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At least 271 records · Page 15Linked to original sources
PubMed2003

The folding mechanism of a two-domain protein: folding kinetics and domain docking of the gene-3 protein of phage fd.

The gene-3 protein (G3P) of filamentous phages is essential for the infection of Escherichia coli. The carboxy-terminal domain anchors this protein in the phage coat, whereas the two amino-terminal domains N1 and N2 protrude from the phage surface. We analyzed the folding mechanism of the two-domain fragment N1-N2 of G3P (G3P(*)) and the interplay between folding and domain assembly. For this analysis, a variant of G3P(*) was used that contained four stabilizing mutations (IIHY-G3P(*)). The observed refolding kinetics extend from 10 ms to several hours. Domain N1 refolds very rapidly (with a time constant of 9.4 ms at 0.5 M guanidinium chloride, 25 degrees C) both as a part of IIHY-G3P(*) and as an isolated protein fragment. The refolding of domain N2 is slower and involves two reactions with time constants of seven seconds and 42 seconds. These folding reactions of the individual domains are followed by a very slow, spectroscopically silent docking process, which shows a time constant of 6200 seconds. This reaction was detected by a kinetic unfolding assay for native molecules. Before docking, N1 and N2 unfold fast and independently, after docking they unfold slowly in a correlated fashion. A high energy barrier is thus created by domain docking, which protects G3P kinetically against unfolding. The slow domain docking is possibly important for the infection of E.coli by the phage. Upon binding to the F pilus, the N2 domain separates from N1 and the binding site for TolA on domain N1 is exposed. Since domain reassembly is so slow, this binding site remains accessible until pilus retraction has brought N1 close to TolA on the bacterial surface.

Bacteriophage M13↗
PubMed1996

c-Jun can recruit JNK to phosphorylate dimerization partners via specific docking interactions.

Structurally related serine/threonine kinases recognize similar phosphoacceptor peptides in vitro yet in vivo, they phosphorylate distinct substrates. To understand the basis for this specificity, we studied the interaction between the Jun kinases (JNKs) and Jun proteins. JNKs phosphorylate c-Jun very efficiently, JunD less efficiently, but they do not phosphorylate JunB. Effective JNK substrates require a separate docking site and specificity-conferring residues flanking the phosphoacceptor. The docking site increases the efficiency and specificity of the phosphorylation reaction. JunB has a functional JNK docking site but lacks specificity-conferring residues. Insertion of such residues brings JunB under JNK control. JunD, by contrast, lacks a JNK docking site, but its phosphoacceptor peptide is identical to that of c-Jun. Substrates such as JunD can be phosphorylated by JNK through heterodimerization with docking competent partners. Therefore, heterodimerization can affect the recognition of transcription factors by signal-regulated protein kinases.

Amino Acid Sequence↗
PubMed1999

Molecular docking studies on interaction of diverse retinol structures with human alcohol dehydrogenases predict a broad role in retinoid ligand synthesis.

Some members of the human alcohol dehydrogenase (ADH) family possess retinol dehydrogenase activity and may thus function in production of the active nuclear receptor ligand retinoic acid. Many diverse natural forms of retinol exist including all-trans-retinol (vitamin A(1)), 9-cis-retinol, 3,4-didehydroretinol (vitamin A(2)), 4-oxo-retinol, and 4-hydroxy-retinol as well as their respective carboxylic acid derivatives which are active ligands for retinoid receptors. This raises the question of whether ADHs can accommodate all these different retinols and thus participate in the activation of several retinoid ligands. The crystal structures of human ADH1B and ADH4 provide the opportunity to examine their active sites for potential binding to many diverse retinol structures using molecular docking algorithms. The criteria used to score successful docking included achievement of distances of 1.9-2.4 A between the catalytic zinc and the hydroxyl oxygen of retinol and 3.2-3.6 A between C-4 of the coenzyme NAD and C-15 of retinol. These distances are sufficient to enable hydride transfer during the oxidation of an alcohol to an aldehyde. By these criteria, all-trans-retinol, 4-oxo-retinol, and 4-hydroxy-retinol were successfully docked to both ADH1B and ADH4. However, 9-cis-retinol and 3,4-didehydroretinol, which have more restrictive conformations, were successfully docked to only ADH4 which possesses a wider active site than ADH1B and more easily accommodates the C-19 methyl group. Furthermore, docking of all retinols was more favorable in the active site of ADH4 rather than ADH1B as measured by force field and contact scores. These findings suggest that ADH1B has a limited capacity to metabolize retinols, but that ADH4 is well suited to function in the metabolism of many diverse retinols and is predicted to participate in the synthesis of the active ligands all-trans-retinoic acid, 9-cis-retinoic acid, 3, 4-didehydroretinoic acid, 4-oxo-retinoic acid, and 4-hydroxy-retinoic acid.

