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PubMed2003

Fat-tailed sheep traits as affected by docking.

The literature mostly indicates that docking fat-tailed lambs initially reduces growth but that post-weaning growth and feed conversion efficiency then increase. The amount of fat deposited, the total separable lean meat to fat ratio and the meat quality all increase, while the percentage of bone in the carcase either decreases or does not change in the carcases of the docked lambs. Wool growth and characteristics are, in general, not affected and reproductive traits in ewes and lambs are improved by docking. The rectal temperature, respiration rate and pulse rate are decreased following docking. The concentrations of immunoreactive beta-endorphin and cortisol in the plasma and the incidence of foot stamping and restlessness, as indicators of stress, increase after docking. Other constituents of the blood are not significantly altered following docking or by the methods of docking. Docking of fat-tailed sheep using rubber rings at one day of age can be recommended.

Animal Husbandry↗
PubMed1997

Transport, docking and exocytosis of single secretory granules in live chromaffin cells.

Neurons maintain a limited pool of synaptic vesicles which are docked at active zones and are awaiting exocytosis. By contrast, endocrine cells releasing large, dense-core secretory granules have no active zones, and there is disagreement about the size and even the existence of the docked pool. It is not known how, and how rapidly, secretory vesicles are replaced at exocytic sites in either neurons or endocrine cells. By using electron microscopy, we have now been able to identify a pool of docked granules in chromaffin cells that is selectively depleted when cells secrete. With evanescent-wave fluorescence microscopy, we observed single granules undergoing exocytosis and leaving behind patches of bare plasmalemma. Fresh granules travelled to the plasmalemma at a top speed of 114 nm s(-1), taking an average of 6 min to arrive. On arrival, their motility diminished 4-fold, probably as a result of docking. Some granules detached and returned to the cytosol. We conclude that a large pool of docked granules turns over slowly, that granules move actively to their docking sites, that docking is reversible, and that the 'rapidly releasable pool' measured electrophysiologically represents a small subset of docked granules.

Acridine Orange↗
PubMed2003

Signalling specificity of Ser/Thr protein kinases through docking-site-mediated interactions.

Signal transduction pathways use protein kinases for the modification of protein function by phosphorylation. A major question in the field is how protein kinases achieve the specificity required to regulate multiple cellular functions. Here we review recent studies that illuminate the mechanisms used by three families of Ser/Thr protein kinases to achieve substrate specificity. These kinases rely on direct docking interactions with substrates, using sites distinct from the phospho-acceptor sequences. Docking interactions also contribute to the specificity and regulation of protein kinase activities. Mitogen-activated protein kinase (MAPK) family members can associate with and phosphorylate specific substrates by virtue of minor variations in their docking sequences. Interestingly, the same MAPK docking pocket that binds substrates also binds docking sequences of positive and negative MAPK regulators. In the case of glycogen synthase kinase 3 (GSK3), the presence of a phosphate-binding site allows docking of previously phosphorylated (primed) substrates; this docking site is also required for the mechanism of GSK3 inhibition by phosphorylation. In contrast, non-primed substrates interact with a different region of GSK3. Phosphoinositide-dependent protein kinase-1 (PDK1) contains a hydrophobic pocket that interacts with a hydrophobic motif present in all known substrates, enabling their efficient phosphorylation. Binding of the substrate hydrophobic motifs to the pocket in the kinase domain activates PDK1 and other members of the AGC family of protein kinases. Finally, the analysis of protein kinase structures indicates that the sites used for docking substrates can also bind N- and C-terminal extensions to the kinase catalytic core and participate in the regulation of its activity.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2004

ERK5 is targeted to myocyte enhancer factor 2A (MEF2A) through a MAPK docking motif.

