a platform for computer-aided drug design.

PubMed

Pevzner, Yuri; Frugier, Emilie; Schalk, Vinushka; Caflisch, Amedeo; Woodcock, H Lee

2014-09-22

Web-based user interfaces to scientific applications are important tools that allow researchers to utilize a broad range of software packages with just an Internet connection and a browser. One such interface, CHARMMing (CHARMM interface and graphics), facilitates access to the powerful and widely used molecular software package CHARMM. CHARMMing incorporates tasks such as molecular structure analysis, dynamics, multiscale modeling, and other techniques commonly used by computational life scientists. We have extended CHARMMing's capabilities to include a fragment-based docking protocol that allows users to perform molecular docking and virtual screening calculations either directly via the CHARMMing Web server or on computing resources using the self-contained job scripts generated via the Web interface. The docking protocol was evaluated by performing a series of "re-dockings" with direct comparison to top commercial docking software. Results of this evaluation showed that CHARMMing's docking implementation is comparable to many widely used software packages and validates the use of the new CHARMM generalized force field for docking and virtual screening.

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.

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.

PSOVina: The hybrid particle swarm optimization algorithm for protein-ligand docking.

PubMed

Ng, Marcus C K; Fong, Simon; Siu, Shirley W I

2015-06-01

Protein-ligand docking is an essential step in modern drug discovery process. The challenge here is to accurately predict and efficiently optimize the position and orientation of ligands in the binding pocket of a target protein. In this paper, we present a new method called PSOVina which combined the particle swarm optimization (PSO) algorithm with the efficient Broyden-Fletcher-Goldfarb-Shannon (BFGS) local search method adopted in AutoDock Vina to tackle the conformational search problem in docking. Using a diverse data set of 201 protein-ligand complexes from the PDBbind database and a full set of ligands and decoys for four representative targets from the directory of useful decoys (DUD) virtual screening data set, we assessed the docking performance of PSOVina in comparison to the original Vina program. Our results showed that PSOVina achieves a remarkable execution time reduction of 51-60% without compromising the prediction accuracies in the docking and virtual screening experiments. This improvement in time efficiency makes PSOVina a better choice of a docking tool in large-scale protein-ligand docking applications. Our work lays the foundation for the future development of swarm-based algorithms in molecular docking programs. PSOVina is freely available to non-commercial users at http://cbbio.cis.umac.mo .

A Drosophila protein-tyrosine phosphatase associates with an adapter protein required for axonal guidance.

PubMed

Clemens, J C; Ursuliak, Z; Clemens, K K; Price, J V; Dixon, J E

1996-07-19

We have used the yeast two-hybrid system to isolate a novel Drosophila adapter protein, which interacts with the Drosophila protein-tyrosine phosphatase (PTP) dPTP61F. Absence of this protein in Drosophila causes the mutant photoreceptor axon phenotype dreadlocks (dock) (Garrity, P. A., Rao, Y., Salecker, I., and Zipursky, S. L.(1996) Cell 85, 639-650). Dock is similar to the mammalian oncoprotein Nck and contains three Src homology 3 (SH3) domains and one Src homology 2 (SH2) domain. The interaction of dPTP61F with Dock was confirmed in vivo by immune precipitation experiments. A sequence containing five PXXP motifs from the non-catalytic domain of the PTP is sufficient for interaction with Dock. This suggests that binding to the PTP is mediated by one or more of the SH3 domains of Dock. Immune precipitations of Dock also co-precipitate two tyrosine-phosphorylated proteins having molecular masses of 190 and 145 kDa. Interactions between Dock and these tyrosine-phosphorylated proteins are likely mediated by the Dock SH2 domain. These findings identify potential signal-transducing partners of Dock and propose a role for dPTP61F and the unidentified phosphoproteins in axonal guidance.

The Rac-specific exchange factors Dock1 and Dock5 are dispensable for the establishment of the glomerular filtration barrier in vivo

PubMed Central

Laurin, Mélanie; Dumouchel, Annie; Fukui, Yoshinori; Côté, Jean-François

2013-01-01

Podocytes are specialized kidney cells that form the kidney filtration barrier through the connection of their foot processes. Nephrin and Neph family transmembrane molecules at the surface of podocytes interconnect to form a unique type of cell-cell junction, the slit diaphragm, which acts as a molecular sieve. The cytoplasmic tails of Nephrin and Neph mediate cytoskeletal rearrangement that contributes to the maintenance of the filtration barrier. Nephrin and Neph1 orthologs are essential to regulate cell-cell adhesion and Rac-dependent actin rearrangement during Drosophila myoblast fusion. We hypothesized here that molecules regulating myoblast fusion in Drosophila could contribute to signaling downstream of Nephrin and Neph1 in podocytes. We found that Nephrin engagement promoted recruitment of the Rac exchange factor Dock1 to the membrane. Furthermore, Nephrin overexpression led to lamellipodia formation that could be blocked by inhibiting Rac1 activity. We generated in vivo mouse models to investigate whether Dock1 and Dock5 contribute to the formation and maintenance of the kidney filtration barrier. Our results indicate that while Dock1 and Dock5 are expressed in podocytes, their functions are not essential for the development of the glomerular filtration barrier. Furthermore, mice lacking Dock1 were not protected from LPS-induced podocyte effacement. Our data suggest that Dock1 and Dock5 are not the important exchange factors regulating Rac activity during the establishment and maintenance of the glomerular barrier. PMID:24365888

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.

HDOCK: a web server for protein-protein and protein-DNA/RNA docking based on a hybrid strategy.

PubMed

Yan, Yumeng; Zhang, Di; Zhou, Pei; Li, Botong; Huang, Sheng-You

2017-07-03

Protein-protein and protein-DNA/RNA interactions play a fundamental role in a variety of biological processes. Determining the complex structures of these interactions is valuable, in which molecular docking has played an important role. To automatically make use of the binding information from the PDB in docking, here we have presented HDOCK, a novel web server of our hybrid docking algorithm of template-based modeling and free docking, in which cases with misleading templates can be rescued by the free docking protocol. The server supports protein-protein and protein-DNA/RNA docking and accepts both sequence and structure inputs for proteins. The docking process is fast and consumes about 10-20 min for a docking run. Tested on the cases with weakly homologous complexes of <30% sequence identity from five docking benchmarks, the HDOCK pipeline tied with template-based modeling on the protein-protein and protein-DNA benchmarks and performed better than template-based modeling on the three protein-RNA benchmarks when the top 10 predictions were considered. The performance of HDOCK became better when more predictions were considered. Combining the results of HDOCK and template-based modeling by ranking first of the template-based model further improved the predictive power of the server. The HDOCK web server is available at http://hdock.phys.hust.edu.cn/. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

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.

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.

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.

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 is freely available at http://istar.cse.cuhk.edu.hk/idock.

Service building. Cross section thru dry dock nos. 4 & ...

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

Service building. Cross section thru dry dock nos. 4 & 5 showing service bldg & 20-75-150 ton cranes (dry dock associates, May 23, 1941). In files of Cushman & Wakefield, building no. 501, Philadelphia Naval Business Center. - Naval Base Philadelphia-Philadelphia Naval Shipyard, Service Building, Dry Docks No. 4 & 5, League Island, Philadelphia, Philadelphia County, PA

21. ORE DOCK, LOOKING SOUTHWEST. THIS VIEW SHOWS THE WEST ...

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

21. ORE DOCK, LOOKING SOUTHWEST. THIS VIEW SHOWS THE WEST END OF THE DOCK. EMPTY CARS ARE MOVED IN FROM THE WEST BY 'SHUNT CARS,' PUT INTO PLACE AS NEEDED BENEATH THE HULETTS, FILLED, THEN SHUNTED TO THE EAST END OF THE YARD WHERE THEY ARE MADE UP INTO TRAINS. THE POWER HOUSE (WITH TALL ARCHED WINDOWS) AND THE TWO-STORY DOCK OFFICE CAN BE SEEN HERE. - Pennsylvania Railway Ore Dock, Lake Erie at Whiskey Island, approximately 1.5 miles west of Public Square, Cleveland, Cuyahoga County, OH

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.

Ensemble-based docking: From hit discovery to metabolism and toxicity predictions

DOE PAGES

Evangelista, Wilfredo; Weir, Rebecca; Ellingson, Sally; ...

2016-07-29

The use of ensemble-based docking for the exploration of biochemical pathways and toxicity prediction of drug candidates is described. We describe the computational engineering work necessary to enable large ensemble docking campaigns on supercomputers. We show examples where ensemble-based docking has significantly increased the number and the diversity of validated drug candidates. Finally, we illustrate how ensemble-based docking can be extended beyond hit discovery and toward providing a structural basis for the prediction of metabolism and off-target binding relevant to pre-clinical and clinical trials.

GENIUS In Silico Screening Technology for HCV Drug Discovery.

PubMed

Patil, Vaishali M; Masand, Neeraj; Gupta, Satya P

2016-01-01

The various reported in silico screening protocols such as molecular docking are associated with various drawbacks as well as benefits. In molecular docking, on interaction with ligand, the protein or receptor molecule gets activated by adopting conformational changes. These conformational changes cannot be utilized to predict the 3D structure of a protein-ligand complex from unbound protein conformations rigid docking, which necessitates the demand for understanding protein flexibility. Therefore, efficiency and accuracy of docking should be achieved and various available/developed protocols may be adopted. One such protocol is GENIUS induced-fit docking and it is used effectively for the development of anti-HCV NS3-4A serine protease inhibitors. The present review elaborates the GENIUS docking protocol along with its benefits and drawbacks.

Performance of a docking/molecular dynamics protocol for virtual screening of nutlin-class inhibitors of Mdmx.

PubMed

Bharatham, Nagakumar; Finch, Kristin E; Min, Jaeki; Mayasundari, Anand; Dyer, Michael A; Guy, R Kiplin; Bashford, Donald

2017-06-01

A virtual screening protocol involving docking and molecular dynamics has been tested against the results of fluorescence polarization assays testing the potency of a series of compounds of the nutlin class for inhibition of the interaction between p53 and Mdmx, an interaction identified as a driver of certain cancers. The protocol uses a standard docking method (AutoDock) with a cutoff based on the AutoDock score (ADscore), followed by molecular dynamics simulation with a cutoff based on root-mean-square-deviation (RMSD) from the docked pose. An analysis of the experimental and computational results shows modest performance of ADscore alone, but dramatically improved performance when RMSD is also used. Published by Elsevier Inc.

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.

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 Impact Docking System (LIDS)

NASA Technical Reports Server (NTRS)

LaBauve, Tobie E.

2009-01-01

Since 1996, NASA has been developing a docking system that will simplify operations and reduce risks associated with mating spacecraft. This effort has focused on developing and testing an original, reconfigurable, active, closed-loop, force-feedback controlled docking system using modern technologies. The primary objective of this effort has been to design a docking interface that is tunable to the unique performance requirements for all types of mating operations (i.e. docking and berthing, autonomous and piloted rendezvous, and in-space assembly of vehicles, modules and structures). The docking system must also support the transfer of crew, cargo, power, fluid, and data. As a result of the past 10 years of docking system advancement, the Low Impact Docking System or LIDS was developed. The current LIDS design incorporates the lessons learned and development experiences from both previous and existing docking systems. LIDS feasibility was established through multiple iterations of prototype hardware development and testing. Benefits of LIDS include safe, low impact mating operations, more effective and flexible mission implementation with an anytime/anywhere mating capability, system level redundancy, and a more affordable and sustainable mission architecture with reduced mission and life cycle costs. In 1996 the LIDS project, then known as the Advanced Docking Berthing System (ADBS) project, launched a four year developmental period. At the end of the four years, the team had built a prototype of the soft-capture hardware and verified the control system that will be used to control the soft-capture system. In 2001, the LIDS team was tasked to work with the X- 38 Crew Return Vehicle (CRV) project and build its first Engineering Development Unit (EDU).

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.

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.

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.

A Steric-inhibition model for regulation of nucleotide exchange via the Dock180 family of GEFs.

PubMed

Lu, Mingjian; Kinchen, Jason M; Rossman, Kent L; Grimsley, Cynthia; Hall, Matthew; Sondek, John; Hengartner, Michael O; Yajnik, Vijay; Ravichandran, Kodi S

2005-02-22

CDM (CED-5, Dock180, Myoblast city) family members have been recently identified as novel, evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases . They regulate multiple processes, including embryonic development, cell migration, apoptotic-cell engulfment, tumor invasion, and HIV-1 infection, in diverse model systems . However, the mechanism(s) of regulation of CDM proteins has not been well understood. Here, our studies on the prototype member Dock180 reveal a steric-inhibition model for regulating the Dock180 family of GEFs. At basal state, the N-terminal SH3 domain of Dock180 binds to the distant catalytic Docker domain and negatively regulates the function of Dock180. Further studies revealed that the SH3:Docker interaction sterically blocks Rac access to the Docker domain. Interestingly, ELMO binding to the SH3 domain of Dock180 disrupted the SH3:Docker interaction, facilitated Rac access to the Docker domain, and contributed to the GEF activity of the Dock180/ELMO complex. Additional genetic rescue studies in C. elegans suggested that the regulation of the Docker-domain-mediated GEF activity by the SH3 domain and its adjoining region is evolutionarily conserved. This steric-inhibition model may be a general mechanism for regulating multiple SH3-domain-containing Dock180 family members and may have implications for a variety of biological processes.

Tyurin packs the docking probe in Node 1 during Expedition Three

NASA Image and Video Library

2001-09-17

ISS003-E-5632 (17 September 2001) --- Cosmonaut Mikhail Tyurin, Expedition Three flight engineer, packs the docking probe in a stowage bag in Unity. Cosmonaut Vladimir Dezhurov, flight engineer, videotapes the event. The docking probe successfully guided the arrival of the Russian-built Pirs docking compartment to the International Space Station (ISS). Tyurin and Dezhurov represent Rosaviakosmos.

Dezhurov removes the docking probe in Zvezda during Expedition Three

NASA Image and Video Library

2001-09-17

ISS003-E-5621 (17 September 2001) --- Cosmonaut Vladimir Dezhurov, Expedition Three flight engineer, prepares to remove the docking probe in the Zvezda Service Module's pressurized adapter. The docking probe successfully guided the arrival of the Russian-built Pirs docking compartment to the International Space Station (ISS). Mikhail Tyurin, flight engineer, is visible in the background. Tyurin and Dezhurov represent Rosaviakosmos.

Orion Handling Qualities During ISS Proximity Operations and Docking

NASA Technical Reports Server (NTRS)

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

2011-01-01

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

STS-112 Flight Day 3 Highlights

NASA Technical Reports Server (NTRS)

2002-01-01

During the third flight day of STS-112 (Commander Jeff Ashby, Pilot Pam Melroy and Mission Specialists Sandy Magnus, Piers Sellers, David Wolf and Fyodor Yurchikhin), the Space Shuttle Atlantis begins its final approach to the International Space Station (ISS) with which it will dock. The Chinese mainland is seen, at night, at a height of 242 statute miles. In one section of video from a camera onboard the ISS, Atlantis can be seen to be almost directly below the station, at a distance of several hundred feet. The orbiter's docking system is shown, as it is slowly guided by Ashby towards the forward docking port on the ISS's Destiny Laboratory Module and its forward docking port. Above the docking port, the S0 truss structure can be seen, to which the S1 truss structure in Atlantis' payload bay will be attached during this mission. Also seen are the Unity airlock and other modules. Following the completion of docking, in which an excellent shot of the docking system in hard dock is visible, the hatches between the two crafts are opened and the members of Atlantis are greeted by the very excited members of Expedition 5, who have been aboard the ISS for several months.

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.

Tail docking in horses: a review of the issues.

PubMed

Lefebvre, D; Lips, D; Odberg, F O; Giffroy, J M

2007-09-01

Routinely performed painful procedures are of increasing interest and, in 2001 (Royal Order, May 17), Belgium prohibited docking in several vertebrates including horses. In 2004, opponents to this decision submitted a Bill (Doc51 0969/001) to Parliament, intending to obtain derogation for Belgian draught horses, which were traditionally docked. The Animal Welfare Council of Belgium, an official body advising the Minister of Public Health, was asked to evaluate this complex question, including biological, ethical and socio-economic aspects, on the basis of the available peer-reviewed studies. In this context, this study reviews legal aspects (overview of the European legislation), zootechnic aspects (uses of the Belgian draught horse) and biological aspects (pain potentially related to docking; horses' welfare linked to insect harassment and hygiene, communication and reproduction) of tail docking in draught horses. We conclude that (1) there is no benefit for horses in tail docking, including Belgian draught horses, (2) potential advantages of docking are essentially in favour of humans and these advantages could be scrupulously re-evaluated, taking into account practices of other countries. Therefore, there is no need to dock any horse other than for veterinary reasons.

HSYMDOCK: a docking web server for predicting the structure of protein homo-oligomers with Cn or Dn symmetry.

PubMed

Yan, Yumeng; Tao, Huanyu; Huang, Sheng-You

2018-05-26

A major subclass of protein-protein interactions is formed by homo-oligomers with certain symmetry. Therefore, computational modeling of the symmetric protein complexes is important for understanding the molecular mechanism of related biological processes. Although several symmetric docking algorithms have been developed for Cn symmetry, few docking servers have been proposed for Dn symmetry. Here, we present HSYMDOCK, a web server of our hierarchical symmetric docking algorithm that supports both Cn and Dn symmetry. The HSYMDOCK server was extensively evaluated on three benchmarks of symmetric protein complexes, including the 20 CASP11-CAPRI30 homo-oligomer targets, the symmetric docking benchmark of 213 Cn targets and 35 Dn targets, and a nonredundant test set of 55 transmembrane proteins. It was shown that HSYMDOCK obtained a significantly better performance than other similar docking algorithms. The server supports both sequence and structure inputs for the monomer/subunit. Users have an option to provide the symmetry type of the complex, or the server can predict the symmetry type automatically. The docking process is fast and on average consumes 10∼20 min for a docking job. The HSYMDOCK web server is available at http://huanglab.phys.hust.edu.cn/hsymdock/.

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.

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.

Molecular Docking Studies to Explore Potential Binding Pockets and Inhibitors for Chikungunya Virus Envelope Glycoproteins.

PubMed

Nguyen, Phuong T V; Yu, Haibo; Keller, Paul A

2017-03-11

The chikungunya virus (CHIKV) envelope glycoproteins are considered important potential targets for anti-CHIKV drug discovery due to their crucial roles in virus attachment and virus entry. In this study, using two available crystal structures of the immature and mature forms of envelope glycoproteins, virtual screenings based on blind dockings and focused dockings were carried out to identify potential binding pockets and hit compounds for the virus. The chemical library database of compounds, NCI Diversity Set II, was used in these docking studies. In addition to reproducing previously reported examples, new binding pockets were identified, e.g., Pocket 2 in the 3N40, and Pocket 2 and Pocket 3 in the 3N42. Convergences in conformational sampling in docking using AutoDock Vina were evaluated. An analysis of docking results was carried out to understand interactions of the envelope glycoproteins complexes. Some key residues for interactions, for example Gly91 and His230, are identified as possessing important roles in the fusion process.

Remote operation of an orbital maneuvering vehicle in simulated docking maneuvers

NASA Technical Reports Server (NTRS)

Brody, Adam R.

1990-01-01

Simulated docking maneuvers were performed to assess the effect of initial velocity on docking failure rate, mission duration, and delta v (fuel consumption). Subjects performed simulated docking maneuvers of an orbital maneuvering vehicle (OMV) to a space station. The effect of the removal of the range and rate displays (simulating a ranging instrumentation failure) was also examined. Naive subjects were capable of achieving a high success rate in performing simulated docking maneuvers without extensive training. Failure rate was a function of individual differences; there was no treatment effect on failure rate. The amount of time subjects reserved for final approach increased with starting velocity. Piloting of docking maneuvers was not significantly affected in any way by the removal of range and rate displays. Radial impulse was significant both by subject and by treatment. NASA's 0.1 percent rule, dictating an approach rate no greater than 0.1 percent of the range, is seen to be overly conservative for nominal docking missions.

ART CONCEPTS - ASTP

NASA Image and Video Library

1975-04-01

S75-27289 (May 1975) --- An artist?s concept depicting the American Apollo spacecraft docked with a Soviet Soyuz spacecraft in Earth orbit. During the joint U.S.-USSR Apollo-Soyuz Test Project mission, scheduled for July 1975, the American and Soviet crews will visit one another?s spacecraft while the Soyuz and Apollo are docked for a maximum period of two days. The mission is designed to test equipment and techniques that will establish international crew rescue capability in space, as well as permit future cooperative scientific missions. Each nation has developed separately docking systems based on a mutually agreeable single set of interface design specifications. The major new U.S. program elements are the docking module and docking system necessary to achieve compatibility of rendezvous and docking systems with the USSR-developed hardware to be used on the Soyuz spacecraft. The DM and docking system together with an Apollo Command/Service Module will be launched by a Saturn 1B launch vehicle. This artwork is by Paul Fjeld.

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.

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.

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/.

Developing a cross-docking network design model under uncertain environment

NASA Astrophysics Data System (ADS)

Seyedhoseini, S. M.; Rashid, Reza; Teimoury, E.

2015-06-01

Cross-docking is a logistic concept, which plays an important role in supply chain management by decreasing inventory holding, order packing, transportation costs and delivery time. Paying attention to these concerns, and importance of the congestion in cross docks, we present a mixed-integer model to optimize the location and design of cross docks at the same time to minimize the total transportation and operating costs. The model combines queuing theory for design aspects, for that matter, we consider a network of cross docks and customers where two M/M/c queues have been represented to describe operations of indoor trucks and outdoor trucks in each cross dock. To prepare a perfect illustration for performance of the model, a real case also has been examined that indicated effectiveness of the proposed model.

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

Cosmetic tail docking: an overview of abuse and report of an interesting case.

PubMed

Eyarefe, Oghenemega David; Oguntoye, Cecilia O

2016-02-29

This paper presents an overview of the global controversies surrounding cosmetic tail docking in puppies, some observed inconsistent practices among dog breeders and Veterinarians in West Africa, and the need for the African Veterinary Profession to take a decisive position on the cosmetic docking procedure. An interesting report of observed complications associated with cosmetic tail docking in a 3 week old male Boerboel is reported alongside the management of the ensuing complications. This paper highlights the still prevalent practice of cosmetic tail docking and seeks to enlighten clinicians towards stemming its abuse in Africa.

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 located in the extracellular domain of GLIC. The predicted affinities correlated significantly with the known EC(50) values for the 6 frequently used anesthetics in GLIC for the site identified in the experimental crystal data (P = 0.006). However, predicted affinities in apoferritin, human serum albumin, and cytochrome C did not correlate with these 6 anesthetics' known experimental EC(50) values. A weak correlation between the predicted affinities and the octanol/water partition coefficients was observed for the sites in GLIC. We demonstrated that anesthetic binding sites and relative affinities can be predicted using docking calculations in an automatic docking server (AutoDock) for both water-soluble and membrane proteins. Correlation of predicted affinity and EC(50) for 6 frequently used general anesthetics was only observed in GLIC, a member of a protein family relevant to anesthetic mechanism.

Analyses of the dynamic docking test system for advanced mission docking system test programs. [Apollo Soyuz Test Project

NASA Technical Reports Server (NTRS)

Gates, R. M.; Williams, J. E.

1974-01-01

Results are given of analytical studies performed in support of the design, implementation, checkout and use of NASA's dynamic docking test system (DDTS). Included are analyses of simulator components, a list of detailed operational test procedures, a summary of simulator performance, and an analysis and comparison of docking dynamics and loads obtained by test and analysis.

NASA Docking System (NDS) Interface Definitions Document (IDD)

NASA Technical Reports Server (NTRS)

Tabakman, Alexander; England, Warren

2013-01-01

The contents of this document define the integrated performance and interface design for NASA Docking System (NDS) Block 1 and the International Docking Adapter. The intent of this IDD is to provide the interface design for using, installing, and interfacing to the NDS Block 1 that will enable successful docking to the IDA. This document is under the control of the ISS Development Projects Office (OG).

Recovery of spinning satellites

NASA Technical Reports Server (NTRS)

Coppey, J. M.; Mahaffey, W. R.

1977-01-01

The behavior of a space tug and a spinning satellite in a coupled configuration was simulated and analyzed. A docking concept was developed to investigate the requirements pertaining to the design of a docking interface. Sensing techniques and control requirements for the chase vehicle were studied to assess the feasibility of an automatic docking. The effects of nutation dampers and liquid propellant slosh motion upon the docking transient were investigated.

Exploring the Stability of Ligand Binding Modes to Proteins by Molecular Dynamics Simulations: A Cross-docking Study.

PubMed

Liu, Kai; Kokubo, Hironori

2017-10-23

Docking has become an indispensable approach in drug discovery research to predict the binding mode of a ligand. One great challenge in docking is to efficiently refine the correct pose from various putative docking poses through scoring functions. We recently examined the stability of self-docking poses under molecular dynamics (MD) simulations and showed that equilibrium MD simulations have some capability to discriminate between correct and decoy poses. Here, we have extended our previous work to cross-docking studies for practical applications. Three target proteins (thrombin, heat shock protein 90-alpha, and cyclin-dependent kinase 2) of pharmaceutical interest were selected. Three comparable poses (one correct pose and two decoys) for each ligand were then selected from the docking poses. To obtain the docking poses for the three target proteins, we used three different protocols, namely: normal docking, induced fit docking (IFD), and IFD against the homology model. Finally, five parallel MD equilibrium runs were performed on each pose for the statistical analysis. The results showed that the correct poses were generally more stable than the decoy poses under MD. The discrimination capability of MD depends on the strategy. The safest way was to judge a pose as being stable if any one run among five parallel runs was stable under MD. In this case, 95% of the correct poses were retained under MD, and about 25-44% of the decoys could be excluded by the simulations for all cases. On the other hand, if we judge a pose as being stable when any two or three runs were stable, with the risk of incorrectly excluding some correct poses, approximately 31-53% or 39-56% of the two decoys could be excluded by MD, respectively. Our results suggest that simple equilibrium simulations can serve as an effective filter to exclude decoy poses that cannot be distinguished by docking scores from the computationally expensive free-energy calculations.

GeauxDock: Accelerating Structure-Based Virtual Screening with Heterogeneous Computing

PubMed Central

Fang, Ye; Ding, Yun; Feinstein, Wei P.; Koppelman, David M.; Moreno, Juana; Jarrell, Mark; Ramanujam, J.; Brylinski, Michal

2016-01-01

Computational modeling of drug binding to proteins is an integral component of direct drug design. Particularly, structure-based virtual screening is often used to perform large-scale modeling of putative associations between small organic molecules and their pharmacologically relevant protein targets. Because of a large number of drug candidates to be evaluated, an accurate and fast docking engine is a critical element of virtual screening. Consequently, highly optimized docking codes are of paramount importance for the effectiveness of virtual screening methods. In this communication, we describe the implementation, tuning and performance characteristics of GeauxDock, a recently developed molecular docking program. GeauxDock is built upon the Monte Carlo algorithm and features a novel scoring function combining physics-based energy terms with statistical and knowledge-based potentials. Developed specifically for heterogeneous computing platforms, the current version of GeauxDock can be deployed on modern, multi-core Central Processing Units (CPUs) as well as massively parallel accelerators, Intel Xeon Phi and NVIDIA Graphics Processing Unit (GPU). First, we carried out a thorough performance tuning of the high-level framework and the docking kernel to produce a fast serial code, which was then ported to shared-memory multi-core CPUs yielding a near-ideal scaling. Further, using Xeon Phi gives 1.9× performance improvement over a dual 10-core Xeon CPU, whereas the best GPU accelerator, GeForce GTX 980, achieves a speedup as high as 3.5×. On that account, GeauxDock can take advantage of modern heterogeneous architectures to considerably accelerate structure-based virtual screening applications. GeauxDock is open-sourced and publicly available at www.brylinski.org/geauxdock and https://figshare.com/articles/geauxdock_tar_gz/3205249. PMID:27420300

A scalable and accurate method for classifying protein-ligand binding geometries using a MapReduce approach.

PubMed

Estrada, T; Zhang, B; Cicotti, P; Armen, R S; Taufer, M

2012-07-01

We present a scalable and accurate method for classifying protein-ligand binding geometries in molecular docking. Our method is a three-step process: the first step encodes the geometry of a three-dimensional (3D) ligand conformation into a single 3D point in the space; the second step builds an octree by assigning an octant identifier to every single point in the space under consideration; and the third step performs an octree-based clustering on the reduced conformation space and identifies the most dense octant. We adapt our method for MapReduce and implement it in Hadoop. The load-balancing, fault-tolerance, and scalability in MapReduce allow screening of very large conformation spaces not approachable with traditional clustering methods. We analyze results for docking trials for 23 protein-ligand complexes for HIV protease, 21 protein-ligand complexes for Trypsin, and 12 protein-ligand complexes for P38alpha kinase. We also analyze cross docking trials for 24 ligands, each docking into 24 protein conformations of the HIV protease, and receptor ensemble docking trials for 24 ligands, each docking in a pool of HIV protease receptors. Our method demonstrates significant improvement over energy-only scoring for the accurate identification of native ligand geometries in all these docking assessments. The advantages of our clustering approach make it attractive for complex applications in real-world drug design efforts. We demonstrate that our method is particularly useful for clustering docking results using a minimal ensemble of representative protein conformational states (receptor ensemble docking), which is now a common strategy to address protein flexibility in molecular docking. Copyright © 2012 Elsevier Ltd. All rights reserved.

DOVIS 2.0: an efficient and easy to use parallel virtual screening tool based on AutoDock 4.0.

PubMed

Jiang, Xiaohui; Kumar, Kamal; Hu, Xin; Wallqvist, Anders; Reifman, Jaques

2008-09-08

Small-molecule docking is an important tool in studying receptor-ligand interactions and in identifying potential drug candidates. Previously, we developed a software tool (DOVIS) to perform large-scale virtual screening of small molecules in parallel on Linux clusters, using AutoDock 3.05 as the docking engine. DOVIS enables the seamless screening of millions of compounds on high-performance computing platforms. In this paper, we report significant advances in the software implementation of DOVIS 2.0, including enhanced screening capability, improved file system efficiency, and extended usability. To keep DOVIS up-to-date, we upgraded the software's docking engine to the more accurate AutoDock 4.0 code. We developed a new parallelization scheme to improve runtime efficiency and modified the AutoDock code to reduce excessive file operations during large-scale virtual screening jobs. We also implemented an algorithm to output docked ligands in an industry standard format, sd-file format, which can be easily interfaced with other modeling programs. Finally, we constructed a wrapper-script interface to enable automatic rescoring of docked ligands by arbitrarily selected third-party scoring programs. The significance of the new DOVIS 2.0 software compared with the previous version lies in its improved performance and usability. The new version makes the computation highly efficient by automating load balancing, significantly reducing excessive file operations by more than 95%, providing outputs that conform to industry standard sd-file format, and providing a general wrapper-script interface for rescoring of docked ligands. The new DOVIS 2.0 package is freely available to the public under the GNU General Public License.

Automated docking of ligands to an artificial active site: augmenting crystallographic analysis with computer modeling

NASA Astrophysics Data System (ADS)

Rosenfeld, Robin J.; Goodsell, David S.; Musah, Rabi A.; Morris, Garrett M.; Goodin, David B.; Olson, Arthur J.

2003-08-01

The W191G cavity of cytochrome c peroxidase is useful as a model system for introducing small molecule oxidation in an artificially created cavity. A set of small, cyclic, organic cations was previously shown to bind in the buried, solvent-filled pocket created by the W191G mutation. We docked these ligands and a set of non-binders in the W191G cavity using AutoDock 3.0. For the ligands, we compared docking predictions with experimentally determined binding energies and X-ray crystal structure complexes. For the ligands, predicted binding energies differed from measured values by ± 0.8 kcal/mol. For most ligands, the docking simulation clearly predicted a single binding mode that matched the crystallographic binding mode within 1.0 Å RMSD. For 2 ligands, where the docking procedure yielded an ambiguous result, solutions matching the crystallographic result could be obtained by including an additional crystallographically observed water molecule in the protein model. For the remaining 2 ligands, docking indicated multiple binding modes, consistent with the original electron density, suggesting disordered binding of these ligands. Visual inspection of the atomic affinity grid maps used in docking calculations revealed two patches of high affinity for hydrogen bond donating groups. Multiple solutions are predicted as these two sites compete for polar hydrogens in the ligand during the docking simulation. Ligands could be distinguished, to some extent, from non-binders using a combination of two trends: predicted binding energy and level of clustering. In summary, AutoDock 3.0 appears to be useful in predicting key structural and energetic features of ligand binding in the W191G cavity.

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.

GeauxDock: Accelerating Structure-Based Virtual Screening with Heterogeneous Computing.

PubMed

Fang, Ye; Ding, Yun; Feinstein, Wei P; Koppelman, David M; Moreno, Juana; Jarrell, Mark; Ramanujam, J; Brylinski, Michal

2016-01-01

Computational modeling of drug binding to proteins is an integral component of direct drug design. Particularly, structure-based virtual screening is often used to perform large-scale modeling of putative associations between small organic molecules and their pharmacologically relevant protein targets. Because of a large number of drug candidates to be evaluated, an accurate and fast docking engine is a critical element of virtual screening. Consequently, highly optimized docking codes are of paramount importance for the effectiveness of virtual screening methods. In this communication, we describe the implementation, tuning and performance characteristics of GeauxDock, a recently developed molecular docking program. GeauxDock is built upon the Monte Carlo algorithm and features a novel scoring function combining physics-based energy terms with statistical and knowledge-based potentials. Developed specifically for heterogeneous computing platforms, the current version of GeauxDock can be deployed on modern, multi-core Central Processing Units (CPUs) as well as massively parallel accelerators, Intel Xeon Phi and NVIDIA Graphics Processing Unit (GPU). First, we carried out a thorough performance tuning of the high-level framework and the docking kernel to produce a fast serial code, which was then ported to shared-memory multi-core CPUs yielding a near-ideal scaling. Further, using Xeon Phi gives 1.9× performance improvement over a dual 10-core Xeon CPU, whereas the best GPU accelerator, GeForce GTX 980, achieves a speedup as high as 3.5×. On that account, GeauxDock can take advantage of modern heterogeneous architectures to considerably accelerate structure-based virtual screening applications. GeauxDock is open-sourced and publicly available at www.brylinski.org/geauxdock and https://figshare.com/articles/geauxdock_tar_gz/3205249.

DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity

PubMed Central

Zhang, Qian; Dove, Christopher G.; Hor, Jyh Liang; Murdock, Heardley M.; Strauss-Albee, Dara M.; Garcia, Jordan A.; Mandl, Judith N.; Grodick, Rachael A.; Jing, Huie; Chandler-Brown, Devon B.; Lenardo, Timothy E.; Crawford, Greg; Matthews, Helen F.; Freeman, Alexandra F.; Cornall, Richard J.; Germain, Ronald N.

2014-01-01

DOCK8 mutations result in an inherited combined immunodeficiency characterized by increased susceptibility to skin and other infections. We show that when DOCK8-deficient T and NK cells migrate through confined spaces, they develop cell shape and nuclear deformation abnormalities that do not impair chemotaxis but contribute to a distinct form of catastrophic cell death we term cytothripsis. Such defects arise during lymphocyte migration in collagen-dense tissues when DOCK8, through CDC42 and p21-activated kinase (PAK), is unavailable to coordinate cytoskeletal structures. Cytothripsis of DOCK8-deficient cells prevents the generation of long-lived skin-resident memory CD8 T cells, which in turn impairs control of herpesvirus skin infections. Our results establish that DOCK8-regulated shape integrity of lymphocytes prevents cytothripsis and promotes antiviral immunity in the skin. PMID:25422492

Mapping multiple potential ATP binding sites on the matrix side of the bovine ADP/ATP carrier by the combined use of MD simulation and docking.

PubMed

Di Marino, Daniele; Oteri, Francesco; della Rocca, Blasco Morozzo; D'Annessa, Ilda; Falconi, Mattia

2012-06-01

The mitochondrial adenosine diphosphate/adenosine triphosphate (ADP/ATP) carrier-AAC-was crystallized in complex with its specific inhibitor carboxyatractyloside (CATR). The protein consists of a six-transmembrane helix bundle that defines the nucleotide translocation pathway, which is closed towards the matrix side due to sharp kinks in the odd-numbered helices. In this paper, we describe the interaction between the matrix side of the AAC transporter and the ATP(4-) molecule using carrier structures obtained through classical molecular dynamics simulation (MD) and a protein-ligand docking procedure. Fifteen structures were extracted from a previously published MD trajectory through clustering analysis, and 50 docking runs were carried out for each carrier conformation, for a total of 750 runs ("MD docking"). The results were compared to those from 750 docking runs performed on the X-ray structure ("X docking"). The docking procedure indicated the presence of a single interaction site in the X-ray structure that was conserved in the structures extracted from the MD trajectory. MD docking showed the presence of a second binding site that was not found in the X docking. The interaction strategy between the AAC transporter and the ATP(4-) molecule was analyzed by investigating the composition and 3D arrangement of the interaction pockets, together with the orientations of the substrate inside them. A relationship between sequence repeats and the ATP(4-) binding sites in the AAC carrier structure is proposed.

Potential interaction of natural dietary bioactive compounds with COX-2.

PubMed

Maldonado-Rojas, Wilson; Olivero-Verbel, Jesus

2011-09-01

Bioactive natural products present in the diet play an important role in several biological processes, and many have been involved in the alleviation and control of inflammation-related diseases. These actions have been linked to both gene expression modulation of pro-inflammatory enzymes, such as cyclooxygenase 2 (COX-2), and to an action involving a direct inhibitory binding on this protein. In this study, several food-related compounds with known gene regulatory action on inflammation have been examined in silico as COX-2 ligands, utilizing AutoDock Vina, GOLD and Surflex-Dock (SYBYL) as docking protocols. Curcumin and all-trans retinoic acid presented the maximum absolute AutoDock Vina-derived binding affinities (9.3 kcal/mol), but genistein, apigenin, cyanidin, kaempferol, and docosahexaenoic acid, were close to this value. AutoDock Vina affinities and GOLD scores for several known COX-2 inhibitors significatively correlated with reported median inhibitory concentrations (R² = 0.462, P < 0.001 and R² = 0.238, P = 0.029, respectively), supporting the computational reliability of the predictions made by our docking simulations. Moreover, docking analysis insinuate the synergistic action of curcumin on celecoxib-induced inhibition of COX-2 may occur allosterically, as this natural compound docks to a place different from the inhibitor binding site. These results suggest that the anti-inflammatory properties of some food-derived molecules could be the result of their direct binding capabilities to COX-2, and this process can be modeled using protein-ligand docking methodologies. Copyright © 2011 Elsevier Inc. All rights reserved.

SpaceDock: A Performance Task Platform for Spaceflight Operations

NASA Technical Reports Server (NTRS)

Marshburn, Thomas H.; Strangman, Gary E.; Strauss, Monica S.; Sutton, Jeffrey P.

2003-01-01

Preliminary evidence during both short- and long-duration spaceflight indicates that perceptual-motor coordination changes occur and persist in-flight. However, there is presently no in-flight method for evaluating astronaut performance on mission-critical tasks such as docking. We present a portable platform we have developed for attempting and evaluating docking, and describe the results of a pilot study wherein flight novices learned the docking task. Methods: A dual-joystick, six degrees of freedom platform-called SpaceDock-was developed to enable portable, adaptable performance testing in a spaceflight operations setting. Upon this platform, a simplified docking task was created, involving a constant rate of approach towards a docking target and requiring the user to correct translation in two dimensions and attitude orientation along one dimension (either pitch or roll). Ten flight naive subjects performed the task over a 45 min period and all joystick inputs and timings were collected, from which we could successfully reconstruct travel paths, input profiles and relative target displacements. Results: Subjects exhibited significant improvements in docking over the course of the experiment. Learning to compensate for roll-alterations was robust, whereas compensation for pitch-alterations was not in evidence in this population and relatively short training period. Conclusion: The SpaceDock platform can provide a novel method for training and testing subjects, on a spaceflight-relevant task, and can be used to examine behavioral learning, strategy use, and has been adapted for use in brain imaging experiments.

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

SDU: A Semidefinite Programming-Based Underestimation Method for Stochastic Global Optimization in Protein Docking

DTIC Science & Technology

2007-04-01

optimization methodology we introduce. State-of-the-art protein - protein docking approaches start by identifying conformations with good surface /chemical com...side-chains on the interface ). The protein - protein docking literature (e.g., [8] and the references therein) is predominantly treating the docking...mations by various measures of surface complementarity which can be efficiently computed using fast Fourier correlation tech- niques (FFTs). However, when

Surfing the Protein-Protein Interaction Surface Using Docking Methods: Application to the Design of PPI Inhibitors.

PubMed

Sable, Rushikesh; Jois, Seetharama

2015-06-23

Blocking protein-protein interactions (PPI) using small molecules or peptides modulates biochemical pathways and has therapeutic significance. PPI inhibition for designing drug-like molecules is a new area that has been explored extensively during the last decade. Considering the number of available PPI inhibitor databases and the limited number of 3D structures available for proteins, docking and scoring methods play a major role in designing PPI inhibitors as well as stabilizers. Docking methods are used in the design of PPI inhibitors at several stages of finding a lead compound, including modeling the protein complex, screening for hot spots on the protein-protein interaction interface and screening small molecules or peptides that bind to the PPI interface. There are three major challenges to the use of docking on the relatively flat surfaces of PPI. In this review we will provide some examples of the use of docking in PPI inhibitor design as well as its limitations. The combination of experimental and docking methods with improved scoring function has thus far resulted in few success stories of PPI inhibitors for therapeutic purposes. Docking algorithms used for PPI are in the early stages, however, and as more data are available docking will become a highly promising area in the design of PPI inhibitors or stabilizers.

In-Silico Analysis of Amotosalen Hydrochloride Binding to CD-61 of Platelets.

PubMed

Chaudhary, Hammad Tufail

2016-11-01

To determine the docking of Amotosalen hydrochloride (AH) at CD-61 of platelets, and to suggest the cause of bleeding in AH treated platelets transfusion. Descriptive study. Medical College, Taif University, Taif, Saudi Arabia, from October 2014 to May 2015. The study was carried out in-silico. PDB (protein data bank) code of Tirofiban bound to CD-61 was 2vdm. CD-61 was docked with Tirofiban using online docking tools, i.e. Patchdock and Firedock. Then, Amotosalen hydrochloride and CD-61 were also docked. Best docking poses to active sites of 2vdm were found. Ligplot of interactions of ligands and CD-61 were obtained. Then comparison of hydrogen bonds, hydrogen bond lengths, and hydrophobic bonds of 2vdm molecule and best poses of docking results were done. Patchdock and Firedock results of best poses were also analysed using SPSS version 16. More amino acids were involved in hydrogen and hydrophobic bonds in Patchdock and Firedock docking of Amotosalen hydrochloride with CD-61 than Patchdock and Firedock docking of CD-61 with Tirofiban. The binding energy was more in latter than former. Amotosalen hydrochloride binds to the active site of CD-61 with weaker binding force. Haemorrhage seen in Amotosalen hydrochloride-treated platelets might be due to binding of Amotosalen hydrochloride to CD-61.

Kinetics of DNA-mediated docking reactions between vesicles tethered to supported lipid bilayers

PubMed Central

Chan, Yee-Hung M.; Lenz, Peter; Boxer, Steven G.

2007-01-01

Membrane–membrane recognition and binding are crucial in many biological processes. We report an approach to studying the dynamics of such reactions by using DNA-tethered vesicles as a general scaffold for displaying membrane components. This system was used to characterize the docking reaction between two populations of tethered vesicles that display complementary DNA. Deposition of vesicles onto a supported lipid bilayer was performed by using a microfluidic device to prevent mixing of the vesicles in bulk during sample preparation. Once tethered onto the surface, vesicles mixed via two-dimensional diffusion. DNA-mediated docking of two reacting vesicles results in their colocalization after collision and their subsequent tandem motion. Individual docking events and population kinetics were observed via epifluorescence microscopy. A lattice-diffusion simulation was implemented to extract from experimental data the probability, Pdock, that a collision leads to docking. For individual vesicles displaying small numbers of docking DNA, Pdock shows a first-order relationship with copy number as well as a strong dependence on the DNA sequence. Both trends are explained by a model that includes both tethered vesicle diffusion on the supported bilayer and docking DNA diffusion over each vesicle's surface. These results provide the basis for the application of tethered vesicles to study other membrane reactions including protein-mediated docking and fusion. PMID:18025472

DOVIS: an implementation for high-throughput virtual screening using AutoDock.

PubMed

Zhang, Shuxing; Kumar, Kamal; Jiang, Xiaohui; Wallqvist, Anders; Reifman, Jaques

2008-02-27

Molecular-docking-based virtual screening is an important tool in drug discovery that is used to significantly reduce the number of possible chemical compounds to be investigated. In addition to the selection of a sound docking strategy with appropriate scoring functions, another technical challenge is to in silico screen millions of compounds in a reasonable time. To meet this challenge, it is necessary to use high performance computing (HPC) platforms and techniques. However, the development of an integrated HPC system that makes efficient use of its elements is not trivial. We have developed an application termed DOVIS that uses AutoDock (version 3) as the docking engine and runs in parallel on a Linux cluster. DOVIS can efficiently dock large numbers (millions) of small molecules (ligands) to a receptor, screening 500 to 1,000 compounds per processor per day. Furthermore, in DOVIS, the docking session is fully integrated and automated in that the inputs are specified via a graphical user interface, the calculations are fully integrated with a Linux cluster queuing system for parallel processing, and the results can be visualized and queried. DOVIS removes most of the complexities and organizational problems associated with large-scale high-throughput virtual screening, and provides a convenient and efficient solution for AutoDock users to use this software in a Linux cluster platform.

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.

PaFlexPepDock: parallel ab-initio docking of peptides onto their receptors with full flexibility based on Rosetta.

PubMed

Li, Haiou; Lu, Liyao; Chen, Rong; Quan, Lijun; Xia, Xiaoyan; Lü, Qiang

2014-01-01

Structural information related to protein-peptide complexes can be very useful for novel drug discovery and design. The computational docking of protein and peptide can supplement the structural information available on protein-peptide interactions explored by experimental ways. Protein-peptide docking of this paper can be described as three processes that occur in parallel: ab-initio peptide folding, peptide docking with its receptor, and refinement of some flexible areas of the receptor as the peptide is approaching. Several existing methods have been used to sample the degrees of freedom in the three processes, which are usually triggered in an organized sequential scheme. In this paper, we proposed a parallel approach that combines all the three processes during the docking of a folding peptide with a flexible receptor. This approach mimics the actual protein-peptide docking process in parallel way, and is expected to deliver better performance than sequential approaches. We used 22 unbound protein-peptide docking examples to evaluate our method. Our analysis of the results showed that the explicit refinement of the flexible areas of the receptor facilitated more accurate modeling of the interfaces of the complexes, while combining all of the moves in parallel helped the constructing of energy funnels for predictions.

Predicting the Accuracy of Protein–Ligand Docking on Homology Models

PubMed Central

BORDOGNA, ANNALISA; PANDINI, ALESSANDRO; BONATI, LAURA

2011-01-01

Ligand–protein docking is increasingly used in Drug Discovery. The initial limitations imposed by a reduced availability of target protein structures have been overcome by the use of theoretical models, especially those derived by homology modeling techniques. While this greatly extended the use of docking simulations, it also introduced the need for general and robust criteria to estimate the reliability of docking results given the model quality. To this end, a large-scale experiment was performed on a diverse set including experimental structures and homology models for a group of representative ligand–protein complexes. A wide spectrum of model quality was sampled using templates at different evolutionary distances and different strategies for target–template alignment and modeling. The obtained models were scored by a selection of the most used model quality indices. The binding geometries were generated using AutoDock, one of the most common docking programs. An important result of this study is that indeed quantitative and robust correlations exist between the accuracy of docking results and the model quality, especially in the binding site. Moreover, state-of-the-art indices for model quality assessment are already an effective tool for an a priori prediction of the accuracy of docking experiments in the context of groups of proteins with conserved structural characteristics. PMID:20607693

Evaluation of the respiratory health of dock workers who load grain cargoes in British Columbia.

PubMed Central

Dimich-Ward, H D; Kennedy, S M; Dittrick, M A; DyBuncio, A; Chan-Yeung, M

1995-01-01

OBJECTIVES--To investigate the respiratory health of dock workers who load grain cargoes. METHODS--The respiratory health of 118 dock workers who load grain cargoes in the ports of Vancouver and Prince Rupert was compared with that of 555 grain elevator workers from the same regions. 128 civic workers were used as an unexposed control group. RESULTS--The prevalences of chronic cough and phlegm were at least as high in dock workers as those found in the elevator workers, and when adjusted for differences in duration of employment and smoking, dock workers had an eightfold higher risk of developing chronic phlegm than did civic workers. Symptoms of eye and skin irritation that were experienced at least monthly were highest for dock workers. Average percentage of the predicted FEV1 and FVC for dock workers (mean 100.6% and 105.3% respectively) were similar to the civic workers but significantly higher than those found for elevator workers. Higher subjective estimates of duration of exposure to grain dust (hours/day) were associated with lower values of FEV1. CONCLUSIONS--The more intermittent grain dust exposure patterns of dock workers may have allowed for some recovery of lung function, but chronic respiratory symptoms were less labile. PMID:7795744

Computational study concerning the effect of some pesticides on the Proteus Mirabilis catalase activity

NASA Astrophysics Data System (ADS)

Isvoran, Adriana

2016-03-01

Assessment of the effects of the herbicides nicosulfuron and chlorsulfuron and the fungicides difenoconazole and drazoxlone upon catalase produced by soil microorganism Proteus mirabilis is performed using the molecular docking technique. The interactions of pesticides with the enzymes are predicted using SwissDock and PatchDock docking tools. There are correlations for predicted binding energy values for enzyme-pesticide complexes obtained using the two docking tools, all the considered pesticides revealing favorable binding to the enzyme, but only the herbicides bind to the catalytic site. These results suggest the inhibitory potential of chlorsulfuron and nicosulfuron on the catalase activity in soil.

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.

2. Substructure of the main dock, looking south beneath the ...

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

2. Substructure of the main dock, looking south beneath the Hay and Grain Warehouse. Original log pilings have been encased in concrete. - Curtis Wharf, Main Dock, O & Second Streets, Anacortes, Skagit County, WA

2. General oblique view of north loading dock showing loading ...

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

2. General oblique view of north loading dock showing loading docks with doors opening into refrigerated rooms - Fort Hood, World War II Temporary Buildings, Cold Storage Building, Seventeenth Street, Killeen, Bell County, TX

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

Apollo Soyuz, mission evaluation report

NASA Technical Reports Server (NTRS)

1975-01-01

The Apollo Soyuz mission was the first manned space flight to be conducted jointly by two nations - the United States and the Union of Soviet Socialist Republics. The primary purpose of the mission was to test systems for rendezvous and docking of manned spacecraft that would be suitable for use as a standard international system, and to demonstrate crew transfer between spacecraft. The secondary purpose was to conduct a program of scientific and applications experimentation. With minor modifications, the Apollo and Soyuz spacecraft were like those flown on previous missions. However, a new module was built specifically for this mission - the docking module. It served as an airlock for crew transfer and as a structural base for the docking mechanism that interfaced with a similar mechanism on the Soyuz orbital module. The postflight evaluation of the performance of the docking system and docking module, as well as the overall performance of the Apollo spacecraft and experiments is presented. In addition, the mission is evaluated from the viewpoints of the flight crew, ground support operations, and biomedical operations. Descriptions of the docking mechanism, docking module, crew equipment and experiment hardware are given.

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.

The use of docking-based comparative intermolecular contacts analysis to identify optimal docking conditions within glucokinase and to discover of new GK activators

NASA Astrophysics Data System (ADS)

Taha, Mutasem O.; Habash, Maha; Khanfar, Mohammad A.

2014-05-01

Glucokinase (GK) is involved in normal glucose homeostasis and therefore it is a valid target for drug design and discovery efforts. GK activators (GKAs) have excellent potential as treatments of hyperglycemia and diabetes. The combined recent interest in GKAs, together with docking limitations and shortages of docking validation methods prompted us to use our new 3D-QSAR analysis, namely, docking-based comparative intermolecular contacts analysis (dbCICA), to validate docking configurations performed on a group of GKAs within GK binding site. dbCICA assesses the consistency of docking by assessing the correlation between ligands' affinities and their contacts with binding site spots. Optimal dbCICA models were validated by receiver operating characteristic curve analysis and comparative molecular field analysis. dbCICA models were also converted into valid pharmacophores that were used as search queries to mine 3D structural databases for new GKAs. The search yielded several potent bioactivators that experimentally increased GK bioactivity up to 7.5-folds at 10 μM.

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 .

Fragment-Based Docking: Development of the CHARMMing Web User Interface as a Platform for Computer-Aided Drug Design

PubMed Central

2015-01-01

Web-based user interfaces to scientific applications are important tools that allow researchers to utilize a broad range of software packages with just an Internet connection and a browser.1 One such interface, CHARMMing (CHARMM interface and graphics), facilitates access to the powerful and widely used molecular software package CHARMM. CHARMMing incorporates tasks such as molecular structure analysis, dynamics, multiscale modeling, and other techniques commonly used by computational life scientists. We have extended CHARMMing’s capabilities to include a fragment-based docking protocol that allows users to perform molecular docking and virtual screening calculations either directly via the CHARMMing Web server or on computing resources using the self-contained job scripts generated via the Web interface. The docking protocol was evaluated by performing a series of “re-dockings” with direct comparison to top commercial docking software. Results of this evaluation showed that CHARMMing’s docking implementation is comparable to many widely used software packages and validates the use of the new CHARMM generalized force field for docking and virtual screening. PMID:25151852

An Elmo–Dock complex locally controls Rho GTPases and actin remodeling during cadherin-mediated adhesion

PubMed Central

Collins, Caitlin

2014-01-01

Cell–cell contact formation is a dynamic process requiring the coordination of cadherin-based cell–cell adhesion and integrin-based cell migration. A genome-wide RNA interference screen for proteins required specifically for cadherin-dependent cell–cell adhesion identified an Elmo–Dock complex. This was unexpected as Elmo–Dock complexes act downstream of integrin signaling as Rac guanine-nucleotide exchange factors. In this paper, we show that Elmo2 recruits Dock1 to initial cell–cell contacts in Madin–Darby canine kidney cells. At cell–cell contacts, both Elmo2 and Dock1 are essential for the rapid recruitment and spreading of E-cadherin, actin reorganization, localized Rac and Rho GTPase activities, and the development of strong cell–cell adhesion. Upon completion of cell–cell adhesion, Elmo2 and Dock1 no longer localize to cell–cell contacts and are not required subsequently for the maintenance of cell–cell adhesion. These studies show that Elmo–Dock complexes are involved in both integrin- and cadherin-based adhesions, which may help to coordinate the transition of cells from migration to strong cell–cell adhesion. PMID:25452388

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

20. VIEW OF EAST END OF SPERRY OCEAN DOCK, SHOWING ...

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

20. VIEW OF EAST END OF SPERRY OCEAN DOCK, SHOWING SOUTH AND EAST ELEVATION, INCLUDING PORTION OF THE SPERRY OCEAN DOCK DECK, LOOKING NORTH - Puget Sound Flouring Mills, 611 Schuster Parkway, Tacoma, Pierce County, WA

Artist's concept of scene in Earth orbit during transposition and docking

NASA Technical Reports Server (NTRS)

1975-01-01

An artist's concept depicting a scene in Earth orbit during the Apollo transposition and docking maneuvers of the Apollo Soyuz Test Project (ASTP) mission. The Command/Service Module is moving into position to dock with the Docking Module. This scene will take place some one hour and twenty-three minutes after the Apollo-Saturn 1B liftoff from the Kennedy Space Center on July 15, 1975. The artwork is by Paul Fjeld.

View of the Pirs Docking Compartment approaching the ISS during Expedition Three

NASA Image and Video Library

2001-09-17

ISS003-E-5620 (16 September 2001) --- The Russian Docking Compartment, named Pirs (the Russian word for pier), is only seconds away from docking with the International Space Station (ISS). One of the Expedition Three crew members, using a digital still camera with a 35mm lens, recorded the image from onboard the orbital outpost. The vehicle was launched on September 14, 2001 and docking occurred on September 16.

Engineering principles to assure compatible docking between future spacecraft of USA and USSR

NASA Technical Reports Server (NTRS)

Johnson, C. C.

1975-01-01

Working jointly the USA and the USSR have selected an androgynous, peripheral type docking mechanism concept. The mechanical principles inherent to the concept, the rationale supporting its selection, and the probable nature of future designs stemming from the concept, are described. Operational situations just prior to docking, impact conditions, energy absorption, and the structural joining of the spacecraft, are specified. Docking procedures for the Apollo-Soyuz missions are discussed.

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.

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.

A High Performance Cloud-Based Protein-Ligand Docking Prediction Algorithm

PubMed Central

Chen, Jui-Le; Yang, Chu-Sing

2013-01-01

The potential of predicting druggability for a particular disease by integrating biological and computer science technologies has witnessed success in recent years. Although the computer science technologies can be used to reduce the costs of the pharmaceutical research, the computation time of the structure-based protein-ligand docking prediction is still unsatisfied until now. Hence, in this paper, a novel docking prediction algorithm, named fast cloud-based protein-ligand docking prediction algorithm (FCPLDPA), is presented to accelerate the docking prediction algorithm. The proposed algorithm works by leveraging two high-performance operators: (1) the novel migration (information exchange) operator is designed specially for cloud-based environments to reduce the computation time; (2) the efficient operator is aimed at filtering out the worst search directions. Our simulation results illustrate that the proposed method outperforms the other docking algorithms compared in this paper in terms of both the computation time and the quality of the end result. PMID:23762864

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

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.

Russian RSC Energia employees inspect DM in SSPF

NASA Technical Reports Server (NTRS)

1995-01-01

Employees of the Russian aerospace company RSC Energia prepare to conduct final inspections of the Russian-built Docking Module in the Space Station Processing Facility at KSC. 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.

Russian RSC Energia employees attach trunnions to DM

NASA Technical Reports Server (NTRS)

1995-01-01

Employees of the Russian aerospace company RSC Energia attach trunnions to the Russian-built docking module in the Space Station Processing Facility at KSC so that it can be mounted in the payload bay of the Space Shuttle orbiter Atlantis. 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.

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 to allow developers to independently design compatible docking systems. The IDSS is intended for uses ranging from crewed to autonomous space vehicles, and from Low Earth Orbit (LEO) to deep-space exploration missions.The purpose of the IDSS IDD is to provide basic common design parameters to allow developers to independently design compatible docking systems. The IDSS is intended for uses ranging from crewed to autonomous space vehicles, and from Low Earth Orbit (LEO) to deep-space exploration missions. The purpose of the IDSS IDD is to provide basic common design parameters to allow developers to independently design compatible docking systems. The IDSS is intended for uses ranging from crewed to autonomous space vehicles, and from Low Earth Orbit (LEO) to deep-space exploration missions.

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 extracellular domain of GLIC. The predicted affinities correlated significantly with the known EC50s for the six commonly used anesthetics in GLIC for the site identified in the experimental crystal data (p=0.006). However, predicted affinities in apoferritin, human serum albumin, and cytochrome C did not correlate with these six anesthetics’ known experimental EC50s. A weak correlation between the predicted affinities and the octanol/water partition coefficients was observed for the sites in GLIC. Conclusion We demonstrated that anesthetic binding sites and relative affinities can be predicted using docking calculations in an automatic docking server (Autodock) for both water soluble and membrane proteins. Correlation of predicted affinity and EC50 for six commonly used general anesthetics was only observed in GLIC, a member of a protein family relevant to anesthetic mechanism. PMID:22392968

An Evaluation of Explicit Receptor Flexibility in Molecular Docking Using Molecular Dynamics and Torsion Angle Molecular Dynamics.

PubMed

Armen, Roger S; Chen, Jianhan; Brooks, Charles L

2009-10-13

Incorporating receptor flexibility into molecular docking should improve results for flexible proteins. However, the incorporation of explicit all-atom flexibility with molecular dynamics for the entire protein chain may also introduce significant error and "noise" that could decrease docking accuracy and deteriorate the ability of a scoring function to rank native-like poses. We address this apparent paradox by comparing the success of several flexible receptor models in cross-docking and multiple receptor ensemble docking for p38α mitogen-activated protein (MAP) kinase. Explicit all-atom receptor flexibility has been incorporated into a CHARMM-based molecular docking method (CDOCKER) using both molecular dynamics (MD) and torsion angle molecular dynamics (TAMD) for the refinement of predicted protein-ligand binding geometries. These flexible receptor models have been evaluated, and the accuracy and efficiency of TAMD sampling is directly compared to MD sampling. Several flexible receptor models are compared, encompassing flexible side chains, flexible loops, multiple flexible backbone segments, and treatment of the entire chain as flexible. We find that although including side chain and some backbone flexibility is required for improved docking accuracy as expected, docking accuracy also diminishes as additional and unnecessary receptor flexibility is included into the conformational search space. Ensemble docking results demonstrate that including protein flexibility leads to to improved agreement with binding data for 227 active compounds. This comparison also demonstrates that a flexible receptor model enriches high affinity compound identification without significantly increasing the number of false positives from low affinity compounds.

An Evaluation of Explicit Receptor Flexibility in Molecular Docking Using Molecular Dynamics and Torsion Angle Molecular Dynamics

PubMed Central

Armen, Roger S.; Chen, Jianhan; Brooks, Charles L.

2009-01-01

Incorporating receptor flexibility into molecular docking should improve results for flexible proteins. However, the incorporation of explicit all-atom flexibility with molecular dynamics for the entire protein chain may also introduce significant error and “noise” that could decrease docking accuracy and deteriorate the ability of a scoring function to rank native-like poses. We address this apparent paradox by comparing the success of several flexible receptor models in cross-docking and multiple receptor ensemble docking for p38α mitogen-activated protein (MAP) kinase. Explicit all-atom receptor flexibility has been incorporated into a CHARMM-based molecular docking method (CDOCKER) using both molecular dynamics (MD) and torsion angle molecular dynamics (TAMD) for the refinement of predicted protein-ligand binding geometries. These flexible receptor models have been evaluated, and the accuracy and efficiency of TAMD sampling is directly compared to MD sampling. Several flexible receptor models are compared, encompassing flexible side chains, flexible loops, multiple flexible backbone segments, and treatment of the entire chain as flexible. We find that although including side chain and some backbone flexibility is required for improved docking accuracy as expected, docking accuracy also diminishes as additional and unnecessary receptor flexibility is included into the conformational search space. Ensemble docking results demonstrate that including protein flexibility leads to to improved agreement with binding data for 227 active compounds. This comparison also demonstrates that a flexible receptor model enriches high affinity compound identification without significantly increasing the number of false positives from low affinity compounds. PMID:20160879

Template-based protein-protein docking exploiting pairwise interfacial residue restraints.

PubMed

Xue, Li C; Rodrigues, João P G L M; Dobbs, Drena; Honavar, Vasant; Bonvin, Alexandre M J J

2017-05-01

Although many advanced and sophisticated ab initio approaches for modeling protein-protein complexes have been proposed in past decades, template-based modeling (TBM) remains the most accurate and widely used approach, given a reliable template is available. However, there are many different ways to exploit template information in the modeling process. Here, we systematically evaluate and benchmark a TBM method that uses conserved interfacial residue pairs as docking distance restraints [referred to as alpha carbon-alpha carbon (CA-CA)-guided docking]. We compare it with two other template-based protein-protein modeling approaches, including a conserved non-pairwise interfacial residue restrained docking approach [referred to as the ambiguous interaction restraint (AIR)-guided docking] and a simple superposition-based modeling approach. Our results show that, for most cases, the CA-CA-guided docking method outperforms both superposition with refinement and the AIR-guided docking method. We emphasize the superiority of the CA-CA-guided docking on cases with medium to large conformational changes, and interactions mediated through loops, tails or disordered regions. Our results also underscore the importance of a proper refinement of superimposition models to reduce steric clashes. In summary, we provide a benchmarked TBM protocol that uses conserved pairwise interface distance as restraints in generating realistic 3D protein-protein interaction models, when reliable templates are available. The described CA-CA-guided docking protocol is based on the HADDOCK platform, which allows users to incorporate additional prior knowledge of the target system to further improve the quality of the resulting models. © The Author 2016. Published by Oxford University Press.

4. South (shore) end of dock as viewed from shore ...

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

4. South (shore) end of dock as viewed from shore looking north includes section of creosote pipe as it leaves the shore. - Pacific Creosoting Plant, Oil-Creosote Unloading Dock, 5350 Creosote Place, Northeast, Bremerton, Kitsap County, WA

IFACEwat: the interfacial water-implemented re-ranking algorithm to improve the discrimination of near native structures for protein rigid docking.

PubMed

Su, Chinh; Nguyen, Thuy-Diem; Zheng, Jie; Kwoh, Chee-Keong

2014-01-01

Protein-protein docking is an in silico method to predict the formation of protein complexes. Due to limited computational resources, the protein-protein docking approach has been developed under the assumption of rigid docking, in which one of the two protein partners remains rigid during the protein associations and water contribution is ignored or implicitly presented. Despite obtaining a number of acceptable complex predictions, it seems to-date that most initial rigid docking algorithms still find it difficult or even fail to discriminate successfully the correct predictions from the other incorrect or false positive ones. To improve the rigid docking results, re-ranking is one of the effective methods that help re-locate the correct predictions in top high ranks, discriminating them from the other incorrect ones. Our results showed that the IFACEwat increased both the numbers of the near-native structures and improved their ranks as compared to the initial rigid docking ZDOCK3.0.2. In fact, the IFACEwat achieved a success rate of 83.8% for Antigen/Antibody complexes, which is 10% better than ZDOCK3.0.2. As compared to another re-ranking technique ZRANK, the IFACEwat obtains success rates of 92.3% (8% better) and 90% (5% better) respectively for medium and difficult cases. When comparing with the latest published re-ranking method F2Dock, the IFACEwat performed equivalently well or even better for several Antigen/Antibody complexes. With the inclusion of interfacial water, the IFACEwat improves mostly results of the initial rigid docking, especially for Antigen/Antibody complexes. The improvement is achieved by explicitly taking into account the contribution of water during the protein interactions, which was ignored or not fully presented by the initial rigid docking and other re-ranking techniques. In addition, the IFACEwat maintains sufficient computational efficiency of the initial docking algorithm, yet improves the ranks as well as the number of the near native structures found. As our implementation so far targeted to improve the results of ZDOCK3.0.2, and particularly for the Antigen/Antibody complexes, it is expected in the near future that more implementations will be conducted to be applicable for other initial rigid docking algorithms.

Docking analysis of verteporfin with YAP WW domain.

PubMed

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

2017-01-01

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

Linear Actuator System for the NASA Docking System

NASA Technical Reports Server (NTRS)

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

2017-01-01

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

GEMINI-TITAN (GT)-9 - EARTH-SKY - AUGMENTED TARGET DOCKING ADAPTER (ATDA) - MSC

NASA Image and Video Library

1966-06-06

S66-37923 (3 June 1966) --- The Augmented Target Docking Adapter (ATDA) as seen from the Gemini-9 spacecraft during one of their three rendezvous in space. The ATDA and Gemini-9 spacecraft are 66.5 feet apart. Failure of the docking adapter protective cover to fully separate on the ATDA prevented the docking of the two spacecraft. The ATDA was described by the Gemini-9 crew as an "angry alligator." Photo credit: NASA

Vinogradov at TORU control system in Zvezda

NASA Image and Video Library

2006-06-26

ISS013-E-42209 (26 June 2006) --- Cosmonaut Pavel V. Vinogradov, Expedition 13 commander representing Russia's Federal Space Agency, practices docking procedures with the TORU teleoperated control system in the Zvezda Service Module of the International Space Station in preparation for the docking of the Progress 22 spacecraft. Vinogradov, 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.

AnchorDock for Blind Flexible Docking of Peptides to Proteins.

PubMed

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

2017-01-01

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

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

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.