Alcohol Dehydrogenase↗
PubMed1999

The SH2/SH3 adaptor protein dock interacts with the Ste20-like kinase misshapen in controlling growth cone motility.

Recent studies suggest that the SH2/SH3 adaptor Dock/Nck transduces tyrosine phosphorylation signals to the actin cytoskeleton in regulating growth cone motility. The signaling cascade linking the action of Dock/Nck to the reorganization of cytoskeleton is poorly understood. We now demonstrate that Dock interacts with the Ste20-like kinase Misshapen (Msn) in the Drosophila photoreceptor (R cell) growth cones. Loss of msn causes a failure of growth cones to stop at the target, a phenotype similar to loss of dock, whereas overexpression of msn induces pretarget growth cone termination. Physical and genetic interactions between Msn and Dock indicate a role for Msn in the Dock signaling pathway. We propose that Msn functions as a key controller of growth cone cytoskeleton in response to Dock-mediated signals.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Slit stimulation recruits Dock and Pak to the roundabout receptor and increases Rac activity to regulate axon repulsion at the CNS midline.

Drosophila Roundabout (Robo) is the founding member of a conserved family of repulsive axon guidance receptors that respond to secreted Slit proteins. Here we present evidence that the SH3-SH2 adaptor protein Dreadlocks (Dock), the p21-activated serine-threonine kinase (Pak), and the Rac1/Rac2/Mtl small GTPases can function during Robo repulsion. Loss-of-function and genetic interaction experiments suggest that limiting the function of Dock, Pak, or Rac partially disrupts Robo repulsion. In addition, Dock can directly bind to Robo's cytoplasmic domain, and the association of Dock and Robo is enhanced by stimulation with Slit. Furthermore, Slit stimulation can recruit a complex of Dock and Pak to the Robo receptor and trigger an increase in Rac1 activity. These results provide a direct physical link between the Robo receptor and an important cytoskeletal regulatory protein complex and suggest that Rac can function in both attractive and repulsive axon guidance.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Docking of sulfonamides to carbonic anhydrase II and IV.

Starting with a known active site of a protein and a database of compounds, one would like to quickly identify a few compounds that "dock" into the active site and obtain "good" binding free energies. The main goal of current automated docking procedures is to predict the "best" substrate-enzyme complex while other programs such as UHBD and DelPhi can be used to compute binding free energies. In this paper, we will focus on the application of docking methods and parameters to study substrate-enzyme interactions of a metalloenzyme system. Specifically, we report on the docking of sulfonamides to carbonic anhydrase II and IV, which are of interest due to their application in glaucoma therapy. Using a standard docking protocol, it is possible to correctly predict not only the orientation of inhibitors to a specific isozyme, but also determine the qualitative affinity for a group of inhibitor for an isozyme.

Algorithms↗
PubMed1998

Evaluation of docking strategies for virtual screening of compound databases: cAMP-dependent serine/threonine kinase as an example.

In an effort to establish efficient docking routines for computational screening of compound databases on protein structures, cAMP-dependent protein kinase has been selected as a test case and a variety of docking options and scoring functions were compared. These included rigid-body and flexible docking and scoring based on surface complementarity and/or force field energy. Inhibitors were removed from complex crystal structures and added to compound libraries in their binding conformations and, in addition, deliberately modified conformations. Rigid-body docking and contact scoring well reproduced two of three experimental enzyme-inhibitor complexes. Ligand docking with flexible torsional angles failed to do so but anchored search of some inhibitors converged near to experimental structures, however, only when energy scoring was applied.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1995

Thermodynamic and activation parameters for binding of a pyrene-labeled substrate by the Tetrahymena ribozyme: docking is not diffusion-controlled and is driven by a favorable entropy change.

Association and dissociation rates for the pyrene-(pyr)-labeled oligoribonucleotide substrate pyrCUCU binding to the L-21 ScaI group I ribozyme are reported as a function of temperature. Combined with thermodynamic parameters for binding of pyrCUCU to rGGAGAA, the results allow calculation of the activation and thermodynamic parameters for docking of pyrCUCU into the catalytic core of the ribozyme. The activation enthalpy for docking is 22 kcal/mol, much larger than the approximately 4 kcal/mol expected for a diffusion-controlled process. Thus, docking is not diffusion-controlled. The activation and equilibrium entropies for docking are favorable at 21 and 37 eu, respectively. The results suggest the rate-limiting step and the driving force for docking may involve desolvation of RNA functional groups or of Mg2+ ions.

