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PubMed2002

Protein-protein docking with multiple residue conformations and residue substitutions.

The protein docking problem has two major aspects: sampling conformations and orientations, and scoring them for fit. To investigate the extent to which the protein docking problem may be attributed to the sampling of ligand side-chain conformations, multiple conformations of multiple residues were calculated for the uncomplexed (unbound) structures of protein ligands. These ligand conformations were docked into both the complexed (bound) and unbound conformations of the cognate receptors, and their energies were evaluated using an atomistic potential function. The following questions were considered: (1) does the ensemble of precalculated ligand conformations contain a structure similar to the bound form of the ligand? (2) Can the large number of conformations that are calculated be efficiently docked into the receptors? (3) Can near-native complexes be distinguished from non-native complexes? Results from seven test systems suggest that the precalculated ensembles do include side-chain conformations similar to those adopted in the experimental complexes. By assuming additivity among the side chains, the ensemble can be docked in less than 12 h on a desktop computer. These multiconformer dockings produce near-native complexes and also non-native complexes. When docked against the bound conformations of the receptors, the near-native complexes of the unbound ligand were always distinguishable from the non-native complexes. When docked against the unbound conformations of the receptors, the near-native dockings could usually, but not always, be distinguished from the non-native complexes. In every case, docking the unbound ligands with flexible side chains led to better energies and a better distinction between near-native and non-native fits. An extension of this algorithm allowed for docking multiple residue substitutions (mutants) in addition to multiple conformations. The rankings of the docked mutant proteins correlated with experimental binding affinities. These results suggest that sampling multiple residue conformations and residue substitutions of the unbound ligand contributes to, but does not fully provide, a solution to the protein docking problem. Conformational sampling allows a classical atomistic scoring function to be used; such a function may contribute to better selectivity between near-native and non-native complexes. Allowing for receptor flexibility may further extend these results.

Amino Acid Substitution↗

PubMed2026

Viscoelastic-Assisted Patient Interface Docking: A Technical Optimization in LenSx Femtosecond Laser-Assisted Cataract Surgery.

PURPOSE: To evaluate the efficacy of viscoelastic-assisted patient interface docking in LenSx (Alcon Laboratories, Inc) femtosecond laser-assisted cataract surgery (FLACS). METHODS: This was a randomized controlled trial. Patients undergoing FLACS from January to August 2025 at Aier Eye Hospital of Wuhan University were randomized via a random number table to receive balanced salt solution (BSS) or visoeleastic as the patient interface docking medium. The primary outcome was docking efficiency, measured by one-time docking success rate, the number of docking attempts, and mean docking time. Secondary outcomes included surgical safety (subconjunctival hemorrhage, capsulotomy completeness/tear rate), laser treatment duration (anterior capsulotomy time, nucleus pretreatment time, total laser emission time), and patient comfort (post-laser pain sensation). RESULTS: A total of 100 patients were enrolled, 50 in each group. Suction loss occurred in 7 patients (14%) in the BSS group and 1 patient (2%) in the viscoelastic group; the one-time docking success rate was significantly higher in the viscoelastic group (98%) than in the BSS group (86%) (chi-square = 3.93, P < .05). The viscoelastic group also had fewer mean docking attempts (1.02 ± 0.14) than the BSS group (1.16 ± 0.42), showing a significant difference (t = 2.23, P < .05). The viscoelastic group exhibited significantly shorter mean docking time (44.66 ± 4.47 seconds) compared to the BSS group (48.62 ± 3.11 seconds) (t = 2.17, P < .05). No significant differences were observed between the groups in subconjunctival hemorrhage, capsulotomy completeness/tear rate, anterior capsulotomy time, nucleus pretreatment time, total femtosecond laser emission time, or patient-reported pain sensation (all P > .05). CONCLUSIONS: Viscoelastic-assisted patient interface docking in FLACS effectively elevates one-time docking success rate, reduces docking attempts, and shortens docking time.

Humans↗

PubMedDate not supplied

Temperature differentially affects encounter and docking thermodynamics of antibody--antigen association.