Dedicator of cytokinesis 8-deficient CD4+ T cells are biased to a TH2 effector fate at the expense of TH1 and TH17 cells.

PubMed

Tangye, Stuart G; Pillay, Bethany; Randall, Katrina L; Avery, Danielle T; Phan, Tri Giang; Gray, Paul; Ziegler, John B; Smart, Joanne M; Peake, Jane; Arkwright, Peter D; Hambleton, Sophie; Orange, Jordan; Goodnow, Christopher C; Uzel, Gulbu; Casanova, Jean-Laurent; Lugo Reyes, Saul Oswaldo; Freeman, Alexandra F; Su, Helen C; Ma, Cindy S

2017-03-01

Dedicator of cytokinesis 8 (DOCK8) deficiency is a combined immunodeficiency caused by autosomal recessive loss-of-function mutations in DOCK8. This disorder is characterized by recurrent cutaneous infections, increased serum IgE levels, and severe atopic disease, including food-induced anaphylaxis. However, the contribution of defects in CD4 + T cells to disease pathogenesis in these patients has not been thoroughly investigated. We sought to investigate the phenotype and function of DOCK8-deficient CD4 + T cells to determine (1) intrinsic and extrinsic CD4 + T-cell defects and (2) how defects account for the clinical features of DOCK8 deficiency. We performed in-depth analysis of the CD4 + T-cell compartment of DOCK8-deficient patients. We enumerated subsets of CD4 + T helper cells and assessed cytokine production and transcription factor expression. Finally, we determined the levels of IgE specific for staple foods and house dust mite allergens in DOCK8-deficient patients and healthy control subjects. DOCK8-deficient memory CD4 + T cells were biased toward a T H 2 type, and this was at the expense of T H 1 and T H 17 cells. In vitro polarization of DOCK8-deficient naive CD4 + T cells revealed the T H 2 bias and T H 17 defect to be T-cell intrinsic. Examination of allergen-specific IgE revealed plasma IgE from DOCK8-deficient patients is directed against staple food antigens but not house dust mites. Investigations into the DOCK8-deficient CD4 + T cells provided an explanation for some of the clinical features of this disorder: the T H 2 bias is likely to contribute to atopic disease, whereas defects in T H 1 and T H 17 cells compromise antiviral and antifungal immunity, respectively, explaining the infectious susceptibility of DOCK8-deficient patients. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. All rights reserved.

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 Control System (RCS) jet angular and position misalignment, RCS thrust magnitude uncertainty, RCS jet force direction uncertainty due to self plume impingement, and Orion center of mass uncertainty.

Nonlinear scoring functions for similarity-based ligand docking and binding affinity prediction.

PubMed

Brylinski, Michal

2013-11-25

A common strategy for virtual screening considers a systematic docking of a large library of organic compounds into the target sites in protein receptors with promising leads selected based on favorable intermolecular interactions. Despite a continuous progress in the modeling of protein-ligand interactions for pharmaceutical design, important challenges still remain, thus the development of novel techniques is required. In this communication, we describe eSimDock, a new approach to ligand docking and binding affinity prediction. eSimDock employs nonlinear machine learning-based scoring functions to improve the accuracy of ligand ranking and similarity-based binding pose prediction, and to increase the tolerance to structural imperfections in the target structures. In large-scale benchmarking using the Astex/CCDC data set, we show that 53.9% (67.9%) of the predicted ligand poses have RMSD of <2 Å (<3 Å). Moreover, using binding sites predicted by recently developed eFindSite, eSimDock models ligand binding poses with an RMSD of 4 Å for 50.0-39.7% of the complexes at the protein homology level limited to 80-40%. Simulations against non-native receptor structures, whose mean backbone rearrangements vary from 0.5 to 5.0 Å Cα-RMSD, show that the ratio of docking accuracy and the estimated upper bound is at a constant level of ∼0.65. Pearson correlation coefficient between experimental and predicted by eSimDock Ki values for a large data set of the crystal structures of protein-ligand complexes from BindingDB is 0.58, which decreases only to 0.46 when target structures distorted to 3.0 Å Cα-RMSD are used. Finally, two case studies demonstrate that eSimDock can be customized to specific applications as well. These encouraging results show that the performance of eSimDock is largely unaffected by the deformations of ligand binding regions, thus it represents a practical strategy for across-proteome virtual screening using protein models. eSimDock is freely available to the academic community as a Web server at http://www.brylinski.org/esimdock .

122. JOB NO. 1347E, SHEET 3S, 1927, DOCK; FORD MOTOR ...

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

122. JOB NO. 1347-E, SHEET 3S, 1927, DOCK; FORD MOTOR COMPANY; DECK PLAN OF DOCK - Ford Motor Company Long Beach Assembly Plant, Assembly Building, 700 Henry Ford Avenue, Long Beach, Los Angeles County, CA

CPdock: the complementarity plot for docking of proteins: implementing multi-dielectric continuum electrostatics.

PubMed

Basu, Sankar

2017-12-07

The complementarity plot (CP) is an established validation tool for protein structures, applicable to both globular proteins (folding) as well as protein-protein complexes (binding). It computes the shape and electrostatic complementarities (S m , E m ) for amino acid side-chains buried within the protein interior or interface and plots them in a two-dimensional plot having knowledge-based probabilistic quality estimates for the residues as well as for the whole structure. The current report essentially presents an upgraded version of the plot with the implementation of the advanced multi-dielectric functionality (as in Delphi version 6.2 or higher) in the computation of electrostatic complementarity to make the validation tool physico-chemically more realistic. The two methods (single- and multi-dielectric) agree decently in their resultant E m values, and hence, provisions for both methods have been kept in the software suite. So to speak, the global electrostatic balance within a well-folded protein and/or a well-packed interface seems only marginally perturbed by the choice of different internal dielectric values. However, both from theoretical as well as practical grounds, the more advanced multi-dielectric version of the plot is certainly recommended for potentially producing more reliable results. The report also presents a new methodology and a variant plot, namely CP dock , based on the same principles of complementarity specifically designed to be used in the docking of proteins. The efficacy of the method to discriminate between good and bad docked protein complexes has been tested on a recent state-of-the-art docking benchmark. The results unambiguously indicate that CP dock can indeed be effective in the initial screening phase of a docking scoring pipeline before going into more sophisticated and computationally expensive scoring functions. CP dock has been made available at https://github.com/nemo8130/CPdock . Graphical Abstract An example showing the efficacy of CP dock to be used in the initial screening phase of a protein-protein docking scoring pipeline.

PEPSI-Dock: a detailed data-driven protein-protein interaction potential accelerated by polar Fourier correlation.

PubMed

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

2016-09-01

Docking prediction algorithms aim to find the native conformation of a complex of proteins from knowledge of their unbound structures. They rely on a combination of sampling and scoring methods, adapted to different scales. Polynomial Expansion of Protein Structures and Interactions for Docking (PEPSI-Dock) improves the accuracy of the first stage of the docking pipeline, which will sharpen up the final predictions. Indeed, PEPSI-Dock benefits from the precision of a very detailed data-driven model of the binding free energy used with a global and exhaustive rigid-body search space. As well as being accurate, our computations are among the fastest by virtue of the sparse representation of the pre-computed potentials and FFT-accelerated sampling techniques. Overall, this is the first demonstration of a FFT-accelerated docking method coupled with an arbitrary-shaped distance-dependent interaction potential. First, we present a novel learning process to compute data-driven distant-dependent pairwise potentials, adapted from our previous method used for rescoring of putative protein-protein binding poses. The potential coefficients are learned by combining machine-learning techniques with physically interpretable descriptors. Then, we describe the integration of the deduced potentials into a FFT-accelerated spherical sampling provided by the Hex library. Overall, on a training set of 163 heterodimers, PEPSI-Dock achieves a success rate of 91% mid-quality predictions in the top-10 solutions. On a subset of the protein docking benchmark v5, it achieves 44.4% mid-quality predictions in the top-10 solutions when starting from bound structures and 20.5% when starting from unbound structures. The method runs in 5-15 min on a modern laptop and can easily be extended to other types of interactions. https://team.inria.fr/nano-d/software/PEPSI-Dock sergei.grudinin@inria.fr. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Do Clinical Results and Return-to-Sport Rates After Ulnar Collateral Ligament Reconstruction Differ Based on Graft Choice and Surgical Technique?

PubMed

Erickson, Brandon J; Cvetanovich, Gregory L; Frank, Rachel M; Bach, Bernard R; Cohen, Mark S; Bush-Joseph, Charles A; Cole, Brian J; Romeo, Anthony A

2016-11-01

Ulnar collateral ligament reconstruction (UCLR) has become a common procedure performed in overhead-throwing athletes of many athletic levels. The purpose of this study was to determine whether clinical outcomes and return-to-sport (RTS) rates differ among patients undergoing UCLR based on graft choice, surgical technique, athletic competition level, handedness, and treatment of the ulnar nerve. We hypothesized that no differences would exist in clinical outcomes or RTS rates between technique, graft choice, or other variables. Cohort study; Level of evidence, 3. All patients who underwent UCLR from January 1, 2004 through December 31, 2014 at a single institution were identified. Charts were reviewed to determine patient age, sex, date of surgery, sport played, handedness, athletic level, surgical technique, graft type, and complications. Patients were contacted via telephone to obtain the RTS rate, Conway-Jobe score, Timmerman-Andrews score, and Kerlan-Jobe Orthopaedic Clinic (KJOC) Shoulder and Elbow score. Eighty-five patients (mean age at surgery, 19.3 ± 4.7 years; 92% male; 78% right hand-dominant) underwent UCLR between 2004 and 2014 and were available for follow-up. Overall, 87% were baseball pitchers, 49.4% were college athletes, and 41.2% were high school athletes. No significant difference existed between the docking and double-docking techniques, graft choice, handedness, sex, activity level, and treatment of the ulnar nerve with regard to clinical outcomes, RTS, or subsequent surgeries (all P > .05). More complications were seen in the docking technique compared with the double-docking technique ( P = .036). Hamstring autograft was used more commonly with the docking technique ( P = .023) while allograft was used more commonly with the double-docking technique ( P = .0006). Both the docking and double-docking techniques produce excellent clinical outcomes in patients undergoing UCLR. No difference in outcome scores was seen between surgical technique or graft type. The double-docking technique had fewer complications than the docking technique.

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 requirements.

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 experimental information (e.g. from mass spectrometry, nuclear magnetic resonance, cryoelectron microscopy, etc.) will remain highly desirable to obtain reliable results.

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).

Casual Dock Work: Profile of Diseases and Injuries and Perception of Influence on Health

PubMed Central

Cezar-Vaz, Marta Regina; de Almeida, Marlise Capa Verde; Bonow, Clarice Alves; Rocha, Laurelize Pereira; Borges, Anelise Miritz; Piexak, Diéssica Roggia

2014-01-01

The present study aimed to identify the profile of diseases and injuries that affect casual dock workers and identify casual dock workers’ perceptions of positive and negative work influences on their health. This study consisted of two phases. The first phase was a quantitative study composed of a retrospective analysis, conducted with 953 medical records. The second phase of the research is a non-random sample with 51 casual dock workers. Data analysis was performed with SPSS 19.0. The average age of the casual dock workers was 48.7. Concerning working time, the majority had more than 19.6 years of dock work experience. In the first phase, 527 pathologic diagnoses were identified. The diagnoses that affected the musculoskeletal system (15.8%, N = 152; p < 0.01) were highlighted. Consequences to physical health produced by accidents stood out, with fracture registration predominating (12.8%, N = 122; p < 0.05). Significant differences were found for positive work influence on the cardiovascular system and family health. It was concluded that the diagnoses obtained are related to the influence of dock work perception and have motivated an introduction of preventive measures. PMID:24557521

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.

New docking target taped to middeck locker

NASA Image and Video Library

1996-09-20

STS79-E-5104 (20 September 1996) --- The STS-79 crew members removed the docking target from the Docking Module (DM) and attached it to a locker door to photograph it and examine a slight peel on the surface, during Flight Day 5.

Service building no. 620. Elevations (dry dock associates, June 12, ...

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

Service building no. 620. Elevations (dry dock associates, June 12, 1941). In files of Cushman & Wakefield, building 501, Philadephia Naval Business Center. - Naval Base Philadelphia-Philadelphia Naval Shipyard, Service Building, Dry Docks No. 4 & 5, League Island, Philadelphia, Philadelphia County, PA

29. ORE DOCK, LOOKING WEST; AT WORK UNLOADING THE 'GEORGE ...

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

29. ORE DOCK, LOOKING WEST; AT WORK UNLOADING THE 'GEORGE M. HUMPHREY'S' CARGO OF 25,000. TONS OF ORE. - Pennsylvania Railway Ore Dock, Lake Erie at Whiskey Island, approximately 1.5 miles west of Public Square, Cleveland, Cuyahoga County, OH

1. Dyea Dock looking south. Note faint evenly spaced circular ...

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

1. Dyea Dock looking south. Note faint evenly spaced circular dark pieces of grass up through the middle of the picture indicating posts making up the pier. Photograph made from park service cherry picker. - Dyea Dock & Association (Ruins), Skagway, Skagway, AK

ASTP crewmen in Docking Module trainer during training session at JSC

NASA Technical Reports Server (NTRS)

1975-01-01

An interior view of the Docking Module trainer in bldg 35 during Apollo Soyuz Test Project (ASTP) joint crew training at JSC. Astronaut Donald K. Slayton (right) is the docking module pilot of the American ASTP prime crew. The other man is Cosmonaut Valeriy N. Kubasov, engineer on the Soviet ASTP first (prime) crew. The training session simulated activities on the second day in space. The Docking module is designed to link the Apollo and Soyuz spacecraft.

Astronaut Vance Brand practices operating Docking Module hatch for ASTP

NASA Technical Reports Server (NTRS)

1975-01-01

Astronaut Vance D. Brand, command module pilot of the American Apollo Soyuz Test Project (ASTP) prime crew, practices operating a Docking Module hatch during ASTP pre-flight training at JSC. The Docking Module is designed to link the Apollo and Soyuz spacecraft during their docking in Earth orbit mission. Gary L. Doerre of JSC's Crew Training and Procedures Division is working with Brand. Doerre is wearing a face mask to help prevent possible exposure to Brand of disease prior to the ASTP launch.

GEMINI-TITAN (GT)-11 - EARTH - SKY - DOCKING - OUTER SPACE

NASA Image and Video Library

1966-07-18

S66-46144 (18 July 1966) --- The Gemini-10 spacecraft is successfully docked with the Agena Target Docking Vehicle 5005. The Agena display panel is clearly visible. After docking with the Agena, astronauts John W. Young, command pilot, and Michael Collins, pilot, fired the 16,000-pound thrust engine of Agena-10's primary propulsion system to boost the combined vehicles into an orbit with an apogee of 413 nautical miles to set a new altitude record for manned spaceflight. Photo credit: NASA

GRAMM-X public web server for protein–protein docking

PubMed Central

Tovchigrechko, Andrey; Vakser, Ilya A.

2006-01-01

Protein docking software GRAMM-X and its web interface () extend the original GRAMM Fast Fourier Transformation methodology by employing smoothed potentials, refinement stage, and knowledge-based scoring. The web server frees users from complex installation of database-dependent parallel software and maintaining large hardware resources needed for protein docking simulations. Docking problems submitted to GRAMM-X server are processed by a 320 processor Linux cluster. The server was extensively tested by benchmarking, several months of public use, and participation in the CAPRI server track. PMID:16845016

Astronaut Richard Truly seen working with Apollo docking mechanism model

NASA Technical Reports Server (NTRS)

1975-01-01

Astronaut Richard H. Truly, an Apollo Soyuz Test Project (ASTP) spacecraft communicator, is seen working with an Apollo docking mechanism in the Mission Control Center during the joint U.S.-USSR ASTP docking in Earth orbit mission. Astronaut Truly, a member of the American ASTP crew support team, was working on the docking probe problem. The crew had notified ground control that there was a problem with removing the probe from the tunnel of the Apollo Command Module.

8. SHEET 2, CONTROL HOUSE FOR DRY DOCK. United Engineering ...

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

8. SHEET 2, CONTROL HOUSE FOR DRY DOCK. United Engineering Company Ltd., Alameda Shipyard, Ship Repair Facilities, Office Building. John Hudspeth, Architect, at foot of Main Street, Alameda, Calif. Sheet no. 2 of 2 sheets, Plan no. 10,507. Various scales. January 4, 1943, last revised 1/19/43. U.S. Navy, Bureau of Yards & Docks, Contract no. bs 76. Approved for construction October 9, 1943. blueprint - United Engineering Company Shipyard, Control House for Dry Dock, 2900 Main Street, Alameda, Alameda County, CA

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

Krikalev works with the TORU teleoperated control system in the SM during Expedition 11

NASA Image and Video Library

2005-06-19

ISS011-E-09184 (18 June 2005) --- Cosmonaut Sergei K. Krikalev, Expedition 11 commander representing Russia's Federal Space Agency, practices docking procedures with the TORU teleoperated control system in the Zvezda Service Module of the International Space Station (ISS) in preparation for the docking of the Progress 18 spacecraft. Krikalev, 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.

Tyurin works with the TORU teleoperated control system in the SM during Expedition 14

NASA Image and Video Library

2007-01-20

ISS014-E-12482 (19 Jan. 2007) --- Cosmonaut Mikhail Tyurin, Expedition 14 flight engineer representing Russia's Federal Space Agency, practices docking procedures with the TORU teleoperated control system in the Zvezda Service Module of the International Space Station in preparation for the docking of the Progress 24 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.

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

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.

A molecular docking study of phytochemical estrogen mimics from dietary herbal supplements.

PubMed

Powers, Chelsea N; Setzer, William N

2015-01-01

The purpose of this study is to use a molecular docking approach to identify potential estrogen mimics or anti-estrogens in phytochemicals found in popular dietary herbal supplements. In this study, 568 phytochemicals found in 17 of the most popular herbal supplements sold in the United States were built and docked with two isoforms of the estrogen receptor, ERα and ERβ (a total of 27 different protein crystal structures). The docking results revealed six strongly docking compounds in Echinacea, three from milk thistle (Silybum marianum), three from Gingko biloba, one from Sambucus nigra, none from maca (Lepidium meyenii), five from chaste tree (Vitex agnus-castus), two from fenugreek (Trigonella foenum-graecum), and two from Rhodiola rosea. Notably, of the most popular herbal supplements for women, there were numerous compounds that docked strongly with the estrogen receptor: Licorice (Glycyrrhiza glabra) had a total of 26 compounds strongly docking to the estrogen receptor, 15 with wild yam (Dioscorea villosa), 11 from black cohosh (Actaea racemosa), eight from muira puama (Ptychopetalum olacoides or P. uncinatum), eight from red clover (Trifolium pratense), three from damiana (Turnera aphrodisiaca or T. diffusa), and three from dong quai (Angelica sinensis). Of possible concern were the compounds from men's herbal supplements that exhibited strong docking to the estrogen receptor: Gingko biloba had three compounds, gotu kola (Centella asiatica) had two, muira puama (Ptychopetalum olacoides or P. uncinatum) had eight, and Tribulus terrestris had six compounds. This molecular docking study has revealed that almost all popular herbal supplements contain phytochemical components that may bind to the human estrogen receptor and exhibit selective estrogen receptor modulation. As such, these herbal supplements may cause unwanted side effects related to estrogenic activity.

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.

ProSelection: A Novel Algorithm to Select Proper Protein Structure Subsets for in Silico Target Identification and Drug Discovery Research.

PubMed

Wang, Nanyi; Wang, Lirong; Xie, Xiang-Qun

2017-11-27

Molecular docking is widely applied to computer-aided drug design and has become relatively mature in the recent decades. Application of docking in modeling varies from single lead compound optimization to large-scale virtual screening. The performance of molecular docking is highly dependent on the protein structures selected. It is especially challenging for large-scale target prediction research when multiple structures are available for a single target. Therefore, we have established ProSelection, a docking preferred-protein selection algorithm, in order to generate the proper structure subset(s). By the ProSelection algorithm, protein structures of "weak selectors" are filtered out whereas structures of "strong selectors" are kept. Specifically, the structure which has a good statistical performance of distinguishing active ligands from inactive ligands is defined as a strong selector. In this study, 249 protein structures of 14 autophagy-related targets are investigated. Surflex-dock was used as the docking engine to distinguish active and inactive compounds against these protein structures. Both t test and Mann-Whitney U test were used to distinguish the strong from the weak selectors based on the normality of the docking score distribution. The suggested docking score threshold for active ligands (SDA) was generated for each strong selector structure according to the receiver operating characteristic (ROC) curve. The performance of ProSelection was further validated by predicting the potential off-targets of 43 U.S. Federal Drug Administration approved small molecule antineoplastic drugs. Overall, ProSelection will accelerate the computational work in protein structure selection and could be a useful tool for molecular docking, target prediction, and protein-chemical database establishment research.

Dock mediates Scar- and WASp-dependent actin polymerization through interaction with cell adhesion molecules in founder cells and fusion-competent myoblasts.

PubMed

Kaipa, Balasankara Reddy; Shao, Huanjie; Schäfer, Gritt; Trinkewitz, Tatjana; Groth, Verena; Liu, Jianqi; Beck, Lothar; Bogdan, Sven; Abmayr, Susan M; Önel, Susanne-Filiz

2013-01-01

The formation of the larval body wall musculature of Drosophila depends on the asymmetric fusion of two myoblast types, founder cells (FCs) and fusion-competent myoblasts (FCMs). Recent studies have established an essential function of Arp2/3-based actin polymerization during myoblast fusion, formation of a dense actin focus at the site of fusion in FCMs, and a thin sheath of actin in FCs and/or growing muscles. The formation of these actin structures depends on recognition and adhesion of myoblasts that is mediated by cell surface receptors of the immunoglobulin superfamily. However, the connection of the cell surface receptors with Arp2/3-based actin polymerization is poorly understood. To date only the SH2-SH3 adaptor protein Crk has been suggested to link cell adhesion with Arp2/3-based actin polymerization in FCMs. Here, we propose that the SH2-SH3 adaptor protein Dock, like Crk, links cell adhesion with actin polymerization. We show that Dock is expressed in FCs and FCMs and colocalizes with the cell adhesion proteins Sns and Duf at cell-cell contact points. Biochemical data in this study indicate that different domains of Dock are involved in binding the cell adhesion molecules Duf, Rst, Sns and Hbs. We emphasize the importance of these interactions by quantifying the enhanced myoblast fusion defects in duf dock, sns dock and hbs dock double mutants. Additionally, we show that Dock interacts biochemically and genetically with Drosophila Scar, Vrp1 and WASp. Based on these data, we propose that Dock links cell adhesion in FCs and FCMs with either Scar- or Vrp1-WASp-dependent Arp2/3 activation.

Vision Based Navigation for Autonomous Cooperative Docking of CubeSats

NASA Astrophysics Data System (ADS)

Pirat, Camille; Ankersen, Finn; Walker, Roger; Gass, Volker

2018-05-01

A realistic rendezvous and docking navigation solution applicable to CubeSats is investigated. The scalability analysis of the ESA Autonomous Transfer Vehicle Guidance, Navigation & Control (GNC) performances and the Russian docking system, shows that the docking of two CubeSats would require a lateral control performance of the order of 1 cm. Line of sight constraints and multipath effects affecting Global Navigation Satellite System (GNSS) measurements in close proximity prevent the use of this sensor for the final approach. This consideration and the high control accuracy requirement led to the use of vision sensors for the final 10 m of the rendezvous and docking sequence. A single monocular camera on the chaser satellite and various sets of Light-Emitting Diodes (LEDs) on the target vehicle ensure the observability of the system throughout the approach trajectory. The simple and novel formulation of the measurement equations allows differentiating unambiguously rotations from translations between the target and chaser docking port and allows a navigation performance better than 1 mm at docking. Furthermore, the non-linear measurement equations can be solved in order to provide an analytic navigation solution. This solution can be used to monitor the navigation filter solution and ensure its stability, adding an extra layer of robustness for autonomous rendezvous and docking. The navigation filter initialization is addressed in detail. The proposed method is able to differentiate LEDs signals from Sun reflections as demonstrated by experimental data. The navigation filter uses a comprehensive linearised coupled rotation/translation dynamics, describing the chaser to target docking port motion. The handover, between GNSS and vision sensor measurements, is assessed. The performances of the navigation function along the approach trajectory is discussed.

Tail Docking of Canine Puppies: Reassessment of the Tail's Role in Communication, the Acute Pain Caused by Docking and Interpretation of Behavioural Responses.

PubMed

Mellor, David J

2018-05-31

Laws, regulations and professional standards increasingly aim to ban or restrict non-therapeutic tail docking in canine puppies. These constraints have usually been justified by reference to loss of tail participation in communication between dogs, the acute pain presumed to be caused during docking itself, subsequent experiences of chronic pain and heightened pain sensitivity, and the occurrence of other complications. These areas are reconsidered here. First, a scientifically robust examination of the dynamic functional foundations, sensory components and key features of body language that are integral to canine communication shows that the role of the tail has been greatly underestimated. More specifically, it shows that tail behaviour is so embedded in canine communication that docking can markedly impede unambiguous interactions between different dogs and between dogs and people. These interactions include the expression of wide ranges of both negative and positive emotions, moods and intentions that are of daily significance for dog welfare. Moreover, all docked dogs may experience these impediments throughout their lives, which challenges assertions by opponents to such bans or restrictions that the tail is a dispensable appendage. Second, and in contrast, a re-examination of the sensory capacities of canine puppies reveals that they cannot consciously experience acute or chronic pain during at least the first week after birth, which is when they are usually docked. The contrary view is based on questionable between-species extrapolation of information about pain from neurologically mature newborns such as calves, lambs, piglets and human infants, which certainly can consciously experience pain in response to injury, to neurologically immature puppies which remain unconscious and therefore unable to experience pain until about two weeks after birth. Third, underpinned by the incorrect conclusion that puppies are conscious at the usual docking age, it is argued here that the well-validated human emotional drive or desire to care for and protect vulnerable young, leads observers to misread striking docking-induced behaviour as indicating that the puppies consciously experience significant acute pain and distress. Fourth, updated information reaffirms the conclusion that a significant proportion of dogs docked as puppies will subsequently experience persistent and significant chronic pain and heightened pain sensitivity. And fifth, other reported negative consequences of docking should also be considered because, although their prevalence is unclear, when they do occur they would have significant negative welfare impacts. It is argued that the present analysis strengthens the rationale for such bans or restrictions on docking of puppies by clarifying which of several justifications previously used are and are not scientifically supportable. In particular, it highlights the major roles the tail plays in canine communication, as well as the lifetime handicaps to communication caused by docking. Thus, it is concluded that non-therapeutic tail docking of puppies represents an unnecessary removal of a necessary appendage and should therefore be banned or restricted.

Space Operations Center, Shuttle Interaction Study. Volume 2: Appendices, Book 1 of 2

NASA Technical Reports Server (NTRS)

1981-01-01

The feasibility of shuttle orbiter docking to the Space Operations Center (SOC) is studied. The in-orbit relative motion of the free flying orbiter and SOC was simulated, accounting for the Orbiter RCS and digital autopilot (DAP) systems, orbital mechanics, center of gravity offset of the orbiter docking port, aero and gravity gradient effects, and other pertinent natural and man-made phenomena. Since there is no specified flight path and procedure for docking, terminal closure sensitivities were investigated. Orbiter approach direction, Orbiter approach attitude out of plane, DAP thruster compensation mode, final ballistic docking distance and time to dock, rate and excursion attitude deadbands, and selection of various thruster combinations (differing from nominal) for translational pulses are considered.

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.

Docking analysis of verteporfin with YAP WW domain

PubMed Central

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

2017-01-01

The YAP oncogene is a known cancer target. Therefore, it is of interest to understand the molecular docking interaction of verteporfin (a derivative of benzo-porphyrin) with the WW domain of YAP (clinically used for photo-dynamic therapy in macular degeneration) as a potential WW domain-ligand modulator by inhibition. A homology protein SWISS MODEL of the human YAP protein was constructed to dock (using AutoDock vina) with the PubChem verteporfin structure for interaction analysis. The docking result shows the possibilities of verteporfin interaction with the oncogenic transcription cofactor YAP having WW1 and WW2 domains. Thus, the ability of verteporfin to bind with the YAP WW domain having modulator activity is implied in this analysis. PMID:28943729

O-desmethylquinine as a cyclooxygenase-2 (COX-2) inhibitors using AutoDock Vina

NASA Astrophysics Data System (ADS)

Damayanti, Sophi; Mahardhika, Andhika Bintang; Ibrahim, Slamet; Chong, Wei Lim; Lee, Vannajan Sanghiran; Tjahjono, Daryono Hadi

2014-10-01

Computational approach was employed to evaluate the biological activity of novel cyclooxygenase-2 COX-2 inhibitor, O-desmethylquinine, in comparison to quinine as common inhibitor which can also be used an agent of antipyretic, antimalaria, analgesic and antiinflamation. The molecular models of the compound were constructed and optimized with the density function theory with at the B3LYP/6-31G (d,p) level using Gaussian 09 program. Molecular docking studies of the compounds were done to obtain the COX-2 complex structures and their binding energies were analyzed using the AutoDock Vina. The results of docking of the two ligands were comparable and cannot be differentiated from the energy scoring function with AutoDock Vina.

Crew around hatch leading into the Soyuz spacecraft

NASA Image and Video Library

2006-09-28

ISS014-E-05015 (28 Sept. 2006) --- European Space Agency (ESA) astronaut Thomas Reiter, Expedition 14 flight engineer, photographed near a docking port in the Pirs Docking Compartment of the International Space Station. A probe-and-cone docking mechanism is visible in the port.

Launch of Agena Target Docking Vehicle atop Atlas launch vehicle

NASA Technical Reports Server (NTRS)

1966-01-01

An Agena Target Docking Vehicle atop its Atlas launch vehicle was launched fromt the Kennedy Space Center's Launch Complex 14 at 6:05 a.m., September 12, 1966. The Agena served as a rendezvous and docking vehicle for the Gemini 11 spacecraft.

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;

Modeling and docking antibody structures with Rosetta

PubMed Central

Weitzner, Brian D.; Jeliazkov, Jeliazko R.; Lyskov, Sergey; Marze, Nicholas; Kuroda, Daisuke; Frick, Rahel; Adolf-Bryfogle, Jared; Biswas, Naireeta; Dunbrack, Roland L.; Gray, Jeffrey J.

2017-01-01

We describe Rosetta-based computational protocols for predicting the three-dimensional structure of an antibody from sequence (RosettaAntibody) and then docking the antibody to protein antigens (SnugDock). Antibody modeling leverages canonical loop conformations to graft large segments from experimentally-determined structures as well as (1) energetic calculations to minimize loops, (2) docking methodology to refine the VL–VH relative orientation, and (3) de novo prediction of the elusive complementarity determining region (CDR) H3 loop. To alleviate model uncertainty, antibody–antigen docking resamples CDR loop conformations and can use multiple models to represent an ensemble of conformations for the antibody, the antigen or both. These protocols can be run fully-automated via the ROSIE web server (http://rosie.rosettacommons.org/) or manually on a computer with user control of individual steps. For best results, the protocol requires roughly 1,000 CPU-hours for antibody modeling and 250 CPU-hours for antibody–antigen docking. Tasks can be completed in under a day by using public supercomputers. PMID:28125104

KSC-95PC-1324

NASA Image and Video Library

1995-09-11

CAPE CANAVERAL, Fla. -- At NASA's Kennedy Space Center in Florida, the Russian-built Docking Module is lowered for installation into the payload bay of the space shuttle Atlantis while it is in bay 2 of the Orbiter Processing Facility. The module will fly as a primary payload on the second Space Shuttle/Mir space station docking mission, STS-74. During the mission, the module will first be attached with the orbiter's robot arm to the Orbiter Docking System 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 spacecraft. 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. Photo Credit: NASA

Optimizing the admission time of outbound trucks entering a cross-dock with uniform arrival time by considering a queuing model

NASA Astrophysics Data System (ADS)

Motaghedi-Larijani, Arash; Aminnayeri, Majid

2017-03-01

Cross-docking is a supply-chain strategy that can reduce transportation and inventory costs. This study is motivated by a fruit and vegetable distribution centre in Tehran, which has cross-docks and a limited time to admit outbound trucks. In this article, outbound trucks are assumed to arrive at the cross-dock with a single outbound door with a uniform distribution (0,L). The total number of assigned trucks is constant and the loading time is fixed. A queuing model is modified for this situation and the expected waiting time of each customer is calculated. Then, a curve for the waiting time is calculated. Finally, the length of window time L is optimized to minimize the total cost, which includes the waiting time of the trucks and the admission cost of the cross-dock. Some illustrative examples of cross-docking are presented and solved using the proposed method.

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

PubMed

Dawood, Shazia; Zarina, Shamshad; Bano, Samina

2014-09-01

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

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.

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.

Slit stimulation recruits Dock and Pak to the roundabout receptor and increases Rac activity to regulate axon repulsion at the CNS midline.

PubMed

Fan, Xueping; Labrador, Juan Pablo; Hing, Huey; Bashaw, Greg J

2003-09-25

Drosophila Roundabout (Robo) is the founding member of a conserved family of repulsive axon guidance receptors that respond to secreted Slit proteins. Here we present evidence that the SH3-SH2 adaptor protein Dreadlocks (Dock), the p21-activated serine-threonine kinase (Pak), and the Rac1/Rac2/Mtl small GTPases can function during Robo repulsion. Loss-of-function and genetic interaction experiments suggest that limiting the function of Dock, Pak, or Rac partially disrupts Robo repulsion. In addition, Dock can directly bind to Robo's cytoplasmic domain, and the association of Dock and Robo is enhanced by stimulation with Slit. Furthermore, Slit stimulation can recruit a complex of Dock and Pak to the Robo receptor and trigger an increase in Rac1 activity. These results provide a direct physical link between the Robo receptor and an important cytoskeletal regulatory protein complex and suggest that Rac can function in both attractive and repulsive axon guidance.

