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At least 235 records · Page 13Linked to original sources
PubMed1997

Acute cortisol responses of lambs castrated and docked using rubber rings with or without a castration clamp.

OBJECTIVE: To measure the plasma cortisol response in lambs castrated and docked by three different methods (ring castration and tail docking, ring and clamp castration and tail docking; ring and clamp castration and ring tail docking) for 4 h after treatment. DESIGN: A physiological study with controls. PROCEDURE: A rubber ring was applied to the scrotum. Then the castration clamp was placed, distal to the ring, on each spermatic cord such that there was no overlap of the crush lines. RESULTS: There were no differences in the cortisol secretion of the lambs castrated and tail docked by the ring only and by the ring plus castration clamp methods. Using the castration clamp in addition to the ring on the tail had no effect on cortisol secretion. CONCLUSIONS: Using the castration clamp did not appear to reduce the cortisol response to ring castration and docking, as demonstrated elsewhere, because the areas of uncrushed tissue between the two castration clamp crush lines allowed nociception from ischemic scrotal tissue to be transmitted cranially via undamaged nerve fibers.

Analysis of Variance↗
PubMed1994

Lamb tail docking: a controlled field study of the effects of tail amputation on health and productivity.

A detailed study of the effects of tail docking on lamb health and productivity was prompted by current concern about the welfare aspects of lamb tail amputation. Using a controlled field trial, comparing over 3000 docked and undocked lambs on seven farms, the effects of tail docking on mortality, blowfly strike and production variables were examined. The incidence of blowfly strike was strongly and consistently higher in undocked than docked lambs (rate ratio 6.03, 95 per cent confidence interval (CI) 2.99 to 12.19 for male lambs and 4.25, 95 per cent CI 2.25 to 8.01 for female lambs). The incidence of faecal soiling of the breech was slightly higher in undocked lambs and was identified as an important independent risk factor for blowfly strike. Both the mortality and production parameters were similar for docked and undocked lambs. It was concluded that tail docking protected against blowfly strike, with little evidence of any detrimental effect on lamb mortality and production.

Amputation, Surgical↗
PubMed2001

Acid prohormone sequence determines size, shape, and docking of secretory vesicles in atrial myocytes.

How vesicles are born in the trans-Golgi network and reach their docking sites at the plasma membrane is still largely unknown and is investigated in the present study on live, primary cultured atrial cardiomyocytes. Secretory vesicles (n=422) are visualized by expressing fusion proteins of proatrial natriuretic peptide (proANP) and green fluorescent protein. Myocytes expressing fusion proteins with intact proANP display two populations of fluorescent vesicles with apparent diameters of 120 and 175 nm, moving at a top velocity of 0.3 microm/s. The number of docked vesicles is significantly correlated with the number of mobile vesicles (r=0.71, P<0.0005). The deletion of the acidic N-terminal proANP[1-44] or point mutations (glu(23,24)-->gln(23,24)) change size and shape-but not velocity-of the vesicles, and, strikingly, abolish their docking at the plasma membrane. The shapes thus change from spheres to larger, irregular floppy bags or vesicle trains. Deletion of the C-terminal proANP[45-127], where the ANP and its disulfide bond reside, does not change size, shape, docking, or velocity of the mobile vesicles. The N-terminal acid calcium-binding sequence of proANP is known to cause protein aggregation at the high calcium concentration prevailing in the trans-Golgi network. Therefore, these results indicate that amino acid residues favoring cargo aggregation are critically important in shaping the secretory vesicles and determining their fate-docking or not docking-at the plasma membrane. The full text of this article is available at http://www.circresaha.org.

Animals↗
PubMed2007

[Docking method for drug discovery].

The effective integration of detailed structural information with computational chemistry, medicinal chemistry, and informatics transforms the dream of virtual screening into reality. One of the most important technologies essential for virtual screening is an effective docking method to find molecules that efficaciously interact with their target molecules. Since an efficient docking method can be a powerful tool for virtual screening, many different approaches to solving docking problems have been proposed. Docking problems have not yet been solved and none of the currently available programs are perfect in predicting all possible scenarios. Despite the limits and imperfections of the methodology, currently available docking methods are very useful for drug discovery. The basic principles and limits of docking methods together with matters for attention in applying the methods are described in this paper.

Binding Sites↗
PubMed2005

Optimal clustering for detecting near-native conformations in protein docking.

