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PubMed2005

Ligand selectivity for the acetylcholine binding site of the rat alpha4beta2 and alpha3beta4 nicotinic subtypes investigated by molecular docking.

The homology models of the extracellular domains of the neuronal alpha4beta2 (pdb code: 1ole) and ganglionic alpha3beta4 (pdb code: 1olf) rat nicotinic acetylcholine receptor (nAChR) subtypes were refined and energetically minimized. In this work, a series of nAChR ligands (1-15) were docked into the modeled binding cavity of both receptors. High-affinity, toxic ligands such as epibatidine (1) and dechloroepibatidine (2) docked into cluster 1 with the charged tertiary amino group, forming a pi-cation interaction with Trp 147 on the (+) side of the alpha4 subunit and establishing a characteristic H-bond with the Lys 77 on the (-) side of the beta2 subunit. The nontoxic ligands such as 33bMet (3), (S)-A-85380 (4), and acetylcholine (6) docked into cluster 2 with the same pi-cation interaction but with the rest of the molecule occupying a different moiety of the binding pocket. Molecular docking into the alpha3beta4 subtype showed that both enantiomers of 1 (1a and 1b) are representative templates for ligands with affinity toward this ganglionic nAChR subtype. The ranking scores of the docked molecules confirm the existence of structure-dependent subtype selectivity and shed light on the design of specific and selective alpha4beta2 nAChR subtype ligands.

Acetylcholine↗

PubMed2005

Unveiling the full potential of flexible receptor docking using multiple crystallographic structures.

One of the current challenges in docking studies is the inclusion of receptor flexibility. This is crucial because the binding sites of many therapeutic targets sample a wide range of conformational states, which has major consequences on molecular recognition. In this paper, we make use of very large sets of X-ray structures of cyclin dependent kinase 2 (CDK2) and heat shock protein 90 (HSP90) to assess the performance of flexible receptor docking in binding-mode prediction and virtual screening experiments. Flexible receptor docking performs much better than rigid receptor docking in the former application. Regarding the latter, we observe a significant improvement in the prediction of binding affinities, but owing to an increase in the number of false positives, this is not translated into better hit rates. A simple scoring scheme to correct this limitation is presented. More importantly, pitfalls inherent to flexible receptor docking have been identified and guidelines are presented to avoid them.

Adenosine Triphosphate↗

PubMed1997

Multiple automatic base selection: protein-ligand docking based on incremental construction without manual intervention.

A possible way of tackling the molecular docking problem arising in computer-aided drug design is the use of the incremental construction method. This method consists of three steps: the selection of a part of a molecule, a so-called base fragment, the placement of the base fragment into the active site of a protein, and the subsequent reconstruction of the complete drug molecule. Assuming that a part of a drug molecule is known, which is specific enough to be a good base fragment, the method is proven to be successful for a large set of docking examples. In addition, it leads to the fastest algorithms for flexible docking published so far. In most real-world applications of docking, large sets of ligands have to be tested for affinity to a given protein. Thus, manual selection of a base fragment is not practical. On the other hand, the selection of a base fragment is critical in that only few selections lead to a low-energy structure. We overcome this limitation by selecting a representative set of base fragments instead of a single one. In this paper, we present a set of rules and algorithms to automate this selection. In addition, we extend the incremental construction method to deal with multiple fragmentations of the drug molecule. Our results show that with multiple automated base selection, the quality of the docking predictions is almost as good as with one manually preselected base fragment. In addition, the set of solutions is more diverse and alternative binding modes with low scores are found. Although the run time of the overall algorithm increases, the method remains fast enough to search through large ligand data sets.

Automation↗

PubMed1999

MCDOCK: a Monte Carlo simulation approach to the molecular docking problem.

Prediction of the binding mode of a ligand (a drug molecule) to its macromolecular receptor, or molecular docking, is an important problem in rational drug design. We have developed a new docking method in which a non-conventional Monte Carlo (MC) simulation technique is employed. A computer program, MCDOCK, was developed to carry out the molecular docking operation automatically. The current version of the MCDOCK program (version 1.0) allows for the full flexibility of ligands in the docking calculations. The scoring function used in MCDOCK is the sum of the interaction energy between the ligand and its receptor, and the conformational energy of the ligand. To validate the MCDOCK method, 19 small ligands, the binding modes of which had been determined experimentally using X-ray diffraction, were docked into their receptor binding sites. To produce statistically significant results, 20 MCDOCK runs were performed for each protein-ligand complex. It was found that a significant percentage of these MCDOCK runs converge to the experimentally observed binding mode. The root-mean-square (rms) of all non-hydrogen atoms of the ligand between the predicted and experimental binding modes ranges from 0.25 to 1.84 A for these 19 cases. The computational time for each run on an SGI Indigo2/R10000 varies from less than 1 min to 15 min, depending upon the size and the flexibility of the ligands. Thus MCDOCK may be used to predict the precise binding mode of ligands in lead optimization and to discover novel lead compounds through structure-based database searching.