One critical component in determining the specificity, and efficiency of MAPK (mitogen-activated protein kinase) substrate phophorylation is the presence of distinct docking domains in the substrate proteins. Docking domains have been shown to be important for the activities of members of the ERK (extracellular-signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38 subfamilies of MAPKs towards their substrates. Here, we demonstrate that docking domains also play an important role in ERK5-mediated substrate phosphorylation. The presence of a docking domain promotes both phosphorylation of myocyte enhancer factor, MEF2A, in vitro and its activation in vivo by ERK5. Mutational analysis of the MEF2A docking domain demonstrates that the specificity determinants for ERK5 are similar to those observed with members of the p38 subfamily. A docking domain recognized by ERK5 can direct ERK5 to activate heterologous substrates. Deletion analysis demonstrates that as with other MAPKs, it is the catalytic domain of ERK5 that recognizes the docking domain. Our data therefore extend previous observations on other MAPKs and demonstrate that the requirement for specific docking domains in promoting MAPK action towards substrates is a general property of MAPKs.

Amino Acid Motifs↗
PubMed2006

Docking-based substrate recognition by the catalytic domain of a protein tyrosine kinase, C-terminal Src kinase (Csk).

Protein tyrosine kinases are key enzymes of mammalian signal transduction. Substrate specificity is a fundamental property that determines the specificity and fidelity of signaling by protein tyrosine kinases. However, how protein tyrosine kinases recognize the protein substrates is not well understood. C-terminal Src kinase (Csk) specifically phosphorylates Src family kinases on a C-terminal Tyr residue, which down-regulates their activities. We have previously determined that Csk recognizes Src using a substrate-docking site away from the active site. In the current study, we identified the docking determinants in Src recognized by the Csk substrate-docking site and demonstrated an interaction between the docking determinants of Src and the Csk substrate-docking site for this recognition. A similar mechanism was confirmed for Csk recognition of another Src family kinase, Yes. Although both Csk and MAP kinases used docking sites for substrate recognition, their docking sites consisted of different substructures in the catalytic domain. These results helped establish a docking-based substrate recognition mechanism for Csk. This model may provide a framework for understanding substrate recognition and specificity of other protein tyrosine kinases.

Amino Acid Sequence↗
PubMed2002

SOFTDOCK: understanding of molecular recognition through a systematic docking study.

Molecular recognition and docking are essential to the biological functions of proteins. SOFTDOCK was one of the first molecular docking methods developed for protein-protein docking. Its ability to represent the molecular surface with different shapes and properties and to dock a variety of molecular complexes with certain conformational changes was demonstrated in a previous study. In the present work, we studied the effects of the docking parameters through statistical analysis. Seventy one typical binary complexes of different categories in PDB were also systematically docked for a test; 57 of them produced correct solutions with one set of docking parameters whereas the other 14 complexes required adjustment of the docking parameters, by decreasing the softness of the recognition and hence the background noise. We found that these 14 complexes had special structural features. Our results suggest that a variety of mechanisms may be involved in molecular recognition rather than the shape complementarity only, which is very helpful in developing more powerful methods for predicting molecular recognition.

Binding Sites↗
PubMed1996

Tail docking in dogs: a sample of attitudes of veterinarians and dog breeders in Queensland.

One hundred veterinarians and 100 breeders of traditionally docked dogs from Queensland were surveyed by telephone to determine their attitudes towards tail docking. Eighty-four percent of the breeders surveyed were in favour of docking, whereas 83% of veterinarians were opposed to the practice. Most pups were docked between 1 and 3 days of age. All veterinarians surgically amputated the tail, whereas 16% of breeders applied rubber bands to the tail. Seventy-six percent of the veterinarians, but only 18% of the breeders believed that docking caused significant to severe pain. No veterinarians, but 25% of the dog breeders believed that docking was painless. Although recent changes to the Queensland Canine Control Council's rulings allow dogs with intact tails to be shown in traditionally docked classes, the requirement of breed standard was cited as the major reason for tail docking by both breeders and veterinarians.

Animals↗
PubMed1999

Acute cortisol responses of lambs to ring castration and docking after the injection of lignocaine into the scrotal neck or testes at the time of ring application.