Animals↗
PubMed1996

Mutations in the Tetrahymena ribozyme internal guide sequence: effects on docking of the P1 helix into the catalytic core and correlation with catalytic activity.

Binding of substrate by the ribozyme derived from the self-splicing intron of Tetrahymena thermophila involves at least two steps. In the first step, base pairing between the ribozyme internal guide sequence (IGS) and the substrate forms a helical duplex (P1). Through specific tertiary interactions between P1 and the ribozyme core, P1 is then docked into the ribozyme active site. We have investigated the effects of compensatory mutations in positions 2-6 of the P1 helix on docking of P1 into the ribozyme core. Equilibrium binding of matching oligonucleotides by catalytically active IGS mutant ribozymes was evaluated by gel-shift analysis. While the strength of base pairing changed with base composition as expected, the strength of tertiary interactions between P1 and the ribozyme core was not affected by the P1 mutations. These results support a model in which efficient docking of P1 is determined by P1 structure and the presence of a conserved G-U pair. Determination of the rate of dissociation of matching oligonucleotides from each ribozyme revealed that mutations in the IGS change the tightness of binding by increasing or decreasing the dissociation rate. Surprisingly, dissociation rates determined in this fashion were 20-900-fold less than the values of the multiple-turnover rate constant for these ribozymes, initially suggesting that turnover did not require product dissociation. A more detailed analysis for the wild-type ribozyme defined two distinct product dissociation rates. The slower rate equaled that determined under the conditions used for the equilibrium binding studies. The weighted average of the two dissociation rates equaled the multiple-turnover rate constant. These results are explained by a model in which ribozyme preparations consist of two ribozyme conformers: one with tight docking of P1 and another with weaker docking of P1.

Animals↗
PubMedDate not supplied

Virtual screening using protein-ligand docking: avoiding artificial enrichment.

This study addresses a number of topical issues around the use of protein-ligand docking in virtual screening. We show that, for the validation of such methods, it is key to use focused libraries (containing compounds with one-dimensional properties, similar to the actives), rather than "random" or "drug-like" libraries to test the actives against. We also show that, to obtain good enrichments, the docking program needs to produce reliable binding modes. We demonstrate how pharmacophores can be used to guide the dockings and improve enrichments, and we compare the performance of three consensus-ranking protocols against ranking based on individual scoring functions. Finally, we show that protein-ligand docking can be an effective aid in the screening for weak, fragment-like binders, which has rapidly become a popular strategy for hit identification. All results presented are based on carefully constructed virtual screening experiments against four targets, using the protein-ligand docking program GOLD.

Ligands↗
PubMedDate not supplied

Screening drug-like compounds by docking to homology models: a systematic study.

In the absence of an experimentally solved structure, a homology model of a protein target can be used instead for virtual screening of drug candidates by docking and scoring. This approach poses a number of questions regarding the choice of the template to use in constructing the model, the accuracy of the screening results, and the importance of allowing for protein flexibility. The present study addresses such questions with compound screening calculations for multiple homology models of five drug targets. A central result is that docking to homology models frequently yields enrichments of known ligands as good as that obtained by docking to a crystal structure of the actual target protein. Interestingly, however, standard measures of the similarity of the template used to build the homology model to the targeted protein show little correlation with the effectiveness of the screening calculations, and docking to the template itself often is as successful as docking to the corresponding homology model. Treating key side chains as mobile produces a modest improvement in the results. The reasons for these sometimes unexpected results, and their implications for future methodologic development, are discussed.

Computer Simulation↗
PubMedDate not supplied

A QXP-based multistep docking procedure for accurate prediction of protein-ligand complexes.

The two great challenges of the docking process are the prediction of ligand poses in a protein binding site and the scoring of the docked poses. Ligands that are composed of extended chains in their molecular structure display the most difficulties, predominantly because of the torsional flexibility. On the basis of the molecular docking program QXP-Flo+0802, we have developed a procedure particularly for ligands with a high degree of rotational freedom that allows the accurate prediction of the orientation and conformation of ligands in protein binding sites. Starting from an initial full Monte Carlo docking experiment, this was achieved by performing a series of successive multistep docking runs using a local Monte Carlo search with a restricted rotational angle, by which the conformational search space is limited. The method was established by using a highly flexible acetylcholinesterase inhibitor and has been applied to a number of challenging protein-ligand complexes known from the literature.

