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PubMed1995

Flexible docking and design.

Docking and design are the major computational steps toward understanding and affecting receptor-ligand interactions. The flexibility of many ligands makes these calculations difficult and requires the development and use of special methods. The need for such tools is illustrated by two examples: the design of protease inhibitors and the analysis and design of peptide antigens binding to specific MHC receptors. We review the computational concepts that have been extended from rigid-body to flexible docking, as well as the following important strategies for flexible docking and design: (a) Monte Carlo/molecular dynamics docking, (b) in-site combinatorial search, (c) ligand build-up, and (d) site mapping and fragment assembly. The use of empirical free energy as a target function is discussed. Due to the rapid development of the methodology, most new methods have been tested on only a limited number of applications and are likely to improve results obtained by more traditional computational or graphic tools.

Algorithms↗
PubMedDate not supplied

Medial collateral ligament reconstruction of the elbow using the docking technique.

BACKGROUND: Medial collateral ligament insufficiency of the elbow with resultant valgus instability in throwing athletes is typically treated with free tendon graft reconstruction as described by Jobe. HYPOTHESIS: Improved results could be obtained with the use of the docking technique. STUDY DESIGN: Uncontrolled retrospective review. METHODS: The study group consisted of 36 athletes who had symptomatic insufficiency of the medial collateral ligament confirmed by magnetic resonance imaging and by surgical findings. Average follow-up was 3.3 years. Key elements of the docking technique included a muscle-splitting approach without routine transposition of the ulnar nerve, routine arthroscopic assessment, treatment of associated lesions, and docking the two ends of the tendon graft into a single humeral tunnel. RESULTS: Thirty-three of 36 patients (92%) returned to or exceeded their previous level of competition for at least 1 year, meeting the Conway-Jobe classification criteria of "excellent." All 22 professional or collegiate athletes returned to or exceeded their previous competition level. CONCLUSIONS: The docking technique allowed simplified graft tensioning and improved graft fixation.

Adolescent↗
PubMed2006

Docking protein domains in contact space.

BACKGROUND: Many biological processes involve the physical interaction between protein domains. Understanding these functional associations requires knowledge of the molecular structure. Experimental investigations though present considerable difficulties and there is therefore a need for accurate and reliable computational methods. In this paper we present a novel method that seeks to dock protein domains using a contact map representation. Rather than providing a full three dimensional model of the complex, the method predicts contacting residues across the interface. We use a scoring function that combines structural, physicochemical and evolutionary information, where each potential residue contact is assigned a value according to the scoring function and the hypothesis is that the real configuration of contacts is the one that maximizes the score. The search is performed with a simulated annealing algorithm directly in contact space. RESULTS: We have tested the method on interacting domain pairs that are part of the same protein (intra-molecular domains). We show that it correctly predicts some contacts and that predicted residues tend to be significantly closer to each other than other pairs of residues in the same domains. Moreover we find that predicted contacts can often discriminate the best model (or the native structure, if present) among a set of optimal solutions generated by a standard docking procedure. CONCLUSION: Contact docking appears feasible and able to complement other computational methods for the prediction of protein-protein interactions. With respect to more standard docking algorithms it might be more suitable to handle protein conformational changes and to predict complexes starting from protein models.

Algorithms↗
PubMed2006

Quaternary structure predictions of transmembrane proteins starting from the monomer: a docking-based approach.

BACKGROUND: We introduce a computational protocol for effective predictions of the supramolecular organization of integral transmembrane proteins, starting from the monomer. Despite the demonstrated constitutive and functional importance of supramolecular assemblies of transmembrane subunits or proteins, effective tools for structure predictions of such assemblies are still lacking. Our computational approach consists in rigid-body docking samplings, starting from the docking of two identical copies of a given monomer. Each docking run is followed by membrane topology filtering and cluster analysis. Prediction of the native oligomer is therefore accomplished by a number of progressive growing steps, each made of one docking run, filtering and cluster analysis. With this approach, knowledge about the oligomerization status of the protein is required neither for improving sampling nor for the filtering step. Furthermore, there are no size-limitations in the systems under study, which are not limited to the transmembrane domains but include also the water-soluble portions. RESULTS: Benchmarks of the approach were done on ten homo-oligomeric membrane proteins with known quaternary structure. For all these systems, predictions led to native-like quaternary structures, i.e. with Calpha-RMSDs lower than 2.5 A from the native oligomer, regardless of the resolution of the structural models. CONCLUSION: Collectively, the results of this study emphasize the effectiveness of the prediction protocol that will be extensively challenged in quaternary structure predictions of other integral membrane proteins.