Binding Sites↗

PubMed1999

DREAM++: flexible docking program for virtual combinatorial libraries.

We present a set of programs, DREAM+2 (Docking and Reaction programs using Efficient seArch Methods written in C++), for docking computationally generated ligands into macromolecular binding sites. DREAM++ is composed of three programs: ORIENT++, REACT++ and SEARCH++. The program ORIENT++ positions molecules in a binding site with the DOCK algorithm. Its output can be used as input to REACT++ and SEARCH+2. The program REACT++ performs user-specific chemical reactions on a docked molecule, so that reaction products can be evaluated for three dimensional complementarity with the macromolecular site. The program SEARCH++ performs an efficient conformation search on the reaction products using a hybrid backtrack and incremental construction algorithm. We have applied the programs to HIV protease-inhibitor complexes as test systems. We found that we can differentiate high-affinity ligands based on several measures: interaction energies, occupancy of protein subsites and the number of successfully docked conformations for each product. Encouraged by the results in the test case, we applied the programs to propose novel inhibitors of HIV protease. These inhibitors can be generated by organic reactions using commercially available reagents. They are alternatives to the inhibitors synthesized by Glaxo.

Algorithms↗

PubMed2001

Protein ligand docking based on empirical method for binding affinity estimation.

An empirical protein-ligand binding affinity estimation method, SCORE, was incorporated into a popular docking program, DOCK4. The combined program, ScoreDock, was used to reconstruct the 200 protein-ligand complex structures and found to give good results for the complexes with high binding affinities. A quality assessment method for docking results from ScoreDock was developed based on the whole test set and tested by additionally selected complexes. The method significantly improves the docking accuracy and was shown to be reliable in docking quality assessment. As a docking tool in structural based drug design, ScoreDock can screen out final hits directly based on the predicted negative logarithms of dissociation equilibrium constants of protein-ligand complexes, and can explicitly deal with structure water molecules, as well as metal atoms.

Computer Simulation↗

PubMed2003

A novel scoring function for molecular docking.

We present a novel scoring function for docking of small molecules to protein binding sites. The scoring function is based on a combination of two main approaches used in the field, the empirical and knowledge-based approaches. To calibrate the scoring function we used an iterative procedure in which a ligand's position and its score were determined self-consistently at each iteration. The scoring function demonstrated superiority in prediction of ligand positions in docking tests against the commonly used Dock, FlexX and Gold docking programs. It also demonstrated good accuracy of binding affinity prediction for the docked ligands.

Binding Sites↗

PubMed2004

Reverse-docking as a computational tool for the study of asymmetric organocatalysis.

A novel methodology for 'reverse-docking' a cationic peptide-based organocatalyst to a rigid anionic transition state (TS) model for the conjugate addition of azide to alpha,beta-unsaturated carbonyl substrates is described. The resulting docking poses serve as simplified TS models for enantioselective catalysis. Molecular mechanics-based scoring and ranking of the docking poses, followed by clustering and structural analysis, reveal a clear energetic preference for docking to the S-enantiomeric azidation TS model, in agreement with experiment. Clear energetic trends emerged from docking the catalyst to both enantiomers of all six azidation TS models of this study. Structural analysis of the most favorable pose suggests a mechanism for enantioselective catalysis that is consistent with principles of molecular recognition, catalysis, and experimental data.

Azides↗

PubMed2002

SNAP-25 and synaptotagmin 1 function in Ca2+-dependent reversible docking of granules to the plasma membrane.