OBJECTIVE: To test whether injecting lignocaine into the scrotal neck 5 to 10 s before or into both testes immediately after ring castration and docking wound significantly reduce the plasma cortisol response to castration and docking. DESIGN: A physiological study with controls. PROCEDURE: Lambs were given one of six treatments: control handling, injection of lignocaine into scrotal neck, injection of lignocaine into both testes, ring castration and docking, ring castration and docking after lignocaine was injected into the scrotal neck, and ring castration and docking before lignocaine was injected into both testes. Blood samples were taken before and regularly after treatment and analysed for plasma cortisol concentrations. RESULTS: The plasma cortisol concentrations of lambs castrated and docked after lignocaine had been injected into the scrotal neck were significantly lower between 20 and 60 min after treatment than in lambs castrated and docked without local anaesthesia. Injecting lignocaine into the testes after ring application did not significantly reduce the cortisol response to ring castration and docking. CONCLUSIONS: Lignocaine injected into the scrotal neck 5 to 10 s before ring castration will reduce the cortisol response and by inference the pain associated with ring castration.

Anesthesia, Local↗
PubMed2004

Docking-dependent regulation of the Rb tumor suppressor protein by Cdk4.

Phosphorylation of target proteins by cyclin D1-Cdk4 requires both substrate docking and kinase activity. In addition to the ability of cyclin D1-Cdk4 to catalyze the phosphorylation of consensus sites within the primary amino acid sequence of a substrate, maximum catalytic activity requires the enzyme complex to anchor at a site remote from the phospho-acceptor site. A novel Cdk4 docking motif has been defined within a stretch of 19 amino acids from the C-terminal domain of the Rb protein that are essential for Cdk4 binding. Mutation or deletion of the docking motif prevents Cdk4-dependent phosphorylation of full-length Rb protein or C-terminal Rb fragments in vitro and in cells, while a peptide encompassing the Cdk4 docking motif specifically inhibits Cdk4-dependent phosphorylation of Rb. Cyclin D1-Cdk4 can overcome the growth-suppressive activity of Rb in both cell cycle progression and colony formation assays; however, while mutants of Rb in which the Cdk4 docking site has been either deleted or mutated retain growth suppressor activity, they are resistant to inactivation by cyclin D1-Cdk4. Finally, binding of Cdk4 to its docking site can inhibit cleavage of exogenous and endogenous Rb in response to distinct apoptotic signals. The Cdk4 docking motif in Rb gives insight into the mechanism by which enzyme specificity is ensured and highlights a role for Cdk4 docking in maintaining the Rb protein in a form that favors cell survival rather than apoptosis.

Amino Acid Motifs↗
PubMed2006

Docking of secretory vesicles is syntaxin dependent.

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

Animals↗
PubMed2006

A sex difference in the cortisol response to tail docking and ACTH develops between 1 and 8 weeks of age in lambs.

It is important to understand factors that may influence responses to stress, as these factors may also influence vulnerability to pathologies that can develop when stress responses are excessive or prolonged. It is clear that, in adults, the sex of an individual can influence the cortisol response to stress in a stressor specific manner. Nevertheless, the stage of development at which these sex differences emerge is unknown. We tested the hypothesis that there are sex differences in the cortisol response to tail docking and ACTH in lambs of 1 and 8 weeks of age. We also established cortisol responses in males when tail docking was imposed alone and in combination with castration at these ages. In experiment 1, 1 and 8 week old male and female lambs were subjected to sham handling, tail docking or, in males, a combination of tail docking and castration. In experiment 2, we administered ACTH (1.0 IU/kg) to male and female lambs at 1 and 8 weeks of age. There were significant cortisol responses to all treatments at both ages. Sex differences in the cortisol responses to tail docking and ACTH developed between 1 and 8 weeks of age, with females having greater responses than males. The data suggest that the mechanism for the sex difference in response to tail docking may involve the adrenal glands. At both ages, in males, the cortisol response to the combined treatment of tail docking and castration was significantly greater than that for tail docking alone.

Adrenal Glands↗
PubMed2006

Docking and scoring--theoretically easy, practically impossible?