Amino Acid Sequence↗
PubMed2003

Dock and Pak regulate olfactory axon pathfinding in Drosophila.

The convergence of olfactory axons expressing particular odorant receptor (Or) genes on spatially invariant glomeruli in the brain is one of the most dramatic examples of precise axon targeting in developmental neurobiology. The cellular and molecular mechanisms by which olfactory axons pathfind to their targets are poorly understood. We report here that the SH2/SH3 adapter Dock and the serine/threonine kinase Pak are necessary for the precise guidance of olfactory axons. Using antibody localization, mosaic analyses and cell-type specific rescue, we observed that Dock and Pak are expressed in olfactory axons and function autonomously in olfactory neurons to regulate the precise wiring of the olfactory map. Detailed analyses of the mutant phenotypes in whole mutants and in small multicellular clones indicate that Dock and Pak do not control olfactory neuron (ON) differentiation, but specifically regulate multiple aspects of axon trajectories to guide them to their cognate glomeruli. Structure/function studies show that Dock and Pak form a signaling pathway that mediates the response of olfactory axons to guidance cues in the developing antennal lobe (AL). Our findings therefore identify a central signaling module that is used by ONs to project to their cognate glomeruli.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Immunoglobulin cross-reactivity examined by library screening, crystallography and docking studies.

Antibodies are extremely diverse with respect to their specificities and affinities for target molecules. Despite rigorous selection, some antibodies are cross-reactive whereby they recognize their natural antigens along with other molecules. In this review, we discuss our efforts toward understanding the cross-reactivity of selected immunoglobulins. Investigations that are discussed employed screens of combinatorial peptide libraries, crystallography of ligand-protein complexes, and computer-based peptide docking simulations. In the first example, two different antibodies (NC6.8 and NC10.14) bound the same trisubstituted guanidine (NC174) with similar affinities, but utilized predominantly dissimilar binding strategies. However, there was one common binding strategy, in which the cyanophenyl portion of NC174 was inserted end-on into the binding crevices of the NC6.8 and NC10.14 antibodies. In the second example, scanning of peptide libraries and X-ray crystallography were used to design and test synthetic peptides for binding to the Mcg L chain dimer. Again, end-on insertion was favored for all peptides larger than dipeptides in the voluminous Mcg binding cavity. Finally, automated docking was used for rapid predictions of complexes for the Fv molecule from a broadly cross-reactive human IgM (Mez) and nearly two thousand peptides. Certain amino acids, including the aromatic residues Trp and Phe, functioned as anchoring groups in automated docking. Anchoring groups acted in most of the peptides that were otherwise accommodated by a variety of binding strategies in the docked complexes. We suggest that anchoring of at least a portion of a ligand in a binding site is a common mechanism for antibody recognition.

Binding Sites, Antibody↗
PubMed2006

Structure selection for protein kinase docking and virtual screening: homology models or crystal structures?

There is currently far more sequence information than structural information available, and the ability to use homology models for virtual screening applications is desirable in many cases where structures have not yet been solved. This review focuses on the application of protein kinase homology models for virtual screening use. In addition to reviewing previous cases in which kinase homology models have been used in inhibitor design, we present new data - useful for template selection in homology modeling applications - indicating that the template structure with the highest sequence or structural similarity with the target structure may not always be the best choice. This new work explored the simple hypothesis that better results might be obtained for docking a ligand to a target receptor using a homology model of the target created from a different kinase template co-crystallized with the ligand, than from a crystal structure of the actual kinase target that is unliganded or bound to an unrelated ligand. This hypothesis was tested in docking studies of staurosporine with eight different kinases: AutoDock was used to dock staurosporine to homology models of each kinase created from staurosporine-bound template structures, and the results were compared with docking staurosporine to crystal structures of the target kinase that were obtained in complex with a non-staurosporine ligand or no ligand. It was found that the homology models performed as well as or better than the crystal structures, suggesting that using a homology model created from a template crystallized with a representative ligand may in some cases be a preferred approach, especially in virtual screening experiments that focus on enriching for members of a particular inhibitor class.