Using BIACORE SPR, we have examined the mechanism of temperature effects on the binding kinetics of two closely related antibody Fabs (H10 and H26) which recognize coincident epitopes on hen egg-white lysozyme (HEL), and whose association and dissociation kinetics are best described by the two-step conformational change model which we interpret as molecular encounter and docking. Time-course series data obtained at a series of six temperatures (6, 10, 15, 25, 30 and 37 degrees C) showed that temperature differentially affects the rate constants of the encounter and docking steps. Docking is more temperature-sensitive than the encounter step, and energetically less favorable at higher temperatures. At elevated temperatures, the time required for docking is longer and the apparent increase in off-rate reflects the greater proportion of the molecules failing to dock and remaining in the less stable encounter state. As a consequence, distribution of free energy change between the encounter and docking steps is altered. At physiological temperature (37 degrees C) the docking step of the H26 complex is energetically unfavorable and most complexes essentially do not dock. There is a significant decrease in total free energy change of the H26 complex at higher temperatures. Elevated temperature changes the rate-limiting step of H26--HEL association from the encounter to the docking step, but not that of H10--HEL. Our results indicate that the mechanism by which elevated temperature reduces the affinities of antigen--antibody complexes is to decrease the net docking rate, and/or stability of the docked complex; at higher temperatures, a smaller proportion of the complexes actually anneal to a more stable docked state. This mechanism may have broad applicability to other receptor--ligand complexes.

Antigen-Antibody Complex↗

PubMed2003

Improved protein-ligand docking using GOLD.

The Chemscore function was implemented as a scoring function for the protein-ligand docking program GOLD, and its performance compared to the original Goldscore function and two consensus docking protocols, "Goldscore-CS" and "Chemscore-GS," in terms of docking accuracy, prediction of binding affinities, and speed. In the "Goldscore-CS" protocol, dockings produced with the Goldscore function are scored and ranked with the Chemscore function; in the "Chemscore-GS" protocol, dockings produced with the Chemscore function are scored and ranked with the Goldscore function. Comparisons were made for a "clean" set of 224 protein-ligand complexes, and for two subsets of this set, one for which the ligands are "drug-like," the other for which they are "fragment-like." For "drug-like" and "fragment-like" ligands, the docking accuracies obtained with Chemscore and Goldscore functions are similar. For larger ligands, Goldscore gives superior results. Docking with the Chemscore function is up to three times faster than docking with the Goldscore function. Both combined docking protocols give significant improvements in docking accuracy over the use of the Goldscore or Chemscore function alone. "Goldscore-CS" gives success rates of up to 81% (top-ranked GOLD solution within 2.0 A of the experimental binding mode) for the "clean list," but at the cost of long search times. For most virtual screening applications, "Chemscore-GS" seems optimal; search settings that give docking speeds of around 0.25-1.3 min/compound have success rates of about 78% for "drug-like" compounds and 85% for "fragment-like" compounds. In terms of producing binding energy estimates, the Goldscore function appears to perform better than the Chemscore function and the two consensus protocols, particularly for faster search settings. Even at docking speeds of around 1-2 min/compound, the Goldscore function predicts binding energies with a standard deviation of approximately 10.5 kJ/mol.

Algorithms↗

PubMed1994

Rational automatic search method for stable docking models of protein and ligand.

An efficient automatic method has been developed for docking a ligand molecule to a protein molecule. The method can construct energetically favorable docking models, considering specific interactions between the two molecules and conformational flexibility in the ligand. In the first stage of docking, likely binding modes are searched and estimated effectively in terms of hydrogen bonds, together with conformations in part of the ligand structure that includes hydrogen bonding groups. After that part is placed in the protein cavity and is optimized, conformations in the remaining part are also examined systematically. Finally, several stable docking models are obtained after optimization of the position, orientation and conformation of the whole ligand molecule. In all the screening processes, the total potential energy including intra- and intermolecular interaction energy, consisting of van der Waals, electrostatic and hydrogen bonding energies, is used as the index. The characteristics of our docking method are high accuracy of the results, fully automatic generation of models and short computational time. The efficiency of the method was confirmed by four docking trials using two enzyme systems. In two attempts to dock methotrexate to dihydrofolate reductase and 2'-GMP to ribonuclease T1, the exact structures of complexes in crystals were reproduced as the most stable docking models, without any assumptions concerning the binding modes and ligand conformations. The most stable docking models of dihydrofolate and trimethoprim, respectively, to dihydrofolate reductase were also in good agreement with those suggested by experiment. In all test cases, it was shown that our method can accurately predict the correct docking structures, discriminating the correct model from incorrect ones. The efficiency of our method was further tested from the viewpoint of ability to predict the relative stability of the docking structures of two triazine derivatives to dihydrofolate reductase. Our docking method provides a useful tool for rational drug design and investigations of biochemical reaction mechanisms.

