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PubMed2003

Protein-protein docking with a reduced protein model accounting for side-chain flexibility.

A protein-protein docking approach has been developed based on a reduced protein representation with up to three pseudo atoms per amino acid residue. Docking is performed by energy minimization in rotational and translational degrees of freedom. The reduced protein representation allows an efficient search for docking minima on the protein surfaces within. During docking, an effective energy function between pseudo atoms has been used based on amino acid size and physico-chemical character. Energy minimization of protein test complexes in the reduced representation results in geometries close to experiment with backbone root mean square deviations (RMSDs) of approximately 1 to 3 A for the mobile protein partner from the experimental geometry. For most test cases, the energy-minimized experimental structure scores among the top five energy minima in systematic docking studies when using both partners in their bound conformations. To account for side-chain conformational changes in case of using unbound protein conformations, a multicopy approach has been used to select the most favorable side-chain conformation during the docking process. The multicopy approach significantly improves the docking performance, using unbound (apo) binding partners without a significant increase in computer time. For most docking test systems using unbound partners, and without accounting for any information about the known binding geometry, a solution within approximately 2 to 3.5 A RMSD of the full mobile partner from the experimental geometry was found among the 40 top-scoring complexes. The approach could be extended to include protein loop flexibility, and might also be useful for docking of modeled protein structures.

Algorithms↗
PubMed2001

Analgesia of newborn lambs before castration and tail docking with rubber rings.

This study assessed the effects of suckled sucrose and parenteral carprofen treatment on behavioural measurements of discomfort and serum haptoglobin concentration in lambs following rubber ring castration and/or tail docking. Twenty-eight male and 20 ewe lambs were allocated to either a male or ewe lamb control group (n=4) or to one of three male and two ewe lamb treatment groups (n=8). Male lambs in one treatment group received carprofen subcutaneously (0.5 mg/kg) 30 minutes before castration and docking. Lambs in all other treatment groups suckled sucrose or colostrum immediately before castration and/or tail docking. Behavioural measurements of discomfort were made following castration or tail docking in treatment groups and also in control animals which were not castrated or tail docked. Blood sampling of animals in treatment groups for analysis of serum haptoglobin, an acute phase protein used as an indicator of an acute inflammatory response, was performed before castration or docking and at 24 and 48 hours after castration or docking. Control lambs were blood sampled at 0, 24 and 48 hours following behavioural assessment Neither suckled sucrose nor carprofen treatment altered discomfort behaviour associated with castration or tail docking. Haptoglobin levels following castration or tail docking remained close to the detection limits of the assay and were similar to those recorded in control animals.

Analgesics, Non-Narcotic↗
PubMed2003

Evaluation of protein docking predictions using Hex 3.1 in CAPRI rounds 1 and 2.

This article describes and reviews our efforts using Hex 3.1 to predict the docking modes of the seven target protein-protein complexes presented in the CAPRI (Critical Assessment of Predicted Interactions) blind docking trial. For each target, the structure of at least one of the docking partners was given in its unbound form, and several of the targets involved large multimeric structures (e.g., Lactobacillus HPr kinase, hemagglutinin, bovine rotavirus VP6). Here we describe several enhancements to our original spherical polar Fourier docking correlation algorithm. For example, a novel surface sphere smothering algorithm is introduced to generate multiple local coordinate systems around the surface of a large receptor molecule, which may be used to define a small number of initial ligand-docking orientations distributed over the receptor surface. High-resolution spherical polar docking correlations are performed over the resulting receptor surface patches, and candidate docking solutions are refined by using a novel soft molecular mechanics energy minimization procedure. Overall, this approach identified two good solutions at rank 5 or less for two of the seven CAPRI complexes. Subsequent analysis of our results shows that Hex 3.1 is able to place good solutions within a list of <or=20 for four of the seven targets. This finding shows that useful in silico protein-protein docking predictions can now be made with increasing confidence, even for very large macromolecular complexes.

Algorithms↗
PubMed1995

Molecular recognition of the inhibitor AG-1343 by HIV-1 protease: conformationally flexible docking by evolutionary programming.