IFACEwat: the interfacial water-implemented re-ranking algorithm to improve the discrimination of near native structures for protein rigid docking

PubMed Central

2014-01-01

Background Protein-protein docking is an in silico method to predict the formation of protein complexes. Due to limited computational resources, the protein-protein docking approach has been developed under the assumption of rigid docking, in which one of the two protein partners remains rigid during the protein associations and water contribution is ignored or implicitly presented. Despite obtaining a number of acceptable complex predictions, it seems to-date that most initial rigid docking algorithms still find it difficult or even fail to discriminate successfully the correct predictions from the other incorrect or false positive ones. To improve the rigid docking results, re-ranking is one of the effective methods that help re-locate the correct predictions in top high ranks, discriminating them from the other incorrect ones. In this paper, we propose a new re-ranking technique using a new energy-based scoring function, namely IFACEwat - a combined Interface Atomic Contact Energy (IFACE) and water effect. The IFACEwat aims to further improve the discrimination of the near-native structures of the initial rigid docking algorithm ZDOCK3.0.2. Unlike other re-ranking techniques, the IFACEwat explicitly implements interfacial water into the protein interfaces to account for the water-mediated contacts during the protein interactions. Results Our results showed that the IFACEwat increased both the numbers of the near-native structures and improved their ranks as compared to the initial rigid docking ZDOCK3.0.2. In fact, the IFACEwat achieved a success rate of 83.8% for Antigen/Antibody complexes, which is 10% better than ZDOCK3.0.2. As compared to another re-ranking technique ZRANK, the IFACEwat obtains success rates of 92.3% (8% better) and 90% (5% better) respectively for medium and difficult cases. When comparing with the latest published re-ranking method F2Dock, the IFACEwat performed equivalently well or even better for several Antigen/Antibody complexes. Conclusions With the inclusion of interfacial water, the IFACEwat improves mostly results of the initial rigid docking, especially for Antigen/Antibody complexes. The improvement is achieved by explicitly taking into account the contribution of water during the protein interactions, which was ignored or not fully presented by the initial rigid docking and other re-ranking techniques. In addition, the IFACEwat maintains sufficient computational efficiency of the initial docking algorithm, yet improves the ranks as well as the number of the near native structures found. As our implementation so far targeted to improve the results of ZDOCK3.0.2, and particularly for the Antigen/Antibody complexes, it is expected in the near future that more implementations will be conducted to be applicable for other initial rigid docking algorithms. PMID:25521441

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.

Service building no. 620. Typical wall sections (Dry Dock Associates, ...

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

Service building no. 620. Typical wall sections (Dry Dock Associates, November 7, 1941). In files of Cushman & Wakefield Building (no. 501, Philadelphia Naval Business Center. - Naval Base Philadelphia-Philadelphia Naval Shipyard, Service Building, Dry Docks No. 4 & 5, League Island, Philadelphia, Philadelphia County, PA

22. Detail of interior corner showing truss system, dock no. ...

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

22. Detail of interior corner showing truss system, dock no. 492. View to south. - Offutt Air Force Base, Looking Glass Airborne Command Post, Nose Docks, On either side of Hangar Access Apron at Northwest end of Project Looking Glass Historic District, Bellevue, Sarpy County, NE

21. Scrapping In Dry Dock #4. Naval Shipyard Philadelphia. February ...

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

21. Scrapping In Dry Dock #4. Naval Shipyard Philadelphia. February 18, 1946. Original Photograph In Collection of National Archives, Mid-Atlantic Regional Records Center, Philadelphia. - Naval Base Philadelphia-Philadelphia Naval Shipyard, Dry Dock No. 4, Broad Street south of Government Avenue, Philadelphia, Philadelphia County, PA

22. ORE STORAGE BRIDGE AT PLANT'S LOWER DOCK, LOOKING SOUTH. ...

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

22. ORE STORAGE BRIDGE AT PLANT'S LOWER DOCK, LOOKING SOUTH. THE WELLMAN ORE BRIDGE (THERE ARE TWO AT THIS DOCK) WERE ERECTED IN 1908 BY THE CORRIGAN, McKINNEY COMPANY. - Corrigan, McKinney Steel Company, 3100 East Forty-fifth Street, Cleveland, Cuyahoga County, OH

33 CFR 401.65 - Communication-ports, docks and anchorages.

Code of Federal Regulations, 2010 CFR

2010-07-01

... anchorages. 401.65 Section 401.65 Navigation and Navigable Waters SAINT LAWRENCE SEAWAY DEVELOPMENT....65 Communication—ports, docks and anchorages. (a) Every vessel entering or leaving a lake port shall... the harbor entrance. (b) Every vessel arriving at a port, dock or anchorage shall report to the...

33 CFR 401.65 - Communication-ports, docks and anchorages.

Code of Federal Regulations, 2014 CFR

2014-07-01

... anchorages. 401.65 Section 401.65 Navigation and Navigable Waters SAINT LAWRENCE SEAWAY DEVELOPMENT....65 Communication—ports, docks and anchorages. (a) Every vessel entering or leaving a lake port shall... the harbor entrance. (b) Every vessel arriving at a port, dock or anchorage shall report to the...

33 CFR 401.65 - Communication-ports, docks and anchorages.

Code of Federal Regulations, 2011 CFR

2011-07-01

... anchorages. 401.65 Section 401.65 Navigation and Navigable Waters SAINT LAWRENCE SEAWAY DEVELOPMENT....65 Communication—ports, docks and anchorages. (a) Every vessel entering or leaving a lake port shall... the harbor entrance. (b) Every vessel arriving at a port, dock or anchorage shall report to the...

33 CFR 401.65 - Communication-ports, docks and anchorages.

Code of Federal Regulations, 2013 CFR

2013-07-01

... anchorages. 401.65 Section 401.65 Navigation and Navigable Waters SAINT LAWRENCE SEAWAY DEVELOPMENT....65 Communication—ports, docks and anchorages. (a) Every vessel entering or leaving a lake port shall... the harbor entrance. (b) Every vessel arriving at a port, dock or anchorage shall report to the...

33 CFR 401.65 - Communication-ports, docks and anchorages.

Code of Federal Regulations, 2012 CFR

2012-07-01

... anchorages. 401.65 Section 401.65 Navigation and Navigable Waters SAINT LAWRENCE SEAWAY DEVELOPMENT....65 Communication—ports, docks and anchorages. (a) Every vessel entering or leaving a lake port shall... the harbor entrance. (b) Every vessel arriving at a port, dock or anchorage shall report to the...

1. Southwest front, dock no. 491. Aircraft tail extends through ...

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

1. Southwest front, dock no. 491. Aircraft tail extends through gasket in center hangar doors. View to east. - Offutt Air Force Base, Looking Glass Airborne Command Post, Nose Docks, On either side of Hangar Access Apron at Northwest end of Project Looking Glass Historic District, Bellevue, Sarpy County, NE

13. Dry Dock No. 4. Plan. Subdivision IV (Frederic R. ...

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

13. Dry Dock No. 4. Plan. Subdivision IV (Frederic R. Harris, Inc., January 10, 1941). In Files of Cushman & Wakefield, Building No. 501, Philadelphia Naval Business Center. - Naval Base Philadelphia-Philadelphia Naval Shipyard, Dry Dock No. 4, Broad Street south of Government Avenue, Philadelphia, Philadelphia County, PA

10. Dry Dock No. 4. Plan. Subdivision I (Frederic R. ...

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

10. Dry Dock No. 4. Plan. Subdivision I (Frederic R. Harris, Inc., January 10, 1941). In Files of Cushman & Wakefield, Building No. 501, Philadelphia Naval Business Center. - Naval Base Philadelphia-Philadelphia Naval Shipyard, Dry Dock No. 4, Broad Street south of Government Avenue, Philadelphia, Philadelphia County, PA

12. Dry Dock No. 4. Plan. Subdivision III (Frederic R. ...

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

12. Dry Dock No. 4. Plan. Subdivision III (Frederic R. Harris, Inc., January 10, 1941). In Files of Cushman & Wakefield, Building No. 501, Philadelphia Naval Business Center. - Naval Base Philadelphia-Philadelphia Naval Shipyard, Dry Dock No. 4, Broad Street south of Government Avenue, Philadelphia, Philadelphia County, PA

9. Dry Dock No. 4. Typical CrossSections (Frederic R. Harris, ...

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

9. Dry Dock No. 4. Typical Cross-Sections (Frederic R. Harris, Inc., January 10, 1941). In Files of Cushman & Wakefield, Building No. 501, Philadelphia Naval Business Center. - Naval Base Philadelphia-Philadelphia Naval Shipyard, Dry Dock No. 4, Broad Street south of Government Avenue, Philadelphia, Philadelphia County, PA

11. Dry Dock No. 4. Plan. Subdivision II (Frederic R. ...

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

11. Dry Dock No. 4. Plan. Subdivision II (Frederic R. Harris, Inc., January 10, 1941). In Files of Cushman & Wakefield, Building No. 501, Philadelphia Naval Business Center. - Naval Base Philadelphia-Philadelphia Naval Shipyard, Dry Dock No. 4, Broad Street south of Government Avenue, Philadelphia, Philadelphia County, PA

18. Dry Dock No. 4. Entrance Details (Frederic R. Harris, ...

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

18. Dry Dock No. 4. Entrance Details (Frederic R. Harris, Inc., January 10, 1941). In Files of Cushman & Wakefield, Building No. 501, Philadelphia Naval Business Center. - Naval Base Philadelphia-Philadelphia Naval Shipyard, Dry Dock No. 4, Broad Street south of Government Avenue, Philadelphia, Philadelphia County, PA

International Space Station (ISS)

NASA Image and Video Library

2001-09-17

Enroute for docking, the 16-foot-long Russian docking compartment Pirs (the Russian word for pier) approaches the International Space Station (ISS). Pirs will provide a docking port for future Russian Soyuz or Progress craft, as well as an airlock for extravehicular activities. Pirs was launched September 14, 2001 from Baikonur in Russia.

36. ORE DOCK, LOOKING WEST. HULETT UNLOADERS AWAIT THE NEXT ...

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

36. ORE DOCK, LOOKING WEST. HULETT UNLOADERS AWAIT THE NEXT ORE BOAT. BY LATE WINTER, THE ORE STORAGE YARD SEEN AT LEFT WILL BE DEPLETED. - Pennsylvania Railway Ore Dock, Lake Erie at Whiskey Island, approximately 1.5 miles west of Public Square, Cleveland, Cuyahoga County, OH

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.

Game Theoretic Approach to Post-Docked Satellite Control

NASA Technical Reports Server (NTRS)

Hiramatsu, Takashi; Fitz-Coy, Norman G.

2007-01-01

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

Dredging Research Program. Dredge Mooring Study, Recommended Design, Phase 2 Report

DTIC Science & Technology

1992-05-01

describes the amount of dock space and staging area required (250 ft by 300 ft of dock space), crane requirements (a 50- to 60-ton crane ), and time and...including a diver) in 1 week or less (5 days minimum). With the addition of a second crane and second anchor handling vessel, the assembly and installation...describes the amount of dock space and staging area required (250 ft by 300 ft of dock space), crane requirements (a 50- to 60-ton crane ), and time and

Structure-based drug design: docking and scoring.

PubMed

Kroemer, Romano T

2007-08-01

This review gives an introduction into ligand - receptor docking and illustrates the basic underlying concepts. An overview of different approaches and algorithms is provided. Although the application of docking and scoring has led to some remarkable successes, there are still some major challenges ahead, which are outlined here as well. Approaches to address some of these challenges and the latest developments in the area are presented. Some aspects of the assessment of docking program performance are discussed. A number of successful applications of structure-based virtual screening are described.

A multipurpose model of Hermes-Columbus docking mechanism

NASA Technical Reports Server (NTRS)

Gonzalez-Vallejo, J. J.; Fehse, W.; Tobias, A.

1992-01-01

One of the foreseen missions of the HERMES spacevehicle is the servicing to the Columbus Free Flying Laboratory (MTFF). Docking between the two spacecraft is a critical operation in which the Docking Mechanism (DM) has a major role. In order to analyze and assess robustness of initially selected concepts and to identify suitable implementation solutions, through the investigation of main parameters involved in the docking functions, a multipurpose model of DM was developed and tested. This paper describes the main design features as well as the process of calibrating and testing.

7. SHEET 1, CONTROL HOUSE FOR DRY DOCK. United Engineering ...

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

7. SHEET 1, CONTROL HOUSE FOR DRY DOCK. United Engineering Company Ltd., Alameda Shipyard, Ship Repair Facilities, Office Building. Plans, elevations, sections, details. John Hudspeth, Architect, at foot of Main Street, Alameda, Calif. Sheet no. 1 of 2 sheets, Plan no. 10,507. Various scales. January 4, 1943, last revised 1/28/43. U.S. Navy, Bureau of Yards & Docks, Contract no. bs 76. Approved for construction October 9, 1943. blueprint - United Engineering Company Shipyard, Control House for Dry Dock, 2900 Main Street, Alameda, Alameda County, CA

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.

Linear Actuator System for the NASA Docking System

NASA Technical Reports Server (NTRS)

Dick, Brandon; Oesch, Chris

2017-01-01

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

Modeling complexes of modeled proteins.

PubMed

Anishchenko, Ivan; Kundrotas, Petras J; Vakser, Ilya A

2017-03-01

Structural characterization of proteins is essential for understanding life processes at the molecular level. However, only a fraction of known proteins have experimentally determined structures. This fraction is even smaller for protein-protein complexes. Thus, structural modeling of protein-protein interactions (docking) primarily has to rely on modeled structures of the individual proteins, which typically are less accurate than the experimentally determined ones. Such "double" modeling is the Grand Challenge of structural reconstruction of the interactome. Yet it remains so far largely untested in a systematic way. We present a comprehensive validation of template-based and free docking on a set of 165 complexes, where each protein model has six levels of structural accuracy, from 1 to 6 Å C α RMSD. Many template-based docking predictions fall into acceptable quality category, according to the CAPRI criteria, even for highly inaccurate proteins (5-6 Å RMSD), although the number of such models (and, consequently, the docking success rate) drops significantly for models with RMSD > 4 Å. The results show that the existing docking methodologies can be successfully applied to protein models with a broad range of structural accuracy, and the template-based docking is much less sensitive to inaccuracies of protein models than the free docking. Proteins 2017; 85:470-478. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

The RCAN carboxyl end mediates calcineurin docking-dependent inhibition via a site that dictates binding to substrates and regulators

PubMed Central

Martínez-Martínez, Sara; Genescà, Lali; Rodríguez, Antonio; Raya, Alicia; Salichs, Eulàlia; Were, Felipe; López-Maderuelo, María Dolores; Redondo, Juan Miguel; de la Luna, Susana

2009-01-01

Specificity of signaling kinases and phosphatases toward their targets is usually mediated by docking interactions with substrates and regulatory proteins. Here, we characterize the motifs involved in the physical and functional interaction of the phosphatase calcineurin with a group of modulators, the RCAN protein family. Mutation of key residues within the hydrophobic docking-cleft of the calcineurin catalytic domain impairs binding to all human RCAN proteins and to the calcineurin interacting proteins Cabin1 and AKAP79. A valine-rich region within the RCAN carboxyl region is essential for binding to the docking site in calcineurin. Although a peptide containing this sequence compromises NFAT signaling in living cells, it does not inhibit calcineurin catalytic activity directly. Instead, calcineurin catalytic activity is inhibited by a motif at the extreme C-terminal region of RCAN, which acts in cis with the docking motif. Our results therefore indicate that the inhibitory action of RCAN on calcineurin-NFAT signaling results not only from the inhibition of phosphatase activity but also from competition between NFAT and RCAN for binding to the same docking site in calcineurin. Thus, competition by substrates and modulators for a common docking site appears to be an essential mechanism in the regulation of Ca2+-calcineurin signaling. PMID:19332797

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/.

ClusPro: an automated docking and discrimination method for the prediction of protein complexes.

PubMed

Comeau, Stephen R; Gatchell, David W; Vajda, Sandor; Camacho, Carlos J

2004-01-01

Predicting protein interactions is one of the most challenging problems in functional genomics. Given two proteins known to interact, current docking methods evaluate billions of docked conformations by simple scoring functions, and in addition to near-native structures yield many false positives, i.e. structures with good surface complementarity but far from the native. We have developed a fast algorithm for filtering docked conformations with good surface complementarity, and ranking them based on their clustering properties. The free energy filters select complexes with lowest desolvation and electrostatic energies. Clustering is then used to smooth the local minima and to select the ones with the broadest energy wells-a property associated with the free energy at the binding site. The robustness of the method was tested on sets of 2000 docked conformations generated for 48 pairs of interacting proteins. In 31 of these cases, the top 10 predictions include at least one near-native complex, with an average RMSD of 5 A from the native structure. The docking and discrimination method also provides good results for a number of complexes that were used as targets in the Critical Assessment of PRedictions of Interactions experiment. The fully automated docking and discrimination server ClusPro can be found at http://structure.bu.edu

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

PubMed

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

2014-10-01

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

Connection stiffness and dynamical docking process of flux pinned spacecraft modules

NASA Astrophysics Data System (ADS)

Lu, Yong; Zhang, Mingliang; Gao, Dong

2014-02-01

This paper describes a novel kind of potential flux pinned docking system that consists of guidance navigation and control system, the traditional extrusion type propulsion system, and a flux pinned docking interface. Because of characteristics of passive stability of flux pinning, the docking control strategy of flux pinned docking system only needs a series of sequential control rather than necessary active feedback control, as well as avoidance of hazardous collision accident. The flux pinned force between YBaCuO (YBCO) high temperature superconductor bulk and permanent magnet is able to be given vent based on the identical current loop model and improved image dipole model, which can be validated experimentally. Thus, the connection stiffness between two flux pinned spacecraft modules can be calculated based on Hooke's law. This connection stiffness matrix at the equilibrium position has the positive definite performance, which can validate the passively stable connection of two flux pinned spacecraft modules theoretically. Furthermore, the relative orbital dynamical equation of two flux pinned spacecraft modules can be established based on Clohessy-Wiltshire's equations and improved image dipole model. The dynamical docking process between two flux pinned spacecraft modules can be obtained by way of numerical simulation, which suggests the feasibility of flux pinned docking system.

Preliminary GN&C Design for the On-Orbit Autonomous Assembly of Nanosatellite Demonstration Mission

NASA Technical Reports Server (NTRS)

Pei, Jing; Walsh, Matt; Roithmayr, Carlos; Karlgaard, Chris; Peck, Mason; Murchison, Luke

2017-01-01

Small spacecraft autonomous rendezvous and docking (ARD) is an essential technology for future space structure assembly missions. The On-orbit Autonomous Assembly of Nanosatellites (OAAN) team at NASA Langley Research Center (LaRC) intends to demonstrate the technology to autonomously dock two nanosatellites to form an integrated system. The team has developed a novel magnetic capture and latching mechanism that allows for docking of two CubeSats without precise sensors and actuators. The proposed magnetic docking hardware not only provides the means to latch the CubeSats, but it also significantly increases the likelihood of successful docking in the presence of relative attitude and position errors. The simplicity of the design allows it to be implemented on many CubeSat rendezvous missions. Prior to demonstrating the docking subsystem capabilities on orbit, the GN&C subsystem should have a robust design such that it is capable of bringing the CubeSats from an arbitrary initial separation distance of as many as a few thousand kilometers down to a few meters. The main OAAN Mission can be separated into the following phases: 1) Launch, checkout, and drift, 2) Far-Field Rendezvous or Drift Recovery, 3) Proximity Operations, 4) Docking. This paper discusses the preliminary GN&C design and simulation results for each phase of the mission.

Connection stiffness and dynamical docking process of flux pinned spacecraft modules

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

Lu, Yong; Zhang, Mingliang, E-mail: niudun12@126.com; Gao, Dong

2014-02-14

This paper describes a novel kind of potential flux pinned docking system that consists of guidance navigation and control system, the traditional extrusion type propulsion system, and a flux pinned docking interface. Because of characteristics of passive stability of flux pinning, the docking control strategy of flux pinned docking system only needs a series of sequential control rather than necessary active feedback control, as well as avoidance of hazardous collision accident. The flux pinned force between YBaCuO (YBCO) high temperature superconductor bulk and permanent magnet is able to be given vent based on the identical current loop model and improvedmore » image dipole model, which can be validated experimentally. Thus, the connection stiffness between two flux pinned spacecraft modules can be calculated based on Hooke's law. This connection stiffness matrix at the equilibrium position has the positive definite performance, which can validate the passively stable connection of two flux pinned spacecraft modules theoretically. Furthermore, the relative orbital dynamical equation of two flux pinned spacecraft modules can be established based on Clohessy-Wiltshire's equations and improved image dipole model. The dynamical docking process between two flux pinned spacecraft modules can be obtained by way of numerical simulation, which suggests the feasibility of flux pinned docking system.« less

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

Wendt, P.H.; Van Dolah, R.F.; Bobo, M.Y.

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

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 fragment assembly constraints are also helping to make possible docking-based predictions of large multimeric protein complexes. In the near future, the closer integration of docking algorithms with protein interface prediction software, structural databases, and sequence analysis techniques should help produce better predictions of protein interaction networks and more accurate structural models of the fundamental molecular interactions within the cell.

Do Clinical Results and Return-to-Sport Rates After Ulnar Collateral Ligament Reconstruction Differ Based on Graft Choice and Surgical Technique?

PubMed Central

Erickson, Brandon J.; Cvetanovich, Gregory L.; Frank, Rachel M.; Bach, Bernard R.; Cohen, Mark S.; Bush-Joseph, Charles A.; Cole, Brian J.; Romeo, Anthony A.

2016-01-01

Background: Ulnar collateral ligament reconstruction (UCLR) has become a common procedure performed in overhead-throwing athletes of many athletic levels. Purpose/Hypothesis: The purpose of this study was to determine whether clinical outcomes and return-to-sport (RTS) rates differ among patients undergoing UCLR based on graft choice, surgical technique, athletic competition level, handedness, and treatment of the ulnar nerve. We hypothesized that no differences would exist in clinical outcomes or RTS rates between technique, graft choice, or other variables. Study Design: Cohort study; Level of evidence, 3. Methods: All patients who underwent UCLR from January 1, 2004 through December 31, 2014 at a single institution were identified. Charts were reviewed to determine patient age, sex, date of surgery, sport played, handedness, athletic level, surgical technique, graft type, and complications. Patients were contacted via telephone to obtain the RTS rate, Conway-Jobe score, Timmerman-Andrews score, and Kerlan-Jobe Orthopaedic Clinic (KJOC) Shoulder and Elbow score. Results: Eighty-five patients (mean age at surgery, 19.3 ± 4.7 years; 92% male; 78% right hand–dominant) underwent UCLR between 2004 and 2014 and were available for follow-up. Overall, 87% were baseball pitchers, 49.4% were college athletes, and 41.2% were high school athletes. No significant difference existed between the docking and double-docking techniques, graft choice, handedness, sex, activity level, and treatment of the ulnar nerve with regard to clinical outcomes, RTS, or subsequent surgeries (all P > .05). More complications were seen in the docking technique compared with the double-docking technique (P = .036). Hamstring autograft was used more commonly with the docking technique (P = .023) while allograft was used more commonly with the double-docking technique (P = .0006). Conclusion: Both the docking and double-docking techniques produce excellent clinical outcomes in patients undergoing UCLR. No difference in outcome scores was seen between surgical technique or graft type. The double-docking technique had fewer complications than the docking technique. PMID:27896290

Machine Vision for Relative Spacecraft Navigation During Approach to Docking

NASA Technical Reports Server (NTRS)

Chien, Chiun-Hong; Baker, Kenneth

2011-01-01

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

Computational Exploration of a Protein Receptor Binding Space with Student Proposed Peptide Ligands

PubMed Central

King, Matthew D.; Phillips, Paul; Turner, Matthew W.; Katz, Michael; Lew, Sarah; Bradburn, Sarah; Andersen, Tim; Mcdougal, Owen M.

2017-01-01

Computational molecular docking is a fast and effective in silico method for the analysis of binding between a protein receptor model and a ligand. The visualization and manipulation of protein to ligand binding in three-dimensional space represents a powerful tool in the biochemistry curriculum to enhance student learning. The DockoMatic tutorial described herein provides a framework by which instructors can guide students through a drug screening exercise. Using receptor models derived from readily available protein crystal structures, docking programs have the ability to predict ligand binding properties, such as preferential binding orientations and binding affinities. The use of computational studies can significantly enhance complimentary wet chemical experimentation by providing insight into the important molecular interactions within the system of interest, as well as guide the design of new candidate ligands based on observed binding motifs and energetics. In this laboratory tutorial, the graphical user interface, DockoMatic, facilitates docking job submissions to the docking engine, AutoDock 4.2. The purpose of this exercise is to successfully dock a 17-amino acid peptide, α-conotoxin TxIA, to the acetylcholine binding protein from Aplysia californica-AChBP to determine the most stable binding configuration. Each student will then propose two specific amino acid substitutions of α-conotoxin TxIA to enhance peptide binding affinity, create the mutant in DockoMatic, and perform docking calculations to compare their results with the class. Students will also compare intermolecular forces, binding energy, and geometric orientation of their prepared analog to their initial α-conotoxin TxIA docking results. PMID:26537635

Docking screens: right for the right reasons?

PubMed

Kolb, Peter; Irwin, John J

2009-01-01

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

Improving Docking Performance Using Negative Image-Based Rescoring.

PubMed

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

2018-01-01

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

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.

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.

1. CONTEXTUAL VIEW OF DRY DOCK NO. 4, LOOKING NORTHEAST ...

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

1. CONTEXTUAL VIEW OF DRY DOCK NO. 4, LOOKING NORTHEAST FROM ROOF OF BUILDING NO. 620. NOTE OVERHEAD CRANE (STRUCTURE NO. 1043) AND STRUCTURAL ASSEMBLY SHOP (BUILDING NO. 541) IN LEFT BACKGROUND. - Naval Base Philadelphia-Philadelphia Naval Shipyard, Dry Dock No. 4, Broad Street south of Government Avenue, Philadelphia, Philadelphia County, PA

17. Dry Dock No. 4. Longitudinal Section. Subdivision V and ...

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

17. Dry Dock No. 4. Longitudinal Section. Subdivision V and Stair Details (Frederic R. Harris, Inc., January 10, 1941). In Files of Cushman & Wakefield, Building No. 501, Philadelphia Naval Business Center. - Naval Base Philadelphia-Philadelphia Naval Shipyard, Dry Dock No. 4, Broad Street south of Government Avenue, Philadelphia, Philadelphia County, PA

15. Dry Dock No. 4. Longitudinal Section. Subdivision Nos. I ...

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

15. Dry Dock No. 4. Longitudinal Section. Subdivision Nos. I and II (Frederic R. Harris, Inc., January 10, 1941). In Files of Cushman & Wakefield, Building no. 501, Philadelphia Naval Business Center. - Naval Base Philadelphia-Philadelphia Naval Shipyard, Dry Dock No. 4, Broad Street south of Government Avenue, Philadelphia, Philadelphia County, PA

16. Dry Dock No. 4. Longitudinal Section. Subdivision Nos. III ...

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

16. Dry Dock No. 4. Longitudinal Section. Subdivision Nos. III and IV (Frederic R. Harris, Inc., January 10, 1941). In Files of Cushman & Wakefield, Building no. 501, Philadelphia Naval Business Center. - Naval Base Philadelphia-Philadelphia Naval Shipyard, Dry Dock No. 4, Broad Street south of Government Avenue, Philadelphia, Philadelphia County, PA

19. Dry Dock No. 4. Details of Drainage and Filling ...

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

19. Dry Dock No. 4. Details of Drainage and Filling Culverts (Frederic R. Harris, Inc., November 1, 1941). In Files of Cushman & Wakefield, Building No. 501, Philadelphia Naval Business Center. - Naval Base Philadelphia-Philadelphia Naval Shipyard, Dry Dock No. 4, Broad Street south of Government Avenue, Philadelphia, Philadelphia County, PA

The Effects of Tail Docking Method on Piglets' Behavioral Responses to a Formalin Pain Test

USDA-ARS?s Scientific Manuscript database

Routine piglet production procedures, for example teeth clipping, tail docking and castration, most likely cause pain and are under increasing scrutiny from the animal rights lobby. The objectives of this study were to assess the impact of 2 alternative methods of tail-docking on subsequent response...

14. Dry Dock No. 4. Plan of subdivision V and ...

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

14. Dry Dock No. 4. Plan of subdivision V and Welding Set Platform Details (Frederick R. Harris, Inc., January 10, 1941). In Files of Cushman & Wakefield, Building No. 501, Philadelphia Naval Business Center. - Naval Base Philadelphia-Philadelphia Naval Shipyard, Dry Dock No. 4, Broad Street south of Government Avenue, Philadelphia, Philadelphia County, PA

Connecting in Space: Docking with the International Space Station. Educational Brief.

ERIC Educational Resources Information Center

National Aeronautics and Space Administration, Washington, DC.

This brief discusses the space shuttle and the docking procedures used with the International Space Station (ISS). Using this activity designed for grades 5-12, students demonstrate and identify procedures for determining the best method for completing the docking activity. Students will also study and identify Newton's Laws of Motion. A mockup…

78 FR 46925 - Western Pacific Fishery Management Council; Public Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-02

... Commercial Dock Development Study A. Contract and Project Status B. Overview of draft Dock Development Plan.... Land-side support facilities a. Outer Cove Mariana b. Puerto Rico Dump c. Echo Dock d. Sea Plan Ramp iv. Environmental Consideration and Permits v. Discussion on Preferred Site Location C. Evaluation of Preliminary...

Mir Mission Chronicle

NASA Technical Reports Server (NTRS)

McDonald, Sue

1998-01-01

Dockings, module additions, configuration changes, crew changes, and major mission events are tracked for Mir missions 17 through 21 (November 1994 through August 1996). The international aspects of these missions are presented, comprising joint missions with ESA and NASA, including three U.S. Space Shuttle dockings. New Mir modules described are Spektr, the Docking Module, and Priroda.

Protein-protein interaction specificity is captured by contact preferences and interface composition.

PubMed

Nadalin, Francesca; Carbone, Alessandra

2018-02-01

Large-scale computational docking will be increasingly used in future years to discriminate protein-protein interactions at the residue resolution. Complete cross-docking experiments make in silico reconstruction of protein-protein interaction networks a feasible goal. They ask for efficient and accurate screening of the millions structural conformations issued by the calculations. We propose CIPS (Combined Interface Propensity for decoy Scoring), a new pair potential combining interface composition with residue-residue contact preference. CIPS outperforms several other methods on screening docking solutions obtained either with all-atom or with coarse-grain rigid docking. Further testing on 28 CAPRI targets corroborates CIPS predictive power over existing methods. By combining CIPS with atomic potentials, discrimination of correct conformations in all-atom structures reaches optimal accuracy. The drastic reduction of candidate solutions produced by thousands of proteins docked against each other makes large-scale docking accessible to analysis. CIPS source code is freely available at http://www.lcqb.upmc.fr/CIPS. alessandra.carbone@lip6.fr. Supplementary data are available at Bioinformatics online. © The Author(s) 2017. Published by Oxford University Press.

Molecular docking studies of curcumin natural derivatives with DNA topoisomerase I and II-DNA complexes.

PubMed

Kumar, Anil; Bora, Utpal

2014-12-01

DNA topoisomerase I (topo I) and II (topo II) are essential enzymes that solve the topological problems of DNA by allowing DNA strands or double helices to pass through each other during cellular processes such as replication, transcription, recombination, and chromatin remodeling. Their critical roles make topoisomerases an attractive drug target against cancer. The present molecular docking study provides insights into the inhibition of topo I and II by curcumin natural derivatives. The binding modes suggested that curcumin natural derivatives docked at the site of DNA cleavage parallel to the axis of DNA base pairing. Cyclocurcumin and curcumin sulphate were predicted to be the most potent inhibitors amongst all the curcumin natural derivatives docked. The binding modes of cyclocurcumin and curcumin sulphate were similar to known inhibitors of topo I and II. Residues like Arg364, Asn722 and base A113 (when docked to topo I-DNA complex) and residues Asp479, Gln778 and base T9 (when docked to topo II-DNA complex) seem to play important role in the binding of curcumin natural derivatives at the site of DNA cleavage.

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.

A dynamic motion simulator for future European docking systems

NASA Technical Reports Server (NTRS)

Brondino, G.; Marchal, PH.; Grimbert, D.; Noirault, P.

1990-01-01

Europe's first confrontation with docking in space will require extensive testing to verify design and performance and to qualify hardware. For this purpose, a Docking Dynamics Test Facility (DDTF) was developed. It allows reproduction on the ground of the same impact loads and relative motion dynamics which would occur in space during docking. It uses a 9 degree of freedom, servo-motion system, controlled by a real time computer, which simulates the docking spacecraft in a zero-g environment. The test technique involves and active loop based on six axis force and torque detection, a mathematical simulation of individual spacecraft dynamics, and a 9 degree of freedom servomotion of which 3 DOFs allow extension of the kinematic range to 5 m. The configuration was checked out by closed loop tests involving spacecraft control models and real sensor hardware. The test facility at present has an extensive configuration that allows evaluation of both proximity control and docking systems. It provides a versatile tool to verify system design, hardware items and performance capabilities in the ongoing HERMES and COLUMBUS programs. The test system is described and its capabilities are summarized.

Assessing the binding of cholinesterase inhibitors by docking and molecular dynamics studies.

PubMed

Ali, M Rejwan; Sadoqi, Mostafa; Møller, Simon G; Boutajangout, Allal; Mezei, Mihaly

2017-09-01

In this report we assessed by docking and molecular dynamics the binding mechanisms of three FDA-approved Alzheimer drugs, inhibitors of the enzyme acetylcholinesterase (AChE): donepezil, galantamine and rivastigmine. Dockings by the softwares Autodock-Vina, PatchDock and Plant reproduced the docked conformations of the inhibitor-enzyme complexes within 2Å of RMSD of the X-ray structure. Free-energy scores show strong affinity of the inhibitors for the enzyme binding pocket. Three independent Molecular Dynamics simulation runs indicated general stability of donepezil, galantamine and rivastigmine in their respective enzyme binding pocket (also referred to as gorge) as well as the tendency to form hydrogen bonds with the water molecules. The binding of rivastigmine in the Torpedo California AChE binding pocket is interesting as it eventually undergoes carbamylation and breaks apart according to the X-ray structure of the complex. Similarity search in the ZINC database and targeted docking on the gorge region of the AChE enzyme gave new putative inhibitor molecules with high predicted binding affinity, suitable for potential biophysical and biological assessments. Copyright © 2017 Elsevier Inc. All rights reserved.

