Data of the molecular dynamics simulations of mutations in the human connexin46 docking interface

The structure of hCx26 derived from the X-ray analysis was used to generate a homology model for hCx46. Interacting connexin molecules were used as starting model for the molecular dynamics (MD) simulation using NAMD and allowed us to predict the dynamic behavior of hCx46wt and the cataract related mutant hCx46N188T as well as two artificial mutants hCx46N188Q and hCx46N188D. Within the 50 ns simulation time the docked complex composed of the mutants dissociate while hCx46wt remains stable. The data indicates that one hCx46 molecule forms 5-7 hydrogen bonds (HBs) with the counterpart connexin of the opposing connexon. These HBs appear essential for a stable docking of the connexons as shown by the simulation of an entire gap junction channel and were lost for all the tested mutants. The data described here are related to the research article entitled "The cataract related mutation N188T in human connexin46 (hCx46) revealed a critical role for residue N188 in the docking process of gap junction channels" (Schadzek et al., 2015) [1].

A Vision Based Target Detection System for Docking of an Autonomous Underwater Vehicle

This paper describes the development and preliminary experimental evaluation of a visionbased docking system to allow an Autonomous Underwater Vehicle (AUV) to identify and attach itself to a set of uniquely identifiable targets. These targets, docking poles, are detected using Haar rectangular features and rotation of integral images. A non-holonomic controller allows the Starbug AUV to orient itself with respect to the target whilst maintaining visual contact during the manoeuvre. Experimental results show the proposed vision system is capable of robustly identifying a pair of docking poles simultaneously in a variety of orientations and lighting conditions. Experiments in an outdoor pool show that this vision system enables the AUV to dock autonomously from a distance of up to 4m with relatively low visibility.

Vision-based docking using an autonomous surface vehicle

This paper describes the development of a novel vision-based autonomous surface vehicle with the purpose of performing coordinated docking manoeuvres with a target, such as an autonomous underwater vehicle, at the water's surface. The system architecture integrates two small processor units; the first performs vehicle control and implements a virtual force based docking strategy, with the second performing vision-based target segmentation and tracking. Furthermore, the architecture utilises wireless sensor network technology allowing the vehicle to be observed by, and even integrated within an ad-hoc sensor network. Simulated and experimental results are presented demonstrating the autonomous vision- based docking strategy on a proof-of-concept vehicle.

Transmembrane/cytoplasmic domain-mediated membrane type 1-matrix metalloprotease docking to invadopodia is required for cellinvasion

The invasion of human malignant melanoma cells into the extracellular matrix (ECM) involves the accumulation of proteases at sites of ECM degradation where activation of matrix metalloproteases (MMP) occurs. Here, we show that when membrane type 1 MMP (MT-MMP) was overexpressed in RPMI7951 human melanoma cells, the cells made contact with the ECM, activated soluble and ECM-bound MMP-2, and degraded and invaded the ECM. Further experiments demonstrated the importance of localization of the MT-MMP to invadopodia. Overexpression of MT-MMP without invadopodial localization caused activation of soluble MMP-2, but did not facilitate ECM degradation or cell invasiveness. Up-regulation of endogenous MT-MMP with concanavalin A caused activation of MMP-2. However, concanavalin A treatment prevented invadopodial localization of MT-MMP and ECM degradation. Neither a truncated MT-MMP mutant lacking transmembrane (TM) and cytoplasmic domains (ΔTM(MT-MMP)), nor a chimeric MT-MMP containing the interleukin 2 receptor α chain (IL-2R) TM and cytoplasmic domains (ΔTM(MT-MMP)/TM(IL-2R)) were localized to invadopodia or exhibited ECM degradation. Furthermore, a chimera of the TM/cytoplasmic domain of MT-MMP (TM(MT-MMP)) with tissue inhibitor of MMP 1 (TIMP-1/TM(MT- MMP)) directed the TIMP-1 molecule to invadopodia. Thus, the MT-MMP TM/cytoplasmic domain mediates the spatial organization of MT-MMP into invadopodia and subsequent degradation of the ECM.