BACKGROUND: An important prerequisite for computational structure-based drug design is prediction of the structures of ligand-protein complexes that have not yet been experimentally determined by X-ray crystallography or NMR. For this task, docking of rigid ligands is inadequate because it assumes knowledge of the conformation of the bound ligand. Docking of flexible ligands would be desirable, but requires one to search an enormous conformational space. We set out to develop a strategy for flexible docking by combining a simple model of ligand-protein interactions for molecular recognition with an evolutionary programming search technique. RESULTS: We have developed an intermolecular energy function that incorporates steric and hydrogen-bonding terms. The parameters in this function were obtained by docking in three different protein systems. The effectiveness of this method was demonstrated by conformationally flexible docking of the inhibitor AG-1343, a potential new drug against AIDS, into HIV-1 protease. For this molecule, which has nine rotatable bonds, the crystal structure was reproduced within 1.5 A root-mean-square deviation 34 times in 100 simulations, each requiring eight minutes on a Silicon Graphics R4400 workstation. The energy function correctly evaluates the crystal structure as the global energy minimum. CONCLUSIONS: We believe that a solution of the docking problem may be achieved by matching a simple model of molecular recognition with an efficient search procedure. The necessary ingredients of a molecular recognition model include only steric and hydrogen-bond interaction terms. Although these terms are not necessarily sufficient to predict binding affinity, they describe ligand-protein interactions faithfully enough to enable a docking program to predict the structure of the bound ligand. This docking strategy thus provides an important tool for the interdisciplinary field of rational drug design.

Biological Evolution↗
PubMed1995

A geometry-based suite of molecular docking processes.

We have developed a geometry-based suite of processes for molecular docking. The suite consists of a molecular surface representation, a docking algorithm, and a surface inter-penetration and contact filter. The surface representation is composed of a sparse set of critical points (with their associated normals) positioned at the face centers of the molecular surface, providing a concise yet representative set. The docking algorithm is based on the Geometric Hashing technique, which indexes the critical points with their normals in a transformation invariant fashion preserving the multi-element geometric constraints. The inter-penetration and surface contact filter features a three-layer scoring system, through which docked models with high contact area and low clashes are funneled. This suite of processes enables a pipelined operation of molecular docking with high efficacy. Accurate and fast docking has been achieved with a rich collection of complexes and unbound molecules, including protein-protein and protein-small molecule associations. An energy evaluation routine assesses the intermolecular interactions of the funneled models obtained from the docking of the bound molecules by pairwise van der Waals and Coulombic potentials. Applications of this routine demonstrate the goodness of the high scoring, geometrically docked conformations of the bound crystal complexes.

Algorithms↗
PubMed1996

Hammerhead: fast, fully automated docking of flexible ligands to protein binding sites.

BACKGROUND: Molecular docking seeks to predict the geometry and affinity of the binding of a small molecule to a given protein of known structure. Rigid docking has long been used to screen databases of small molecules, because docking techniques that account for ligand flexibility have either been too slow or have required significant human intervention. Here we describe a docking algorithm, Hammerhead, which is a fast, automated tool to screen for the binding of flexible molecules to protein binding sites. RESULTS: We used Hammerhead to successfully dock a variety of positive control ligands into their cognate proteins. The empirically tuned scoring function of the algorithm predicted binding affinities within 1.3 log units of the known affinities for these ligands. Conformations and alignments close to those determined crystallographically received the highest scores. We screened 80 000 compounds for binding to streptavidin, and biotin was predicted as the top-scoring ligand, with other known ligands included among the highest-scoring dockings. The screen ran in a few days on commonly available hardware. CONCLUSIONS: Hammerhead is suitable for screening large databases of flexible molecules for binding to a protein of known structure. It correctly docks a variety of known flexible ligands, and it spends an average of only a few seconds on each compound during a screen. The approach is completely automated, from the elucidation of protein binding sites, through the docking of molecules, to the final selection of compounds for assay.

Algorithms↗
PubMedDate not supplied

VRDD: applying virtual reality visualization to protein docking and design.

We have developed an interactive docking program called VRDD. It offers various modes of displaying molecules in an immersive, three-dimensional virtual reality (VR) environment. It allows a user to interactively perform molecular docking aided by automatic docking and side chain conformational search. Binding free energies are computed in real time, and the program enables the user to explore only clash-free orientations of a ligand. VRDD also supplies visual and auditory feedback during docking and side chain search, indicating the levels of atomic overlap and interaction energy. The stunning VR graphics immerse users in the scene and can maximally stimulate their design intuition. We have tested VRDD on three cases with increasing complexity: a nine-residue-long peptide bound to a major histocompatibility complex (MHC) molecule, barstar bound to barnase, and an antibody bound to a hemagglutinin. Without prior knowledge, combinations of hand-docking and automatic refinement led to accurate complex structures for the first two complexes. The third case, for which all automatic docking algorithms failed to identify the correct complex in a previous blind test, also failed for VRDD. Our results show that the combination of VR docking and automatic docking can make unique contributions to molecular modeling.