Implementation of the Hungarian Algorithm to Account for Ligand Symmetry and Similarity in Structure-Based Design

PubMed Central

2015-01-01

False negative docking outcomes for highly symmetric molecules are a barrier to the accurate evaluation of docking programs, scoring functions, and protocols. This work describes an implementation of a symmetry-corrected root-mean-square deviation (RMSD) method into the program DOCK based on the Hungarian algorithm for solving the minimum assignment problem, which dynamically assigns atom correspondence in molecules with symmetry. The algorithm adds only a trivial amount of computation time to the RMSD calculations and is shown to increase the reported overall docking success rate by approximately 5% when tested over 1043 receptor–ligand systems. For some families of protein systems the results are even more dramatic, with success rate increases up to 16.7%. Several additional applications of the method are also presented including as a pairwise similarity metric to compare molecules during de novo design, as a scoring function to rank-order virtual screening results, and for the analysis of trajectories from molecular dynamics simulation. The new method, including source code, is available to registered users of DOCK6 (http://dock.compbio.ucsf.edu). PMID:24410429

Molecular Docking Studies of Flavonoids Derivatives on the Flavonoid 3- O-Glucosyltransferase.

PubMed

Harsa, Alexandra M; Harsa, Teodora E; Diudea, Mircea V; Janezic, Dusanka

2015-01-01

A study of 30 flavonoid derivatives, taken from PubChem database and docked on flavonoid 3-O-glucosyltransferase 3HBF, next submitted to a QSAR study, performed within a hypermolecule frame, to model their LD50 values, is reported. The initial set of molecules was split into a training set and the test set (taken from the best scored molecules in the docking test); the predicted LD50 values, computed on similarity clusters, built up for each of the molecules of the test set, surpassed in accuracy the best model. The binding energies to 3HBF protein, provided by the docking step, are not related to the LD50 of these flavonoids, more protein targets are to be investigated in this respect. However, the docking step was useful in choosing the test set of molecules.

Knowing when to give up: early-rejection stratagems in ligand docking

NASA Astrophysics Data System (ADS)

Skone, Gwyn; Voiculescu, Irina; Cameron, Stephen

2009-10-01

Virtual screening is an important resource in the drug discovery community, of which protein-ligand docking is a significant part. Much software has been developed for this purpose, largely by biochemists and those in related disciplines, who pursue ever more accurate representations of molecular interactions. The resulting tools, however, are very processor-intensive. This paper describes some initial results from a project to review computational chemistry techniques for docking from a non-chemistry standpoint. An abstract blueprint for protein-ligand docking using empirical scoring functions is suggested, and this is used to discuss potential improvements. By introducing computer science tactics such as lazy function evaluation, dramatic increases to throughput can and have been realized using a real-world docking program. Naturally, they can be extended to any system that approximately corresponds to the architecture outlined.

STS-74 leaves O&C Building for TCDT

NASA Technical Reports Server (NTRS)

1995-01-01

The STS-74 flight crew walks out of the Operations and Checkout Building on their way to conduct Terminal Countdown Demostration Test (TCDT) exercises while aboard the Space Shuttle orbiter Atlantis at Launch Pad 39A. They are (from right): Mission Commander Kenneth Cameron; Pilot James Halsell; and Mission Specialists William McArthur Jr., Chris Hadfield, and Jerry Ross (back). Hadfield is an international mission specialist representing the Canadian Space Agency. This flight will feature the second docking of the Space Shuttle with the Russian Mir space station. Docking operations will be conducted with the Russian-built Docking Module attached to the end of the Orbiter Docking System (ODS) located in Atlantis payload bay. The DM will be left attached to the Mir when Atlantis undocks. This module will serve as a means to improve future Shuttle-Mir docking operations.

Role of mammalian homologue of Caenorhabditis elegans unc-13-1 (Munc13-1) in the recruitment of newcomer insulin granules in both first and second phases of glucose-stimulated insulin secretion in mouse islets.

PubMed

Xie, L; Zhu, D; Gaisano, H Y

2012-10-01

We have previously reported that the haplodeficient Munc13-1(+/-) mouse exhibits impaired biphasic glucose-stimulated insulin secretion (GSIS), causing glucose intolerance mimicking type 2 diabetes. Glucagon-like peptide-1 (GLP-1) can bypass these insulin-secretory defects in type 2 diabetes, but the mechanism of exocytotic events mediated by GLP-1 in rescuing insulin secretion is unclear. The total internal reflection fluorescence microscopy (TIRFM) technique was used to examine single insulin granule fusion events in mouse islet beta cells. There was no difference in the density of docked granules in the resting state between Munc13-1(+/+) and Munc13-1(+/-) mouse islet beta cells. While exocytosis of previously docked granules in Munc13-1(+/-) beta cells is reduced during high-K(+) stimulation as expected, we now find a reduction in additional exocytosis events that account for the major portion of GSIS, namely two types of newcomer granules, one which has a short docking time (short-dock) and another undergoing no docking before exocytosis (no-dock). As mammalian homologue of Caenorhabditis elegans unc-13-1 (Munc13-1) is a phorbol ester substrate, phorbol ester could partially rescue biphasic GSIS in Munc13-1-deficient beta cells by enhancing recruitment of short-dock newcomer granules for exocytosis. The more effective rescue of biphasic GSIS by GLP-1 than by phorbol was due to increased recruitment of both short-dock and no-dock newcomer granules. Phorbol ester and GLP-1 potentiation of biphasic GSIS are brought about by recruitment of distinct populations of newcomer granules for exocytosis, which may be mediated by Munc13-1 interaction with syntaxin-SNARE complexes other than that formed by syntaxin-1A.

CDOCKER and lambda λ -dynamics for prospective prediction in D3R Grand Challenge 2

NASA Astrophysics Data System (ADS)

Ding, Xinqiang; Hayes, Ryan L.; Vilseck, Jonah Z.; Charles, Murchtricia K.; Brooks, Charles L.

2018-01-01

The opportunity to prospectively predict ligand bound poses and free energies of binding to the Farnesoid X Receptor in the D3R Grand Challenge 2 provided a useful exercise to evaluate CHARMM based docking (CDOCKER) and λ-dynamics methodologies for use in "real-world" applications in computer aided drug design. In addition to measuring their current performance, several recent methodological developments have been analyzed retrospectively to highlight best procedural practices in future applications. For pose prediction with CDOCKER, when the protein structure used for rigid receptor docking was close to the crystallographic holo structure, reliable poses were obtained. Benzimidazoles, with a known holo receptor structure, were successfully docked with an average RMSD of 0.97 Å. Other non-benzimidazole ligands displayed less accuracy largely because the receptor structures we chose for docking were too different from the experimental holo structures. However, retrospective analysis has shown that when these ligands were re-docked into their holo structures, the average RMSD dropped to 1.18 Å for all ligands. When sulfonamides and spiros were docked with the apo structure, which agrees more with their holo structure than the structures we chose, five out of six ligands were correctly docked. These docking results emphasize the need for flexible receptor docking approaches. For λ-dynamics techniques, including multisite λ-dynamics (MSλD), reasonable agreement with experiment was observed for the 33 ligands investigated; root mean square errors of 2.08 and 1.67 kcal/mol were obtained for free energy sets 1 and 2, respectively. Retrospectively, soft-core potentials, adaptive landscape flattening, and biasing potential replica exchange (BP-REX) algorithms were critical to model large substituent perturbations with sufficient precision and within restrictive timeframes, such as was required with participation in Grand Challenge 2. These developments, their associated benefits, and proposed procedures for their use in future applications are discussed.

CDOCKER and λ-dynamics for prospective prediction in D₃R Grand Challenge 2.

PubMed

Ding, Xinqiang; Hayes, Ryan L; Vilseck, Jonah Z; Charles, Murchtricia K; Brooks, Charles L

2018-01-01

The opportunity to prospectively predict ligand bound poses and free energies of binding to the Farnesoid X Receptor in the D3R Grand Challenge 2 provided a useful exercise to evaluate CHARMM based docking (CDOCKER) and [Formula: see text]-dynamics methodologies for use in "real-world" applications in computer aided drug design. In addition to measuring their current performance, several recent methodological developments have been analyzed retrospectively to highlight best procedural practices in future applications. For pose prediction with CDOCKER, when the protein structure used for rigid receptor docking was close to the crystallographic holo structure, reliable poses were obtained. Benzimidazoles, with a known holo receptor structure, were successfully docked with an average RMSD of 0.97 [Formula: see text]. Other non-benzimidazole ligands displayed less accuracy largely because the receptor structures we chose for docking were too different from the experimental holo structures. However, retrospective analysis has shown that when these ligands were re-docked into their holo structures, the average RMSD dropped to 1.18 [Formula: see text] for all ligands. When sulfonamides and spiros were docked with the apo structure, which agrees more with their holo structure than the structures we chose, five out of six ligands were correctly docked. These docking results emphasize the need for flexible receptor docking approaches. For [Formula: see text]-dynamics techniques, including multisite [Formula: see text]-dynamics (MS[Formula: see text]D), reasonable agreement with experiment was observed for the 33 ligands investigated; root mean square errors of 2.08 and 1.67 kcal/mol were obtained for free energy sets 1 and 2, respectively. Retrospectively, soft-core potentials, adaptive landscape flattening, and biasing potential replica exchange (BP-REX) algorithms were critical to model large substituent perturbations with sufficient precision and within restrictive timeframes, such as was required with participation in Grand Challenge 2. These developments, their associated benefits, and proposed procedures for their use in future applications are discussed.

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 then, investigate the trajectories of both satellites to take place the successful capture process.

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.

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. In addition, the testing of the brassboard and proto-type NGAVGS units will be discussed along with the use of the NGAVGS as a proximity operations and docking sensor.

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.

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 the Conference on the Role of Simulation in Space Technology, August 17-21, 1964.

Improved Ball-and-Socket Docking Mechanism

NASA Technical Reports Server (NTRS)

Cloyd, Richard; Bryan, Tom

2004-01-01

A proposed docking mechanism would form a ball-and-socket joint in the docked condition. The mechanism could tolerate significant initial misalignment because it would include an alignment cone that would guide the ball into the socket. Like other ball-and-socket joints, the joint would have three rotational degrees of freedom. This docking mechanism would be a successor to the one described in Passive Capture Joint With Three Degrees of Freedom (MFS-31146), NASA Tech Briefs, Vol. 22, No. 7 (July 1998), page 65. It would contain most of the components of the prior mechanism, plus some additional components that would expand its capabilities.

Towards the development of universal, fast and highly accurate docking/scoring methods: a long way to go

PubMed Central

Moitessier, N; Englebienne, P; Lee, D; Lawandi, J; Corbeil, C R

2008-01-01

Accelerating the drug discovery process requires predictive computational protocols capable of reducing or simplifying the synthetic and/or combinatorial challenge. Docking-based virtual screening methods have been developed and successfully applied to a number of pharmaceutical targets. In this review, we first present the current status of docking and scoring methods, with exhaustive lists of these. We next discuss reported comparative studies, outlining criteria for their interpretation. In the final section, we describe some of the remaining developments that would potentially lead to a universally applicable docking/scoring method. PMID:18037925

Molecular Docking Studies of Catechin and Its Derivatives as Anti-bacterial Inhibitor for Glucosamine-6-Phosphate Synthase

NASA Astrophysics Data System (ADS)

Fikrika, H.; Ambarsari, L.; Sumaryada, T.

2016-01-01

Molecular docking simulation of catechin and its derivatives on Glucosamine-6- Phosphate Synthase (GlmS) has been performed in this research. GlmS inhibition by a particular ligand will suppress the production of bacterial cell wall and significantly reduce the population of invading bacteria. In this study, catechin derivatives i.e epicatechin, galloatechin and epigalloatechin were found to have stronger binding affinities as compared to natural ligand of GlmS, Fructose-6-Phosphate (F6P). Those three ligands were docked on the same pocket in GlmS target as F6P, with 70% binding sites similarity. Based on the docking results, gallocatechin turns out to be the most potent ligand for anti-bacterial agent with ΔG= -8.00 kcal/mol. The docking between GlmS and catechin derivatives are characterized by a constant present of a strong hydrogen bond between functional group O3 and Ser-349. This hydrogen bond most likely plays a significant role in the docking mechanism and binding modes selection. The surprising result is catechin itself exhibited a quite strong binding with GlmS (ΔG= -7.80 kcal.mol), but docked on a completely different pocket compared to other ligands. This results suggest that catechin might still have a curing effect but with a completely different pathway and mechanism as compared to its derivatives.

Structure-based design and evaluation of novel N-phenyl-1H-indol-2-amine derivatives for fat mass and obesity-associated (FTO) protein inhibition.

PubMed

Padariya, Monikaben; Kalathiya, Umesh

2016-10-01

Fat mass and obesity-associated (FTO) protein contributes to non-syndromic human obesity which refers to excessive fat accumulation in human body and results in health risk. FTO protein has become a promising target for anti-obesity medicines as there is an immense need for the rational design of potent inhibitors to treat obesity. In our study, a new scaffold N-phenyl-1H-indol-2-amine was selected as a base for FTO protein inhibitors by applying scaffold hopping approach. Using this novel scaffold, different derivatives were designed by extending scaffold structure with potential functional groups. Molecular docking simulations were carried out by using two different docking algorithm implemented in CDOCKER (flexible docking) and AutoDock programs (rigid docking). Analyzing results of rigid and flexible docking, compound MU06 was selected based on different properties and predicted binding affinities for further analysis. Molecular dynamics simulation of FTO/MU06 complex was performed to characterize structure rationale and binding stability. Certainly, Arg96 and His231 residue of FTO protein showed stable interaction with inhibitor MU06 throughout the production dynamics phase. Three residues of FTO protein (Arg96, Asp233, and His231) were found common in making H-bond interactions with MU06 during molecular dynamics simulation and CDOCKER docking. Copyright © 2016 Elsevier Ltd. All rights reserved.

Docking and molecular dynamics simulation of quinone compounds with trypanocidal activity.

PubMed

de Molfetta, Fábio Alberto; de Freitas, Renato Ferreira; da Silva, Albérico Borges Ferreira; Montanari, Carlos Alberto

2009-10-01

In this work, two different docking programs were used, AutoDock and FlexX, which use different types of scoring functions and searching methods. The docking poses of all quinone compounds studied stayed in the same region in the trypanothione reductase. This region is a hydrophobic pocket near to Phe396, Pro398 and Leu399 amino acid residues. The compounds studied displays a higher affinity in trypanothione reductase (TR) than glutathione reductase (GR), since only two out of 28 quinone compounds presented more favorable docking energy in the site of human enzyme. The interaction of quinone compounds with the TR enzyme is in agreement with other studies, which showed different binding sites from the ones formed by cysteines 52 and 58. To verify the results obtained by docking, we carried out a molecular dynamics simulation with the compounds that presented the highest and lowest docking energies. The results showed that the root mean square deviation (RMSD) between the initial and final pose were very small. In addition, the hydrogen bond pattern was conserved along the simulation. In the parasite enzyme, the amino acid residues Leu399, Met400 and Lys402 are replaced in the human enzyme by Met406, Tyr407 and Ala409, respectively. In view of the fact that Leu399 is an amino acid of the Z site, this difference could be explored to design selective inhibitors of TR.

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 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)

33 CFR 165.504 - Newport News Shipbuilding and Dry Dock Company Shipyard, James River, Newport News, Va.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 33 Navigation and Navigable Waters 2 2014-07-01 2014-07-01 false Newport News Shipbuilding and Dry Dock Company Shipyard, James River, Newport News, Va. 165.504 Section 165.504 Navigation and Navigable... Coast Guard District § 165.504 Newport News Shipbuilding and Dry Dock Company Shipyard, James River...

33 CFR 165.504 - Newport News Shipbuilding and Dry Dock Company Shipyard, James River, Newport News, Va.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 33 Navigation and Navigable Waters 2 2011-07-01 2011-07-01 false Newport News Shipbuilding and Dry Dock Company Shipyard, James River, Newport News, Va. 165.504 Section 165.504 Navigation and Navigable... Coast Guard District § 165.504 Newport News Shipbuilding and Dry Dock Company Shipyard, James River...

33 CFR 165.504 - Newport News Shipbuilding and Dry Dock Company Shipyard, James River, Newport News, Va.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 33 Navigation and Navigable Waters 2 2013-07-01 2013-07-01 false Newport News Shipbuilding and Dry Dock Company Shipyard, James River, Newport News, Va. 165.504 Section 165.504 Navigation and Navigable... Coast Guard District § 165.504 Newport News Shipbuilding and Dry Dock Company Shipyard, James River...

33 CFR 165.504 - Newport News Shipbuilding and Dry Dock Company Shipyard, James River, Newport News, Va.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false Newport News Shipbuilding and Dry Dock Company Shipyard, James River, Newport News, Va. 165.504 Section 165.504 Navigation and Navigable... Coast Guard District § 165.504 Newport News Shipbuilding and Dry Dock Company Shipyard, James River...

33 CFR 165.504 - Newport News Shipbuilding and Dry Dock Company Shipyard, James River, Newport News, Va.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 33 Navigation and Navigable Waters 2 2012-07-01 2012-07-01 false Newport News Shipbuilding and Dry Dock Company Shipyard, James River, Newport News, Va. 165.504 Section 165.504 Navigation and Navigable... Coast Guard District § 165.504 Newport News Shipbuilding and Dry Dock Company Shipyard, James River...

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)

"Soft docking": matching of molecular surface cubes.

PubMed

Jiang, F; Kim, S H

1991-05-05

Molecular recognition is achieved through the complementarity of molecular surface structures and energetics with, most commonly, associated minor conformational changes. This complementarity can take many forms: charge-charge interaction, hydrogen bonding, van der Waals' interaction, and the size and shape of surfaces. We describe a method that exploits these features to predict the sites of interactions between two cognate molecules given their three-dimensional structures. We have developed a "cube representation" of molecular surface and volume which enables us not only to design a simple algorithm for a six-dimensional search but also to allow implicitly the effects of the conformational changes caused by complex formation. The present molecular docking procedure may be divided into two stages. The first is the selection of a population of complexes by geometric "soft docking", in which surface structures of two interacting molecules are matched with each other, allowing minor conformational changes implicitly, on the basis of complementarity in size and shape, close packing, and the absence of steric hindrance. The second is a screening process to identify a subpopulation with many favorable energetic interactions between the buried surface areas. Once the size of the subpopulation is small, one may further screen to find the correct complex based on other criteria or constraints obtained from biochemical, genetic, and theoretical studies, including visual inspection. We have tested the present method in two ways. First is a control test in which we docked the components of a molecular complex of known crystal structure available in the Protein Data Bank (PDB). Two molecular complexes were used: (1) a ternary complex of dihydrofolate reductase, NADPH and methotrexate (3DFR in PDB) and (2) a binary complex of trypsin and trypsin inhibitor (2PTC in PDB). The components of each complex were taken apart at an arbitrary relative orientation and then docked together again. The results show that the geometric docking alone is sufficient to determine the correct docking solutions in these ideal cases, and that the cube representation of the molecules does not degrade the docking process in the search for the correct solution. The second is the more realistic experiment in which we docked the crystal structures of uncomplexed molecules and then compared the structures of docked complexes with the crystal structures of the corresponding complexes. This is to test the capability of our method in accommodating the effects of the conformational changes in the binding sites of the molecules in docking.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

Modulation of interaction of mutant TP53 and wild type BRCA1 by alkaloids: a computational approach towards targeting protein-protein interaction as a futuristic therapeutic intervention strategy for breast cancer impediment.

PubMed

Tiwari, Sameeksha; Awasthi, Manika; Singh, Swati; Pandey, Veda P; Dwivedi, Upendra N

2017-10-23

Protein-protein interactions (PPI) are a new emerging class of novel therapeutic targets. In order to probe these interactions, computational tools provide a convenient and quick method towards the development of therapeutics. Keeping this in view the present study was initiated to analyse interaction of tumour suppressor protein p53 (TP53) and breast cancer associated protein (BRCA1) as promising target against breast cancer. Using computational approaches such as protein-protein docking, hot spot analyses, molecular docking and molecular dynamics simulation (MDS), stepwise analyses of the interactions of the wild type and mutant TP53 with that of wild type BRCA1 and their modulation by alkaloids were done. Protein-protein docking method was used to generate both wild type and mutant complexes of TP53-BRCA1. Subsequently, the complexes were docked using sixteen different alkaloids, fulfilling ADMET and Lipinski's rule of five criteria, and were compared with that of a well-known inhibitor of PPI, namely nutlin. The alkaloid dicentrine was found to be the best docked alkaloid among all the docked alklaloids as well as that of nutlin. Furthermore, MDS analyses of both wild type and mutant complexes with the best docked alkaloid i.e. dicentrine, revealed higher stability of mutant complex than that of the wild one, in terms of average RMSD, RMSF and binding free energy, corroborating the results of docking. Results suggested more pronounced interaction of BRCA1 with mutant TP53 leading to increased expression of mutated TP53 thus showing a dominant negative gain of function and hampering wild type TP53 function leading to tumour progression.

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.

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

NASA Astrophysics Data System (ADS)

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

2017-06-01

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

Distilling the essential features of a protein surface for improving protein-ligand docking, scoring, and virtual screening

NASA Astrophysics Data System (ADS)

Zavodszky, Maria I.; Sanschagrin, Paul C.; Kuhn, Leslie A.; Korde, Rajesh S.

2002-12-01

For the successful identification and docking of new ligands to a protein target by virtual screening, the essential features of the protein and ligand surfaces must be captured and distilled in an efficient representation. Since the running time for docking increases exponentially with the number of points representing the protein and each ligand candidate, it is important to place these points where the best interactions can be made between the protein and the ligand. This definition of favorable points of interaction can also guide protein structure-based ligand design, which typically focuses on which chemical groups provide the most energetically favorable contacts. In this paper, we present an alternative method of protein template and ligand interaction point design that identifies the most favorable points for making hydrophobic and hydrogen-bond interactions by using a knowledge base. The knowledge-based protein and ligand representations have been incorporated in version 2.0 of SLIDE and resulted in dockings closer to the crystal structure orientations when screening a set of 57 known thrombin and glutathione S-transferase (GST) ligands against the apo structures of these proteins. There was also improved scoring enrichment of the dockings, meaning better differentiation between the chemically diverse known ligands and a ˜15,000-molecule dataset of randomly-chosen small organic molecules. This approach for identifying the most important points of interaction between proteins and their ligands can equally well be used in other docking and design techniques. While much recent effort has focused on improving scoring functions for protein-ligand docking, our results indicate that improving the representation of the chemistry of proteins and their ligands is another avenue that can lead to significant improvements in the identification, docking, and scoring of ligands.

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.

Role of binding entropy in the refinement of protein-ligand docking predictions: analysis based on the use of 11 scoring functions.

PubMed

Ruvinsky, Anatoly M

2007-06-01

We present results of testing the ability of eleven popular scoring functions to predict native docked positions using a recently developed method (Ruvinsky and Kozintsev, J Comput Chem 2005, 26, 1089) for estimation the entropy contributions of relative motions to protein-ligand binding affinity. The method is based on the integration of the configurational integral over clusters obtained from multiple docked positions. We use a test set of 100 PDB protein-ligand complexes and ensembles of 101 docked positions generated by (Wang et al. J Med Chem 2003, 46, 2287) for each ligand in the test set. To test the suggested method we compared the averaged root-mean square deviations (RMSD) of the top-scored ligand docked positions, accounting and not accounting for entropy contributions, relative to the experimentally determined positions. We demonstrate that the method increases docking accuracy by 10-21% when used in conjunction with the AutoDock scoring function, by 2-25% with G-Score, by 7-41% with D-Score, by 0-8% with LigScore, by 1-6% with PLP, by 0-12% with LUDI, by 2-8% with F-Score, by 7-29% with ChemScore, by 0-9% with X-Score, by 2-19% with PMF, and by 1-7% with DrugScore. We also compared the performance of the suggested method with the method based on ranking by cluster occupancy only. We analyze how the choice of a clustering-RMSD and a low bound of dense clusters impacts on docking accuracy of the scoring methods. We derive optimal intervals of the clustering-RMSD for 11 scoring functions.

Comparing sixteen scoring functions for predicting biological activities of ligands for protein targets.

PubMed

Xu, Weijun; Lucke, Andrew J; Fairlie, David P

2015-04-01

Accurately predicting relative binding affinities and biological potencies for ligands that interact with proteins remains a significant challenge for computational chemists. Most evaluations of docking and scoring algorithms have focused on enhancing ligand affinity for a protein by optimizing docking poses and enrichment factors during virtual screening. However, there is still relatively limited information on the accuracy of commercially available docking and scoring software programs for correctly predicting binding affinities and biological activities of structurally related inhibitors of different enzyme classes. Presented here is a comparative evaluation of eight molecular docking programs (Autodock Vina, Fitted, FlexX, Fred, Glide, GOLD, LibDock, MolDock) using sixteen docking and scoring functions to predict the rank-order activity of different ligand series for six pharmacologically important protein and enzyme targets (Factor Xa, Cdk2 kinase, Aurora A kinase, COX-2, pla2g2a, β Estrogen receptor). Use of Fitted gave an excellent correlation (Pearson 0.86, Spearman 0.91) between predicted and experimental binding only for Cdk2 kinase inhibitors. FlexX and GOLDScore produced good correlations (Pearson>0.6) for hydrophilic targets such as Factor Xa, Cdk2 kinase and Aurora A kinase. By contrast, pla2g2a and COX-2 emerged as difficult targets for scoring functions to predict ligand activities. Although possessing a high hydrophobicity in its binding site, β Estrogen receptor produced reasonable correlations using LibDock (Pearson 0.75, Spearman 0.68). These findings can assist medicinal chemists to better match scoring functions with ligand-target systems for hit-to-lead optimization using computer-aided drug design approaches. Copyright © 2015 Elsevier Inc. All rights reserved.

Computational exploration of a protein receptor binding space with student proposed peptide ligands.

PubMed

King, Matthew D; Phillips, Paul; Turner, Matthew W; Katz, Michael; Lew, Sarah; Bradburn, Sarah; Andersen, Tim; McDougal, Owen M

2016-01-01

Computational molecular docking is a fast and effective in silico method for the analysis of binding between a protein receptor model and a ligand. The visualization and manipulation of protein to ligand binding in three-dimensional space represents a powerful tool in the biochemistry curriculum to enhance student learning. The DockoMatic tutorial described herein provides a framework by which instructors can guide students through a drug screening exercise. Using receptor models derived from readily available protein crystal structures, docking programs have the ability to predict ligand binding properties, such as preferential binding orientations and binding affinities. The use of computational studies can significantly enhance complimentary wet chemical experimentation by providing insight into the important molecular interactions within the system of interest, as well as guide the design of new candidate ligands based on observed binding motifs and energetics. In this laboratory tutorial, the graphical user interface, DockoMatic, facilitates docking job submissions to the docking engine, AutoDock 4.2. The purpose of this exercise is to successfully dock a 17-amino acid peptide, α-conotoxin TxIA, to the acetylcholine binding protein from Aplysia californica-AChBP to determine the most stable binding configuration. Each student will then propose two specific amino acid substitutions of α-conotoxin TxIA to enhance peptide binding affinity, create the mutant in DockoMatic, and perform docking calculations to compare their results with the class. Students will also compare intermolecular forces, binding energy, and geometric orientation of their prepared analog to their initial α-conotoxin TxIA docking results. © 2015 The International Union of Biochemistry and Molecular Biology.

The Next Generation Advanced Video Guidance Sensor: Flight Heritage and Current Development

NASA Technical Reports Server (NTRS)

Howard, Richard T.; Bryan, Thomas C.

2009-01-01

The Next Generation Advanced Video Guidance Sensor (NGAVGS) is the latest in a line of sensors that have flown four times in the last 10 years. The NGAVGS has been under development for the last two 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. This paper presents the flight heritage and results of the sensor technology, some hardware trades for the current sensor, and discusses 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. In addition, the testing of the various NGAVGS development units will be discussed along with the use of the NGAVGS as a proximity operations and docking sensor.

New insights about HERG blockade obtained from protein modeling, potential energy mapping, and docking studies.

PubMed

Farid, Ramy; Day, Tyler; Friesner, Richard A; Pearlstein, Robert A

2006-05-01

We created a homology model of the homo-tetrameric pore domain of HERG using the crystal structure of the bacterial potassium channel, KvAP, as a template. We docked a set of known blockers with well-characterized effects on channel function into the lumen of the pore between the selectivity filter and extracellular entrance using a novel docking and refinement procedure incorporating Glide and Prime. Key aromatic groups of the blockers are predicted to form multiple simultaneous ring stacking and hydrophobic interactions among the eight aromatic residues lining the pore. Furthermore, each blocker can achieve these interactions via multiple docking configurations. To further interpret the docking results, we mapped hydrophobic and hydrophilic potentials within the lumen of each refined docked complex. Hydrophilic iso-potential contours define a 'propeller-shaped' volume at the selectivity filter entrance. Hydrophobic contours define a hollow 'crown-shaped' volume located above the 'propeller', whose hydrophobic 'rim' extends along the pore axis between Tyr652 and Phe656. Blockers adopt conformations/binding orientations that closely mimic the shapes and properties of these contours. Blocker basic groups are localized in the hydrophilic 'propeller', forming electrostatic interactions with Ser624 rather than a generally accepted pi-cation interaction with Tyr652. Terfenadine, cisapride, sertindole, ibutilide, and clofilium adopt similar docked poses, in which their N-substituents bridge radially across the hollow interior of the 'crown' (analogous to the hub and spokes of a wheel), and project aromatic/hydrophobic portions into the hydrophobic 'rim'. MK-499 docks with its longitudinal axis parallel to the axis of the pore and 'crown', and its hydrophobic groups buried within the hydrophobic 'rim'.

Methodology for Developing a Probabilistic Risk Assessment Model of Spacecraft Rendezvous and Dockings

NASA Technical Reports Server (NTRS)

Farnham, Steven J., II; Garza, Joel, Jr.; Castillo, Theresa M.; Lutomski, Michael

2011-01-01

In 2007 NASA was preparing to send two new visiting vehicles carrying logistics and propellant to the International Space Station (ISS). These new vehicles were the European Space Agency s (ESA) Automated Transfer Vehicle (ATV), the Jules Verne, and the Japanese Aerospace and Explorations Agency s (JAXA) H-II Transfer Vehicle (HTV). The ISS Program wanted to quantify the increased risk to the ISS from these visiting vehicles. At the time, only the Shuttle, the Soyuz, and the Progress vehicles rendezvoused and docked to the ISS. The increased risk to the ISS was from an increase in vehicle traffic, thereby, increasing the potential catastrophic collision during the rendezvous and the docking or berthing of the spacecraft to the ISS. A universal method of evaluating the risk of rendezvous and docking or berthing was created by the ISS s Risk Team to accommodate the increasing number of rendezvous and docking or berthing operations due to the increasing number of different spacecraft, as well as the future arrival of commercial spacecraft. Before the first docking attempt of ESA's ATV and JAXA's HTV to the ISS, a probabilistic risk model was developed to quantitatively calculate the risk of collision of each spacecraft with the ISS. The 5 rendezvous and docking risk models (Soyuz, Progress, Shuttle, ATV, and HTV) have been used to build and refine the modeling methodology for rendezvous and docking of spacecrafts. This risk modeling methodology will be NASA s basis for evaluating the addition of future ISS visiting spacecrafts hazards, including SpaceX s Dragon, Orbital Science s Cygnus, and NASA s own Orion spacecraft. This paper will describe the methodology used for developing a visiting vehicle risk model.

JADOPPT: java based AutoDock preparing and processing tool.

PubMed

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

2017-02-15

AutoDock is a very popular software package for docking and virtual screening. However, currently it is hard work to visualize more than one result from the virtual screening at a time. To overcome this limitation we have designed JADOPPT, a tool for automatically preparing and processing multiple ligand-protein docked poses obtained from AutoDock. It allows the simultaneous visual assessment and comparison of multiple poses through clustering methods. Moreover, it permits the representation of reference ligands with known binding modes, binding site residues, highly scoring regions for the ligand, and the calculated binding energy of the best ranked results. JADOPPT, supplementary material (Case Studies 1 and 2) and video tutorials are available at http://visualanalytics.land/cgarcia/JADOPPT.html. carlosgarcia@usal.es or pelaez@usal.es. Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Apollo Docking with the LEM Target

NASA Image and Video Library

2012-09-07

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. This picture shows a later configuration of the Apollo docking with the LEM target. 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.

FPGA acceleration of rigid-molecule docking codes

PubMed Central

Sukhwani, B.; Herbordt, M.C.

2011-01-01

Modelling the interactions of biological molecules, or docking, is critical both to understanding basic life processes and to designing new drugs. The field programmable gate array (FPGA) based acceleration of a recently developed, complex, production docking code is described. The authors found that it is necessary to extend their previous three-dimensional (3D) correlation structure in several ways, most significantly to support simultaneous computation of several correlation functions. The result for small-molecule docking is a 100-fold speed-up of a section of the code that represents over 95% of the original run-time. An additional 2% is accelerated through a previously described method, yielding a total acceleration of 36× over a single core and 10× over a quad-core. This approach is found to be an ideal complement to graphics processing unit (GPU) based docking, which excels in the protein–protein domain. PMID:21857870

Supervised machine learning techniques to predict binding affinity. A study for cyclin-dependent kinase 2.

PubMed

de Ávila, Maurício Boff; Xavier, Mariana Morrone; Pintro, Val Oliveira; de Azevedo, Walter Filgueira

2017-12-09

Here we report the development of a machine-learning model to predict binding affinity based on the crystallographic structures of protein-ligand complexes. We used an ensemble of crystallographic structures (resolution better than 1.5 Å resolution) for which half-maximal inhibitory concentration (IC 50 ) data is available. Polynomial scoring functions were built using as explanatory variables the energy terms present in the MolDock and PLANTS scoring functions. Prediction performance was tested and the supervised machine learning models showed improvement in the prediction power, when compared with PLANTS and MolDock scoring functions. In addition, the machine-learning model was applied to predict binding affinity of CDK2, which showed a better performance when compared with AutoDock4, AutoDock Vina, MolDock, and PLANTS scores. Copyright © 2017 Elsevier Inc. All rights reserved.