In neuroendocrine cells, Ca2+ triggers fusion of granules with the plasma membrane and functions at earlier steps by increasing the size of the readily releasable pool of vesicles. The effect of Ca2+ at early steps of secretion may be due to the recruitment at the plasma membrane of granules localized in the cytoplasm. To study the mechanism of granule docking, a new in vitro assay is designed using membrane fractions from mouse pituitary AtT-20 cells. By using this assay, it is found that granule docking to the plasma membrane is controlled by Ca2+ concentrations in the micromolar range, is reversible and requires intact SNAP-25, but not VAMP-2. In the docking assay, addition of Ca2+ induces the formation of a SNAP-25-Synaptotagmin 1 complex. The cytosolic domain C2AB of Synaptotagmin 1 and anti-Synaptotagmin 1 antibodies block granule docking. These results show that Ca2+ modulates dynamic docking of granules to the plasma membrane and that this process is due to a Ca2+-dependent interaction between SNAP-25 and Synaptotagmin 1.

Animals↗

PubMed1989

Homology of 54K protein of signal-recognition particle, docking protein and two E. coli proteins with putative GTP-binding domains.

Most proteins exported from mammalian cells contain a signal sequence which mediates targeting to and insertion into the membrane of the endoplasmic reticulum (ER). Involved in this process are the signal-recognition particle (SRP) and docking protein (DP), the receptor for SRP in the ER membrane. SRP interacts with the signal sequence on nascent polypeptide chains and retards their further elongation, which resumes only after interaction of the arrested ribosomal complex with the docking protein. SRP is a ribonucleoprotein particle comprising a 7S RNA and six polypeptides with relative molecular masses (Mr) of 9,000 (9K) 14K, 19K, 54K, 68K and 72K (ref. 1). The 9K and 14K proteins are essential for elongation arrest and the 68K-72K heterodimer is required for docking to the ER membrane. The 54K protein binds to the signal sequence when it emerges from the ribosome. Docking protein consists of two polypeptides, a 72K alpha-subunit (DP alpha) and a 30K beta-subunit (DP beta). No components structurally homologous to SRP and docking protein have yet been found in yeast or Escherichia coli. To understand the molecular nature of the interaction between the signal sequence and its receptor(s) we have characterized a complementary DNA coding for the 54K protein of SRP. Significant sequence homology was found to part of DP alpha and two E. coli proteins of unknown function. The homologous region includes a putative GTP-binding domain.

Amino Acid Sequence↗

PubMed2003

Docking sites on mitogen-activated protein kinase (MAPK) kinases, MAPK phosphatases and the Elk-1 transcription factor compete for MAPK binding and are crucial for enzymic activity.

Mitogen-activated protein kinase (MAPK) cascades control gene expression patterns in response to extracellular stimuli. MAPK/ERK (extracellular-signal-regulated kinase) kinases (MEKs) activate MAPKs by phosphorylating them; activated MAPKs, in turn, phosphorylate target transcription factors, and are deactivated by phosphatases. One mechanism for maintaining signal specificity and efficiency is the interaction of MAPKs with their substrates and regulators through high-affinity docking sites. In the present study, we show that peptides corresponding to the MAPK-docking sites of MEK1, MEK2, Ste7, Elk-1 and MAPK phosphatase (MKP)-2 potently inhibit MEK2 phosphorylation of ERK2, ERK2 phosphorylation of Elk-1, and MKP-1 dephosphorylation of ERK2. Each peptide inhibited multiple reactions; for example, the MEK2 peptide inhibited not only MEK2, but also ERK2 and MKP-1. In addition, these docking-site peptides inhibited MEK2-ERK2 binding. The MAPK-docking site of MEK1 also potently stimulated ERK2-mediated phosphorylation of a target site on the same peptide. Control peptides with mutations of conserved basic and hydrophobic residues of the MAPK-docking site consensus lacked biological activity. We conclude that MEKs, MKPs and the Elk-1 transcription factor compete for binding to the same region of ERK2 via protein-protein interactions that are crucial for kinase/phosphatase activity.

Amino Acid Sequence↗

PubMed2001

The relationship between tail biting in pigs, docking procedure and other management practices.

The tail length (docked, tipped or undocked) and tail status (bitten or unbitten) of 27,870 pigs from 450 units was recorded at six UK abattoirs. A farm survey of the final finishing stage was used to investigate the relationship between management practice and tail biting. This showed that docking was the most important factor influencing the probability of being not bitten, with 2.4% of docked and 8.5% of long-tailed pigs being tail-bitten. The following factors reduced the probability of long-tailed pigs being tail-bitten; light straw provision, use of natural ventilation or artificially controlled natural ventilation (ACNV), mixed sex grouping, meal or liquid feeding, and use of double or multi-space feeders. Docked and long-tailed pigs provided with light straw and natural ventilation/ACNV had levels of tail biting of 1.2% and 4.3% respectively; 3.9% of docked pigs with artificial ventilation and no straw were tail-bitten. Long-tailed pigs fed via double or multi-space feeders also had 3.9% of tails bitten.