Crystallography, X-Ray↗
PubMed2006

eHiTS: an innovative approach to the docking and scoring function problems.

Virtual Ligand Screening (VLS) has become an integral part of the drug design process for many pharmaceutical companies. In protein structure based VLS the aim is to find a ligand that has a high binding affinity to the target receptor whose 3D structure is known. This review will describe the docking tool eHiTS. eHiTS is an exhaustive and systematic docking tool which contains many automated features that simplify the drug design workflow. A description of the unique docking algorithm and novel approach to scoring used within eHiTS is presented. In addition a validation study is presented that demonstrates the accuracy and wide applicability of eHiTS in re-docking bound ligands into their receptors.

Algorithms↗
PubMed2001

Tail docking dairy cattle: effects on cow cleanliness and udder health.

To determine whether tail docking would influence cow cleanliness and udder health in a free-stall system, we monitored milking cows after half the animals in a herd were docked. A sample of 223 docked and 190 undocked cows (reducing to 169 and 105 over the study as cows were dried off) were monitored for 8 wk. Cow cleanliness was scored in two areas: along the spine, and the rump adjacent to the tail at 1, 2, 3, 5, and 8 wk after docking. Cleanliness was evaluated by counting squares that were soiled (0 to 14 on a 5- x 17.5-cm grid) and judging soiling severity on a scale from 0 (clean) to 3 (thickly caked). Udder cleanliness was scored with the same scale (0 to 3) and by counting the number of teats with debris on them. Udder health was assessed by measuring SCC of two milk samples and the number of animals diagnosed as mastitic by the on-farm veterinarian. No treatment differences were found in four measures of cow cleanliness, two measures of udder cleanliness, or udder health. However, cow cleanliness did differ over time, and analysis of a subsample of cows illustrated individual differences in cleanliness.

Animal Welfare↗
PubMed2002

Effects of tail docking using a rubber ring with or without anesthetic on behavior and production of lactating cows.

Production and behavioral measures were recorded to determine the level of stress and pain associated with tail docking adult dairy cows with a rubber ring. The possible advantages of using an epidural anesthetic were also examined. Sixty-four lactating, mixed-parity, Holstein cows were randomly assigned to one of four treatment groups. The treatments were rubber ring docking with epidural anesthetic (RRA), rubber ring docking without anesthetic (RR), control with epidural anesthetic (CA), and control without anesthetic (C). Behavior was examined on d 0, +1, +2, and +6. Milk production and feed intake were monitored. Cows exhibited subtle behavioral changes following application of rubber rings, as well as after epidural administration on d 0 and tail amputation on d +6. After treatment on d 0, the RR, RRA, and CA groups displayed less tail shaking than the C group. The RR and RRA cows continued to exhibit less tail shaking on d +1, +2, and +6. Also on d 0, the RR and RRA groups held their tails in the raised position less than the C and CA groups. After amputation on d +6, the RR and RRA groups spent longer with their tails pressed to their bodies than the C and CA groups. No significant differences in milk production or feed intake were found. Results suggest that tail-docking adult dairy cattle with rubber rings causes, at most, mild discomfort and that there is no benefit in using an epidural anesthetic. However, long-term effects need to be investigated.

Amputation, Surgical↗
PubMed2002

Effects of tail docking on milk quality and cow cleanliness.