Structure-based Drug Design (SBDD) is an essential part of the modern medicinal chemistry, and has led to the acceleration of many projects, and even to drugs on the market. Programs that perform docking and scoring of ligands to receptors are powerful tools in the drug designer's armoury that enhance the process of SBDD. They are even deployed on the desktop of many bench chemists. It is timely to review the state of the art, to understand how good our docking programs are, and what are the issues. In this review we would like to provide a guide around the reliable aspects of docking and scoring and the associated pitfalls aiming at an audience of medicinal chemists rather than modellers. For convenience, we will divide the review into two parts: docking and scoring. Docking concerns the preparation of the receptor and the ligand(s), the sampling of conformational space and stereochemistry (if appropriate). Scoring concerns the evaluation of all of the ligand-receptor poses generated by docking. The two processes are not truly independent, and this will be discussed here in detail. The preparation of the receptor and ligand(s) before docking requires great care. For the receptor, issues of protonation, tautomerisation and hydration are key, and we will discuss current approaches to these issues. Even more important is the degree of sampling: can the algorithms reproduce what is observed experimentally? If they can, are the scoring algorithms good enough to recognise this pose as the best? Do the scores correlate with observed binding affinity? How does local knowledge of the target (for example hinge-binding to a kinase) affect the accuracy of the predictions? We will review the key findings from several evaluation studies and present conclusions about when and how to interpret and trust the results of docking and scoring. Finally, we will present an outline of some of the latest developments in the area of scoring functions.

Cluster Analysis↗
PubMed1999

Automated docking of maltose, 2-deoxymaltose, and maltotetraose into the soybean beta-amylase active site.

In this study, products and substrates were docked into the active site of beta-amylase using the simulated annealing algorithm AutoDock. Lowest-energy conformers reproduced known crystallographic atom positions within 0.4 to 0.8 A rmsd. Docking studies were carried out with both open and closed configurations of the beta-amylase mobile flap, a loop comprising residues 96 to 103. Ligands with two rings docked within the cleft near the active site when the flap was open, but those with four rings did not. The flap must be closed for alpha-maltotetraose to adopt a conformation allowing it to dock near the crystallographically determined subsites. The closed flap is necessary for productive but not for nonproductive binding, and therefore it plays a essential role in catalysis. The gain in total binding energy upon closing of the flap for alpha-maltose docked to subsites -2, -1 and +1, +2 is about 22 kcal/mol, indicating more favorable interactions are possible with the flap closed. Larger intermolecular interaction energies are observed for two alpha-maltose molecules docked to subsites -2, -1 and +1, +2 than for one alpha-maltotetraose molecule docked from subsites -2 to +2, suggesting that it is only upon cleavage of the alpha-1,4 linkage that optimal closed-flap binding can occur with the crytallographically determined enzyme structure.

Binding Sites↗
PubMed2004

Development and evaluation of a generic evolutionary method for protein-ligand docking.

We have developed a generic evolutionary method with an empirical scoring function for the protein-ligand docking, which is a problem of paramount importance in structure-based drug design. This approach, referred to as the GEMDOCK (Generic Evolutionary Method for molecular DOCKing), combines both continuous and discrete search mechanisms. We tested our approach on seven protein-ligand complexes, and the docked lowest energy structures have root-mean-square derivations ranging from 0.32 to 0.99 A with respect to the corresponding crystal ligand structures. In addition, we evaluated GEMDOCK on crossdocking experiments, in which some complexes with an identical protein used for docking all crystallized ligands of these complexes. GEMDOCK yielded 98% docked structures with RMSD below 2.0 A when the ligands were docked into foreign protein structures. We have reported the validation and analysis of our approach on various search spaces and scoring functions. Experimental results show that our approach is robust, and the empirical scoring function is simple and fast to recognize compounds. We found that if GEMDOCK used the RMSD scoring function, then the prediction accuracy was 100% and the docked structures had RMSD below 0.1 A for each test system. These results suggest that GEMDOCK is a useful tool, and may systematically improve the forms and parameters of a scoring function, which is one of major bottlenecks for molecular recognition.

Drug Design↗
PubMed2007

SODOCK: swarm optimization for highly flexible protein-ligand docking.