Animal Husbandry↗

PubMed2004

Resolution of organelle docking and fusion kinetics in a cell-free assay.

In vitro assays of compartment mixing have been key tools in the biochemical dissection of organelle docking and fusion. Many such assays measure compartment mixing through the enzymatic modification of reporter proteins. Homotypic fusion of yeast vacuoles is measured with a coupled assay of proteolytic maturation of pro-alkaline phosphatase (pro-ALP). A kinetic lag is observed between the end of docking, marked by the acquisition of resistance to anti-SNARE reagents, and ALP maturation. We therefore asked whether the time taken for pro-ALP maturation adds a kinetic lag to the measured fusion signal. Prb1p promotes ALP maturation; overproduction of Prb1p accelerates ALP activation in detergent lysates but does not alter the measured kinetics of docking or fusion. Thus, the lag between docking and ALP activation reflects a lag between docking and fusion. Many vacuoles in the population undergo multiple rounds of fusion; methods are presented for distinguishing the first round of fusion from ongoing rounds of fusion. A simple kinetic model distinguishes between two rates, the rate of fusion and the rate at which fusion competence is lost, and allows estimation of the number of rounds of fusion completed.

Alkaline Phosphatase↗

PubMed2006

Structural basis of docking interactions between ERK2 and MAP kinase phosphatase 3.

Mitogen-activated protein (MAP) kinases are central components of signal transduction pathways for cell proliferation, stress responses, and differentiation. Signaling efficiency and specificity are modulated in large part by docking interactions between individual MAP kinase and the kinase interaction motif (KIM), (R/K)(2-3)-X(1-6)-Phi(A)-X-Phi(B), in its cognate kinases, phosphatases, scaffolding proteins, and substrates. We have determined the crystal structure of extracellular signal-regulated protein kinase 2 bound to the KIM peptide from MAP kinase phosphatase 3, an extracellular signal-regulated protein kinase 2-specific phosphatase. The structure reveals that the KIM docking site, situated in a noncatalytic region opposite of the kinase catalytic pocket, is comprised of a highly acidic patch and a hydrophobic groove, which engage the basic and Phi(A)-X-Phi(B) residues, respectively, in the KIM sequence. The specific docking interactions observed in the structure consolidate all known biochemical data. In addition, structural comparison indicates that the KIM docking site is conserved in all MAP kinases. The results establish a structural model for understanding how MAP kinases interact with their regulators and substrates and provide new insights into how MAP kinase docking specificity can be achieved.

Amino Acid Motifs↗

PubMed2000

The docking of primed vacuoles can be reversibly arrested by excess Sec17p (alpha-SNAP).

Homotypic vacuole fusion occurs in ordered stages of priming, docking, and fusion. Priming, which prepares vacuoles for productive association, requires Sec17p (the yeast homolog of alpha-SNAP), Sec18p (the yeast NSF, an ATP-driven chaperone), and ATP. Sec17p is initially an integral part of the cis-SNARE complex together with vacuolar SNARE proteins and Sec18p (NSF). Previous studies have shown that Sec17p is rapidly released from the vacuole membrane during priming as the cis-SNARE complex is disassembled, but the order and causal relationship of these subreactions has not been known. We now report that the addition of excess recombinant his(6)-Sec17p to primed vacuoles can block subsequent docking. This inhibition is reversible by Sec18p, but the reaction cannot proceed to the tethering and trans-SNARE pairing steps of docking while the Sec17p block is in place. Once docking has occurred, excess Sec17p does not inhibit membrane fusion per se. Incubation of cells with thermosensitive Sec17-1p at nonpermissive temperature causes SNARE complex disassembly. These data suggest that Sec17p can stabilize vacuolar cis-SNARE complexes and that the release of Sec17p by Sec18p and ATP allows disassembly of this complex and activates its components for docking.

Carrier Proteins↗

PubMed2000

Identification of domain-domain docking sites within Clostridium symbiosum pyruvate phosphate dikinase by amino acid replacement.

