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PubMed2005

Refinement of unbound protein docking studies using biological knowledge.

In this work we present two methods for the reranking of protein-protein docking studies. One scoring method searches the InterDom database for domains that are available in the proteins to be docked and evaluates the interaction of these domains in other complexes of known structure. The second one analyzes the interface of each proposed conformation with regard to the conservation of Phe, Met, and Trp and their polar neighbor residues. The special relevance of these residues is based on a publication by Ma et al. (Proc Natl Acad Sci USA 2003;100:5772-5777), who compared the conservation of all residues in the interface region to the conservation on the rest of the protein's surface. The scoring functions were tested on 30 unbound docking test cases. The evaluation of the methods is based on the ability to rerank the output of a Fast Fourier Transformation (FFT) docking. Both were able to improve the ranking of the docking output. The best improvement was achieved for enzyme-inhibitor examples. Especially the domain-based scoring function was successful and able to place a near-native solution on one of the first six ranks for 13 of 17 (76%) enzyme-inhibitor complexes [in 53% (nine complexes) even on the first rank]. The method evaluating residue conservation allowed us to increase the number of good solutions within the first 100 ranks out of approximately 9000 in 82% of the 17 enzyme-inhibitor test cases, and for seven (41%) out of 17 enzyme-inhibitor complexes, a near native solution was placed within the first seven ranks.

Binding Sites↗
PubMed2006

WHISCY: what information does surface conservation yield? Application to data-driven docking.

Protein-protein interactions play a key role in biological processes. Identifying the interacting residues is a first step toward understanding these interactions at a structural level. In this study, the interface prediction program WHISCY is presented. It combines surface conservation and structural information to predict protein-protein interfaces. The accuracy of the predictions is more than three times higher than a random prediction. These predictions have been combined with another interface prediction program, ProMate [Neuvirth et al. J Mol Biol 2004;338:181-199], resulting in an even more accurate predictor. The usefulness of the predictions was tested using the data-driven docking program HADDOCK [Dominguez et al. J Am Chem Soc 2003;125:1731-1737] in an unbound docking experiment, with the goal of generating as many near-native structures as possible. Unrefined rigid body docking solutions within 10 A ligand RMSD from the true structure were generated for 22 out of 25 docked complexes. For 18 complexes, more than 100 of the 8000 generated models were correct. Our results demonstrates the potential of using interface predictions to drive protein-protein docking.

Binding Sites↗
PubMed2001

Docking ligands onto binding site representations derived from proteins built by homology modelling.

Due to the abundant sequence information available from genome projects, an increasing number of structurally unknown proteins, homologous to examples of known 3D structure, will be discovered as new targets for drug design. Since homology models do not provide sufficient accuracy to apply common drug design tools, a new approach, DragHome, has been developed to dock ligands into such approximate protein models. DragHome combines information from homology modelling with ligand data, used by and derived from 3D quantitative structure-activity relationships (QSAR). The binding-site of a model-built protein is analysed in terms of putative ligand interaction sites and translated via Gaussian functions into a functional binding-site description represented by physico-chemical properties. Ligands to be docked onto these binding-site representations are similarly translated into a description based on Gaussian functions. The docking is computed by optimising the overlap between the functional description of the binding site and the ligand, generating multiple solutions. For a set of different ligands, these solutions are ranked according to the internal similarity consistance among the various ligands in the binding modes obtained from docking. DragHome has been validated at examples for which crystal structures are available: structurally distinct thrombin inhibitors were docked onto models of thrombin generated from serine proteases of 28 to 40 % sequence identity, yielding ligand binding modes with an average RMS deviation of 1.4 A. Mostly the near-native solutions are ranked best. Molecular flexibility of ligands can be considered in terms of pre-calculated multiple conformers. DragHome has been used to automatically generate an alignment of 88 thrombin inhibitors, for which a significant 3D QSAR model could be derived. The contribution maps resulting from this analysis can be interpreted with respect to the surrounding protein model. They highlight inconsistencies and deficiencies present in the model. In future developments, this information could be fed back into a subsequent modelling step to improve the protein model.

Algorithms↗
PubMed2002

Flexible docking of an acetoxyethoxymethyl derivative of thiosemicarbazone into three different species of dihydrofolate reductase.