Towards coordinated vision-based docking using an Autonomous Surface Vehicle

This paper describes the development and experimental evaluation of a novel vision-based Autonomous Surface Vehicle with the purpose of performing coordinated docking manoeuvres with a target, such as an Autonomous Underwater Vehicle, on the water’s surface. The system architecture integrates two small processor units; the first performs vehicle control and implements a virtual force obstacle avoidance and docking strategy, with the second performing vision-based target segmentation and tracking. Furthermore, the architecture utilises wireless sensor network technology allowing the vehicle to be observed by, and even integrated within an ad-hoc sensor network. The system performance is demonstrated through real-world experiments.

Genetic alternatives to mulesing and tail docking in sheep: a review

A genetic solution to breech strike control is attractive, as it is potentially permanent, cumulative, would not involve increased use of chemicals and may ultimately reduce labour inputs. There appears to be significant opportunity to reduce the susceptibility of Merinos to breech strike by genetic means although it is unlikely that in the short term breeding alone will be able to confer the degree of protection provided by mulesing and tail docking. Breeding programmes that aim to replace surgical techniques of flystrike prevention could potentially: reduce breech wrinkle; increase the area of bare skin in the perineal area; reduce tail length and wool cover on and near the tail; increase shedding of breech wool; reduce susceptibility to internal parasites and diarrhoea; and increase immunological resistance to flystrike. The likely effectiveness of these approaches is reviewed and assessed here. Any breeding programme that seeks to replace surgical mulesing and tail docking will need to make sheep sufficiently resistant that the increased requirement for other strike management procedures remains within practically acceptable bounds and that levels of strike can be contained to ethically acceptable levels.

Design, Development, Synthesis, and Docking Analysis of 2-substituted Triclosan Analogs as Inhibitors for Plasmodium falciparum Enoyl-ACP Reductase

A structure-based approach has been adopted to develop 2'substituted analogs of triclosan. The Cl at position 2' in ring B of triclosan was chemically substituted with other functional groups like NH2, NO2 and their inhibitory potencies against PfENR were determined. The binding energies of the 2' substituted analogs of triclosan for enoyl-acyl carrier protein reductase (ENR) of Plasmodium falciparum were determined using Autodock. Based on the autodock results, we synthesized the potential compounds. The IC50 and inhibition constant (K-i) of 2' substituted analogs of triclosan were determined against purified PfENR. Among them, two compounds,2-(2'-Amino-4'-chloro-phenoxy)-5-chloro-phenol (compound 4) and 5-chloro-2-(4'-chloro-2'-nitro-phenoxy)-phenol) (compound 5) exhibited good potencies. Compound 4 followed uncompetitive inhibition kinetics with crotonoyl CoA and competitive with NADH. It was shown to have an IC50 of 110 nM; inhibition constant was 104 nM with the substrate and 61 nM with the cofactor. IC50 Of compound 5 was determined to be 229 nM. Compounds 4 and 5 showed significant inhibition of the parasite growth in P. falciparum culture. (C) 2009 IUBMB IUBMB Life, 61(11):1083-1091, 2009.

Conformationally locked thiosugars alpha-mannosidase inhibitors: Synthesis, and docking studies as potent biochemical

series of thiosugar derivatives (thiolevomannosans) derived from mannose were synthesized and their inhibitory activity was tested against alpha-mannosidase (jack bean). These inhibitors were found to be more potent than the well-known inhibitors like kifunensine and deoxymannojirimycin based on docking and biochemical studies. The sulfone derivative 10 was shown to be the best inhibitor of alpha-mannosidase with the K-i value of 350 nM. (c) 2007 Elsevier Ltd. All rights reserved.