Algorithms↗

PubMed2002

TreeDock: a tool for protein docking based on minimizing van der Waals energies.

Predicting protein-protein and protein-ligand docking remains one of the challenging topics of structural biology. The main problems are (i) to reliably estimate the binding free energies of docked states, (ii) to enumerate possible docking orientations at a high resolution, and (iii) to consider mobility of the docking surfaces and structural rearrangements upon interaction. Here we present a novel algorithm, TreeDock, that addresses the enumeration problem in a rigid-body docking search. By representing molecules as multidimensional binary search trees and by exploring a sufficient number of docking orientations such that two chosen atoms, one from each molecule, are always in contact, TreeDock is able to explore all clash-free orientations at very fine resolution in a reasonable amount of time. Due to the speed of the program, many contact pairs can be examined to search partial or complete surface areas. The deterministic systematic search of TreeDock is in contrast to most other docking programs that use stochastic searches such as Monte Carlo or simulated annealing methods. At this point, we have used the Lennard-Jones potential as the only scoring function and show that this can predict the correct docked conformation for a number of protein-protein and protein-ligand complexes. The program is most powerful if some information is known about the location of binding faces from NMR chemical-shift perturbation studies, orientation information from residual dipolar coupling, or mutational screening. The approach has the potential to include docking-site mobility by performing molecular dynamics or other randomization methods of the docking site and docking families to families of structures. The performance of the algorithm is demonstrated by docking three complexes of immunoglobulin superfamily domains, CD2 to CD58, the V(alpha) domain of a T-cell receptor to its V(beta) domain, and a T-cell receptor to a pMHC complex as well as a small molecule inhibitor to a phosphatase.

Algorithms↗

PubMed2000

DoMCoSAR: a novel approach for establishing the docking mode that is consistent with the structure-activity relationship. Application to HIV-1 protease inhibitors and VEGF receptor tyrosine kinase inhibitors.

DoMCoSAR is a novel approach for statistically determining the docking mode that is consistent with a structure-activity relationship. The approach establishes the binding mode for the compounds in a chemical series with the assumption that all molecules exhibit the same binding mode. It involves three stages. In the first stage all molecules that belong to a given chemical series are docked to the active site of the protein target. The only bias used in the docking at this stage involves the location of the protein binding site. Coordinates of the common substructure (CS) that results from the unbiased docking are then clustered to establish the major substructure docking modes. In the second stage all molecules are docked to the major docking modes (MDMs) with constraints based on the common substructure. The third stage generates, for the major docking modes, interaction-based descriptors that include electrostatic, VDW, strain, and solvation contributions. The problem of docking mode evaluation is now reduced to the question of which descriptor set is more predictive. To establish a quantitative comparison of the descriptor sets associated with the major docking modes, we use 50 instances of random 4-fold cross-validation. For each 4-fold cross-validation the predictive squared correlation coefficient (R(2)) is computed. t-Tests are applied to establish significance of the differences in mean R(2) for one docking mode versus another. We test the methodology on two test cases: HIV-1 protease inhibitors (Holloway et al. J. Med. Chem. 1995, 38, 305-317) and vascular endothelial growth factor (VEGF) receptor tyrosine kinase oxoindoles (Sun et al. J. Med. Chem. 1998, 41, 2588-2603). For both test cases there is statistically significant preference for the binding mode consistent with the X-ray structure. The appeal of this methodology is that researchers gain the objectivity of statistical justification for the selected docking mode. The methodology is relatively insensitive to subtle variations of the protein structure that include, but are not limited to, side chain and small backbone rearrangement during binding. In addition, predictive models that result from the approach can be used to further optimize chemical series.

Crystallography, X-Ray↗

PubMed1999

Tail docking and beliefs about the practice in the Victorian dairy industry.