Dihydrofolate reductases (DHFR) of human, Candida albicans and E coli were docked with their original ligands of X-ray crystal complex using QXP (Quick eXPlore), a docking program. Conditions to reproduce the crystal structures within the root mean square deviation (rmsd) of 2.00 A were established. Applying these conditions, binding modes and species-specificities of a novel antibacterial compound, N4-(2-acetoxyethoxymethyl)-2-acetylpyridine thiosemicarbazone (AATSC), were studied. As the results, the docking program reproduced the crystal structures with average rmsd of six ligands as 0.91 A ranging from 0.49 to 1.45 A. The interactions including the numbers of hydrogen bonds and hydrophobic interactions were the same as the crystal structures and superposition of the crystal and docked structures almost coincided with each other. For AATSC, the results demonstrated that it could bind to either the substrate or coenzyme sites of DHFR in all three species with different degrees of affinity. It confirms the experimentally determined kinetic behavior of uncompetitive inhibition against either the inhibitor or the coenzyme. The docked AATSC overlapped well with the original ligands and major interactions were consistent with the ones in the crystal complexes. The information generated from this work should be useful for future development of antibacterial and antifungal agents.

Binding Sites↗
PubMed2003

Computational docking of L-arginine and its structural analogues to C-terminal domain of Escherichia coli arginine repressor protein (ArgRc).

The arginine repressor (ArgR) of Escherichia coli binds to six L-arginine molecules that act as its co-repressor in order to bind to DNA. The binding of L-arginine molecules as well as its structural analogues is compared by means of computational docking. A grid-based energy evaluation method combined with a Monte Carlo simulated annealing process was used in the automated docking. For all ligands, the docking procedure proposed more than one binding site in the C-terminal domain of ArgR (ArgRc). Interaction patterns of ArgRc with L-arginine were also observed for L-canavanine and L-citrulline. L-lysine and L-homoarginine, on the other hand, were shown to bind poorly at the binding site. Figure A general overview of the sites found from docking the various ligands into ArgRc ( grey ribbons). Red coloured sticks: residues in binding site H that was selected for docking

Arginine↗
PubMed2006

A fast surface-matching procedure for protein-ligand docking.

A very simple, fast, and efficient scheme is proposed for performing preliminary protein-ligand docking as the first step of intensive high-throughput virtual screening. The procedure acts as a surface-complementarity filter that first calculates the 2D-contour maps of both the protein cavity and of the ligands using a spherical harmonics description of the associated molecular surfaces. Next, the obtained 2D-fingerprint images are compared to detect their complementarity. This scheme was tested on three typical cases of protein cavities, namely, a well-closed pocket, a small open pocket, and a large open one. For that purpose, for each case, a sample of 101 ligand conformers was generated (the X-ray one and 100 different conformers generated using simulated annealing), and these conformational samples were ranked according to the complementarity with the protein cavity surface. Compared to traditional docking procedures such as FRED (considered as typical of a very fast rigid body docking algorithms) and GOLD (considered as typical of the more accurate flexible docking algorithms), our procedure was much faster and more successful in detecting the right X-ray conformation. We did, however, identify a certain weakness in the case of the very large pocket where results were not as expected. In general, our method could be used for incorporating indirectly flexibility in protein-ligand docking calculations as such a scheme can easily handle several conformational states of both the protein and the ligand.

Binding Sites↗
PubMed2004

Unsupervised guided docking of covalently bound ligands.

An approach for docking covalently bound ligands in protein enzymes or receptors was implemented in MacDOCK, a similarity-driven docking program based on DOCK 4.0. This approach was tested with a small number of covalent ligand-protein structures, using both native and non-native protein structures. In all cases, MacDOCK was able to generate orientations consistent with the known covalent binding mode of these complexes, with a performance similar to that of other docking programs. This method was also applied to search for known covalent thrombin inhibitors in a medium-sized molecular database (ca. 11,000 compounds). Detection of functional groups suitable for covalent docking was carried out automatically. A significant enrichment in known active molecules in the first 5% of the database was obtained, showing that MacDOCK can be used efficiently for the virtual screening of covalently bound ligands.

Computer Simulation↗
PubMed1992

New algorithm to model protein-protein recognition based on surface complementarity. Applications to antibody-antigen docking.