The objective of this study was to determine the effect of tail docking on somatic cell count (SCC), intramammary infection (IMI), and udder and leg cleanliness in commercial dairy herds. Lactating dairy cows (n = 1250) from eight Wisconsin farms were blocked by farm and randomly allocated to tail docked (D) or control (C) groups. Milk samples, somatic cell counts, and hygiene scores were collected for 8 to 9 mo. The prevalence of IMI was determined for each of the five occasions when milk samples were obtained. Udder and leg cleanliness were assessed during milk sample collection. Docked and control animals were compared by logSCC, prevalence of IMI, and leg and udder cleanliness score. Variables were analyzed according to all treatment, period, and farm interactions. At the end of the study period 76 (12.2%) and 81 (13%) of cows were culled in the D and C groups, respectively. There were no significant differences in the initial data for parity, daily milk yield, logSCC, or DIM between treatment groups. Effects significant to farms were identified for all variables over all periods. Period was significant for all variables except for the prevalence of environmental pathogens, but no period x treatment interactions were detected. There was no significant difference between treatment groups for somatic cell count. The prevalence of contagious, environmental, or minor pathogens did not differ significantly between treatment groups. This study did not identify any differences in udder or leg hygiene or milk quality that could be attributed to tail docking.

Amputation, Surgical↗
PubMed1999

Use of pair potentials across protein interfaces in screening predicted docked complexes.

Empirical residue-residue pair potentials are used to screen possible complexes for protein-protein dockings. A correct docking is defined as a complex with not more than 2.5 A root-mean-square distance from the known experimental structure. The complexes were generated by "ftdock" (Gabb et al. J Mol Biol 1997;272:106-120) that ranks using shape complementarity. The complexes studied were 5 enzyme-inhibitors and 2 antibody-antigens, starting from the unbound crystallographic coordinates, with a further 2 antibody-antigens where the antibody was from the bound crystallographic complex. The pair potential functions tested were derived both from observed intramolecular pairings in a database of nonhomologous protein domains, and from observed intermolecular pairings across the interfaces in sets of nonhomologous heterodimers and homodimers. Out of various alternate strategies, we found the optimal method used a mole-fraction calculated random model from the intramolecular pairings. For all the systems, a correct docking was placed within the top 12% of the pair potential score ranked complexes. A combined strategy was developed that incorporated "multidock," a side-chain refinement algorithm (Jackson et al. J Mol Biol 1998;276:265-285). This placed a correct docking within the top 5 complexes for enzyme-inhibitor systems, and within the top 40 complexes for antibody-antigen systems.

Algorithms↗
PubMed1999

Exhaustive docking of molecular fragments with electrostatic solvation.

A new method is presented for docking molecular fragments to a rigid protein with evaluation of the binding energy. Polar fragments are docked with at least one hydrogen bond with the protein while apolar fragments are positioned in the hydrophobic pockets. The electrostatic contribution to the binding energy, which consists of screened intermolecular energy and protein and fragment desolvation terms, is evaluated efficiently by a numerical approach based on the continuum dielectric approximation. The latter is also used to predetermine the hydrophobic pockets of the protein by rolling a low dielectric sphere over the protein surface and calculating the electrostatic desolvation of the protein and van der Waals interaction energy. The method was implemented in the program SEED (solvation energy for exhaustive docking). The SEED continuum electrostatic approach has been successfully validated by a comparison with finite difference solutions of the Poisson equation for more than 2,500 complexes of small molecules with thrombin and the monomer of HIV-1 aspartic proteinase. The fragments docked by SEED in the active site of thrombin reproduce the structural features of the interaction patterns between known inhibitors and thrombin. Moreover, the combinatorial connection of these fragments yields a number of compounds that are very similar to potent inhibitors of thrombin. Proteins 1999;37:88-105.

Computer Simulation↗
PubMed2000

Protein docking using spherical polar Fourier correlations.

We present a new computational method of docking pairs of proteins by using spherical polar Fourier correlations to accelerate the search for candidate low-energy conformations. Interaction energies are estimated using a hydrophobic excluded volume model derived from the notion of "overlapping surface skins," augmented by a rigorous but "soft" model of electrostatic complementarity. This approach has several advantages over former three-dimensional grid-based fast Fourier transform (FFT) docking correlation methods even though there is no analogue to the FFT in a spherical polar representation. For example, a complete search over all six rigid-body degrees of freedom can be performed by rotating and translating only the initial expansion coefficients, many unfeasible orientations may be eliminated rapidly using only low-resolution terms, and the correlations are easily localized around known binding epitopes when this knowledge is available. Typical execution times on a single processor workstation range from 2 hours for a global search (5 x 10(8) trial orientations) to a few minutes for a local search (over 6 x 10(7) orientations). The method is illustrated with several domain dimer and enzyme-inhibitor complexes and 20 large antibody-antigen complexes, using both the bound and (when available) unbound subunits. The correct conformation of the complex is frequently identified when docking bound subunits, and a good docking orientation is ranked within the top 20 in 11 out of 18 cases when starting from unbound subunits. Proteins 2000;39:178-194.