OBJECTIVE: To determine the occurrence of tail docking and beliefs about the practice in the Victorian dairy industry. DESIGN: Survey responses were analysed using chi-square tests and by correlation and regression analyses to determine associations between husbandry practices and beliefs and to identify possible predictive variables in relation to docking. PROCEDURE: A survey of the occurrence of docking and beliefs about the practice was conducted in 1997 using face-to-face interviews of 313 respondents at 234 Victorian dairy farms. RESULTS: On average, 35% of dairy farms routinely docked cattle. The practice varied from 11 to 63% in different regions and 12% of stud farms docked their cows. Rubber rings were used on 75% of farms and the average age of the cow at docking was 18 months. Twenty-two percent of cows were docked at a level above the top of the udder and 54% were docked level with the top of the udder. Respondents that docked believed that milking was finished quicker, the risks of leptospirosis for the operator and mastitis for the cow were reduced, the cows were easier to handle, fly numbers were reduced and milk quality was improved. There was a general belief that intact tails could cause significant discomfort to the operator and that docking resulted in acute but not chronic pain. CONCLUSIONS: Docking is an entrenched practice in the Victorian dairy industry. Those farmers who docked generally believed that it was a highly desirable farming practice with particular benefits for the operator.

Animal Welfare↗

PubMed2001

Tail-docking alters fly numbers, fly-avoidance behaviors, and cleanliness, but not physiological measures.

Tail docking is an animal well-being issue not only regarding the docking procedures but also because of concerns during fly season. To address the latter question, we selected eight cows that had been tail-docked in a previous experiment and eight nondocked cows matched by stage of lactation. Physiological, immunological, and behavioral measures were used to evaluate the well being of those cows housed in a tie-stall barn during fly season for 5 consecutive days. Behavior was observed for 5-min interval instantaneous scan samples for 1 h each at 0800, 1200, and 1600 h. Flies were counted before behavior observations. Blood samples were taken daily for plasma and leukocyte separation. Cows were scored on d 5 for cleanliness on a five-point scale. Docked cows were cleaner, but fly counts of docked cows were greater for total fly counts and rear leg counts. However, counts were not different on front legs. Time of day was significant, so each time of day was analyzed separately. Docked cows were observed to exhibit fewer tail swings at 0800 h, but docked cows tended to ruminate more at that time. Docked cows tended to stand less at the 1200 h observation. Total fly-avoidance behaviors were greater for all cows at the 1600-h observation. Only tail swings tended to be more frequent with docked cows, but foot stomps occurred only in the docked cows. Lymphocyte phenotypes, acute-phase proteins, and immunoglobulin concentrations did not differ. In conclusion, although docked cows were cleaner, as the fly numbers increase throughout the day, fly-avoidance behaviors also increased and foot stomping appeared as an alternative method for fly avoidance by docked cows.

Acute-Phase Proteins↗

PubMed1999

Examination of shape complementarity in docking of unbound proteins.

Here we carry out an examination of shape complementarity as a criterion in protein-protein docking and binding. Specifically, we examine the quality of shape complementarity as a critical determinant not only in the docking of 26 protein-protein "bound" complexed cases, but in particular, of 19 "unbound" protein-protein cases, where the structures have been determined separately. In all cases, entire molecular surfaces are utilized in the docking, with no consideration of the location of the active site, or of particular residues/atoms in either the receptor or the ligand that participate in the binding. To evaluate the goodness of the strictly geometry-based shape complementarity in the docking process as compared to the main favorable and unfavorable energy components, we study systematically a potential correlation between each of these components and the root mean square deviation (RMSD) of the "unbound" protein-protein cases. Specifically, we examine the non-polar buried surface area, polar buried surface area, buried surface area relating to groups bearing unsatisfied buried charges, and the number of hydrogen bonds in all docked protein-protein interfaces. For these cases, where the two proteins have been crystallized separately, and where entire molecular surfaces are considered without a predefinition of the binding site, no correlation is observed. None of these parameters appears to consistently improve on shape complementarity in the docking of unbound molecules. These findings argue that simplicity in the docking process, utilizing geometrical shape criteria may capture many of the essential features in protein-protein docking. In particular, they further reinforce the long held notion of the importance of molecular surface shape complementarity in the binding, and hence in docking. This is particularly interesting in light of the fact that the structures of the docked pairs have been determined separately, allowing side chains on the surface of the proteins to move relatively freely. This study has been enabled by our efficient, computer vision-based docking algorithms. The fast CPU matching times, on the order of minutes on a PC, allow such large-scale docking experiments of large molecules, which may not be feasible by other techniques. Proteins 1999;36:307-317.