Potential domain-domain docking residues, identified from the x-ray structure of the Clostridium symbiosum apoPPDK, were replaced by site-directed mutagenesis. The steady-state and transient kinetic properties of the mutant enzymes were determined as a way of evaluating docking efficiency. PPDK mutants, in which one of two stringently conserved docking residues located on the N-terminal domain (Arg(219) and Glu(271)) was substituted, displayed largely unimpeded catalysis of the phosphoenolpyruvate partial reaction at the C-terminal domain, but significantly impaired catalysis (>10(4)) of the ATP pyrophosphorylation of His(455) at the N-terminal domain. In contrast, alanine mutants of two potential docking residues located on the N-terminal domain (Ser(262) and Lys(149)), which are not conserved among the PPDKs, exhibited essentially normal catalytic turnover. Arg(219) and Glu(271) were thus proposed to play an important role in guiding the central domain and, hence, the catalytic His(455) into position for catalysis. Substitution of central domain residues Glu(434)/Glu(437) and Thr(453), the respective docking partners of Arg(219) and Glu(271), resulted in mutants impaired in catalysis at the ATP active site. The x-ray crystal structure of the apo-T453A PPDK mutant was determined to test for possible misalignment of residues at the N-terminal domain-central domain interface that might result from loss of the Thr(453)-Glu(271) binding interaction. With the exception of the mutation site, the structure of T453A PPDK was found to be identical to that of the wild-type enzyme. It is hypothesized that the two Glu(271) interfacial binding sites that remain in the T453A PPDK mutant, Thr(453) backbone NH and Met(452) backbone NH, are sufficient to stabilize the native conformation as observed in the crystalline state but may be less effective in populating the reactive conformation in solution.

Adenosine Triphosphate↗

PubMed2000

A conserved docking site in MEKs mediates high-affinity binding to MAP kinases and cooperates with a scaffold protein to enhance signal transmission.

The recognition of mitogen-activated protein kinases (MAPKs) by their upstream activators, MAPK/ERK kinases (MEKs), is crucial for the effective and accurate transmission of many signals. We demonstrated previously that the yeast MAPKs Kss1 and Fus3 bind with high affinity to the N terminus of the MEK Ste7, and proposed that a conserved motif in Ste7, the MAPK-docking site, mediates this interaction. Here we show that the corresponding sequences in human MEK1 and MEK2 are necessary and sufficient for the direct binding of the MAPKs ERK1 and ERK2. Mutations in MEK1, MEK2, or Ste7 that altered conserved residues in the docking site diminished binding of the cognate MAPKs. Furthermore, short peptides corresponding to the docking sites in these MEKs inhibited MEK1-mediated phosphorylation of ERK2 in vitro. In yeast cells, docking-defective alleles of Ste7 were modestly compromised in their ability to transmit the mating pheromone signal. This deficiency was dramatically enhanced when the ability of the Ste5 scaffold protein to associate with components of the MAPK cascade was also compromised. Thus, both the MEK-MAPK docking interaction and binding to the Ste5 scaffold make mutually reinforcing contributions to the efficiency of signaling by this MAPK cascade in vivo.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Docking sites on substrate proteins direct extracellular signal-regulated kinase to phosphorylate specific residues.

Mitogen-activated protein (MAP) kinases such as extracellular signal-regulated kinase (ERK) are important signaling proteins that phosphorylate (S/T)P sites in many different protein substrates. ERK binding to substrate proteins is mediated by docking sites including the FXFP motif and the D-domain. We characterized the sequence of amino acids that can constitute the FXFP motif using peptide and protein substrates. Substitutions of the phenylalanines at positions 1 and 3 had significant effects, indicating that these phenylalanines provide substantial binding affinity, whereas substitutions of the residues at positions 2 and 4 had less effect. The FXFP and D-domain docking sites were analyzed in a variety of positions and arrangements in the proteins ELK-1 and KSR-1. Our results indicate that the FXFP and D-domain docking sites form a flexible, modular system that has two functions. First, the affinity of a substrate for ERK can be regulated by the number, type, position, and arrangement of docking sites. Second, in substrates with multiple potential phosphorylation sites, docking sites can direct phosphorylation of specific (S/T)P residues. In particular, the FQFP motif of ELK-1 is necessary and sufficient to direct phosphorylation of serine 383, whereas the D-domain directs phosphorylation of other (S/T)P sites in ELK-1.

Amino Acid Sequence↗