Using Correlated Parameters for Improved Ranking of Protein-Protein Docking Decoys

A successful protein-protein docking study culminates in identification of decoys at top ranks with near-native quaternary structures. However, this task remains enigmatic because no generalized scoring functions exist that effectively infer decoys according to the similarity to near-native quaternary structures. Difficulties arise because of the highly irregular nature of the protein surface and the significant variation of the nonbonding and solvation energies based on the chemical composition of the protein-protein interface. In this work, we describe a novel method combining an interface-size filter, a regression model for geometric compatibility (based on two correlated surface and packing parameters), and normalized interaction energy (calculated from correlated nonbonded and solvation energies), to effectively rank decoys from a set of 10,000 decoys. Tests on 30 unbound binary protein-protein complexes show that in 16 cases we can identify at least one decoy in top three ranks having <= 10 angstrom backbone root mean square deviation from true binding geometry. Comparisons with other state-of-art methods confirm the improved ranking power of our method without the use of any experiment-guided restraints, evolutionary information, statistical propensities, or modified interaction energy equations. Tests on 118 less-difficult bound binary protein-protein complexes with <= 35% sequence redundancy at the interface showed that in 77% cases, at least 1 in 10,000 decoys were identified with <= 5 angstrom backbone root mean square deviation from true geometry at first rank. The work will promote the use of new concepts where correlations among parameters provide more robust scoring models. It will facilitate studies involving molecular interactions, including modeling of large macromolecular assemblies and protein structure prediction. (C) 2010 Wiley Periodicals, Inc. J Comput Chem 32: 787-796, 2011.

DockYard-a repository to assist modeling of protein-protein docking

In the absence of interlogs, building docking models is a time intensive task, involving generation of a large pool of docking decoys followed by refinement and screening to identify near native docking solutions. This limits the researcher interested in building docking methods with the choice of benchmarking only a limited number of protein complexes. We have created a repository called dockYard (http://pallab.serc.iisc.ernet.in/dockYard), that allows modelers interested in protein-protein interaction to access large volume of information on protein dimers and their interlogs, and also download decoys for their work if they are interested in building modeling methods. dockYard currently offers four categories of docking decoys derived from: Bound (native dimer co-crystallized), Unbound (individual subunits are crystallized, as well as the target dimer), Variants (match the previous two categories in at least one subunit with 100% sequence identity), and Interlogs (match the previous categories in at least one subunit with >= 90% or >= 50% sequence identity). The web service offers options for full or selective download based on search parameters. Our portal also serves as a repository to modelers who may want to share their decoy sets with the community.

PRUNE and PROBE-two modular web services for protein-protein docking

The protein-protein docking programs typically perform four major tasks: (i) generation of docking poses, (ii) selecting a subset of poses, (iii) their structural refinement and (iv) scoring, ranking for the final assessment of the true quaternary structure. Although the tasks can be integrated or performed in a serial order, they are by nature modular, allowing an opportunity to substitute one algorithm with another. We have implemented two modular web services, (i) PRUNE: to select a subset of docking poses generated during sampling search (http://pallab.serc.iisc.ernet.in/prune) and (ii) PROBE: to refine, score and rank them (http://pallab.serc.iisc.ernet.in/probe). The former uses a new interface area based edge-scoring function to eliminate > 95% of the poses generated during docking search. In contrast to other multi-parameter-based screening functions, this single parameter based elimination reduces the computational time significantly, in addition to increasing the chances of selecting native-like models in the top rank list. The PROBE server performs ranking of pruned poses, after structure refinement and scoring using a regression model for geometric compatibility, and normalized interaction energy. While web-service similar to PROBE is infrequent, no web-service akin to PRUNE has been described before. Both the servers are publicly accessible and free for use.