Fusion competent synaptic vesicles persist upon active zone disruption and loss of vesicle docking

PubMed Central

Wang, Shan Shan H.; Held, Richard G.; Wong, Man Yan; Liu, Changliang; Karakhanyan, Aziz; Kaeser, Pascal S.

2016-01-01

In a nerve terminal, synaptic vesicle docking and release are restricted to an active zone. The active zone is a protein scaffold that is attached to the presynaptic plasma membrane and opposed to postsynaptic receptors. Here, we generated conditional knockout mice removing the active zone proteins RIM and ELKS, which additionally led to loss of Munc13, Bassoon, Piccolo, and RIM-BP, indicating disassembly of the active zone. We observed a near complete lack of synaptic vesicle docking and a strong reduction in vesicular release probability and the speed of exocytosis, but total vesicle numbers, SNARE protein levels, and postsynaptic densities remained unaffected. Despite loss of the priming proteins Munc13 and RIM and of docked vesicles, a pool of releasable vesicles remained. Thus, the active zone is necessary for synaptic vesicle docking and to enhance release probability, but releasable vesicles can be localized distant from the presynaptic plasma membrane. PMID:27537483

Centrosome docking at the immunological synapse is controlled by Lck signaling

PubMed Central

Tsun, Andy; Qureshi, Ihjaaz; Stinchcombe, Jane C.; Jenkins, Misty R.; de la Roche, Maike; Kleczkowska, Joanna; Zamoyska, Rose

2011-01-01

Docking of the centrosome at the plasma membrane directs lytic granules to the immunological synapse. To identify signals controlling centrosome docking at the synapse, we have studied cytotoxic T lymphocytes (CTLs) in which expression of the T cell receptor–activated tyrosine kinase Lck is ablated. In the absence of Lck, the centrosome is able to translocate around the nucleus toward the immunological synapse but is unable to dock at the plasma membrane. Lytic granules fail to polarize and release their contents, and target cells are not killed. In CTLs deficient in both Lck and the related tyrosine kinase Fyn, centrosome translocation is impaired, and the centrosome remains on the distal side of the nucleus relative to the synapse. These results show that repositioning of the centrosome in CTLs involves at least two distinct steps, with Lck signaling required for the centrosome to dock at the plasma membrane. PMID:21339332

SPACEHAB module at LC-39B for STS-76

NASA Technical Reports Server (NTRS)

1996-01-01

At Launch Pad 39B, the SPACEHAB module has been installed in the payload bay of the Space Shuttle Atlantis, which was rolled out to the pad a day previously. Already located in the payload bay was the Orbiter Docking System (ODS), to which the SPACEHAB was connected via a tunnel. During the upcoming flight of Atlantis on Mission STS-76, the ODS will be docked to the Docking Module located on the Kristall module docking port on the Russian Space Station Mir. The SPACEHAB will be filled with Russian and U.S. logistics equipment for transfer to Mir. Also located in the mini-research laboratory is the European Space Agency's Biorack, which houses experiments to be conducted by the U.S. astronauts during the nine-day flight. Atlantis is scheduled to lift off on the third Shuttle-Mir docking mission on March 21.

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.

The Importance of Ligand Conformational Energies in Carbohydrate Docking: Sorting the Wheat from the Chaff

PubMed Central

Nivedha, Anita K.; Makeneni, Spandana; Foley, B. Lachele; Tessier, Matthew B.; Woods, Robert J.

2014-01-01

Docking algorithms that aim to be applicable to a broad range of ligands suffer reduced accuracy because they are unable to incorporate ligand-specific conformational energies. Here, we develop internal energy functions, Carbohydrate Intrinsic (CHI), to account for the rotational preferences of the glycosidic torsion angles in carbohydrates. The relative energies predicted by the CHI energy functions mirror the conformational distributions of glycosidic linkages determined from a survey of oligosaccharide-protein complexes in the Protein Data Bank. Addition of CHI energies to the standard docking scores in Autodock 3, 4.2, and Vina consistently improves pose ranking of oligosaccharides docked to a set of anti-carbohydrate antibodies. The CHI energy functions are also independent of docking algorithm, and with minor modifications, may be incorporated into both theoretical modeling methods, and experimental NMR or X-ray structure refinement programs. PMID:24375430

Dissecting Nck/Dock signaling pathways in Drosophila visual system.

PubMed

Rao, Yong

2005-01-01

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

Dissecting Nck/Dock Signaling Pathways in Drosophila Visual System

PubMed Central

2005-01-01

The establishment of neuronal connections during embryonic development requires the precise guidance and targeting of the neuronal growth cone, an expanded cellular structure at the leading tip of a growing axon. The growth cone contains sophisticated signaling systems that allow the rapid communication between guidance receptors and the actin cytoskeleton in generating directed motility. Previous studies demonstrated a specific role for the Nck/Dock SH2/SH3 adapter protein in photoreceptor (R cell) axon guidance and target recognition in the Drosophila visual system, suggesting strongly that Nck/Dock is one of the long-sought missing links between cell surface receptors and the actin cytoskeleton. In this review, I discuss the recent progress on dissecting the Nck/Dock signaling pathways in R-cell growth cones. These studies have identified additional key components of the Nck/Dock signaling pathways for linking the receptor signaling to the remodeling of the actin cytoskeleton in controlling growth-cone motility. PMID:15951852

Trio combines with dock to regulate Pak activity during photoreceptor axon pathfinding in Drosophila.

PubMed

Newsome, T P; Schmidt, S; Dietzl, G; Keleman, K; Asling, B; Debant, A; Dickson, B J

2000-04-28

Correct pathfinding by Drosophila photoreceptor axons requires recruitment of p21-activated kinase (Pak) to the membrane by the SH2-SH3 adaptor Dock. Here, we identify the guanine nucleotide exchange factor (GEF) Trio as another essential component in photoreceptor axon guidance. Regulated exchange activity of one of the two Trio GEF domains is critical for accurate pathfinding. This GEF domain activates Rac, which in turn activates Pak. Mutations in trio result in projection defects similar to those observed in both Pak and dock mutants, and trio interacts genetically with Rac, Pak, and dock. These data define a signaling pathway from Trio to Rac to Pak that links guidance receptors to the growth cone cytoskeleton. We propose that distinct signals transduced via Trio and Dock act combinatorially to activate Pak in spatially restricted domains within the growth cone, thereby controlling the direction of axon extension.

Prediction of protein-peptide interactions: application of the XPairIt API to anthrax lethal factor and substrates

NASA Astrophysics Data System (ADS)

Hurley, Margaret M.; Sellers, Michael S.

2013-05-01

As software and methodology develop, key aspects of molecular interactions such as detailed energetics and flexibility are continuously better represented in docking simulations. In the latest iteration of the XPairIt API and Docking Protocol, we perform a blind dock of a peptide into the cleavage site of the Anthrax lethal factor (LF) metalloprotein. Molecular structures are prepared from RCSB:1JKY and we demonstrate a reasonably accurate docked peptide through analysis of protein motion and, using NCI Plot, visualize and characterize the forces leading to binding. We compare our docked structure to the 1JKY crystal structure and the more recent 1PWV structure, and discuss both captured and overlooked interactions. Our results offer a more detailed look at secondary contact and show that both van der Waals and electrostatic interactions from peptide residues further from the enzyme's catalytic site are significant.

Virtual Screening with AutoDock: Theory and Practice

PubMed Central

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

2011-01-01

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

Astronaut Vance Brand seen in hatchway leading to Apollo Docking module

NASA Technical Reports Server (NTRS)

1975-01-01

Astronaut Vance D. Brand, command module pilot of the American Apollo Soyuz Test Project (ASTP) crew, is seen in the hatchway leading from the Apollo Command Module (CM) into the Apollo Docking Module (DM) during joint U.S.-USSR ASTP docking in Earth orbit mission. The 35mm camera is looking from the DM into the CM.

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

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)

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)

Dynamic Docking Test System (DDTS) active table computer program NASA Advanced Docking System (NADS)

NASA Technical Reports Server (NTRS)

Gates, R. M.; Jantz, R. E.

1974-01-01

A computer program was developed to describe the three-dimensional motion of the Dynamic Docking Test System active table. The input consists of inertia and geometry data, actuator structural data, forcing function data, hydraulics data, servo electronics data, and integration control data. The output consists of table responses, actuator bending responses, and actuator responses.

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)

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)

Apollo 7/S-IVB Rendezvous in space

NASA Technical Reports Server (NTRS)

1968-01-01

The expended Saturn IVB stage as photographed from the Apollo 7 spacecraft during transposition and docking maneuvers. This photograph was taken over Sonora, Mexico, during Apollo 7's second revolution of the Earth. The round, white disc inside the open panels of the Saturn IVB is a simulated docking target similar to that used on the lunar module for docking during lunar missions.

78 FR 25069 - South Carolina Electric & Gas Company; Notice of Application Accepted for Filing and Soliciting...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-29

... Murray Docks, Inc./Windward Point Yacht Club to use project waters to expand an existing boat dock facility through the addition of an 8-slip floating dock to accommodate a maximum of 12 additional boats. The proposed new structures would be for the private use of members of the Windward Point Yacht Club...

Terminal Homing for Autonomous Underwater Vehicle Docking

DTIC Science & Technology

2016-06-01

underwater domain, accurate navigation. Above the water, light and electromagnetic signals travel well through air and space, mediums that allow for a...DISTRIBUTION CODE 13. ABSTRACT The use of docking stations for autonomous underwater vehicles (AUV) provides the ability to keep a vehicle on...Mechanical and Aerospace Engineering iv THIS PAGE INTENTIONALLY LEFT BLANK v ABSTRACT The use of docking stations for autonomous underwater

Astronaut Brand and Cosmonaut Ivanchenko in Docking Module trainer

NASA Technical Reports Server (NTRS)

1974-01-01

Astronaut Vance D. Brand (foreground) and Cosmonaut Aleksandr S. Ivanchenko are seated in the Docking Module trainer in bldg 35 during Apollo Soyuz Test Project (ASTP) simulation training at JSC. Brand is the command module pilot of the American ASTP prime crew. Ivanchenko is the engineer on the Soviet ASTP fourth crew (back-up). During the exercise the American ASTP crew and the Soviet ASTP crew simulated docking the Apollo and Soyuz in Earth orbit and transferring to each other's spacecraft. This view is looking from inside the Command Module into the Docking Module. The hatchway leading into the Soyuz spacecraft orbital module mock-up is in the background.

System and Method for Automated Rendezvous, Docking and Capture of Autonomous Underwater Vehicles

NASA Technical Reports Server (NTRS)

Clark, Evan (Inventor); Richmond, Kristof (Inventor); Paulus, Jeremy (Inventor); Kimball, Peter (Inventor); Scully, Mark (Inventor); Kapit, Jason (Inventor); Stone, William C. (Inventor)

2018-01-01

A system for automated rendezvous, docking, and capture of autonomous underwater vehicles at the conclusion of a mission comprising of comprised of a docking rod having lighted, pulsating (in both frequency and light intensity) series of LED light strips thereon, with the LEDs at a known spacing, and the autonomous underwater vehicle specially designed to detect and capture the docking rod and then be lifted structurally by a spherical end strop about which the vehicle can be pivoted and hoisted up (e.g., onto a ship). The method of recovery allows for very routine and reliable automated recovery of an unmanned underwater asset.

Electro-optical rendezvous and docking sensors

NASA Technical Reports Server (NTRS)

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

1991-01-01

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

KSC-98pc222

NASA Image and Video Library

1998-01-22

The Space Shuttle Endeavour cuts a bright swath through the dark sky as it blazes a trail toward the Russian Space Station Mir. Endeavour lifted off successfully at its scheduled time of 9:48:15 p.m. EST on Jan. 22 from Pad 39A. STS-89 is the eighth docking with the Russian Space Station Mir, the first Mir docking for Endeavour (all previous dockings were made by Atlantis), and the first launch of 1998. After docking with Mir, Mission Specialist Andrew Thomas, Ph.D., will transfer to the space station, succeeding David Wolf, M.D., who will return to Earth aboard Endeavour. Dr. Thomas will live and work on Mir until June

KSC-98pc223

NASA Image and Video Library

1998-01-22

The Space Shuttle Endeavour cuts a bright swath through the dark sky as it blazes a trail toward the Russian Space Station Mir. Endeavour lifted off successfully at its scheduled time of 9:48:15 p.m. EST on Jan. 22 from Pad 39A. STS-89 is the eighth docking with the Russian Space Station Mir, the first Mir docking for Endeavour (all previous dockings were made by Atlantis), and the first launch of 1998. After docking with Mir, Mission Specialist Andrew Thomas, Ph.D., will transfer to the space station, succeeding David Wolf, M.D., who will return to Earth aboard Endeavour. Dr. Thomas will live and work on Mir until June

CD147 regulates cancer migration via direct interaction with Annexin A2 and DOCK3-β-catenin-WAVE2 signaling.

PubMed

Cui, Hong-Yong; Wang, Shi-Jie; Miao, Ji-Yu; Fu, Zhi-Guang; Feng, Fei; Wu, Jiao; Yang, Xiang-Min; Chen, Zhi-Nan; Jiang, Jian-Li

2016-02-02

The acquisition of inappropriate migratory feature is crucial for tumor metastasis. It has been suggested that CD147 and Annexin A2 are involved in regulating tumor cell movement, while the regulatory mechanisms are far from clear. In this study, we demonstrated that CD147 physically interacted with the N-terminal domain of Annexin A2 and decreased Annexin A2 phosphorylation on tyrosine 23. In vitro kinase assay showed that the I domain of CD147 was indispensable for CD147-mediated downregulation of Annexin A2 phosphorylation by Src. Furthermore, we determined that p-Annexin A2 promoted the expression of dedicator of cytokinesis 3 (DOCK3) and DOCK3 blocked β-catenin nuclear translocation, resulting in inhibition of β-catenin signaling. In addition, DOCK3 inhibited lamellipodium dynamics and tumor cell movement. Also, we found that β-catenin signaling increased WAVE2 expression. Therefore, DOCK3 was characterized as a negative regulator of WAVE2 expression via inhibiting β-catenin signaling. Our study provides the first evidence that CD147 promotes tumor cell movement and metastasis via direct interaction with Annexin A2 and DOCK3-β-catenin-WAVE2 signaling axis.

The Advanced Video Guidance Sensor: Orbital Express and the Next Generation

NASA Technical Reports Server (NTRS)

Howard, Richard T.; Heaton, Andrew F.; Pinson, Robin M.; Carrington, Connie L.; Lee, James E.; Bryan, Thomas C.; Robertson, Bryan A.; Spencer, Susan H.; Johnson, Jimmie E.

2008-01-01

The Orbital Express (OE) mission performed the first autonomous rendezvous and docking in the history of the United States on May 5-6, 2007 with the Advanced Video Guidance Sensor (AVGS) acting as one of the primary docking sensors. Since that event, the OE spacecraft performed four more rendezvous and docking maneuvers, each time using the AVGS as one of the docking sensors. The Marshall Space Flight Center's (MSFC's) AVGS is a nearfield proximity operations sensor that was integrated into the Autonomous Rendezvous and Capture Sensor System (ARCSS) on OE. The ARCSS provided the relative state knowledge to allow the OE spacecraft to rendezvous and dock. The AVGS is a mature sensor technology designed to support Automated Rendezvous and Docking (AR&D) operations. It is a video-based laser-illuminated sensor that can determine the relative position and attitude between itself and its target. Due to parts obsolescence, the AVGS that was flown on OE can no longer be manufactured. MSFC has been working on the next generation of AVGS for application to future Constellation missions. This paper provides an overview of the performance of the AVGS on Orbital Express and discusses the work on the Next Generation AVGS (NGAVGS).

A benchmark testing ground for integrating homology modeling and protein docking.

PubMed

Bohnuud, Tanggis; Luo, Lingqi; Wodak, Shoshana J; Bonvin, Alexandre M J J; Weng, Zhiping; Vajda, Sandor; Schueler-Furman, Ora; Kozakov, Dima

2017-01-01

Protein docking procedures carry out the task of predicting the structure of a protein-protein complex starting from the known structures of the individual protein components. More often than not, however, the structure of one or both components is not known, but can be derived by homology modeling on the basis of known structures of related proteins deposited in the Protein Data Bank (PDB). Thus, the problem is to develop methods that optimally integrate homology modeling and docking with the goal of predicting the structure of a complex directly from the amino acid sequences of its component proteins. One possibility is to use the best available homology modeling and docking methods. However, the models built for the individual subunits often differ to a significant degree from the bound conformation in the complex, often much more so than the differences observed between free and bound structures of the same protein, and therefore additional conformational adjustments, both at the backbone and side chain levels need to be modeled to achieve an accurate docking prediction. In particular, even homology models of overall good accuracy frequently include localized errors that unfavorably impact docking results. The predicted reliability of the different regions in the model can also serve as a useful input for the docking calculations. Here we present a benchmark dataset that should help to explore and solve combined modeling and docking problems. This dataset comprises a subset of the experimentally solved 'target' complexes from the widely used Docking Benchmark from the Weng Lab (excluding antibody-antigen complexes). This subset is extended to include the structures from the PDB related to those of the individual components of each complex, and hence represent potential templates for investigating and benchmarking integrated homology modeling and docking approaches. Template sets can be dynamically customized by specifying ranges in sequence similarity and in PDB release dates, or using other filtering options, such as excluding sets of specific structures from the template list. Multiple sequence alignments, as well as structural alignments of the templates to their corresponding subunits in the target are also provided. The resource is accessible online or can be downloaded at http://cluspro.org/benchmark, and is updated on a weekly basis in synchrony with new PDB releases. Proteins 2016; 85:10-16. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Spacecraft flight simulation: A human factors investigation into the man-machine interface between an astronaut and a spacecraft performing docking maneuvers and other proximity operations

NASA Technical Reports Server (NTRS)

Brody, Adam R.

1988-01-01

The anticipated increase in rendezvous and docking activities in the various space programs in the Space Station era necessitates a renewed interest in manual docking procedures. Ten test subjects participated in computer simulated docking missions in which the influence of initial velocity was examined. All missions started from a resting position of 304.8 meters (1000 feet) along the space station's +V-bar axis. Test subjects controlled their vehicle with a translational hand controller and digital auto pilot which are both virtually identical to their space shuttle counterparts. While the 0.1 percent rule (range rate is equal to 0.1 percent of the range) used by space shuttle pilots is comfortably safe, it is revealed to be extremely inefficient in terms of time and not justifiable in terms of marginal safety. Time is worth money, not only because of training and launch costs, but because the sooner a pilot and spacecraft return from a mission, the sooner they can begin the next one. Inexperienced test subjects reduced the costs of simulated docking by close to a factor of 2 and achieved safe dockings in less than 4 percent of the time the baseline approach would entail. This reduction in time can be used to save lives in the event of an accident on orbit, and can tremendously reduce docking costs if fuel is produced from waste water on orbit.

Conformational Heterogeneity of Unbound Proteins Enhances Recognition in Protein-Protein Encounters.

PubMed

Pallara, Chiara; Rueda, Manuel; Abagyan, Ruben; Fernández-Recio, Juan

2016-07-12

To understand cellular processes at the molecular level we need to improve our knowledge of protein-protein interactions, from a structural, mechanistic, and energetic point of view. Current theoretical studies and computational docking simulations show that protein dynamics plays a key role in protein association and support the need for including protein flexibility in modeling protein interactions. Assuming the conformational selection binding mechanism, in which the unbound state can sample bound conformers, one possible strategy to include flexibility in docking predictions would be the use of conformational ensembles originated from unbound protein structures. Here we present an exhaustive computational study about the use of precomputed unbound ensembles in the context of protein docking, performed on a set of 124 cases of the Protein-Protein Docking Benchmark 3.0. Conformational ensembles were generated by conformational optimization and refinement with MODELLER and by short molecular dynamics trajectories with AMBER. We identified those conformers providing optimal binding and investigated the role of protein conformational heterogeneity in protein-protein recognition. Our results show that a restricted conformational refinement can generate conformers with better binding properties and improve docking encounters in medium-flexible cases. For more flexible cases, a more extended conformational sampling based on Normal Mode Analysis was proven helpful. We found that successful conformers provide better energetic complementarity to the docking partners, which is compatible with recent views of binding association. In addition to the mechanistic considerations, these findings could be exploited for practical docking predictions of improved efficiency.

A systematic analysis of scoring functions in rigid-body protein docking: The delicate balance between the predictive rate improvement and the risk of overtraining.

PubMed

Barradas-Bautista, Didier; Moal, Iain H; Fernández-Recio, Juan

2017-07-01

Protein-protein interactions play fundamental roles in biological processes including signaling, metabolism, and trafficking. While the structure of a protein complex reveals crucial details about the interaction, it is often difficult to acquire this information experimentally. As the number of interactions discovered increases faster than they can be characterized, protein-protein docking calculations may be able to reduce this disparity by providing models of the interacting proteins. Rigid-body docking is a widely used docking approach, and is often capable of generating a pool of models within which a near-native structure can be found. These models need to be scored in order to select the acceptable ones from the set of poses. Recently, more than 100 scoring functions from the CCharPPI server were evaluated for this task using decoy structures generated with SwarmDock. Here, we extend this analysis to identify the predictive success rates of the scoring functions on decoys from three rigid-body docking programs, ZDOCK, FTDock, and SDOCK, allowing us to assess the transferability of the functions. We also apply set-theoretic measure to test whether the scoring functions are capable of identifying near-native poses within different subsets of the benchmark. This information can provide guides for the use of the most efficient scoring function for each docking method, as well as instruct future scoring functions development efforts. Proteins 2017; 85:1287-1297. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Protein-Protein Docking in Drug Design and Discovery.

PubMed

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

2018-01-01

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

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.

Optimization of pyDock for the new CAPRI challenges: Docking of homology-based models, domain-domain assembly and protein-RNA binding.

PubMed

Pons, Carles; Solernou, Albert; Perez-Cano, Laura; Grosdidier, Solène; Fernandez-Recio, Juan

2010-11-15

We describe here our results in the last CAPRI edition. We have participated in all targets, both as predictors and as scorers, using our pyDock docking methodology. The new challenges (homology-based modeling of the interacting subunits, domain-domain assembling, and protein-RNA interactions) have pushed our computer tools to the limits and have encouraged us to devise new docking approaches. Overall, the results have been quite successful, in line with previous editions, especially considering the high difficulty of some of the targets. Our docking approaches succeeded in five targets as predictors or as scorers (T29, T34, T35, T41, and T42). Moreover, with the inclusion of available information on the residues expected to be involved in the interaction, our protocol would have also succeeded in two additional cases (T32 and T40). In the remaining targets (except T37), results were equally poor for most of the groups. We submitted the best model (in ligand RMSD) among scorers for the unbound-bound target T29, the second best model among scorers for the protein-RNA target T34, and the only correct model among predictors for the domain assembly target T35. In summary, our excellent results for the new proposed challenges in this CAPRI edition showed the limitations and applicability of our approaches and encouraged us to continue developing methodologies for automated biomolecular docking. © 2010 Wiley-Liss, Inc.

Multiple ligand simultaneous docking: orchestrated dancing of ligands in binding sites of protein.

PubMed

Li, Huameng; Li, Chenglong

2010-07-30

Present docking methodologies simulate only one single ligand at a time during docking process. In reality, the molecular recognition process always involves multiple molecular species. Typical protein-ligand interactions are, for example, substrate and cofactor in catalytic cycle; metal ion coordination together with ligand(s); and ligand binding with water molecules. To simulate the real molecular binding processes, we propose a novel multiple ligand simultaneous docking (MLSD) strategy, which can deal with all the above processes, vastly improving docking sampling and binding free energy scoring. The work also compares two search strategies: Lamarckian genetic algorithm and particle swarm optimization, which have respective advantages depending on the specific systems. The methodology proves robust through systematic testing against several diverse model systems: E. coli purine nucleoside phosphorylase (PNP) complex with two substrates, SHP2NSH2 complex with two peptides and Bcl-xL complex with ABT-737 fragments. In all cases, the final correct docking poses and relative binding free energies were obtained. In PNP case, the simulations also capture the binding intermediates and reveal the binding dynamics during the recognition processes, which are consistent with the proposed enzymatic mechanism. In the other two cases, conventional single-ligand docking fails due to energetic and dynamic coupling among ligands, whereas MLSD results in the correct binding modes. These three cases also represent potential applications in the areas of exploring enzymatic mechanism, interpreting noisy X-ray crystallographic maps, and aiding fragment-based drug design, respectively. 2010 Wiley Periodicals, Inc.

Lessons from (co-)evolution in the docking of proteins and peptides for CAPRI Rounds 28-35.

PubMed

Yu, Jinchao; Andreani, Jessica; Ochsenbein, Françoise; Guerois, Raphaël

2017-03-01

Computational protein-protein docking is of great importance for understanding protein interactions at the structural level. Critical assessment of prediction of interactions (CAPRI) experiments provide the protein docking community with a unique opportunity to blindly test methods based on real-life cases and help accelerate methodology development. For CAPRI Rounds 28-35, we used an automatic docking pipeline integrating the coarse-grained co-evolution-based potential InterEvScore. This score was developed to exploit the information contained in the multiple sequence alignments of binding partners and selectively recognize co-evolved interfaces. Together with Zdock/Frodock for rigid-body docking, SOAP-PP for atomic potential and Rosetta applications for structural refinement, this pipeline reached high performance on a majority of targets. For protein-peptide docking and interfacial water position predictions, we also explored different means of taking evolutionary information into account. Overall, our group ranked 1 st by correctly predicting 10 targets, composed of 1 High, 7 Medium and 2 Acceptable predictions. Excellent and Outstanding levels of accuracy were reached for each of the two water prediction targets, respectively. Altogether, in 15 out of 18 targets in total, evolutionary information, either through co-evolution or conservation analyses, could provide key constraints to guide modeling towards the most likely assemblies. These results open promising perspectives regarding the way evolutionary information can be valuable to improve docking prediction accuracy. Proteins 2017; 85:378-390. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

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)

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)

Earth Observations taken by Expedition 30 crewmember

NASA Image and Video Library

2011-12-31

ISS030-E-038578 (31 Dec. 2011) --- Clouds form the backdrop for this scene photographed by one of the Expedition 30 crew members aboard the International Space Station, with two Russian spacecraft docked to the orbital outpost. A Soyuz (near foreground) is docked to Rassvet, also known as the Mini-Research Module 1 (MRM-1), and a Progress is linked to the Pirs Docking Compartment.

View of the Pirs Docking Compartment approaching the ISS during Expedition Three

NASA Image and Video Library

2001-09-17

ISS003-E-5677 (16 September 2001) --- The Russian Docking Compartment, named Pirs, the Russian word for pier, approaches the International Space Station (ISS). One of the Expedition Three crew members, using a digital still camera with a 180mm lens, recorded the image from onboard the orbital outpost. The vehicle was launched on September 14, 2001 and docking occurred on September 16.

View of the Pirs Docking Compartment approaching the ISS during Expedition Three

NASA Image and Video Library

2001-09-17

ISS003-E-5678 (16 September 2001) --- The Russian Docking Compartment, named Pirs, the Russian word for pier, approaches the International Space Station (ISS). One of the Expedition Three crew members, using a digital still camera with a 180mm lens, recorded the image from onboard the orbital outpost. The vehicle was launched on September 14, 2001 and docking occurred on September 16.

Engineering principles to assure compatible docking between future spacecraft of USA and USSR

NASA Technical Reports Server (NTRS)

Johnson, C. C.

1973-01-01

An androgynous peripheral type docking mechanism concept selected by the U.S. and the USSR is described. The rationale supporting the selection of the concept, the mechanical principles inherent to the concept, and the probable nature of future designs stemming from the concept are discussed. Operational situations prior to docking, impact conditions, energy absorption, and structural joining of two spacecraft are examined.

Expedition 19 Docks to ISS

NASA Image and Video Library

2009-03-27

Managers from NASA, Roscosmos, RSC-Energia, TsNIIMash 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)

Overview of Shipyard coast line with Piers G1, G2, G3, ...

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

Overview of Shipyard coast line with Piers G-1, G-2, G-3, G-4, and G-5 in view, view facing east-southeast - U.S. Naval Base, Pearl Harbor, Pier & Quay Walls, Entrance to Dry Dock No. 2 & Repair Wharfs, east & west sides of Dry Dock No. 2 & west side of Dry Dock No. 3, Pearl City, Honolulu County, HI

Artist's concept of Apollo/Soyuz spacecraft docking approach

NASA Image and Video Library

1973-08-01

S73-02395 (August 1973) --- An artist?s concept illustrating an Apollo-type spacecraft (on left) about to dock with a Soviet Soyuz-type spacecraft. A recent agreement between the United States and the Union of Soviet Socialist Republics provides for the docking in space of the Soyuz and Apollo-type spacecraft in Earth orbit in 1975. The joint venture is called the Apollo-Soyuz Test Project.

Hurley in the FWD FD during docking activities of Space Shuttle Endeavour

NASA Image and Video Library

2009-07-17

S127-E-006573 (17 July 2009) --- Astronaut Doug Hurley is at the pilot station on Endeavour's flight deck during rendezvous and docking activities between space shuttle and the the International Space Station. Later the STS-127 crew docked the shuttle with the orbital outpost and ingressed it, bringing the population of the ISS to a record 13 people for the time being.

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

Technical Note: Mobile accelerator guidance using an optical tracker during docking in IOERT procedures.

PubMed

Marinetto, Eugenio; Victores, Juan González; García-Sevilla, Mónica; Muñoz, Mercedes; Calvo, Felipe Ángel; Balaguer, Carlos; Desco, Manuel; Pascau, Javier

2017-10-01

Intraoperative electron radiation therapy (IOERT) involves the delivery of a high radiation dose during tumor resection in a shorter time than other radiation techniques, thus improving local control of tumors. However, a linear accelerator device is needed to produce the beam safely. Mobile linear accelerators have been designed as dedicated units that can be moved into the operating room and deliver radiation in situ. Correct and safe dose delivery is a key concern when using mobile accelerators. The applicator is commonly fixed to the patient's bed to ensure that the dose is delivered to the prescribed location, and the mobile accelerator is moved to dock the applicator to the radiation beam output (gantry). In a typical clinical set-up, this task is time-consuming because of safety requirements and the limited degree of freedom of the gantry. The objective of this study was to present a navigation solution based on optical tracking for guidance of docking to improve safety and reduce procedure time. We used an optical tracker attached to the mobile linear accelerator to track the prescribed localization of the radiation collimator inside the operating room. Using this information, the integrated navigation system developed computes the movements that the mobile linear accelerator needs to perform to align the applicator and the radiation gantry and warns the physician if docking is unrealizable according to the available degrees of freedom of the mobile linear accelerator. Furthermore, we coded a software application that connects all the necessary functioning elements and provides a user interface for the system calibration and the docking guidance. The system could safeguard against the spatial limitations of the operating room, calculate the optimal arrangement of the accelerator and reduce the docking time in computer simulations and experimental setups. The system could be used to guide docking with any commercial linear accelerator. We believe that the docking navigator we present is a major contribution to IOERT, where docking is critical when attempting to reduce surgical time, ensure patient safety and guarantee that the treatment administered follows the radiation oncologist's prescription. © 2017 American Association of Physicists in Medicine.

Description of the docking module ECS for the Apollo-Soyuz Test Project.

NASA Technical Reports Server (NTRS)

Guy, W. W.; Jaax, J. R.

1973-01-01

The role of the Docking Module ECS (Environmental Control System) to be used on the Apollo-Soyuz Test mission is to provide a means for crewmen to transfer safely between the Apollo and Soyuz vehicles in a shirtsleeve environment. This paper describes the Docking Module ECS and includes the philosophy and rationale used in evaluating and selecting the capabilities that are required to satisfy the Docking Module's airlock function: (1) adjusting the pressure and composition of the atmosphere to effect crew transfer and (2) providing a shirtsleeve environment during transfer operations. An analytical evaluation is given of the environmental parameters (including CO2 level, humidity, and temperature) during a normal transfer timeline.

One Year Crew Docking to the International Space Station

NASA Image and Video Library

2015-05-27

This video was taken by the crew members aboard the Soyuz TMA-16M spacecraft which docked to the International Space Station at 9:33 p.m. EDT March 27, 2015. NASA astronaut Scott Kelly and Russian cosmonauts Mikhail Kornienko and Gennady Padalka arrived just six hours after launching from Baikonur, Kazakhstan, completing four orbits around the Earth before catching up with the orbiting laboratory. The vehicle docked to the Poisk module (also known as the Mini-Research Module 2) on the space-facing side of the Russian Service Module. The spinning object in view is an antenna that is part of the automatic rendezvous and docking system known as KURS.

Domain requirements for the Dock adapter protein in growth- cone signaling.

PubMed

Rao, Y; Zipursky, S L

1998-03-03

Tyrosine phosphorylation has been implicated in growth-cone guidance through genetic, biochemical, and pharmacological studies. Adapter proteins containing src homology 2 (SH2) domains and src homology 3 (SH3) domains provide a means of linking guidance signaling through phosphotyrosine to downstream effectors regulating growth-cone motility. The Drosophila adapter, Dreadlocks (Dock), the homolog of mammalian Nck containing three N-terminal SH3 domains and a single SH2 domain, is highly specialized for growth-cone guidance. In this paper, we demonstrate that Dock can couple signals in either an SH2-dependent or an SH2-independent fashion in photoreceptor (R cell) growth cones, and that Dock displays different domain requirements in different neurons.

Predicting receptor functionality of signaling lymphocyte activation molecule for measles virus hemagglutinin by docking simulation.

PubMed

Suzuki, Yoshiyuki

2017-05-01

Predicting susceptibility of various species to a virus assists assessment of risk of interspecies transmission. Evaluation of receptor functionality may be useful in screening for susceptibility. In this study, docking simulation was conducted for measles virus hemagglutinin (MV-H) and immunoglobulin-like variable domain of signaling lymphocyte activation molecule (SLAM-V). It was observed that the docking scores for MV-H and SLAM-V correlated with the activity of SLAM as an MV receptor. These results suggest that the receptor functionality may be predicted from the docking scores of virion surface proteins and cellular receptor molecules. © 2017 The Societies and John Wiley & Sons Australia, Ltd.