Clustering is one of the most powerful tools in computational biology. The conventional wisdom is that events that occur in clusters are probably not random. In protein docking, the underlying principle is that clustering occurs because long-range electrostatic and/or desolvation forces steer the proteins to a low free-energy attractor at the binding region. Something similar occurs in the docking of small molecules, although in this case shorter-range van der Waals forces play a more critical role. Based on the above, we have developed two different clustering strategies to predict docked conformations based on the clustering properties of a uniform sampling of low free-energy protein-protein and protein-small molecule complexes. We report on significant improvements in the automated prediction and discrimination of docked conformations by using the cluster size and consensus as a ranking criterion. We show that the success of clustering depends on identifying the appropriate clustering radius of the system. The clustering radius for protein-protein complexes is consistent with the range of the electrostatics and desolvation free energies (i.e., between 4 and 9 Angstroms); for protein-small molecule docking, the radius is set by van der Waals interactions (i.e., at approximately 2 Angstroms). Without any a priori information, a simple analysis of the histogram of distance separations between the set of docked conformations can evaluate the clustering properties of the data set. Clustering is observed when the histogram is bimodal. Data clustering is optimal if one chooses the clustering radius to be the minimum after the first peak of the bimodal distribution. We show that using this optimal radius further improves the discrimination of near-native complex structures.

Amino Acid Sequence↗
PubMed2003

Length of docked tail and the incidence of rectal prolapse in lambs.

A multistate cooperative study was conducted to study the current issue of tail length in docked lambs and its relationship to incidence of rectal prolapse. A total of 1,227 lambs at six locations were randomly allocated to two or three tail dock treatments: 1) short--tail was removed as close to the body as possible, 2) medium--tail was removed at a location midway between the attachment of the tail to the body and the attachment of the caudal folds to the tail, and 3) long--tail was removed at the attachment of the caudal folds to the tail. Short-docked lambs had a greater (P < 0.05) incidence of rectal prolapse (7.8%) than lambs with a medium (4.0%) or a long (1.8%) dock. Female lambs had a higher (P < 0.05) incidence of rectal prolapse than male lambs. At two stations, lambs were finished either in a feedlot on a high-concentrate diet or on pasture with no grain supplementation. At one station, with a very low incidence of rectal prolapse, there was no difference in incidence between lambs finished in the feedlot or on pasture; however, at the station with a relatively high incidence of rectal prolapse, lambs in the feedlot had a higher (P < 0.05) incidence than lambs on pasture. The half-sib estimate of heritability for the incidence of rectal prolapse was low (0.14). The results of this study strongly implicate short dock length as a cause of rectal prolapse in lambs finished on high-concentrate diets. Furthermore, the results of this study and the only other study known conducted on this issue strongly suggest that docking lambs at the site of the attachment of the caudal folds to the tail will result in a negligible incidence of rectal prolapse.

Animal Husbandry↗
PubMed1999

Flexible ligand docking: a multistep strategy approach.

A flexible ligand docking protocol based on a divide-and-conquer strategy is investigated. This approach first separates total search space into conformation and orientation space. It uses a grid-based method to sample the conformation of an unbound ligand and to select the low-energy conformers. Rigid docking is then carried out to locate the low-energy binding orientations for these conformers. These docking structures are subsequently subjected to structure refinement including molecular mechanics minimization, conformational scanning at the binding site and a short period of molecular dynamics-based simulated annealing. This approach has been applied to twelve ligand-protein complexes with three to sixteen rotatable bonds. The docked lowest-energy structures have root mean square deviations ranging from 0.64 A to 2.01 A with respect to the corresponding crystal structures. The effect of atomic charges and van der Waals parameters on the docking results, and the role of the dielectric constant in the conformation sampling are discussed in detail. A fragment-based docking approach that takes advantages of the divide-and-conquer strategy has also been explored and the results are compared with those produced by a whole molecule-based approach.

Hydrogen Bonding↗
PubMed1985

A structural and functional analysis of the docking protein. Characterization of active domains by proteolysis and specific antibodies.

Docking protein is a 73-kDa integral membrane protein of the rough endoplasmic reticulum. It is essential for translocation of nascent secretory proteins into the lumen of the endoplasmic reticulum. Monoclonal and polyclonal antibodies have been generated which, in conjunction with limited proteolysis, have been used to characterize several subspecies of docking protein. These proteolytic fragments have been analyzed with respect to the various functions ascribed to docking protein which can be assayed in vitro. Proteolytic digestion of membrane-associated or of affinity-purified intact docking protein showed that: elastase cleavage generates a 59-kDa soluble fragment and one of 14 kDa which contains the membrane anchoring domain; trypsin as well as endogenous proteolysis generates a 46-kDa fragment, leaving a 27-kDa domain containing the membrane anchor. This 27-kDa fragment can be reduced to a 13- and a 14-kDa piece by elastase digestion. The characteristics of these various subspecies were examined. The 59-kDa soluble fragment, which can reconstitute full translocation activity to docking protein-depleted microsomes (Meyer, D. I., and Dobberstein, B. (1980) J. Cell Biol. 87, 503-508) was capable of releasing a signal recognition particle-mediated translation arrest. The 46-kDa fragment was neither able to reassociate with nor to reconstitute the activity of docking protein-depleted microsomes. Moreover this fragment was unable to release a signal recognition particle-mediated arrest. This suggests that the 13-kDa fragment (the difference between 46 and 59 kDa) is both essential for association with the membrane, and for the release of translation arrests.