Algorithms↗

PubMed2005

Molecular docking of balanol to dynamics snapshots of protein kinase A.

Even if the structure of a receptor has been determined experimentally, it may not be a conformation to which a ligand would bind when induced fit effects are significant. Molecular docking using such a receptor structure may thus fail to recognize a ligand to which the receptor can bind with reasonable affinity. Here, we examine one way to alleviate this problem by using an ensemble of receptor conformations generated from a molecular dynamics simulation for molecular docking. Two molecular dynamics simulations were conducted to generate snapshots for protein kinase A: one with the ligand bound, the other without. The ligand, balanol, was then docked to conformations of the receptors presented by these trajectories. The Lamarckian genetic algorithm in Autodock [Goodsell et al. J Mol Recognit 1996;9(1):1-5; Morris et al. J Comput Chem 1998;19(14):1639-1662] was used in the docking. Three ligand models were used: rigid, flexible, and flexible with torsional potentials. When the snapshots were taken from the molecular dynamics simulation of the protein-ligand complex, the correct docking structure could be recovered easily by the docking algorithm in all cases. This was an easier case for challenging the docking algorithm because, by using the structure of the protein in a protein-ligand complex, one essentially assumed that the protein already had a pocket to which the ligand can fit well. However, when the snapshots were taken from the ligand-free protein simulation, which is more useful for a practical application when the structure of the protein-ligand complex is not known, several clusters of structures were found. Of the 10 docking runs for each snapshot, at least one structure was close to the correctly docked structure when the flexible-ligand models were used. We found that a useful way to identify the correctly docked structure was to locate the structure that appeared most frequently as the lowest energy structure in the docking experiments to different snapshots.

Azepines↗

PubMed2004

Lessons in molecular recognition: the effects of ligand and protein flexibility on molecular docking accuracy.

The key to success for computational tools used in structure-based drug design is the ability to accurately place or "dock" a ligand in the binding pocket of the target of interest. In this report we examine the effect of several factors on docking accuracy, including ligand and protein flexibility. To examine ligand flexibility in an unbiased fashion, a test set of 41 ligand-protein cocomplex X-ray structures were assembled that represent a diversity of size, flexibility, and polarity with respect to the ligands. Four docking algorithms, DOCK, FlexX, GOLD, and CDOCKER, were applied to the test set, and the results were examined in terms of the ability to reproduce X-ray ligand positions within 2.0A heavy atom root-mean-square deviation. Overall, each method performed well (>50% accuracy) but for all methods it was found that docking accuracy decreased substantially for ligands with eight or more rotatable bonds. Only CDOCKER was able to accurately dock most of those ligands with eight or more rotatable bonds (71% accuracy rate). A second test set of structures was gathered to examine how protein flexibility influences docking accuracy. CDOCKER was applied to X-ray structures of trypsin, thrombin, and HIV-1-protease, using protein structures bound to several ligands and also the unbound (apo) form. Docking experiments of each ligand to one "average" structure and to the apo form were carried out, and the results were compared to docking each ligand back to its originating structure. The results show that docking accuracy falls off dramatically if one uses an average or apo structure. In fact, it is shown that the drop in docking accuracy mirrors the degree to which the protein moves upon ligand binding.

Algorithms↗

PubMed1999

The sensitivity of the results of molecular docking to induced fit effects: application to thrombin, thermolysin and neuraminidase.