A novel algorithm is presented which models protein-protein interactions using surface complementarity. The method is applied to antibody-antigen docking. A steric scoring scheme, based upon a soft potential, is used to assess complementarity, and a simple electrostatic model is then used to remove infeasible interactions. The soft potential allows for structural changes that occur during docking. Biochemical knowledge is necessary to reduce the number of docking orientations produced by the method to a manageable size. The information used includes the known epitope residues and a single loose distance constraint. The method is applied to all three crystallographically determined antibody-lysozyme complexes, HyHEL-10, D1.3 and HyHEL-5. For the first time, a predicted antibody structure (that of D1.3) is used as a docking target. In the four systems modelled, the method identifies between 15 and 40 possible docking orientations. The root-mean-square (r.m.s.) deviation between these orientations and the relevant crystallographic complex is measured in the interface region. For all four complexes an orientation is found with r.m.s. deviation in the range 1.9 A and 4.8 A. The algorithm is implemented on a single instruction/multiple datastream (SI/MD) architecture computer. The use of a parallel architecture computer ensures detailed coverage of the search space, whilst still maintaining a search time of two days.

Algorithms↗
PubMed2004

On proteins, grids, correlations, and docking.

The activity of a living cell can be portrayed as a network of interactions involving proteins and nucleic acids that transfer biological information. Intervention in cellular processes requires thorough understanding of the interactions between the molecules, which can be provided by docking techniques. Docking methods attempt to predict the structures of complexes given the structures of the component molecules. We focus hereby on protein-protein docking procedures that employ grid representations of the molecules, and use correlation for searching the solution space and evaluating putative complexes. Geometric surface complementarity is the dominant descriptor in docking. Inclusion of electrostatics often improves the results of geometric docking for soluble proteins, whereas hydrophobic complementarity is more important in construction of oligomers. Using binding-site information in the scan or as a filter helps to identify and up-rank nearly correct solutions.

Binding Sites↗
PubMed2005

Spatially separate docking sites on ERK2 regulate distinct signaling events in vivo.

Inhibitors of the oncogenic Ras-MAPK pathway have been intensely pursued as therapeutics. Targeting this pathway, however, presents challenges due to the essential role of MAPK in homeostatic functions. The phosphorylation and activation of MAPK substrates is regulated by protein-protein interactions with MAPK docking sites. Active ERK1/2 (extracellular signal-regulated kinase 1/2)-MAPKs localize to effectors containing DEF (docking site for ERK, (F)/(Y) -X-(F)/(Y) -P)- or D-domain (docking domain) motifs. We have examined the in vivo activity of ERK2 mutants with impaired ability to signal via either docking site. Mutations in the DEF-domain binding pocket prevent activation of DEF-domain-containing effectors but not RSK (90 kDa ribosomal S6 kinase), which contains a D domain. Conversely, mutation of the ERK2 CD domain, which interacts with D domains, prevents RSK activation but not DEF-domain signaling. Uncoupling docking interactions does not compromise ERK2 phosphotransferase activity. ERK2 DEF mutants undergo regulated nuclear translocation but are defective for Elk-1/TCF transactivation and target gene induction. Thus, downstream branches of ERK2 signaling can be selectively inhibited without blocking total pathway activity. Significantly, several protooncogenes contain DEF domains and are regulated by ERK1/2. Therefore, disrupting ERK-DEF domain interactions could be an alternative to inhibiting oncogenic Ras-MAPK signaling.

Animals↗
PubMed2005

Docking and fusion of insulin secretory granules in SUR1 knock out mouse beta-cells observed by total internal reflection fluorescence microscopy.

To explore how the sulfonylurea receptor (SUR1) is involved in docking and fusion of insulin granules, dynamic motion of single insulin secretory granules near the plasma membrane was examined in SUR1 knock-out (Sur1KO) beta-cells by total internal reflection fluorescence microscopy. Sur1KO beta-cells exhibited a marked reduction in the number of fusion events from previously docked granules. However, the number of docked granules declined during stimulation as a consequence of the release of docked granules into the cytoplasm vs. fusion with the plasma membrane. Thus, the impaired docking and fusion results in decreased insulin exocytosis from Sur1KO beta-cells.

ATP-Binding Cassette Transporters↗
PubMed2005

Spatial variation in Bacillus thuringiensis/cereus populations within the phyllosphere of broad-leaved dock (Rumex obtusifolius) and surrounding habitats.