Animals↗
PubMed1998

Surface solid angle-based site points for molecular docking.

We are developing a new site descriptor for the DOCK molecular modeling program suite. Sphgen, the current site description program for the DOCK suite, describes the pockets of a macromolecule by filling a volume with intersecting spheres. DOCK then identifies possible ligand orientations in the pocket by overlapping the atoms of proposed ligands with the sphere centers. Sphgen limits use of the DOCK program to concave binding regions, but macromolecular binding regions can be solvent-exposed rather than buried pockets. We present a more general site descriptor, based on the surface solid angle, which generates site points by determining the solid angle of exposure for points on the surface of the molecule, then identifying patches of surface with similar solid angle values which are then built into site points. We find possible ligand orientations by matching shape-based site points on the ligand and protein and demanding complementary solid angle values. Orientations are evaluated using the DOCK's force field-based score, which evaluates the Coulombic and van der Waals energy. The surface solid angle descriptor displays the complementary characteristics of the interfaces of our test systems: trypsin/trypsin inhibitor, chymotrypsin/turkey ovomucoid third domain, and subtilisin/chymotrypsin inhibitor. The solid angle site points can be used by DOCK to generate orientations within 1.5 A r.m.s.d. of the crystal structure orientation.

Algorithms↗
PubMed1998

Flexible docking allowing induced fit in proteins: insights from an open to closed conformational isomers.

Here we dock a ligand onto a receptor surface allowing hinge-bending domain/substructural movements. Our approach mimics and manifests induced fit in molecular recognition. All angular rotations are allowed on the one hand, while a conformational space search is avoided on the other. Rather than dock each of the molecular parts separately with subsequent reconstruction of the consistently docked molecules, all parts are docked simultaneously while still utilizing the position of the hinge from the start. Like pliers closing on a screw, the receptor automatically closes on its ligand in the best surface-matching way. Movements are allowed either in the ligand or in the larger receptor, hence reproducing induced molecular fit. Hinge bending movements are frequently observed when molecules associate. There are numerous examples of open versus closed conformations taking place upon binding. Such movements are observed when the substrate binds to its respective enzyme. In particular, such movements are of interest in allosteric enzymes. The movements can involve entire domains, subdomains, loops, (other) secondary structure elements, or between any groups of atoms connected by flexible joints. We have implemented the hinges at points and at bonds. By allowing 3-dimensional (3-D) rotation at the hinge, several rotations about (consecutive or nearby) bonds are implicitly taken into account. Alternatively, if required, the point rotation can be restricted to bond rotation. Here we illustrate this hinge-bending docking approach and the insight into flexibility it provides on a complex of the calmodulin with its M13 ligand, positioning the hinges either in the ligand or in the larger receptor. This automated and efficient method is adapted from computer vision and robotics. It enables utilizing entire molecular surfaces rather than focusing a priori on active sites. Hence, allows attaining the overall optimally matching surfaces, the extent and type of motions which are involved. Here we do not treat the conformational flexibility of side-chains or of very small pieces of the molecules. Therefore, currently available methods addressing these issues and the method presented here, are complementary to each other, expanding the repertoire of computational docking tools foreseen to aid in studies of recognition, conformational flexibility and drug design.

Algorithms↗
PubMed1998

Flexible docking using Tabu search and an empirical estimate of binding affinity.

This article describes the implementation of a new docking approach. The method uses a Tabu search methodology to dock flexibly ligand molecules into rigid receptor structures. It uses an empirical objective function with a small number of physically based terms derived from fitting experimental binding affinities for crystallographic complexes. This means that docking energies produced by the searching algorithm provide direct estimates of the binding affinities of the ligands. The method has been tested on 50 ligand-receptor complexes for which the experimental binding affinity and binding geometry are known. All water molecules are removed from the structures and ligand molecules are minimized in vacuo before docking. The lowest energy geometry produced by the docking protocol is within 1.5 A root-mean square of the experimental binding mode for 86% of the complexes. The lowest energies produced by the docking are in fair agreement with the known free energies of binding for the ligands.