This paper describes the application of PRO_LEADS to the flexible docking of ligands into crystallographically derived enzyme structures that are assumed to be rigid. PRO_LEADS uses a Tabu search methodology to perform the flexible search and an empirically derived estimate of the binding affinity to drive the docking process. The paper tests the extent to which the assumption of a rigid enzyme compromises the accuracy of the results. All-pairs docking experiments are performed for three enzymes (thrombin, thermolysin and influenza virus neuraminidase) based on six or more ligand-enzyme crystal structures for each enzyme. In 76% of the cases, PRO_LEADS can successfully identify the correct ligand conformation as the lowest energy configuration when the enzyme structure is derived from that ligand's crystal structure, but the methodology only docks 49% of the cases successfully when the ligand is docked against enzyme crystal structures derived from other ligands. Small movements in the enzyme structure lead to an under-prediction in the energy of the correct binding mode by up to 14 kJ/mol and in some cases this under-prediction can lead to the native mode not being recognised as the lowest energy solution. The type of movements responsible for mis-docking are: the movement of sidechains as a result of changes in C alpha position; the movement of sidechains without changes in C alpha position; the movement of flexible portions of main chains to facilitate the formation of hydrogen bonds; and the movement of metal atoms bound to the enzyme active site. The work illustrates that the assumption of a rigid active site can lead to errors in identification of the correct binding mode and the assessment of binding affinity, even for enzymes which show relatively small shift in atomic positions from one ligand to the next. A good docking code, such as PRO_LEADS, can usually dock successfully if there is induced fit in relatively rigid enzymes but there remains the need to develop improved strategies for dealing with enzyme flexibility. The work implies that treatments of enzyme flexibility which focus only on sidechain rotations will not deal with the critical shifts responsible for mis-docking of ligands in thrombin, thermolysin and neuraminidase. The paper demonstrates the utility of all pairs docking experiments as a method of assessing the effectiveness of docking methodologies in dealing with enzyme flexibility.

Binding Sites↗

PubMed2003

Comparative study of several algorithms for flexible ligand docking.

We have performed a comparative assessment of several programs for flexible molecular docking: DOCK 4.0, FlexX 1.8, AutoDock 3.0, GOLD 1.2 and ICM 2.8. This was accomplished using two different studies: docking experiments on a data set of 37 protein-ligand complexes and screening a library containing 10,037 entries against 11 different proteins. The docking accuracy of the methods was judged based on the corresponding rank-one solutions. We have found that the fraction of molecules docked with acceptable accuracy is 0.47, 0.31, 0.35, 0.52 and 0.93 for, respectively, AutoDock, DOCK, FlexX, GOLD and ICM. Thus ICM provided the highest accuracy in ligand docking against these receptors. The results from the other programs are found to be less accurate and of approximately the same quality. A speed comparison demonstrated that FlexX was the fastest and AutoDock was the slowest among the tested docking programs. The database screening was performed using DOCK, FlexX and ICM. ICM was able to identify the original ligands within the top 1% of the total library in 17 cases. The corresponding number for DOCK and FlexX was 7 and 8, respectively. We have estimated that in virtual database screening, 50% of the potentially active compounds will be found among approximately 1.5% of the top scoring solutions found with ICM and among approximately 9% of the top scoring solutions produced by DOCK and FlexX.

Algorithms↗

PubMed2002

Electrostatics in protein-protein docking.

A novel geometric-electrostatic docking algorithm is presented, which tests and quantifies the electrostatic complementarity of the molecular surfaces together with the shape complementarity. We represent each molecule to be docked as a grid of complex numbers, storing information regarding the shape of the molecule in the real part and information regarding the electrostatic character of the molecule in the imaginary part. The electrostatic descriptors are derived from the electrostatic potential of the molecule. Thus, the electrostatic character of the molecule is represented as patches of positive, neutral, or negative values. The potential for each molecule is calculated only once and stored as potential spheres adequate for exhaustive rotation/translation scans. The geometric-electrostatic docking algorithm is applied to 17 systems, starting form the structures of the unbound molecules. The results-in terms of the complementarity scores of the nearly correct solutions, their ranking in the lists of sorted solutions, and their statistical uniqueness-are compared with those of geometric docking, showing that the inclusion of electrostatic complementarity in docking is very important, in particular in docking of unbound structures. Based on our results, we formulate several "good electrostatic docking rules": The geometric-electrostatic docking procedure is more successful than geometric docking when the potential patches are large and when the potential extends away from the molecular surface and protrudes into the solvent. In contrast, geometric docking is recommended when the electrostatic potential around the molecules to be docked appears homogeneous, that is, with a similar sign all around the molecule.

Algorithms↗

PubMed2000

Tail-docking influences on behavioral, immunological, and endocrine responses in dairy heifers.