The aim of this study was to determine the prevalence and toxin gene diversity of Bacillus thuringiensis/B. cereus in the phyllosphere of broad-leaved dock (Rumex obtusifolius) at a small spatial scale. B. thuringiensis/cereus populations were isolated from the phyllosphere of dock and neighbouring grass and in neighbouring soil using commercially available selective media which avoided the disadvantageous heat-shock selection procedure. The maximum density of B. thuringiensis/cereus in the dock phyllosphere was 1.9 x 10(4) CFU g(-1) but the between-leaf variation in numbers was found to follow a lognormal distribution. B. thuringiensis/cereus was also found at significant densities in soil and the phyllosphere of grass adjacent to the dock plants. PCR screening indicated that genes encoding cry1 toxin were present in the plasmids of 36.9% of B. thuringiensis/cereus isolates tested, 11.9% contained cry2, and none of the dock leaf isolates tested contained cry3, cry4, cry7 or cry8 genes. The diversity of cry genes is similar to that found from other studies focused on other parts of the world. This work is the first concerning the prevalence of B. thuringiensis/cereus on leaves in the UK, finding population sizes of previously unrecorded levels and a greater relative proportion of B. thuringiensis. We have also illustrated that before any ecological function can be investigated, suitable sampling scales need to be considered -- here we have shown that the minimum sampling unit should be individual leaves, to account for the log-normal distribution.

Bacillus cereus↗
PubMed2005

The relationship between the flexibility of proteins and their conformational states on forming protein-protein complexes with an application to protein-protein docking.

We investigate the extent to which the conformational fluctuations of proteins in solution reflect the conformational changes that they undergo when they form binary protein-protein complexes. To do this, we study a set of 41 proteins that form such complexes and whose three-dimensional structures are known, both bound in the complex and unbound. We carry out molecular dynamics simulations of each protein, starting from the unbound structure, and analyze the resulting conformational fluctuations in trajectories of 5 ns in length, comparing with the structure in the complex. It is found that fluctuations take some parts of the molecules into regions of conformational space close to the bound state (or give information about it), but at no point in the simulation does each protein as whole sample the complete bound state. Subsequent use of conformations from a clustered MD ensemble in rigid-body docking is nevertheless partially successful when compared to docking the unbound conformations, as long as the unbound conformations are themselves included with the MD conformations and the whole globally rescored. For one key example where sub-domain motion is present, a ribonuclease inhibitor, principal components analysis of the MD was applied and was also able to produce conformations for docking that gave enhanced results compared to the unbound. The most significant finding is that core interface residues show a tendency to be less mobile (by size of fluctuation or entropy) than the rest of the surface even when the other binding partner is absent, and conversely the peripheral interface residues are more mobile. This surprising result, consistent across up to 40 of the 41 proteins, suggests different roles for these regions in protein recognition and binding, and suggests ways that docking algorithms could be improved by treating these regions differently in the docking process.

Cluster Analysis↗
PubMed2006

Computational sampling of a cryptic drug binding site in a protein receptor: explicit solvent molecular dynamics and inhibitor docking to p38 MAP kinase.

An increasing number of structural studies reveal alternative binding sites in protein receptors that become apparent only when an inhibitor binds, and correct prediction of these situations presents a significant challenge to computer-aided drug design efforts. A striking example is provided by recent crystal structures of the p38 MAP kinase, where a 10A movement of the Phe169 side-chain creates a new binding site adjacent to the ATP binding site that is exploited by the diaryl urea inhibitor BIRB796. Here, we show that this binding site can be successfully and repeatedly identified in explicit-solvent molecular dynamics (MD) simulations of the protein that begin from an unliganded p38 crystal structure. Ligand-docking calculations performed on 5000 different structural snapshots generated during MD indicate that the conformations sampled are often surprisingly competent to bind the inhibitor BIRB796 in the crystallographically correct position and with docked energies that are generally more favorable than those of other positions. Similar docking studies with an ATP-binding site-directed inhibitor suggest that it may be possible to develop hybrid inhibitors that target both the ATP and cryptic binding sites simultaneously. Intriguingly, both inhibitors are occasionally found to dock correctly even with p38's "DFG" motif in the "wrong" conformation and BIRB796 can successfully dock, albeit infrequently, without significant displacement of the Phe169 side-chain; this suggests that the inhibitor might facilitate the latter's conformational change. Finally, two quite different conformations of p38's DFG motif are also sampled for extended periods of time during the simulations; these may provide new opportunities for inhibitor development. The MD simulations reported here, which total 390 ns in length, therefore demonstrate that existing computational methods may be of surprising utility in predicting cryptic binding sites in protein receptors prior to their experimental discovery.