Ligand-protein docking using a quantum stochastic tunneling optimization method.

PubMed

Mancera, Ricardo L; Källblad, Per; Todorov, Nikolay P

2004-04-30

A novel hybrid optimization method called quantum stochastic tunneling has been recently introduced. Here, we report its implementation within a new docking program called EasyDock and a validation with the CCDC/Astex data set of ligand-protein complexes using the PLP score to represent the ligand-protein potential energy surface and ScreenScore to score the ligand-protein binding energies. When taking the top energy-ranked ligand binding mode pose, we were able to predict the correct crystallographic ligand binding mode in up to 75% of the cases. By using this novel optimization method run times for typical docking simulations are significantly shortened. Copyright 2004 Wiley Periodicals, Inc. J Comput Chem 25: 858-864, 2004

Docking simulation analysis of range data requirements for the orbital maneuvering vehicle

NASA Technical Reports Server (NTRS)

Micheal, J. D.; Vinz, F. L.

1985-01-01

The results of an initial study are reported assess the controllability of the Orbital Maneuvering Vehicle (OMV) for terminal closure and docking are reported. The vehicle characteristics used in this study are those of the Marshall Space Flight Center (MSFC) baseline OMV which were published with the request for proposals for preliminary design of this vehicle. This simulation was conducted at MSFC using the Target Motion Simulator. The study focused on the OMV manual mode capability to accommodate both stabilized and tumbling target engagements with varying complements of range and range rate data displayed to the OMV operator. Four trained test subjects performed over 400 simulated orbital dockings during this study. A firm requirement for radar during the terminal closure and dock phase of the OMV mission was not established by these simulations. Fifteen pound thrusters recommended in the MSFC baseline design were found to be advantageous for initial rate matching maneuvers with unstabilized targets; however, lower thrust levels were desirable for making the final docking maneuvers.

Directory of Useful Decoys, Enhanced (DUD-E): Better Ligands and Decoys for Better Benchmarking

PubMed Central

2012-01-01

A key metric to assess molecular docking remains ligand enrichment against challenging decoys. Whereas the directory of useful decoys (DUD) has been widely used, clear areas for optimization have emerged. Here we describe an improved benchmarking set that includes more diverse targets such as GPCRs and ion channels, totaling 102 proteins with 22886 clustered ligands drawn from ChEMBL, each with 50 property-matched decoys drawn from ZINC. To ensure chemotype diversity, we cluster each target’s ligands by their Bemis–Murcko atomic frameworks. We add net charge to the matched physicochemical properties and include only the most dissimilar decoys, by topology, from the ligands. An online automated tool (http://decoys.docking.org) generates these improved matched decoys for user-supplied ligands. We test this data set by docking all 102 targets, using the results to improve the balance between ligand desolvation and electrostatics in DOCK 3.6. The complete DUD-E benchmarking set is freely available at http://dude.docking.org. PMID:22716043

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.

Development of an autonomous video rendezvous and docking system, phase 2

NASA Technical Reports Server (NTRS)

Tietz, J. C.; Richardson, T. E.

1983-01-01

The critical elements of an autonomous video rendezvous and docking system were built and used successfully in a physical laboratory simulation. The laboratory system demonstrated that a small, inexpensive electronic package and a flight computer of modest size can analyze television images to derive guidance information for spacecraft. In the ultimate application, the system would use a docking aid consisting of three flashing lights mounted on a passive target spacecraft. Television imagery of the docking aid would be processed aboard an active chase vehicle to derive relative positions and attitudes of the two spacecraft. The demonstration system used scale models of the target spacecraft with working docking aids. A television camera mounted on a 6 degree of freedom (DOF) simulator provided imagery of the target to simulate observations from the chase vehicle. A hardware video processor extracted statistics from the imagery, from which a computer quickly computed position and attitude. Computer software known as a Kalman filter derived velocity information from position measurements.

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

PubMed

Davidson, Timothy M

2012-09-01

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

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)

Autonomous spacecraft rendezvous and docking

NASA Technical Reports Server (NTRS)

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

1985-01-01

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

Autonomous spacecraft rendezvous and docking

NASA Astrophysics Data System (ADS)

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

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

Expedition 19 Docks to ISS

NASA Image and Video Library

2009-03-27

Mike Hawes, NASA's Acting Associate Administrator, left, looks on as Kirk Shireman, NASA's deputy ISS program manager, 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)

AGOR 28

DTIC Science & Technology

2015-11-20

unclassified c. THIS PAGE unclassified Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std Z39-18 2 Exhaust Baffles • December Dry ...Docking Canceled – The floating dry dock is not certified so the docking has been canceled. Divers should do hull and prop cleaning prior to builders...operating temperature of 125-degrees F. A cooler may be necessary to correct this issue. • Uncontaminated Sea Chest – Reports from Armstrong indicate

UT088 ATV docking_239C

NASA Image and Video Library

2012-03-28

ISS030-E-175366 (28 March 2012) --- European Space Agency?s ?Edoardo Amaldi? Automated Transfer Vehicle-3 (ATV-3) docks with the International Space Station, delivering 220 pounds of oxygen, 628 pounds of water, 4.5 tons of propellant, and nearly 2.5 tons of dry cargo, including experiment hardware, spare parts, food and clothing. Docking of the two spacecraft occurred at 6:31 p.m. (EDT) on March 28, 2012.

Apollo 7/S-IVB Rendezvous in space

NASA Image and Video Library

1968-10-11

AS07-03-1538 (11 Oct. 1968) --- The expended Saturn IVB stage as photographed from the Apollo 7 spacecraft during transposition and docking maneuvers. This photograph was taken during Apollo 7's second revolution of Earth. Earth below has heavy cloud cover. The round, white disc inside the open panels of the Saturn IVB is a simulated docking target similar to that used on the lunar module for docking during lunar missions.

Apollo 7/S-IVB Rendezvous in space

NASA Image and Video Library

1968-10-11

AS07-03-1531 (11 Oct. 1968) --- The expended Saturn IVB stage as photographed from the Apollo 7 spacecraft during transposition and docking maneuvers. This photograph was taken over Sonora, Mexico, during Apollo 7's second revolution of Earth. The round, white disc inside the open panels of the Saturn IVB is a simulated docking target similar to that used on the lunar module for docking during lunar missions.

76 FR 31851 - Safety Zone; Put-in-Bay Fireworks, Fox's the Dock Pier; South Bass Island, Put-in-Bay, OH

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-02

... DEPARTMENT OF HOMELAND SECURITY Coast Guard 33 CFR Part 165 [Docket No. USCG-2011-0417] RIN 1625-AA00 Safety Zone; Put-in-Bay Fireworks, Fox's the Dock Pier; South Bass Island, Put-in-Bay, OH AGENCY.... Add Sec. 165.T09-0417 as follows: Sec. 165.T09-0417 Safety Zone; Put-In-Bay Fireworks, Fox's the Dock...

A primer on wood as dock construction material

Treesearch

Stan Lebow

2007-01-01

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

In Silico Analyses of Substrate Interactions with Human Serum Paraoxonase 1

DTIC Science & Technology

2008-01-01

substrate interactions of HuPON1 remains elusive. In this study, we apply homology modeling, docking, and molecular dynamic (MD) simulations to probe the...mod- eling; docking; molecular dynamics simulations ; binding free energy decomposition. 486 PROTEINS Published 2008 WILEY-LISS, INC. yThis article is a...apply homology modeling, docking, and molecular dynamic (MD) simulations to probe the binding interactions of HuPON1 with representative substrates. The

NESDI FY10 Year in Review Report: The Case For Success 2010

DTIC Science & Technology

2010-01-01

36 CASE STUDY: Motion Assisted Environmental Enclosure for Capturing Paint Overspray in Dry Docks...and to outline a means to assess its environmental impact. 8. Motion Assisted Environmental Enclosure for Capturing Paint Overspray in Dry Docks...in dry docks. 9. Cleaning Solvents for the 21st Century. As part of the Department of Defense’s (DoD) response to eliminating the use of volatile

iScreen: world's first cloud-computing web server for virtual screening and de novo drug design based on TCM database@Taiwan

NASA Astrophysics Data System (ADS)

Tsai, Tsung-Ying; Chang, Kai-Wei; Chen, Calvin Yu-Chian

2011-06-01

The rapidly advancing researches on traditional Chinese medicine (TCM) have greatly intrigued pharmaceutical industries worldwide. To take initiative in the next generation of drug development, we constructed a cloud-computing system for TCM intelligent screening system (iScreen) based on TCM Database@Taiwan. iScreen is compacted web server for TCM docking and followed by customized de novo drug design. We further implemented a protein preparation tool that both extract protein of interest from a raw input file and estimate the size of ligand bind site. In addition, iScreen is designed in user-friendly graphic interface for users who have less experience with the command line systems. For customized docking, multiple docking services, including standard, in-water, pH environment, and flexible docking modes are implemented. Users can download first 200 TCM compounds of best docking results. For TCM de novo drug design, iScreen provides multiple molecular descriptors for a user's interest. iScreen is the world's first web server that employs world's largest TCM database for virtual screening and de novo drug design. We believe our web server can lead TCM research to a new era of drug development. The TCM docking and screening server is available at http://iScreen.cmu.edu.tw/.

Synthesis of 4-aminophenyl substituted indole derivatives for the instrumental analysis and molecular docking evaluation studies

NASA Astrophysics Data System (ADS)

Singh, Navneet; Kumar, Keshav

2017-07-01

The Indole has been known to maintain celebrity status since so many decades and has been a centre point at the spectrum of pharmacological research. The present work stimulates an idea of generating a pool of library of lead compounds. The data collected can be used for the mapping of biologically active compounds. The reported derivatives of 4-aminophenyl substituted Indole were prepared by the methods of Fischer Indole synthesis and Vilsemeier reaction followed by screening for instrumental analysis and molecular docking studies. The synthesized compounds 4-(1-(2-phenylhydrazono)ethyl)aniline, 1, 4-(1H-indol-2-yl)aniline, 2 and 2-(4-aminophenyl)-1H-indole-3-carbaldehyde, 3 were found to have remarkable yield and instrumental data analysis and also showed remarkable docked characteristic. The molecular docking studies revealed that ligand (amino acids) of comp. 1, 2 and 3 had been docked successfully on the binding site of the 3JUS protein selected from PDB with H bonding. The molecular docking data showed that compound 1, would possess remarkable biological activity and compd. 2 and 3 would possess mild to moderate biological activity. Thus this research work paves the way to synthesize new derivatives and thus to develop new compounds in future with accurate prediction.

Docking of Natural Products against Neurodegenerative Diseases: General Concepts.

PubMed

Ribeiro, Frederico F; Mendonca Junior, Francisco J B; Ghasemi, Jahan B; Ishiki, Hamilton M; Scotti, Marcus T; Scotti, Luciana

2018-01-01

Since antiquity, humanity has used medicinal plant preparations to cure its ills, and, as research has progressed, new technologies have enabled more investigations on natural compounds which originate from plants, fungi, and marine species. The health benefits that these natural products provide have become a motive for treatment studies of various diseases. Among them, the neurodegenerative diseases like Alzheimer's and Parkinson's, a major age-related neurodegenerative disorder. Studies with natural products for neurodegenerative diseases (particularly through molecular docking) search for, and then focus on those ligands which offer effective inhibition of the enzymes monoamine oxidase and acetylcholinesterase. This review introduces the main concepts involved in docking studies with natural products: and also in our group, which has conducted a docking study of natural products isolated from Tetrapterys mucronata for inhibition of acetylcholinesterase. We observed that compounds 4 and 5 formed more interactions than the theoretical ligand, but that ligands with greater activity also interacted with residues HIS 381 and GLN 527. We have reported on our docking study performed with AChE and alkaloids isolated from the plant Tetrapterys mucronata. Our docking results corroborate the experiments conducted, and emphasize the positive contribution that these theoretical studies involving natural products bring to the fight against neurodegenerative diseases. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

iScreen: world's first cloud-computing web server for virtual screening and de novo drug design based on TCM database@Taiwan.

PubMed

Tsai, Tsung-Ying; Chang, Kai-Wei; Chen, Calvin Yu-Chian

2011-06-01

The rapidly advancing researches on traditional Chinese medicine (TCM) have greatly intrigued pharmaceutical industries worldwide. To take initiative in the next generation of drug development, we constructed a cloud-computing system for TCM intelligent screening system (iScreen) based on TCM Database@Taiwan. iScreen is compacted web server for TCM docking and followed by customized de novo drug design. We further implemented a protein preparation tool that both extract protein of interest from a raw input file and estimate the size of ligand bind site. In addition, iScreen is designed in user-friendly graphic interface for users who have less experience with the command line systems. For customized docking, multiple docking services, including standard, in-water, pH environment, and flexible docking modes are implemented. Users can download first 200 TCM compounds of best docking results. For TCM de novo drug design, iScreen provides multiple molecular descriptors for a user's interest. iScreen is the world's first web server that employs world's largest TCM database for virtual screening and de novo drug design. We believe our web server can lead TCM research to a new era of drug development. The TCM docking and screening server is available at http://iScreen.cmu.edu.tw/.

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.

Molecular Docking and Drug Discovery in β-Adrenergic Receptors.

PubMed

Vilar, Santiago; Sobarzo-Sanchez, Eduardo; Santana, Lourdes; Uriarte, Eugenio

2017-01-01

Evolution in computer engineering, availability of increasing amounts of data and the development of new and fast docking algorithms and software have led to improved molecular simulations with crucial applications in virtual high-throughput screening and drug discovery. Moreover, analysis of protein-ligand recognition through molecular docking has become a valuable tool in drug design. In this review, we focus on the applicability of molecular docking on a particular class of G protein-coupled receptors: the β-adrenergic receptors, which are relevant targets in clinic for the treatment of asthma and cardiovascular diseases. We describe the binding site in β-adrenergic receptors to understand key factors in ligand recognition along with the proteins activation process. Moreover, we focus on the discovery of new lead compounds that bind the receptors, on the evaluation of virtual screening using the active/ inactive binding site states, and on the structural optimization of known families of binders to improve β-adrenergic affinity. We also discussed strengths and challenges related to the applicability of molecular docking in β-adrenergic receptors. Molecular docking is a valuable technique in computational chemistry to deeply analyze ligand recognition and has led to important breakthroughs in drug discovery and design in the field of β-adrenergic receptors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Shared control on lunar spacecraft teleoperation rendezvous operations with large time delay

NASA Astrophysics Data System (ADS)

Ya-kun, Zhang; Hai-yang, Li; Rui-xue, Huang; Jiang-hui, Liu

2017-08-01

Teleoperation could be used in space on-orbit serving missions, such as object deorbits, spacecraft approaches, and automatic rendezvous and docking back-up systems. Teleoperation rendezvous and docking in lunar orbit may encounter bottlenecks for the inherent time delay in the communication link and the limited measurement accuracy of sensors. Moreover, human intervention is unsuitable in view of the partial communication coverage problem. To solve these problems, a shared control strategy for teleoperation rendezvous and docking is detailed. The control authority in lunar orbital maneuvers that involves two spacecraft as rendezvous and docking in the final phase was discussed in this paper. The predictive display model based on the relative dynamic equations is established to overcome the influence of the large time delay in communication link. We discuss and attempt to prove via consistent, ground-based simulations the relative merits of fully autonomous control mode (i.e., onboard computer-based), fully manual control (i.e., human-driven at the ground station) and shared control mode. The simulation experiments were conducted on the nine-degrees-of-freedom teleoperation rendezvous and docking simulation platform. Simulation results indicated that the shared control methods can overcome the influence of time delay effects. In addition, the docking success probability of shared control method was enhanced compared with automatic and manual modes.

PyGOLD: a python based API for docking based virtual screening workflow generation.

PubMed

Patel, Hitesh; Brinkjost, Tobias; Koch, Oliver

2017-08-15

Molecular docking is one of the successful approaches in structure based discovery and development of bioactive molecules in chemical biology and medicinal chemistry. Due to the huge amount of computational time that is still required, docking is often the last step in a virtual screening approach. Such screenings are set as workflows spanned over many steps, each aiming at different filtering task. These workflows can be automatized in large parts using python based toolkits except for docking using the docking software GOLD. However, within an automated virtual screening workflow it is not feasible to use the GUI in between every step to change the GOLD configuration file. Thus, a python module called PyGOLD was developed, to parse, edit and write the GOLD configuration file and to automate docking based virtual screening workflows. The latest version of PyGOLD, its documentation and example scripts are available at: http://www.ccb.tu-dortmund.de/koch or http://www.agkoch.de. PyGOLD is implemented in Python and can be imported as a standard python module without any further dependencies. oliver.koch@agkoch.de, oliver.koch@tu-dortmund.de. Supplementary data are available at Bioinformatics online. © The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Structural Basis of Membrane Targeting by the Dock180 Family of Rho Family Guanine Exchange Factors (Rho-GEFs)*

PubMed Central

Premkumar, Lakshmanane; Bobkov, Andrey A.; Patel, Manishha; Jaroszewski, Lukasz; Bankston, Laurie A.; Stec, Boguslaw; Vuori, Kristiina; Côté, Jean-Francois; Liddington, Robert C.

2010-01-01

The Dock180 family of atypical Rho family guanine nucleotide exchange factors (Rho-GEFs) regulate a variety of processes involving cellular or subcellular polarization, including cell migration and phagocytosis. Each contains a Dock homology region-1 (DHR-1) domain that is required to localize its GEF activity to a specific membrane compartment where levels of phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) are up-regulated by the local activity of PtdIns 3-kinase. Here we define the structural and energetic bases of phosphoinositide specificity by the DHR-1 domain of Dock1 (a GEF for Rac1), and show that DHR-1 utilizes a C2 domain scaffold and surface loops to create a basic pocket on its upper surface for recognition of the PtdIns(3,4,5)P3 head group. The pocket has many of the characteristics of those observed in pleckstrin homology domains. We show that point mutations in the pocket that abolish phospholipid binding in vitro ablate the ability of Dock1 to induce cell polarization, and propose a model that brings together recent mechanistic and structural studies to rationalize the central role of DHR-1 in dynamic membrane targeting of the Rho-GEF activity of Dock180. PMID:20167601

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

PubMed

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

2011-10-01

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

New Additions to the ClusPro Server Motivated by CAPRI

PubMed Central

Vajda, Sandor; Yueh, Christine; Beglov, Dmitri; Bohnuud, Tanggis; Mottarella, Scott E.; Xia, Bing; Hall, David R.; Kozakov, Dima

2016-01-01

The heavily used protein-protein docking server ClusPro performs three computational steps as follows: (1) rigid body docking, (2) RMSD based clustering of the 1000 lowest energy structures, and (3) the removal of steric clashes by energy minimization. In response to challenges encountered in recent CAPRI targets, we added three new options to ClusPro. These are (1) accounting for Small Angle X-ray Scattering (SAXS) data in docking; (2) considering pairwise interaction data as restraints; and (3) enabling discrimination between biological and crystallographic dimers. In addition, we have developed an extremely fast docking algorithm based on 5D rotational manifold FFT, and an algorithm for docking flexible peptides that include known sequence motifs. We feel that these developments will further improve the utility of ClusPro. However, CAPRI emphasized several shortcomings of the current server, including the problem of selecting the right energy parameters among the five options provided, and the problem of selecting the best models among the 10 generated for each parameter set. In addition, results convinced us that further development is needed for docking homology models. Finally we discuss the difficulties we have encountered when attempting to develop a refinement algorithm that would be computationally efficient enough for inclusion in a heavily used server. PMID:27936493

Berthing simulator for space station and orbiter

NASA Technical Reports Server (NTRS)

Veerasamy, Sam

1991-01-01

The development of a real-time man-in-the-loop berthing simulator is in progress at NASA Lyndon B. Johnson Space Center (JSC) to conduct a parametric study and to measure forces during contact conditions of the actual docking mechanisms for the Space Station Freedom and the orbiter. In berthing, the docking ports of the Space Station and the orbiter are brought together using the orbiter robotic arm to control the relative motion of the vehicles. The berthing simulator consists of a dynamics docking test system (DDTS), computer system, simulator software, and workstations. In the DDTS, the Space Station, and the orbiter docking mechanisms are mounted on a six-degree-of-freedom (6 DOF) table and a fixed platform above the table. Six load cells are used on the fixed platform to measure forces during contact conditions of the docking mechanisms. Two Encore Concept 32/9780 computers are used to simulate the orbiter robotic arm and to operate the berthing simulator. A systematic procedure for a real-time dynamic initialization is being developed to synchronize the Space Station docking port trajectory with the 6 DOF table movement. The berthing test can be conducted manually or automatically and can be extended for any two orbiting vehicles using a simulated robotic arm. The real-time operation of the berthing simulator is briefly described.

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.

CD147 regulates cancer migration via direct interaction with Annexin A2 and DOCK3-β-catenin-WAVE2 signaling

PubMed Central

Feng, Fei; Wu, Jiao; Yang, Xiang-Min; Chen, Zhi-Nan; Jiang, Jian-Li

2016-01-01

The acquisition of inappropriate migratory feature is crucial for tumor metastasis. It has been suggested that CD147 and Annexin A2 are involved in regulating tumor cell movement, while the regulatory mechanisms are far from clear. In this study, we demonstrated that CD147 physically interacted with the N-terminal domain of Annexin A2 and decreased Annexin A2 phosphorylation on tyrosine 23. In vitro kinase assay showed that the I domain of CD147 was indispensable for CD147-mediated downregulation of Annexin A2 phosphorylation by Src. Furthermore, we determined that p-Annexin A2 promoted the expression of dedicator of cytokinesis 3 (DOCK3) and DOCK3 blocked β-catenin nuclear translocation, resulting in inhibition of β-catenin signaling. In addition, DOCK3 inhibited lamellipodium dynamics and tumor cell movement. Also, we found that β-catenin signaling increased WAVE2 expression. Therefore, DOCK3 was characterized as a negative regulator of WAVE2 expression via inhibiting β-catenin signaling. Our study provides the first evidence that CD147 promotes tumor cell movement and metastasis via direct interaction with Annexin A2 and DOCK3-β-catenin-WAVE2 signaling axis. PMID:26716413

Optimization of protein-protein docking for predicting Fc-protein interactions.

PubMed

Agostino, Mark; Mancera, Ricardo L; Ramsland, Paul A; Fernández-Recio, Juan

2016-11-01

The antibody crystallizable fragment (Fc) is recognized by effector proteins as part of the immune system. Pathogens produce proteins that bind Fc in order to subvert or evade the immune response. The structural characterization of the determinants of Fc-protein association is essential to improve our understanding of the immune system at the molecular level and to develop new therapeutic agents. Furthermore, Fc-binding peptides and proteins are frequently used to purify therapeutic antibodies. Although several structures of Fc-protein complexes are available, numerous others have not yet been determined. Protein-protein docking could be used to investigate Fc-protein complexes; however, improved approaches are necessary to efficiently model such cases. In this study, a docking-based structural bioinformatics approach is developed for predicting the structures of Fc-protein complexes. Based on the available set of X-ray structures of Fc-protein complexes, three regions of the Fc, loosely corresponding to three turns within the structure, were defined as containing the essential features for protein recognition and used as restraints to filter the initial docking search. Rescoring the filtered poses with an optimal scoring strategy provided a success rate of approximately 80% of the test cases examined within the top ranked 20 poses, compared to approximately 20% by the initial unrestrained docking. The developed docking protocol provides a significant improvement over the initial unrestrained docking and will be valuable for predicting the structures of currently undetermined Fc-protein complexes, as well as in the design of peptides and proteins that target Fc. Copyright © 2016 John Wiley & Sons, Ltd.

Fast Approximations of the Rotational Diffusion Tensor and their Application to Structural Assembly of Molecular Complexes

PubMed Central

Berlin, Konstantin; O’Leary, Dianne P.; Fushman, David

2011-01-01

We present and evaluate a rigid-body, deterministic, molecular docking method, called ELMDOCK, that relies solely on the three-dimensional structure of the individual components and the overall rotational diffusion tensor of the complex, obtained from nuclear spin-relaxation measurements. We also introduce a docking method, called ELMPATIDOCK, derived from ELMDOCK and based on the new concept of combining the shape-related restraints from rotational diffusion with those from residual dipolar couplings, along with ambiguous contact/interface-related restraints obtained from chemical shift perturbations. ELMDOCK and ELMPATIDOCK use two novel approximations of the molecular rotational diffusion tensor that allow computationally efficient docking. We show that these approximations are accurate enough to properly dock the two components of a complex without the need to recompute the diffusion tensor at each iteration step. We analyze the accuracy, robustness, and efficiency of these methods using synthetic relaxation data for a large variety of protein-protein complexes. We also test our method on three protein systems for which the structure of the complex and experimental relaxation data are available, and analyze the effect of flexible unstructured tails on the outcome of docking. Additionally, we describe a method for integrating the new approximation methods into the existing docking approaches that use the rotational diffusion tensor as a restraint. The results show that the proposed docking method is robust against experimental errors in the relaxation data or structural rearrangements upon complex formation and is computationally more efficient than current methods. The developed approximations are accurate enough to be used in structure refinement protocols. PMID:21604302

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.

Application of Shape Similarity in Pose Selection and Virtual Screening in CSARdock2014 Exercise.

PubMed

Kumar, Ashutosh; Zhang, Kam Y J

2016-06-27

To evaluate the applicability of shape similarity in docking-based pose selection and virtual screening, we participated in the CSARdock2014 benchmark exercise for identifying the correct docking pose of inhibitors targeting factor XA, spleen tyrosine kinase, and tRNA methyltransferase. This exercise provides a valuable opportunity for researchers to test their docking programs, methods, and protocols in a blind testing environment. In the CSARdock2014 benchmark exercise, we have implemented an approach that uses ligand 3D shape similarity to facilitate docking-based pose selection and virtual screening. We showed here that ligand 3D shape similarity between bound poses could be used to identify the native-like pose from an ensemble of docking-generated poses. Our method correctly identified the native pose as the top-ranking pose for 73% of test cases in a blind testing environment. Moreover, the pose selection results also revealed an excellent correlation between ligand 3D shape similarity scores and RMSD to X-ray crystal structure ligand. In the virtual screening exercise, the average RMSD for our pose prediction was found to be 1.02 Å, and it was one of the top performances achieved in CSARdock2014 benchmark exercise. Furthermore, the inclusion of shape similarity improved virtual screening performance of docking-based scoring and ranking. The coefficient of determination (r(2)) between experimental activities and docking scores for 276 spleen tyrosine kinase inhibitors was found to be 0.365 but reached 0.614 when the ligand 3D shape similarity was included.

Fast approximations of the rotational diffusion tensor and their application to structural assembly of molecular complexes.

PubMed

Berlin, Konstantin; O'Leary, Dianne P; Fushman, David

2011-07-01

We present and evaluate a rigid-body, deterministic, molecular docking method, called ELMDOCK, that relies solely on the three-dimensional structure of the individual components and the overall rotational diffusion tensor of the complex, obtained from nuclear spin-relaxation measurements. We also introduce a docking method, called ELMPATIDOCK, derived from ELMDOCK and based on the new concept of combining the shape-related restraints from rotational diffusion with those from residual dipolar couplings, along with ambiguous contact/interface-related restraints obtained from chemical shift perturbations. ELMDOCK and ELMPATIDOCK use two novel approximations of the molecular rotational diffusion tensor that allow computationally efficient docking. We show that these approximations are accurate enough to properly dock the two components of a complex without the need to recompute the diffusion tensor at each iteration step. We analyze the accuracy, robustness, and efficiency of these methods using synthetic relaxation data for a large variety of protein-protein complexes. We also test our method on three protein systems for which the structure of the complex and experimental relaxation data are available, and analyze the effect of flexible unstructured tails on the outcome of docking. Additionally, we describe a method for integrating the new approximation methods into the existing docking approaches that use the rotational diffusion tensor as a restraint. The results show that the proposed docking method is robust against experimental errors in the relaxation data or structural rearrangements upon complex formation and is computationally more efficient than current methods. The developed approximations are accurate enough to be used in structure refinement protocols. Copyright © 2011 Wiley-Liss, Inc.

Docking Offset Between the Space Shuttle and the International Space Station and Resulting Impacts to the Transfer of Attitude Reference and Control

NASA Technical Reports Server (NTRS)

Helms, W. Jason; Pohlkamp, Kara M.

2011-01-01

The Space Shuttle does not dock at an exact 90 degrees to the International Space Station (ISS) x-body axis. This offset from 90 degrees, along with error sources within their respective attitude knowledge, causes the two vehicles to never completely agree on their attitude, even though they operate as a single, mated stack while docked. The docking offset can be measured in flight when both vehicles have good attitude reference and is a critical component in calculations to transfer attitude reference from one vehicle to another. This paper will describe how the docking offset and attitude reference errors between both vehicles are measured and how this information would be used to recover Shuttle attitude reference from ISS in the event of multiple failures. During STS-117, ISS on-board Guidance, Navigation and Control (GNC) computers began having problems and after several continuous restarts, the systems failed. The failure took the ability for ISS to maintain attitude knowledge. This paper will also demonstrate how with knowledge of the docking offset, the contingency procedure to recover Shuttle attitude reference from ISS was reversed in order to provide ISS an attitude reference from Shuttle. Finally, this paper will show how knowledge of the docking offset can be used to speed up attitude control handovers from Shuttle to ISS momentum management. By taking into account the docking offset, Shuttle can be commanded to hold a more precise attitude which better agrees with the ISS commanded attitude such that start up transients with the ISS momentum management controllers are reduced. By reducing start-up transients, attitude control can be transferred from Shuttle to ISS without the use of ISS thrusters saving precious on-board propellant, crew time and minimizing loads placed upon the mated stack.

In-silico Investigation of Antitrypanosomal Phytochemicals from Nigerian Medicinal Plants

PubMed Central

Setzer, William N.; Ogungbe, Ifedayo V.

2012-01-01

Background Human African trypanosomiasis (HAT), a parasitic protozoal disease, is caused primarily by two subspecies of Trypanosoma brucei. HAT is a re-emerging disease and currently threatens millions of people in sub-Saharan Africa. Many affected people live in remote areas with limited access to health services and, therefore, rely on traditional herbal medicines for treatment. Methods A molecular docking study has been carried out on phytochemical agents that have been previously isolated and characterized from Nigerian medicinal plants, either known to be used ethnopharmacologically to treat parasitic infections or known to have in-vitro antitrypanosomal activity. A total of 386 compounds from 19 species of medicinal plants were investigated using in-silico molecular docking with validated Trypanosoma brucei protein targets that were available from the Protein Data Bank (PDB): Adenosine kinase (TbAK), pteridine reductase 1 (TbPTR1), dihydrofolate reductase (TbDHFR), trypanothione reductase (TbTR), cathepsin B (TbCatB), heat shock protein 90 (TbHSP90), sterol 14α-demethylase (TbCYP51), nucleoside hydrolase (TbNH), triose phosphate isomerase (TbTIM), nucleoside 2-deoxyribosyltransferase (TbNDRT), UDP-galactose 4′ epimerase (TbUDPGE), and ornithine decarboxylase (TbODC). Results This study revealed that triterpenoid and steroid ligands were largely selective for sterol 14α-demethylase; anthraquinones, xanthones, and berberine alkaloids docked strongly to pteridine reductase 1 (TbPTR1); chromenes, pyrazole and pyridine alkaloids preferred docking to triose phosphate isomerase (TbTIM); and numerous indole alkaloids showed notable docking energies with UDP-galactose 4′ epimerase (TbUDPGE). Polyphenolic compounds such as flavonoid gallates or flavonoid glycosides tended to be promiscuous docking agents, giving strong docking energies with most proteins. Conclusions This in-silico molecular docking study has identified potential biomolecular targets of phytochemical components of antitrypanosomal plants and has determined which phytochemical classes and structural manifolds likely target trypanosomal enzymes. The results could provide the framework for synthetic modification of bioactive phytochemicals, de novo synthesis of structural motifs, and lead to further phytochemical investigations. PMID:22848767

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

NASA Technical Reports Server (NTRS)

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

2015-01-01

This paper will describe the technology development efforts NASA has underway for Automated Rendezvous and Docking/Capture (AR&D/C) sensors and a docking mechanism and the challenges involved. The paper will additionally address how these technologies will be extended to other missions requiring AR&D/C whether robotic or manned. NASA needs AR&D/C sensors for both the robotic and crewed segments of the Asteroid Redirect Mission (ARM). NASA recently conducted a commonality assessment of the concept of operations for the robotic Asteroid Redirect Vehicle (ARV) and the crewed mission segment using the Orion crew vehicle. The commonality assessment also considered several future exploration and science missions requiring an AR&D/C capability. Missions considered were asteroid sample return, satellite servicing, and planetary entry, descent, and landing. This assessment determined that a common sensor suite consisting of one or more visible wavelength cameras, a threedimensional LIDAR along with long-wavelength infrared cameras for robustness and situational awareness could be used on each mission to eliminate the cost of multiple sensor developments and qualifications. By choosing sensor parameters at build time instead of at design time and, without having to requalify flight hardware, a specific mission can design overlapping bearing, range, relative attitude, and position measurement availability to suit their mission requirements with minimal nonrecurring engineering costs. The resulting common sensor specification provides the union of all performance requirements for each mission and represents an improvement over the current systems used for AR&D/C today. These sensor specifications are tightly coupled to the docking system capabilities and requirements for final docking conditions. The paper will describe NASA's efforts to develop a standard docking system for use across NASA human spaceflight missions to multiple destinations. It will describe the current design status and the considerations and technologies involved in developing this docking mechanism.