Algorithms↗
PubMed2000

Rab3A and Rab3D control the total granule number and the fraction of granules docked at the plasma membrane in PC12 cells.

Rab proteins are Ras-like GTPases that regulate traffic along the secretory or endocytic pathways. Within the Rab family, Rab3 proteins are expressed at high levels in neurons and endocrine cells where they regulate release of dense core granules and synaptic vesicles. Immunoelectron microscopy shows that Rab3A and Rab3D can coexist on the same granule before and after docking. Using electron microscopy of transfected PC12 cells, we report that expression of wild-type Rab3A (or Rab3D) increases the total number of granules and the percentage that is docked at the plasma membrane. Mutated Rab3A N135I (or Rab3D N135I) decreases the total granule number and the fraction of granules docked to the plasma membrane. These data show that at least one of the functions of Rab3A and Rab3D proteins is to control the number of granules docked at the plasma membrane.

Animals↗
PubMed1985

Restriction of docking protein to the rough endoplasmic reticulum: immunocytochemical localization in rat liver.

Docking protein (or SRP receptor) is an integral membrane protein essential for translocation of nascent polypeptides across the membrane of the endoplasmic reticulum (ER). Anti-docking protein antibodies were used to localize this protein in situ in thin frozen sections using protein A-gold detection methods. The majority of gold particles was restricted to ribosome-studded membranes, whereas particles were rarely seen in areas rich in smooth ER. Quantitative evaluation of labeling suggests that there is one molecule of docking protein for roughly 10 to 20 bound ribosomes. On the basis of these results we conclude that docking protein is the first functionally-characterized integral marker protein specific for the rough membranes of ER.

Animals↗
PubMed1985

[A monoclonal antibody against ragweed pollen cross-reacting with yellow dock pollen].

Using monoclonal antibodies with different specificity against the major allergenic components of ragweed pollen, we analyzed their cross-reactivity with two tree pollens, two grass pollens and five other weed pollens which are common in Taiwan by the immunoblot method. It was found that besides reacting with AgE and AgK of the ragweed pollen, the monoclonal antibody 48-5 also reacted with antigens of yellow dock pollen with molecular weights of 40K, 38K, 24K, and 21K. In a preliminary study, sera of two patients containing IgE antibodies to ragweed pollen antigens also reacted to the 40K component of the yellow dock pollen. Furthermore, from the results of allergenic skin testings on 109 patients with bronchial asthma, we found that of 22 patients who had a positive reaction to a crude extract of ragweed pollen, 18(81.8%) also reacted to the crude extract of yellow dock pollen. In conclusion, our results suggest that there exists a common allergenic determinant between pollens of ragweed and yellow dock. It may play an important role in the expression of the sensitivity of patients to these two kinds of pollens.

Allergens↗
PubMed1995

Solvent accessible surface representation in a database system for protein docking.

Protein docking is a new and challenging application for query processing in database systems. Our architecture for an efficient support of docking queries is based on the multistep query processing paradigm, a technique well-known from spatial database system. Along with physicochemical parameters, the geometry of the molecules plays a fundamental role for docking retrieval. Thus, 3D structures and 3D surfaces of molecules are basic objects in molecular databases. We specify a molecular surface representation based on topology, define a class of neighborhood queries, and sketch some applications with respect to the docking problem. We suggest a patch-based data structure called the TriEdge structure, first, to efficiently support topological query processing, and second, to save space in comparison to common planar graph representations such as the quad-edge structure. In analogy to the quad-edge structure, the TriEdge structure has an algebraic interface and is implemented via complex pointers. However, we achieve a reduction of the space requirement by a factor of four. Finally, we investigate the time performance of our prototype.

Computer Graphics↗