Animals↗
PubMed2004

A practical approach to docking of zinc metalloproteinase inhibitors.

Forty zinc-dependent metalloproteinase/ligand complexes with known crystal structures were re-docked using five docking/scoring approaches (DOCK, FlexX, DrugScore, GOLD, and AutoDock). Correct geometry of the coordination bonds between the ligand's zinc binding group (ZBG) and the catalytic zinc is important for docking accuracy and scoring reliability. More than 75% of docked poses with RMSD less than 2A were found to have appropriate ZBG binding, but for poor ZBG binding, about 95% of poses failed to dock correctly. Elimination of poses with inappropriate zinc binding resulted in better binding energy predictions that were further improved by dividing the ligands into subsets according to the ZBG (carboxylates, hydroxamates, and phosphorus containing groups). After a subset re-scoring using the regression functions obtained for individual subsets, DrugScore was able to explain 77% and the consensus scoring scheme X-CSCORE even 88% of variance in binding energies. The approach combining ZBG-based pose selection and subset re-scoring improved the hit rate in virtual screening for metalloproteinase inhibitors for all tested methods by 4-16%.

Algorithms↗
PubMed2006

eHiTS: a new fast, exhaustive flexible ligand docking system.

The flexible ligand docking problem is divided into two subproblems: pose/conformation search and scoring function. For successful virtual screening the search algorithm must be fast and able to find the optimal binding pose and conformation of the ligand. Statistical analysis of experimental data of bound ligand conformations is presented with conclusions about the sampling requirements for docking algorithms. eHiTS is an exhaustive flexible-docking method that systematically covers the part of the conformational and positional search space that avoids severe steric clashes, producing highly accurate docking poses at a speed practical for virtual high-throughput screening. The customizable scoring function of eHiTS combines novel terms (based on local surface point contact evaluation) with traditional empirical and statistical approaches. Validation results of eHiTS are presented and compared to three other docking software on a set of 91 PDB structures that are common to the validation sets published for the other programs.

Algorithms↗
PubMed2004

Protein-protein docking: is the glass half-full or half-empty?

Are current docking methods capable of building complexes from putative component protein structures? Results of recent computational studies, including those of the CAPRI (Critical Assessment of Protein Interactions) competition, were used to determine the key properties for successful docking and introduce a classification of protein complexes based on docking difficulty. Enzyme-inhibitor complexes could be determined with reasonable accuracy - possibly to within a few alternative structures. Results for antigen-antibody pairs are less predictable, and data for small signaling complexes are generally poor. However, moderate amounts of experimental data can remove uncertainty and the methodology is rapidly improving. Transient complexes with large interface areas undergo substantial conformational change and are beyond the reach of current docking methods. The docking of such complexes might therefore require fundamentally new approaches.

Algorithms↗
PubMed2006

Dock6, a Dock-C subfamily guanine nucleotide exchanger, has the dual specificity for Rac1 and Cdc42 and regulates neurite outgrowth.

Small GTPases of the Rho family, Rho, Rac, and Cdc42, are critical regulators of the changes in the actin cytoskeleton. Rho GTPases are typically activated by Dbl-homology (DH)-domain-containing guanine nucleotide exchange factors (GEFs). Recent genetic and biochemical studies revealed a new type of GEF for the Rho GTPases. This family is composed of 11 genes, designated as Dock1 to Dock11, and is structurally divided into four classes Dock-A, -B, -C, and -D. Dock-A and -B subfamilies are typically GEFs specific for Rac1, while the Dock-D subfamily is specific for Cdc42. Here we show that Dock6, a member of the Dock-C subfamily, exchanges GDP for GTP for Rac1 and Cdc42 in vitro and in vivo. Furthermore, we find that, in mouse N1E-115 neuroblastoma cells, expression of Dock6 is increased following differentiation. Transfection of the catalytic Dock Homology Region-2 (DHR-2) domain of Dock6 promotes neurite outgrowth mediated by Rac1 and Cdc42. Conversely, knockdown of endogenous Dock6 by small interference RNA reduces activation of Rac1 and Cdc42 and neurite outgrowth. Taken together, these results suggest that Dock6 differs from all of the identified Dock180-related proteins, in that it is the GEF specific for both Rac1 and Cdc42 and may be one of physiological regulators of neurite outgrowth.

Animals↗