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

NASA Technical Reports Server (NTRS)

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

2015-01-01

This paper will describe the technology development efforts NASA has underway for Automated Rendezvous and Docking/Capture (AR and D/C) sensors and a docking mechanism and the challenges involved. The paper will additionally address how these technologies will be extended to other missions requiring AR and D/C whether robotic or manned. NASA needs AR&D/C sensors for both the robotic and crewed segments of the Asteroid Redirect Mission (ARM). NASA recently conducted a commonality assessment of the concept of operations for the robotic Asteroid Redirect Vehicle (ARV) and the crewed mission segment using the Orion crew vehicle. The commonality assessment also considered several future exploration and science missions requiring an AR and D/C capability. Missions considered were asteroid sample return, satellite servicing, and planetary entry, descent, and landing. This assessment determined that a common sensor suite consisting of one or more visible wavelength cameras, a threedimensional LIDAR along with long-wavelength infrared cameras for robustness and situational awareness could be used on each mission to eliminate the cost of multiple sensor developments and qualifications. By choosing sensor parameters at build time instead of at design time and, without having to requalify flight hardware, a specific mission can design overlapping bearing, range, relative attitude, and position measurement availability to suit their mission requirements with minimal nonrecurring engineering costs. The resulting common sensor specification provides the union of all performance requirements for each mission and represents an improvement over the current systems used for AR and D/C today. These sensor specifications are tightly coupled to the docking system capabilities and requirements for final docking conditions. The paper will describe NASA's efforts to develop a standard docking system for use across NASA human spaceflight missions to multiple destinations. It will describe the current design status and the considerations and technologies involved in developing this docking mechanism.

Machine-learning scoring functions for identifying native poses of ligands docked to known and novel proteins.

PubMed

Ashtawy, Hossam M; Mahapatra, Nihar R

2015-01-01

Molecular docking is a widely-employed method in structure-based drug design. An essential component of molecular docking programs is a scoring function (SF) that can be used to identify the most stable binding pose of a ligand, when bound to a receptor protein, from among a large set of candidate poses. Despite intense efforts in developing conventional SFs, which are either force-field based, knowledge-based, or empirical, their limited docking power (or ability to successfully identify the correct pose) has been a major impediment to cost-effective drug discovery. Therefore, in this work, we explore a range of novel SFs employing different machine-learning (ML) approaches in conjunction with physicochemical and geometrical features characterizing protein-ligand complexes to predict the native or near-native pose of a ligand docked to a receptor protein's binding site. We assess the docking accuracies of these new ML SFs as well as those of conventional SFs in the context of the 2007 PDBbind benchmark dataset on both diverse and homogeneous (protein-family-specific) test sets. Further, we perform a systematic analysis of the performance of the proposed SFs in identifying native poses of ligands that are docked to novel protein targets. We find that the best performing ML SF has a success rate of 80% in identifying poses that are within 1 Å root-mean-square deviation from the native poses of 65 different protein families. This is in comparison to a success rate of only 70% achieved by the best conventional SF, ASP, employed in the commercial docking software GOLD. In addition, the proposed ML SFs perform better on novel proteins that they were never trained on before. We also observed steady gains in the performance of these scoring functions as the training set size and number of features were increased by considering more protein-ligand complexes and/or more computationally-generated poses for each complex.

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

NASA Technical Reports Server (NTRS)

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

2016-01-01

This paper will describe the technology development efforts NASA has underway for Automated Rendezvous and Docking/Capture (AR&D/C) sensors and a docking mechanism and the challenges involved. The paper will additionally address how these technologies will be extended to other missions requiring AR&D/C whether robotic or manned. NASA needs AR&D/C sensors for both the robotic and crewed segments of the Asteroid Redirect Mission (ARM). NASA recently conducted a commonality assessment of the concept of operations for the robotic Asteroid Redirect Vehicle (ARV) and the crewed mission segment using the Orion spacecraft. The commonality assessment also considered several future exploration and science missions requiring an AR&D/C capability. Missions considered were asteroid sample return, satellite servicing, and planetary entry, descent, and landing. This assessment determined that a common sensor suite consisting of one or more visible wavelength cameras, a three-dimensional LIDAR along with long-wavelength infrared cameras for robustness and situational awareness could be used on each mission to eliminate the cost of multiple sensor developments and qualifications. By choosing sensor parameters at build-time instead of at design-time and, without having to requalify flight hardware, a specific mission can design overlapping bearing, range, relative attitude, and position measurement availability to suit their mission requirements with minimal non-recurring engineering costs. The resulting common sensor specification provides the union of all performance requirements for each mission and represents an improvement over the current systems used for AR&D/C today. These sensor specifications are tightly coupled to the docking system capabilities and requirements for final docking conditions. The paper will describe NASA's efforts to develop a standard docking system for use across NASA human spaceflight missions to multiple destinations. It will describe the current design status and the considerations and technologies involved in developing this docking mechanism.

Machine-learning scoring functions for identifying native poses of ligands docked to known and novel proteins

PubMed Central

2015-01-01

Background Molecular docking is a widely-employed method in structure-based drug design. An essential component of molecular docking programs is a scoring function (SF) that can be used to identify the most stable binding pose of a ligand, when bound to a receptor protein, from among a large set of candidate poses. Despite intense efforts in developing conventional SFs, which are either force-field based, knowledge-based, or empirical, their limited docking power (or ability to successfully identify the correct pose) has been a major impediment to cost-effective drug discovery. Therefore, in this work, we explore a range of novel SFs employing different machine-learning (ML) approaches in conjunction with physicochemical and geometrical features characterizing protein-ligand complexes to predict the native or near-native pose of a ligand docked to a receptor protein's binding site. We assess the docking accuracies of these new ML SFs as well as those of conventional SFs in the context of the 2007 PDBbind benchmark dataset on both diverse and homogeneous (protein-family-specific) test sets. Further, we perform a systematic analysis of the performance of the proposed SFs in identifying native poses of ligands that are docked to novel protein targets. Results and conclusion We find that the best performing ML SF has a success rate of 80% in identifying poses that are within 1 Å root-mean-square deviation from the native poses of 65 different protein families. This is in comparison to a success rate of only 70% achieved by the best conventional SF, ASP, employed in the commercial docking software GOLD. In addition, the proposed ML SFs perform better on novel proteins that they were never trained on before. We also observed steady gains in the performance of these scoring functions as the training set size and number of features were increased by considering more protein-ligand complexes and/or more computationally-generated poses for each complex. PMID:25916860

C2 Domain of Protein Kinase Cα: Elucidation of the Membrane Docking Surface by Site-Directed Fluorescence and Spin Labeling†

PubMed Central

Kohout, Susy C.; Corbalán-García, Senena; Gómez-Fernández, Juan C.; Falke, Joseph J.

2013-01-01

The C2 domain is a conserved signaling motif that triggers membrane docking in a Ca2+-dependent manner, but the membrane docking surfaces of many C2 domains have not yet been identified. Two extreme models can be proposed for the docking of the protein kinase Cα (PKCα) C2 domain to membranes. In the parallel model, the membrane-docking surface includes the Ca2+ binding loops and an anion binding site on β-strands 3–4, such that the β-strands are oriented parallel to the membrane. In the perpendicular model, the docking surface is localized to the Ca2+ binding loops and the β-strands are oriented perpendicular to the membrane surface. The present study utilizes site-directed fluorescence and spin-labeling to map out the membrane docking surface of the PKCα C2 domain. Single cysteine residues were engineered into 18 locations scattered over all regions of the protein surface, and were used as attachment sites for spectroscopic probes. The environmentally sensitive fluorescein probe identified positions where Ca2+ activation or membrane docking trigger measurable fluorescence changes. Ca2+ binding was found to initiate a global conformational change, while membrane docking triggered the largest fluorescein environmental changes at labeling positions on the three Ca2+ binding loops (CBL), thereby localizing these loops to the membrane docking surface. Complementary EPR power saturation measurements were carried out using a nitroxide spin probe to determine a membrane depth parameter, Φ, for each spin-labeled mutant. Positive membrane depth parameters indicative of membrane insertion were found for three positions, all located on the Ca2+ binding loops: N189 on CBL 1, and both R249 and R252 on CBL 3. In addition, EPR power saturation revealed that five positions near the anion binding site are partially protected from collisions with an aqueous paramagnetic probe, indicating that the anion binding site lies at or near the surface of the headgroup layer. Together, the fluorescence and EPR results indicate that the Ca2+ first and third Ca2+ binding loops insert directly into the lipid headgroup region of the membrane, and that the anion binding site on β-strands 3–4 lies near the headgroups. The data support a model in which the β-strands are tilted toward the parallel orientation relative to the membrane surface. PMID:12564928

Coding and quantification of a facial expression for pain in lambs.

PubMed

Guesgen, M J; Beausoleil, N J; Leach, M; Minot, E O; Stewart, M; Stafford, K J

2016-11-01

Facial expressions are routinely used to assess pain in humans, particularly those who are non-verbal. Recently, there has been an interest in developing coding systems for facial grimacing in non-human animals, such as rodents, rabbits, horses and sheep. The aims of this preliminary study were to: 1. Qualitatively identify facial feature changes in lambs experiencing pain as a result of tail-docking and compile these changes to create a Lamb Grimace Scale (LGS); 2. Determine whether human observers can use the LGS to differentiate tail-docked lambs from control lambs and differentiate lambs before and after docking; 3. Determine whether changes in facial action units of the LGS can be objectively quantified in lambs before and after docking; 4. Evaluate effects of restraint of lambs on observers' perceptions of pain using the LGS and on quantitative measures of facial action units. By comparing images of lambs before (no pain) and after (pain) tail-docking, the LGS was devised in consultation with scientists experienced in assessing facial expression in other species. The LGS consists of five facial action units: Orbital Tightening, Mouth Features, Nose Features, Cheek Flattening and Ear Posture. The aims of the study were addressed in two experiments. In Experiment I, still images of the faces of restrained lambs were taken from video footage before and after tail-docking (n=4) or sham tail-docking (n=3). These images were scored by a group of five naïve human observers using the LGS. Because lambs were restrained for the duration of the experiment, Ear Posture was not scored. The scores for the images were averaged to provide one value per feature per period and then scores for the four LGS action units were averaged to give one LGS score per lamb per period. In Experiment II, still images of the faces nine lambs were taken before and after tail-docking. Stills were taken when lambs were restrained and unrestrained in each period. A different group of five human observers scored the images from Experiment II. Changes in facial action units were also quantified objectively by a researcher using image measurement software. In both experiments LGS scores were analyzed using a linear MIXED model to evaluate the effects of tail docking on observers' perception of facial expression changes. Kendall's Index of Concordance was used to measure reliability among observers. In Experiment I, human observers were able to use the LGS to differentiate docked lambs from control lambs. LGS scores significantly increased from before to after treatment in docked lambs but not control lambs. In Experiment II there was a significant increase in LGS scores after docking. This was coupled with changes in other validated indicators of pain after docking in the form of pain-related behaviour. Only two components, Mouth Features and Orbital Tightening, showed significant quantitative changes after docking. The direction of these changes agree with the description of these facial action units in the LGS. Restraint affected people's perceptions of pain as well as quantitative measures of LGS components. Freely moving lambs were scored lower using the LGS over both periods and had a significantly smaller eye aperture and smaller nose and ear angles than when they were held. Agreement among observers for LGS scores were fair overall (Experiment I: W=0.60; Experiment II: W=0.66). This preliminary study demonstrates changes in lamb facial expression associated with pain. The results of these experiments should be interpreted with caution due to low lamb numbers. Copyright © 2016 Elsevier B.V. All rights reserved.

A Comparison of Workers Employed in Hazardous Jobs in Terms of Job Satisfaction, Perceived Job Risk and Stress: Turkish Jean Sandblasting Workers, Dock Workers, Factory Workers and Miners

ERIC Educational Resources Information Center

Sunal, Ayda Buyuksahin; Sunal, Onur; Yasin, Fatma

2011-01-01

The purpose of this study is to compare job satisfaction, perception of job risk, stress symptoms and vulnerability to stress of miners, dock workers, jean sandblasting workers and factory workers. A job satisfaction scale and stress audit scale were applied to 220 workers. Results revealed that dock and jean sandblasting workers perceived their…

APOLLO SOYUZ TEST PROJECT [ASTP] COSMONAUT PEERS THROUGH ACCESS HATCH TRUSS

NASA Technical Reports Server (NTRS)

1975-01-01

Soviet prime crewman for the Apollo Soyuz Test Project Aleksey Leonov looks through an access hatch at the truss which will hold the Docking Module in the Spacecraft Lunar Adapter for the ASTP mission. The Docking Module will provide access between the Apollo and the Soyuz while they are docked in orbit. Leonov and his crewmen for the joint US/USSR mission spent three days in the KSC area.

View of the Pirs Docking Compartment approaching the ISS during Expedition Three

NASA Image and Video Library

2001-09-17

ISS003-E-5615 (16 September 2001) --- Appearing almost as a silhouette against Earth, the Russian Docking Compartment, named Pirs (the Russian word for pier), approaches the International Space Station (ISS). One of the Expedition Three crew members, using a digital still camera with a 70mm lens, recorded the image from onboard the orbital outpost. The vehicle was launched on September 14, 2001 and docking occurred on September 16.

How to benchmark methods for structure-based virtual screening of large compound libraries.

PubMed

Christofferson, Andrew J; Huang, Niu

2012-01-01

Structure-based virtual screening is a useful computational technique for ligand discovery. To systematically evaluate different docking approaches, it is important to have a consistent benchmarking protocol that is both relevant and unbiased. Here, we describe the designing of a benchmarking data set for docking screen assessment, a standard docking screening process, and the analysis and presentation of the enrichment of annotated ligands among a background decoy database.

GEMINI-9 - EARTH SKY - ATDA

NASA Image and Video Library

1966-06-06

S66-37972 (3 June 1966) ?-- The Augmented Target Docking Adapter (ATDA) is photographed from the Gemini-9 spacecraft during one of three rendezvous occasions in space. The ATDA and Gemini-9 spacecraft are 35.5 feet apart in this view. Failure of the docking adapter protective cover on the ATDA to fully separate prevented the docking of the two spacecraft. The ATDA was described by the Gemini-9 crew members as an ?angry alligator.? Photo credit: NASA

Skylab

NASA Image and Video Library

1971-08-01

This August 1971 interior photograph of Skylab's Multiple Docking Adapter (MDA) flight article, undergoing outfitting at the Martin-Marietta Corporation's Space Center facility in Denver, Colorado, shows the forward cone area and docking tunnel (center) that attached to the Apollo Command Module. Designed and manufactured by the Marshall Space Flight Center, the MDA housed the control units for the Apollo Telescope Mount, Earth Resources Experiment Package, and Zero-Gravity Materials Processing Facility and provided a docking port for the Apollo Command Module.

33 CFR 165.T09-0417 - Safety Zone; Put-In-Bay Fireworks, Fox's the Dock Pier, South Bass Island; Put-In-Bay, OH.

Code of Federal Regulations, 2011 CFR

2011-07-01

..., Fox's the Dock Pier, South Bass Island; Put-In-Bay, OH. 165.T09-0417 Section 165.T09-0417 Navigation... the Dock Pier, South Bass Island; Put-In-Bay, OH. (a) Location. The following area is a temporary safety zone: All U.S. navigable waters of Lake Erie, South Bass Island, Put-In-Bay, OH within a 50-yard...

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.

Blinded evaluation of farnesoid X receptor (FXR) ligands binding using molecular docking and free energy calculations

NASA Astrophysics Data System (ADS)

Selwa, Edithe; Elisée, Eddy; Zavala, Agustin; Iorga, Bogdan I.

2018-01-01

Our participation to the D3R Grand Challenge 2 involved a protocol in two steps, with an initial analysis of the available structural data from the PDB allowing the selection of the most appropriate combination of docking software and scoring function. Subsequent docking calculations showed that the pose prediction can be carried out with a certain precision, but this is dependent on the specific nature of the ligands. The correct ranking of docking poses is still a problem and cannot be successful in the absence of good pose predictions. Our free energy calculations on two different subsets provided contrasted results, which might have the origin in non-optimal force field parameters associated with the sulfonamide chemical moiety.

Test - Apollo-Soyuz Test Project (ASTP)

NASA Image and Video Library

1974-07-01

S74-24671 (10 July 1974) --- Three Apollo-Soyuz Test Project (ASTP) engineers look over a Soyuz spacecraft docking system prior to an ASTP docking mechanism fitness test conducted in Building 13 at the Johnson Space Center (JSC). They are (left to right) Robert White, Vladimir Syromyatnikov and Yevgeniy Bobrov. White is the American chairman of ASTP Working Group Number 3, and Syromyatnikov is his Soviet counterpart. This working group is concerned with ASTP docking problems and procedures. White is with JSC's Spacecraft Design Division. Syromyatnikov is senior researcher of the Soviet State Research Institute of Machine Building. Bobrov is a junior researcher with the Institute of Machine Building. The joint United States - USSR ASTP docking mission in Earth orbit is scheduled for the summer of 1975.

Domain requirements for the Dock adapter protein in growth- cone signaling

PubMed Central

Rao, Yong; Zipursky, S. Lawrence

1998-01-01

Tyrosine phosphorylation has been implicated in growth-cone guidance through genetic, biochemical, and pharmacological studies. Adapter proteins containing src homology 2 (SH2) domains and src homology 3 (SH3) domains provide a means of linking guidance signaling through phosphotyrosine to downstream effectors regulating growth-cone motility. The Drosophila adapter, Dreadlocks (Dock), the homolog of mammalian Nck containing three N-terminal SH3 domains and a single SH2 domain, is highly specialized for growth-cone guidance. In this paper, we demonstrate that Dock can couple signals in either an SH2-dependent or an SH2-independent fashion in photoreceptor (R cell) growth cones, and that Dock displays different domain requirements in different neurons. PMID:9482841

Saturn Apollo Program

NASA Image and Video Library

1974-06-01

This illustration shows the docking configuration of the Apollo-Soyuz Test Project (ASTP). The ASTP was the first international docking of the U.S.'s Apollo spacecraft and the U.S.S.R.'s Soyuz spacecraft in space. A joint engineering team from the two countries met to develop a docking system that permitted the two spacecraft to link in space and allowed the two crews to travel from one spacecraft to the other. This system entailed developing a large habitable Docking Module (DM) to be carried on the Apollo spacecraft to facilitate the joining of two dissimilar spacecraft. The Marshall Space Flight Center was responsible for development and sustaining engineering of the Saturn IB launch vehicle during the mission. The ASTP marked the last use of the Saturn Launch Vehicle.

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.

Accuracy of binding mode prediction with a cascadic stochastic tunneling method.

PubMed

Fischer, Bernhard; Basili, Serena; Merlitz, Holger; Wenzel, Wolfgang

2007-07-01

We investigate the accuracy of the binding modes predicted for 83 complexes of the high-resolution subset of the ASTEX/CCDC receptor-ligand database using the atomistic FlexScreen approach with a simple forcefield-based scoring function. The median RMS deviation between experimental and predicted binding mode was just 0.83 A. Over 80% of the ligands dock within 2 A of the experimental binding mode, for 60 complexes the docking protocol locates the correct binding mode in all of ten independent simulations. Most docking failures arise because (a) the experimental structure clashed in our forcefield and is thus unattainable in the docking process or (b) because the ligand is stabilized by crystal water. 2007 Wiley-Liss, Inc.

Conserved electrostatic fields at the Ras-effector interface measured through vibrational Stark effect spectroscopy explain the difference in tilt angle in the Ras binding domains of Raf and RalGDS.

PubMed

Walker, David M; Wang, Ruifei; Webb, Lauren J

2014-10-07

Vibrational Stark effect (VSE) spectroscopy was used to measure the electrostatic fields present at the interface of the human guanosine triphosphatase (GTPase) Ras docked with the Ras binding domain (RBD) of the protein kinase Raf. Nine amino acids located on the surface of Raf were selected for labeling with a nitrile vibrational probe. Eight of the probe locations were situated along the interface of Ras and Raf, and one probe was 2 nm away on the opposite side of Raf. Vibrational frequencies of the nine Raf nitrile probes were compared both in the monomeric, solvated protein and when docked with wild-type (WT) Ras to construct a comprehensive VSE map of the Ras-Raf interface. Molecular dynamics (MD) simulations employing an umbrella sampling strategy were used to generate a Boltzmann-weighted ensemble of nitrile positions in both the monomeric and docked complexes to determine the effect that docking has on probe location and orientation and to aid in the interpretation of VSE results. These results were compared to an identical study that was previously conducted on nine nitrile probes on the RBD of Ral guanidine dissociation stimulator (RalGDS) to make comparisons between the docked complexes formed when either of the two effectors bind to WT Ras. This comparison finds that there are three regions of conserved electrostatic fields that are formed upon docking of WT Ras with both downstream effectors. Conservation of this pattern in the docked complex then results in different binding orientations observed in otherwise structurally similar proteins. This work supports an electrostatic cause of the known binding tilt angle between the Ras-Raf and Ras-RalGDS complexes.

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.

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.

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

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

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

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

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.

Ginger (Zingiber officinale) phytochemicals-gingerenone-A and shogaol inhibit SaHPPK: molecular docking, molecular dynamics simulations and in vitro approaches.

PubMed

Rampogu, Shailima; Baek, Ayoung; Gajula, Rajesh Goud; Zeb, Amir; Bavi, Rohit S; Kumar, Raj; Kim, Yongseong; Kwon, Yong Jung; Lee, Keun Woo

2018-04-02

Antibiotic resistance is a defense mechanism, harbored by pathogens to survive under unfavorable conditions. Among several antibiotic resistant microbial consortium, Staphylococcus aureus is one of the most havoc microorganisms. Staphylococcus aureus encodes a unique enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (SaHPPK), against which, none of existing antibiotics have been reported. Computational approaches have been instrumental in designing and discovering new drugs for several diseases. The present study highlights the impact of ginger phytochemicals on Staphylococcus aureus SaHPPK. Herein, we have retrieved eight ginger phytochemicals from published literature and investigated their inhibitory interactions with SaHPPK. To authenticate our work, the investigation proceeds considering the known antibiotics alongside the phytochemicals. Molecular docking was performed employing GOLD and CDOCKER. The compounds with the highest dock score from both the docking programmes were tested for their inhibitory capability in vitro. The binding conformations that were seated within the binding pocket showing strong interactions with the active sites residues rendered by highest dock score were forwarded towards the molecular dynamic (MD) simulation analysis. Based on molecular dock scores, molecular interaction with catalytic active residues and MD simulations studies, two ginger phytochemicals, gingerenone-A and shogaol have been proposed as candidate inhibitors against Staphylococcus aureus. They have demonstrated higher dock scores than the known antibiotics and have represented interactions with the key residues within the active site. Furthermore, these compounds have rendered considerable inhibitory activity when tested in vitro. Additionally, their superiority was corroborated by stable MD results conducted for 100 ns employing GROMACS package. Finally, we suggest that gingerenone-A and shogaol may either be potential SaHPPK inhibitors or can be used as fundamental platforms for novel SaHPPK inhibitor development.

Rapid activity prediction of HIV-1 integrase inhibitors: harnessing docking energetic components for empirical scoring by chemometric and artificial neural network approaches

NASA Astrophysics Data System (ADS)

Thangsunan, Patcharapong; Kittiwachana, Sila; Meepowpan, Puttinan; Kungwan, Nawee; Prangkio, Panchika; Hannongbua, Supa; Suree, Nuttee

2016-06-01

Improving performance of scoring functions for drug docking simulations is a challenging task in the modern discovery pipeline. Among various ways to enhance the efficiency of scoring function, tuning of energetic component approach is an attractive option that provides better predictions. Herein we present the first development of rapid and simple tuning models for predicting and scoring inhibitory activity of investigated ligands docked into catalytic core domain structures of HIV-1 integrase (IN) enzyme. We developed the models using all energetic terms obtained from flexible ligand-rigid receptor dockings by AutoDock4, followed by a data analysis using either partial least squares (PLS) or self-organizing maps (SOMs). The models were established using 66 and 64 ligands of mercaptobenzenesulfonamides for the PLS-based and the SOMs-based inhibitory activity predictions, respectively. The models were then evaluated for their predictability quality using closely related test compounds, as well as five different unrelated inhibitor test sets. Weighting constants for each energy term were also optimized, thus customizing the scoring function for this specific target protein. Root-mean-square error (RMSE) values between the predicted and the experimental inhibitory activities were determined to be <1 (i.e. within a magnitude of a single log scale of actual IC50 values). Hence, we propose that, as a pre-functional assay screening step, AutoDock4 docking in combination with these subsequent rapid weighted energy tuning methods via PLS and SOMs analyses is a viable approach to predict the potential inhibitory activity and to discriminate among small drug-like molecules to target a specific protein of interest.

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

PubMed

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.

In silico molecular docking studies of new potential 4-phthalazinyl-hydrazones on selected Trypanosoma cruzi and Leishmania enzyme targets.

PubMed

Romero, Angel H; López, Simón E

2017-09-01

Recently, a series of 4-phthalazinyl-hydrazones under its E-configuration have exhibited excellent in vitro antichagasic and antileishmanial profiles. Preliminary assays on both parasites suggested that the most active derivatives act through oxidative and nitrosative stress mechanisms; however, their exact mode of actions as anti-trypanosomal and anti-leishmanial agents have not been completely elucidated. This motivated to perform a molecular docking study on essential trypanosomatid enzymes such as superoxide dismutase (SOD), trypanothione reductase (TryR), cysteine-protease (CP) and pteridine reductase 1 (PTR1). In addition, to understand the experimental results of nitric oxide production obtained for infected macrophages with Leishmania parasite, a molecular docking was evaluated on nitric oxide synthase (iNOS) enzyme of Rattus norvegicus. Both diastereomers (E and Z) of the 4-phthalazinyl-hydrazones were docked on the mentioned targets. In general, molecular docking on T. cruzi enzymes revealed that the E-diastereomers exhibited lower binding energies than Z-diastereomers on the Fe-SOD and CP enzymes, while Z-diastereomers showed lower docking energies than E-isomers on TryR enzyme. For the Leishmania docking studies, the Z-isomers exhibited the best binding affinities on the PTR1 and iNOS enzymes, while the TryR enzyme showed a minor dependence with the stereoselectivity of the tested phthalazines. However, either the structural information of the ligand-enzyme complexes or the experimental data suggest that the significant antitrypanosomatid activity of the most active derivatives is not associated to the inhibition of the SOD, CP and PTR1 enzymes, while the TryR inhibition and nitric oxide generation in host cells emerge as interesting antitrypanosomatid therapeutic targets. Copyright © 2017 Elsevier Inc. All rights reserved.

Automated Rendezvous and Capture System Development and Simulation for NASA

NASA Technical Reports Server (NTRS)

Roe, Fred D.; Howard, Richard T.; Murphy, Leslie

2004-01-01

The United States does not have an Automated Rendezvous and Capture/Docking (AR and C) capability and is reliant on manned control for rendezvous and docking of orbiting spacecraft. This reliance on the labor intensive manned interface for control of rendezvous and docking vehicles has a significant impact on the cost of the operation of the International Space Station (ISS) and precludes the use of any U.S. expendable launch capabilities for Space Station resupply. The Soviets have the capability to autonomously dock in space, but their system produces a hard docking with excessive force and contact velocity. Automated Rendezvous and Capture/Docking has been identified as a key enabling technology for the Space Launch Initiative (SLI) Program, DARPA Orbital Express and other DOD Programs. The development and implementation of an AR&C capability can significantly enhance system flexibility, improve safety, and lower the cost of maintaining, supplying, and operating the International Space Station. The Marshall Space Flight Center (MSFC) has conducted pioneering research in the development of an automated rendezvous and capture (or docking) (AR and C) system for U.S. space vehicles. This AR&C system was tested extensively using hardware-in-the-loop simulations in the Flight Robotics Laboratory, and a rendezvous sensor, the Video Guidance Sensor was developed and successfully flown on the Space Shuttle on flights STS-87 and STS-95, proving the concept of a video- based sensor. Further developments in sensor technology and vehicle and target configuration have lead to continued improvements and changes in AR&C system development and simulation. A new Advanced Video Guidance Sensor (AVGS) with target will be utilized on the Demonstration of Autonomous Rendezvous Technologies (DART) flight experiment in 2004.

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

Kring, C.T.; Varma, V.K.; Jatko, W.B.

The US Army and Team Crusader (United Defense, Lockheed Martin Armament Systems, etc.) are developing the next generation howitzer, the Crusader. The development program includes an advanced, self-propelled liquid propellant howitzer and a companion resupply vehicle. The resupply vehicle is intended to rendezvous with the howitzer near the battlefront and replenish ammunition, fuel, and other material. The Army has recommended that Crusader incorporate new and innovative technologies to improve performance and safety. One conceptual design proposes a robotic resupply boom on the resupply vehicle to upload supplies to the howitzer. The resupply boom would normally be retracted inside the resupplymore » vehicle during transit. When the two vehicles are within range of the resupply boom, the boom would be extended to a receiving port on the howitzer. In order to reduce exposure to small arms fire or nuclear, biological, and chemical hazards, the crew would remain inside the resupply vehicle during the resupply operation. The process of extending the boom and linking with the receiving port is called docking. A boom operator would be designated to maneuver the boom into contact with the receiving port using a mechanical joystick. The docking operation depends greatly upon the skill of the boom operator to manipulate the boom into docking position. Computer simulations at the National Aeronautics and Space Administration have shown that computer-assisted or autonomous docking can improve the ability of the operator to dock safely and quickly. This document describes the present status of the Crusader Autonomous Docking System (CADS) implemented at Oak Ridge National laboratory (ORNL). The purpose of the CADS project is to determine the feasibility and performance limitations of vision systems to satisfy the autonomous docking requirements for Crusader and conduct a demonstration under controlled conditions.« less

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.

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.

Protein-ligand docking with multiple flexible side chains

NASA Astrophysics Data System (ADS)

Zhao, Yong; Sanner, Michel F.

2008-09-01

In this work, we validate and analyze the results of previously published cross docking experiments and classify failed dockings based on the conformational changes observed in the receptors. We show that a majority of failed experiments (i.e. 25 out of 33, involving four different receptors: cAPK, CDK2, Ricin and HIVp) are due to conformational changes in side chains near the active site. For these cases, we identify the side chains to be made flexible during docking calculation by superimposing receptors and analyzing steric overlap between various ligands and receptor side chains. We demonstrate that allowing these side chains to assume rotameric conformations enables the successful cross docking of 19 complexes (ligand all atom RMSD < 2.0 Å) using our docking software FLIPDock. The number of side receptor side chains interacting with a ligand can vary according to the ligand's size and shape. Hence, when starting from a complex with a particular ligand one might have to extend the region of potential interacting side chains beyond the ones interacting with the known ligand. We discuss distance-based methods for selecting additional side chains in the neighborhood of the known active site. We show that while using the molecular surface to grow the neighborhood is more efficient than Euclidian-distance selection, the number of side chains selected by these methods often remains too large and additional methods for reducing their count are needed. Despite these difficulties, using geometric constraints obtained from the network of bonded and non-bonded interactions to rank residues and allowing the top ranked side chains to be flexible during docking makes 22 out of 25 complexes successful.

Molecular docking, molecular modeling, and molecular dynamics studies of azaisoflavone as dual COX-2 inhibitors and TP receptor antagonists.

PubMed

Hadianawala, Murtuza; Mahapatra, Amarjyoti Das; Yadav, Jitender K; Datta, Bhaskar

2018-02-26

Designed multi-target ligand (DML) is an emerging strategy for the development of new drugs and involves the engagement of multiple targets with the same moiety. In the context of NSAIDs it has been suggested that targeting the thromboxane prostanoid (TP) receptor along with cyclooxygenase-2 (COX-2) may help to overcome cardiovascular (CVS) complications associated with COXIBs. In the present work, azaisoflavones were studied for their COX-2 and TP receptor binding activities using structure based drug design (SBDD) techniques. Flavonoids were selected as a starting point based on their known COX-2 inhibitory and TP receptor antagonist activity. Iterative design and docking studies resulted in the evolution of a new class scaffold replacing the benzopyran-4-one ring of flavonoids with quinolin-4-one. The docking and binding parameters of these new compounds are found to be promising in comparison to those of selective COX-2 inhibitors, such as SC-558 and celecoxib. Owing to the lack of structural information, a model for the TP receptor was generated using a threading base alignment method with loop optimization performed using an ab initio method. The model generated was validated against known antagonists for TP receptor using docking/MMGBSA. Finally, the molecules that were designed for selective COX-2 inhibition were docked into the active site of the TP receptor. Iterative structural modifications and docking on these molecules generated a series which displays optimum docking scores and binding interaction for both targets. Molecular dynamics studies on a known TP receptor antagonist and a designed molecule show that both molecules remain in contact with protein throughout the simulation and interact in similar binding modes. Graphical abstract ᅟ.

Spectroscopic and theoretical investigation of oxali-palladium interactions with β-lactoglobulin.

PubMed

Ghalandari, Behafarid; Divsalar, Adeleh; Saboury, Ali Akbar; Haertlé, Thomas; Parivar, Kazem; Bazl, Roya; Eslami-Moghadam, Mahbube; Amanlou, Massoud

2014-01-24

The possibility of using a small cheap dairy protein, β-lactoglobulin (β-LG), as a carrier for oxali-palladium for drug delivery was studied. Their binding in an aqueous solution at two temperatures of 25 and 37°C was investigated using spectroscopic techniques in combination with a molecular docking study. Fluorescence intensity changes showed combined static and dynamic quenching during β-LG oxali-palladium binding, with the static mode being predominant in the quenching mechanism. The binding and thermodynamic parameters were determined by analyzing the results of quenching and those of the van't Hoff equation. According to obtained results the binding constants at two temperatures of 25 and 37°C are 3.3×10(9) M(-1) and 18.4×10(6) M(-1) respectively. Fluorescence resonance energy transfer (FRET) showed that the experimental results and the molecular docking results were coherent. An absence change of β-LG secondary structure was confirmed by the CD results. Molecular docking results agreed fully with the experimental results since the fluorescence studies also revealed the presence of two binding sites with a negative value for the Gibbs free energy of binding of oxali-palladium to β-LG. Furthermore, molecular docking and experimental results suggest that the hydrophobic effect plays a critical role in the formation of the oxali-palladium complex with β-LG. This agreement between molecular docking and experimental results implies that docking studies may be a suitable method for predicting and confirming experimental results, as shown in this study. Hence, the combination of molecular docking and spectroscopy methods is an effective innovative approach for binding studies, particularly for pharmacophores. Copyright © 2013 Elsevier B.V. All rights reserved.