Algorithms↗
PubMed1997

Critical evaluation of the research docking program for the CASP2 challenge.

The binding positions of six small-molecule ligands in their complexes with target proteins were predicted using our Research docking program for the CASP2 challenge. Research uses a Monte Carlo procedure with pairwise energies and allows for the conformational searching of ligand torsional space. We were able to predict 2 of the 5 noncovalent complexes within 2 A root-mean-square (RMS) of the experimental structures as ranked by interaction energy or by a score calculated using our interaction evaluation program, Out-rank. In addition, for 4 of the 5 noncovalent structures we found a docking within 2 A RMS of the experimental structure within the top 20 dockings as ranked by energy. The main limitation in our approach is in the ability of the energy function and Outrank to discriminate among the lowest energy dockings. On the other hand, our success in exploring the multi-dimensional docking space of position, orientation and conformation is encouraging.

Arabinose↗
PubMed1999

Efficacy and selectivity in flexible database docking.

Flexible database docking with DOCK 4.0 has been evaluated for its ability to retrieve biologically active molecules from a database of approximately 1,000 compounds with known activities against thrombin and the progesterone receptor. The retrieval of known actives and chemically similar but inactive molecules was monitored as a function of conformational and orientational sampling. The largest enrichment of actives among the 10% highest ranking molecules is obtained when only five conformations are used to seed the next round of ligand reconstruction and limited sampling is applied to place the base fragment in the binding site. The performance of energy and chemical scoring, as implemented in DOCK 4.0, was found to depend on the protein used for docking. For the progesterone receptor, energy scoring yields the largest enrichments (64%) in terms of actives retrieved among the 10% top scoring molecules, while chemical scoring performs best for thrombin (94%). With the exception of the application of energy scoring to the progesterone receptor, both energy-based scoring schemes applied in this study do not discriminate well between true actives and chemically similar but inactive compounds. In conclusion, flexible docking is able to effectively prioritize high-throughput screening databases, using less conformational sampling than normally required for appropriate reconstruction of protein-ligand complexes. The more subtle discrimination between chemically similar classes of active and inactive compounds remains, however, problematic.

Algorithms↗
PubMedDate not supplied

Prediction of IgE(Lb4)-ligand complex structures by automated docking.

A mouse monoclonal anti-2,4,6-trinitrophenyl IgE (clone Lb4) was screened with a random set of over 2000 compounds, and several ligands were found to bind with affinities comparable to that of the immunizing hapten (KD in the microM range). An automated docking algorithm was used for the prediction of complex structures formed by 2,4-dinitrophenyl (DNP) and non-DNP ligands in the fragment variable region of IgE(Lb4). All ligands were found to dock in an L-shaped cavity of 15 x 16 x 10 A, surrounded by complementary-determining regions L1, L3, H2 and H3. The ligands were found to occupy the same binding site in different orientations. For rigid ligands the most stable orientation could be predicted with high probability, based on the calculated energy of binding and the occurrence frequencies of identical complexes obtained by repeated simulations. The localization of a flexible ligand (cycrimine-R) was more ambiguous, but it still docked in the same site. The results support a model for heteroligating antibody (Ab) binding sites, where different ligands utilize the total set of available contacts in different combinations. It is suggested that although pseudoenergies calculated by the docking algorithm do not correlate with experimentally measured binding energies, the screening-and-docking procedure can be useful for the mapping of Ab and other receptor binding sites ligating small molecules.

2,4-Dinitrophenol↗
PubMed2006

Structure of the virus capsid protein VP1 of enterovirus 71 predicted by some homology modeling and molecular docking studies.

The homology modeling technique has been used to construct the structure of enterovirus 71 (EV 71) capsid protein VP1. The protein is consisted of 297 amino acid residues and treated as the target. The amino acid sequence identity between the target protein and sequences of template proteins 1EAH, 1PIV, and 1D4M searched from NCBI protein BLAST and WorkBench protein tools were 38, 37, and 36%, respectively. Based on these template structures, the protein model was constructed by using the InsightII/Homology program. The protein model was briefly refined by energy minimization and molecular dynamics (MD) simulation steps. The protein model was validated using some web available servers such as ERRAT, PROCHECK, PROVE, and PROSA2003. However, an inconsistency between the docking scores and the measured activity was observed for a series of EV 71 VP1 inhibitors synthesized by Shia et al. (J Med Chem 2002, 45, 1644) and docked into the binding pocket of the protein model using the DOCK 4.0.2 program. The protein model with an EV 71 VP1 inhibitor docked and engulfed was then refined further by some MD simulation steps in the presence of water molecules. The docking scores obtained for these inhibitors after such a MD refinement were well correlated with the activities. The structure-activity relationships for the ligand-protein model system was also analyzed using the GRID-VOLSURF programs and the corresponding noncrossvalidated and crossvalidated (by leave-one-out) r2 and q2 were 0.99 and 0.61, respectively. The hydrophobic nature of the binding pocket of the protein model was also examined using the GRID21 program. The possibility of improving the potency of the current series of EV 71 VP1 inhibitors was discussed based on all the studies presented.