Protein-ligand docking can be formulated as a parameter optimization problem associated with an accurate scoring function, which aims to identify the translation, orientation, and conformation of a docked ligand with the lowest energy. The parameter optimization problem for highly flexible ligands with many rotatable bonds is more difficult than that for less flexible ligands using genetic algorithm (GA)-based approaches, due to the large numbers of parameters and high correlations among these parameters. This investigation presents a novel optimization algorithm SODOCK based on particle swarm optimization (PSO) for solving flexible protein-ligand docking problems. To improve efficiency and robustness of PSO, an efficient local search strategy is incorporated into SODOCK. The implementation of SODOCK adopts the environment and energy function of AutoDock 3.05. Computer simulation results reveal that SODOCK is superior to the Lamarckian genetic algorithm (LGA) of AutoDock, in terms of convergence performance, robustness, and obtained energy, especially for highly flexible ligands. The results also reveal that PSO is more suitable than the conventional GA in dealing with flexible docking problems with high correlations among parameters. This investigation also compared SODOCK with four state-of-the-art docking methods, namely GOLD 1.2, DOCK 4.0, FlexX 1.8, and LGA of AutoDock 3.05. SODOCK obtained the smallest RMSD in 19 of 37 cases. The average 2.29 A of the 37 RMSD values of SODOCK was better than those of other docking programs, which were all above 3.0 A.

Algorithms↗
PubMed2006

Combining docking and molecular dynamic simulations in drug design.

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

Computer Simulation↗
PubMed1995

Monte Carlo docking with ubiquitin.

The development of general strategies for the performance of docking simulations is prerequisite to the exploitation of this powerful computational method. Comprehensive strategies can only be derived from docking experiences with a diverse array of biological systems, and we have chosen the ubiquitin/diubiquitin system as a learning tool for this process. Using our multiple-start Monte Carlo docking method, we have reconstructed the known structure of diubiquitin from its two halves as well as from two copies of the uncomplexed monomer. For both of these cases, our relatively simple potential function ranked the correct solution among the lowest energy configurations. In the experiments involving the ubiquitin monomer, various structural modifications were made to compensate for the lack of flexibility and for the lack of a covalent bond in the modeled interaction. Potentially flexible regions could be identified using available biochemical and structural information. A systematic conformational search ruled out the possibility that the required covalent bond could be formed in one family of low-energy configurations, which was distant from the observed dimer configuration. A variety of analyses was performed on the low-energy dockings obtained in the experiment involving structurally modified ubiquitin. Characterization of the size and chemical nature of the interface surfaces was a powerful adjunct to our potential function, enabling us to distinguish more accurately between correct and incorrect dockings. Calculations with the structure of tetraubiquitin indicated that the dimer configuration in this molecule is much less favorable than that observed in the diubiquitin structure, for a simple monomer-monomer pair. Based on the analysis of our results, we draw conclusions regarding some of the approximations involved in our simulations, the use of diverse chemical and biochemical information in experimental design and the analysis of docking results, as well as possible modifications to our docking protocol.

Algorithms↗
PubMed2002

Docking of non-nucleoside inhibitors: neotripterifordin and its derivatives to HIV-1 reverse transcriptase.

The docking of small molecules to proteins has played an important role in the understanding of drug/receptor interactions. An important drug/receptor interaction is between non-nucleoside inhibitors of HIV-1 RT and the non-nucleoside binding pocket. We report the results of docking calculations in which we have docked known and proposed non-nucleoside reverse transcriptase inhibitors to the type 1 virus. The proposed NNRTIs dock in a similar position and orientation as known inhibitors. In addition, we observe a linear correlation between the calculated interaction energy and EC50 for the inhibitors, suggesting that the docked structure orientation and the interaction energies are reasonable. Two hydrogen bonds between nevirapine and RT (3HVT and 1VRT) are observed and are reproduced across different docking schemes. Since we used two different HIV-1 RT crystal structures (3HVT and 1VRT), which are at different levels of resolution (2.9 and 2.2 A, respectively), we propose that structures with resolutions better than 3 A can be used to produce reasonable docking results.

Anti-HIV Agents↗