Antibodies↗
PubMed2000

Docking-based development of purine-like inhibitors of cyclin-dependent kinase-2.

The cell division cycle is controlled by cyclin-dependent kinases (cdk), which consist of a catalytic subunit (cdk1-cdk8) and a regulatory subunit (cyclin A-H). Purine-like inhibitors of cyclin-dependent kinases have recently been found to be of potential use as anticancer drugs. Rigid and flexible docking techniques were used for analysis of binding mode and design of new inhibitors. X-ray structures of three (ATP, olomoucine, roscovitine) cdk2 complexes were available at the beginning of the study and were used to optimize the docking parameters. The new potential inhibitors were then docked into the cdk2 enzyme, and the enzyme/inhibitor interaction energies were calculated and tested against the assayed activities of cdk1 (37 compounds) and cdk2 (9 compounds). A significant rank correlation between the activity and the rigid docking interaction energy has been found. This implies that (i) the rigid docking can be used as a tool for qualitative prediction of activity and (ii) values obtained by the rigid docking technique into the cdk2 active site can also be used for the prediction of cdk1 activity. While the resulting geometries obtained by the rigid docking are in good agreement with the X-ray data, the flexible docking did not always produce the same inhibitor conformation as that found in the crystal.

CDC2 Protein Kinase↗
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↗
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↗
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↗
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↗
PubMed1994

Predicting molecular interactions and inducible complementarity: fragment docking of Fab-peptide complexes.

Antibody-antigen interactions are representative of a broad class of receptor-ligand interactions involving both specificity and potential inducible complementarity. To test possible mechanisms of antigen-antibody recognition and specificity computationally, we have used a Metropolis Monte Carlo algorithm to dock fragments of the epitope Glu-Val-Val-Pro-His-Lys-Lys to the X-ray structures of both the free and the complexed Fab of the antibody B13I2 (raised against the C-helix of myohemerythrin). The fragments Pro-His and Val-Pro-His, which contain residues experimentally identified as important for binding, docked correctly to both structures, but all tetrapeptide and larger fragments docked correctly only to the complexed Fab, even when torsional flexibility was added to the ligand. However, only tetrapeptide and larger fragments showed significantly more favorable energies when docked to the complexed Fab coordinates than when docked to either the free Fab or a non-specific site remote from the combining site. Comparison of the free and complexed B13I2 structures revealed that atoms within 5 A of Val-Pro-His showed little movement upon peptide binding, but atoms within 5 A of the other four epitope residues showed greater movements. These results computationally distinguished recognition and binding processes with practical implications for drug design strategies. Overall, this new fragment docking approach establishes distinct roles for the "lock-and-key" (recognition) and the "handshake" (binding) paradigms in antibody-antigen interaction, suggests an incremental approach to incorporating flexibility in computational docking, and identifies critical regions within receptor binding sites for ligand recognition.

Algorithms↗
PubMed1997

Modelling protein docking using shape complementarity, electrostatics and biochemical information.

A protein docking study was performed for two classes of biomolecular complexes: six enzyme/inhibitor and four antibody/antigen. Biomolecular complexes for which crystal structures of both the complexed and uncomplexed proteins are available were used for eight of the ten test systems. Our docking experiments consist of a global search of translational and rotational space followed by refinement of the best predictions. Potential complexes are scored on the basis of shape complementarity and favourable electrostatic interactions using Fourier correlation theory. Since proteins undergo conformational changes upon binding, the scoring function must be sufficiently soft to dock unbound structures successfully. Some degree of surface overlap is tolerated to account for side-chain flexibility. Similarly for electrostatics, the interaction of the dispersed point charges of one protein with the Coulombic field of the other is measured rather than precise atomic interactions. We tested our docking protocol using the native rather than the complexed forms of the proteins to address the more scientifically interesting problem of predictive docking. In all but one of our test cases, correctly docked geometries (interface Calpha RMS deviation </=2 A from the experimental structure) are found during a global search of translational and rotational space in a list that was always less than 250 complexes and often less than 30. Varying degrees of biochemical information are still necessary to remove most of the incorrectly docked complexes.

Algorithms↗