Behavioral and physiological changes were measured following tail-docking in primiparous heifers. One month before projected first parturition, 21 heifers were assigned to control (nondocked), docked, or docked with lidocaine groups. Heifers were banded to initiate tail-docking and the necrotic tail was removed after 144 h. Physiological, immunological, and behavioral measures were taken for 240 h following banding. Cortisol was not different for control and treated heifers. Haptoglobin increased for docked heifers by 168 h postbanding (24 h postdocking). Alpha1-acid glycoprotein decreased as haptoglobin increased, and alpha1-acid glycoprotein increased until 240 h postbanding. Tumor necrosis factor-alpha increased only with lidocaine and did not show an effect of docking by 240 h postbanding. Lymphocyte phenotyping demonstrated increased CD4+ and CD8+ peripheral blood mononuclear cells for docked plus lidocaine heifers and gammadelta+ cells of those heifers tended to be reduced compared with docked heifers. Eating was the only maintenance behavior affected by banding in both docked groups (increased with banding and decreased with docking). The initial banding procedure did not alter heifer physiology and altered only eating behavior, but the cutting of the tail (docking) increased haptoglobin in response to the tissue damage and returned eating behavior to baseline. The use of lidocaine to anesthetize the tail before banding affected lymphocyte phenotypes and TNF-alpha (banding alone did not alter these parameters).

Amputation, Surgical↗

PubMed2006

Short communication: behavioral and physiological indicators of sensitivity or chronic pain following tail docking.

Docking the tails of dairy cattle causes mild to moderate behavior changes and physiological indicators of acute pain, but no studies have investigated the possibility that tail docking may lead to chronic pain. In human amputees, an incidence of increased limb surface temperature is associated with phantom limb pain, a central nervous system representation that survives peripheral loss. The objectives of this study were to assess indicators of sensitivity or chronic pain in heifers by using behavioral indicators and thermography. We tested 14 Holstein heifers, 7 docked and 7 intact, from a previous neonatal tail-docking experiment. All 14 animals were videotaped during a test sequence of alternating cold (-9 degrees C), hot (54 degrees C), and neutral packs applied to the underside of the tail. Packs were placed approximately 30.5 cm from the tail head on all animals. A thermal image of the tail was taken using infrared imagery prior to and after temperature sensitivity testing. Docked heifers tended to have greater changes in surface temperatures following the test sequence than did nondocked heifers. In docked heifers, temperatures on the underside of the tail were higher than those at the tip of the tail, both prior to and following the test sequence. Docked heifers also showed substantially higher stomping activity following application of the cold pack. Shifting increased in intact heifers after application of the hot pack, but shifting of the docked heifers did not change. Greater changes were observed in the tail surface temperatures of the docked heifers following temperature manipulation, similar to human amputees who are experiencing phantom limb pain, indicating that similar mechanisms are present in the stump of the docked tail. The behaviors of docked heifers indicated changes in their sensitivity to heat and cold.

Animal Welfare↗

PubMed2001

FlexE: efficient molecular docking considering protein structure variations.

Side-chain or even backbone adjustments upon docking of different ligands to the same protein structure, a phenomenon known as induced fit, are frequently observed. Sometimes point mutations within the active site influence the ligand binding of proteins. Furthermore, for homology derived protein structures there are often ambiguities in side-chain placement and uncertainties in loop modeling which may be critical for docking applications. Nevertheless, only very few molecular docking approaches have taken into account such variations in protein structures. We present the new software tool FlexE which addresses the problem of protein structure variations during docking calculations. FlexE can dock flexible ligands into an ensemble of protein structures which represents the flexibility, point mutations, or alternative models of a protein. The FlexE approach is based on a united protein description generated from the superimposed structures of the ensemble. For varying parts of the protein, discrete alternative conformations are explicitly taken into account, which can be combinatorially joined to create new valid protein structures.FlexE was evaluated using ten protein structure ensembles containing 105 crystal structures from the PDB and one modeled structure with 60 ligands in total. For 50 ligands (83 %) FlexE finds a placement with an RMSD to the crystal structure below 2.0 A. In all cases our results are of similar quality to the best solution obtained by sequentially docking the ligands into all protein structures (cross docking). In most cases the computing time is significantly lower than the accumulated run times for the single structures. FlexE takes about five and a half minutes on average for placing one ligand into the united protein description on a common workstation. The example of the aldose reductase demonstrates the necessity of considering protein structure variations for docking calculations. We docked three potent inhibitors into four protein structures with substantial conformational changes within the active site. Using only one rigid protein structure for screening would have missed potential inhibitors whereas all inhibitors can be docked taking all protein structures into account.

Aldehyde Reductase↗