Amino Acid Sequence↗
PubMed1998

Flexible ligand docking using conformational ensembles.

Molecular docking algorithms suggest possible structures for molecular complexes. They are used to model biological function and to discover potential ligands. A present challenge for docking algorithms is the treatment of molecular flexibility. Here, the rigid body program, DOCK, is modified to allow it to rapidly fit multiple conformations of ligands. Conformations of a given molecule are pre-calculated in the same frame of reference, so that each conformer shares a common rigid fragment with all other conformations. The ligand conformers are then docked together, as an ensemble, into a receptor binding site. This takes advantage of the redundancy present in differing conformers of the same molecule. The algorithm was tested using three organic ligand protein systems and two protein-protein systems. Both the bound and unbound conformations of the receptors were used. The ligand ensemble method found conformations that resembled those determined in X-ray crystal structures (RMS values typically less than 1.5 A). To test the method's usefulness for inhibitor discovery, multi-compound and multi-conformer databases were screened for compounds known to bind to dihydrofolate reductase and compounds known to bind to thymidylate synthase. In both cases, known inhibitors and substrates were identified in conformations resembling those observed experimentally. The ligand ensemble method was 100-fold faster than docking a single conformation at a time and was able to screen a database of over 34 million conformations from 117,000 molecules in one to four CPU days on a workstation.

Algorithms↗
PubMed2003

Combination of scoring functions improves discrimination in protein-protein docking.

Two structure-based potentials are used for both filtering (i.e., selecting a subset of conformations generated by rigid-body docking), and rescoring and ranking the selected conformations. ACP (atomic contact potential) is an atom-level extension of the Miyazawa-Jernigan potential parameterized on protein structures, whereas RPScore (residue pair potential score) is a residue-level potential, based on interactions in protein-protein complexes. These potentials are combined with other energy terms and applied to 13 sets of protein decoys, as well as to the results of docking 10 pairs of unbound proteins. For both potentials, the ability to discriminate between near-native and non-native docked structures is substantially improved by refining the structures and by adding a van der Waals energy term. It is observed that ACP and RPScore complement each other in a number of ways (e.g., although RPScore yields more hits than ACP, mainly as a result of its better performance for charged complexes, ACP usually ranks the near-native complexes better). As a general solution to the protein-docking problem, we have found that the best discrimination strategies combine either an RPScore filter with an ACP-based scoring function, or an ACP-based filter with an RPScore-based scoring function. Thus, ACP and RPScore capture complementary structural information, and combining them in a multistage postprocessing protocol provides substantially better discrimination than the use of the same potential for both filtering and ranking the docked conformations.

Algorithms↗
PubMed2005

Optimal docking area: a new method for predicting protein-protein interaction sites.

Understanding energetics and mechanism of protein-protein association remains one of the biggest theoretical problems in structural biology. It is assumed that desolvation must play an essential role during the association process, and indeed protein-protein interfaces in obligate complexes have been found to be highly hydrophobic. However, the identification of protein interaction sites from surface analysis of proteins involved in non-obligate protein-protein complexes is more challenging. Here we present Optimal Docking Area (ODA), a new fast and accurate method of analyzing a protein surface in search of areas with favorable energy change when buried upon protein-protein association. The method identifies continuous surface patches with optimal docking desolvation energy based on atomic solvation parameters adjusted for protein-protein docking. The procedure has been validated on the unbound structures of a total of 66 non-homologous proteins involved in non-obligate protein-protein hetero-complexes of known structure. Optimal docking areas with significant low-docking surface energy were found in around half of the proteins. The 'ODA hot spots' detected in X-ray unbound structures were correctly located in the known protein-protein binding sites in 80% of the cases. The role of these low-surface-energy areas during complex formation is discussed. Burial of these regions during protein-protein association may favor the complexed configurations with near-native interfaces but otherwise arbitrary orientations, thus driving the formation of an encounter complex. The patch prediction procedure is freely accessible at http://www.molsoft.com/oda and can be easily scaled up for predictions in structural proteomics.

Binding Sites↗