Docking and free energy simulations to predict conformational domains involved in hCG-LH receptor interactions using recombinant antibodies

Single chain fragment variables (ScFvs) have been extensively employed in studying the protein-protein interactions. ScFvs derived from phage display libraries have an additional advantage of being generated against a native antigen, circumventing loss of information on conformational epitopes. In the present study, an attempt has been made to elucidate human chorionic gonadotropin (hCG)-luteinizing hormone (LH) receptor interactions by using a neutral and two inhibitory ScFvs against hCG. The objective was to dock a computationally derived model of these ScFvs onto the crystal structure of hCG and understand the differential roles of the mapped epitopes in hCG-LH receptor interactions. An anti-hCG ScFv, whose epitope was mapped previously using biochemical tools, served as the positive control for assessing the quality of docking analysis. To evaluate the role of specific side chains at the hCG-ScFv interface, binding free energy as well as residue interaction energies of complexes in solution were calculated using molecular mechanics Poisson-Boltzmann/surface area method after performing the molecular dynamic simulations on the selected hCG-ScFv models and validated using biochemical and SPR analysis. The robustness of these calculations was demonstrated by comparing the theoretically determined binding energies with the experimentally obtained kinetic parameters for hCG-ScFv complexes. Superimposition of hCG-ScFv model onto a model of hCG complexed with the 51-266 residues of LH receptor revealed importance of the residues previously thought to be unimportant for hormone binding and response. This analysis provides an alternate tool for understanding the structure-function analysis of ligand-receptor interactions. Proteins 2011;79:3108-3122. (C) 2011 Wiley-Liss, Inc.

Design, synthesis and docking studies of new quinoline-3-carbohydrazide derivatives as antitubercular agents

Three new series of 4-hydroxy-8-trifluoromethyl-quinoline derivatives were synthesized through multi step reactions. All the newly synthesized compounds were characterized by spectral and elemental analyses. The structure of 5j was evidenced by X-ray crystallographic study. The newly synthesized title compounds were evaluated for their antimicrobial activities including antimycobacterial activity. Amongst the tested compounds, 5b, 5e, 5h, 5j, 6c and 7c displayed promising antimicrobial activity. The mode of action of these active compounds was carried out by docking of receptor enoyl-ACP reductase with newly synthesized candidate ligands, 5b, 5e, 5h, 5j and 6c. (C) 2011 Elsevier Masson SAS. All rights reserved.

Binding of BIS like and other ligands with the GSK-3 beta kinase: a combined docking and MM-PBSA study

Binding of several bisindolylmaleimide (BIS) like (BIS-3, BIS-8 and UCN1) and other ligands (H89, SB203580 and Y27632) with the glycogen synthase kinase-3 (GSK-3 beta) has been studied using combined docking, molecular dynamics and Poisson-Boltzmann surface area analysis approaches. The study generated novel binding modes of these ligands that can rationalize why some ligands inhibit GSK-3 beta while others do not. The relative binding free energies associated with these binding modes are in agreement with the corresponding measured specificities. This study further provides useful insight regarding possible existence of multiple conformations of some ligands like H89 and BIS-8. It is also found that binding modes of BIS-3, BIS-8 and UCN1 with GSK-3 beta and PDK1 kinases are similar. These new insights are expected to be useful for future rational design of novel, more potent GSK-3 beta-specific inhibitors as promising therapeutics.

Molecular Docking Studies of Novel Palmitoyl-ligands for Cyclooxygenase-2

An in silico approach was adopted to identify potential cyclooxygenase-2 inhibitors through molecular docking studies. The in vivo studies indicated that synthetic palmitoyl derivatives of salicylic acid, para amino phenol, para amino benzoic acid, and anthranilic acid possessed significant pharmacological activities like anti-inflammatory, analgesic, and antipyretic activities. None of the tested substances produced any significant gastric lesions in experimental animals. In an attempt to understand the ligandprotein interactions in terms of the binding affinity, the above synthetic molecules were subjected to docking analysis using AutoDock. The palmitoyl derivatives palmitoyl anthranilic acid, palmitoyl para amino benzoic acid, palmitoyl para amino phenol, and palmitoyl salicylic acid showed better binding energy than the known inhibitor diclofenac bound to 1PXX. All the palmitoyl derivatives made similar interactions with the binding site residues of cyclooxygenase-2 as compared to that of the known inhibitor. Thus, structure-based drug discovery approach was successfully employed to identify some promising pro-drugs for the treatment of pain and inflammation.