Binding Sites↗
PubMedDate not supplied

Prediction of multiple binding modes of the CDK2 inhibitors, anilinopyrazoles, using the automated docking programs GOLD, FlexX, and LigandFit: an evaluation of performance.

Anilinopyrazoles as CDK2 inhibitors can adopt multiple binding modes depending on the substituents at the 5-position of the pyrazole ring, based on CDK2/cyclin A crystallographic studies. Three commercially available docking programs, FlexX, GOLD, and LigandFit, were tested with 63 anilinopyrazole analogues in an attempt to reproduce the binding modes observed in the crystal structures. Each docking program gave different ligand conformations depending on the scoring or energy functions used. FlexX/drugscore, GOLD/chemscore, and LigandFit/plp were the best combinations of each docking program in reproducing the ligand conformations observed in the crystal structures. The 63 analogues were divided into two groups, type-A and type-B, depending on the substituent at the 5-position of the pyrazole ring. Although an alternate binding mode, observed in a crystal structure of one type-B compound, could not be reproduced with any of the above docking/scoring combinations, GOLD, with a template constraint based on the crystal structure coordinates, was able to reproduce the pose. As for type-A compounds, all docking conditions yielded similar poses to those observed in crystal structures. When predicting activities by scoring programs, the combination of docking with LigandFit/plp and scoring with LIGSCORE1_CFF gave the best correlation coefficient (r=0.60) between experimental pIC50 values and top-ranked rescores of 30 poses of each compound. With regard to type-A compounds, the correlation was 0.69. However, when 11 compounds, whose top-ranked rescored poses did not demonstrate the correct binding modes in reference to the crystal structure, were removed, the correlation rose to 0.75. Consequently, predicting activity on the basis of correct binding modes was found to be reliable.

Algorithms↗
PubMed2000

New approach to molecular docking and its application to virtual screening of chemical databases

This paper describes the validation of a molecular docking method and its application to virtual database screening. The code flexibly docks ligand molecules into rigid receptor structures using a tabu search methodology driven by an empirically derived function for estimating the binding affinity of a protein-ligand complex. The docking method has been tested on 70 ligand-receptor complexes for which the experimental binding affinity and binding geometry are known. The lowest energy geometry produced by the docking protocol is within 2.0 A root mean square of the experimental binding mode for 79% of the complexes. The method has been applied to the problem of virtual database screening to identify known ligands for thrombin, factor Xa, and the estrogen receptor. A database of 10,000 randomly chosen "druglike" molecules has been docked into the three receptor structures. In each case known receptor ligands were included in the study. The results showed good separation between the predicted binding affinities of the known ligand set and the database subset.

Journal Article↗
PubMed2004

Structural mining: self-consistent design on flexible protein-peptide docking and transferable binding affinity potential.

A flexible protein-peptide docking method has been designed to consider not only ligand flexibility but also the flexibility of the protein. The method is based on a Monte Carlo annealing process. Simulations with a distance root-mean-square (dRMS) virtual energy function revealed that the flexibility of protein side chains was as important as ligand flexibility for successful protein-peptide docking. On the basis of mean field theory, a transferable potential was designed to evaluate distance-dependent protein-ligand interactions and atomic solvation energies. The potential parameters were developed using a self-consistent process based on only 10 known complex structures. The effectiveness of each intermediate potential was judged on the basis of a Z score, approximating the gap between the energy of the native complex and the average energy of a decoy set. The Z score was determined using experimentally determined native structures and decoys generated by docking with the intermediate potentials. Using 6600 generated decoys and the Z score optimization criterion proposed in this work, the developed potential yielded an acceptable correlation of R(2) = 0.77, with binding free energies determined for known MHC I complexes (Class I Major Histocompatibility protein HLA-A(*)0201) which were not present in the training set. Test docking on 25 complexes further revealed a significant correlation between energy and dRMS, important for identifying native-like conformations. The near-native structures always belonged to one of the conformational classes with lower predicted binding energy. The lowest energy docked conformations are generally associated with near-native conformations, less than 3.0 Angstrom dRMS (and in many cases less than 1.0 Angstrom) from the experimentally determined structures.

Algorithms↗
PubMed2005

A flexible docking procedure for the exploration of peptide binding selectivity to known structures and homology models of PDZ domains.

PDZ domains are important scaffolding modules that typically bind to the C-termini of their interaction partners. Several structures of such complexes have been solved, revealing a conserved binding site in the PDZ domain and an extended conformation of the bound peptide. A compendium of information regarding PDZ complexes demonstrates that dissimilar C-terminal peptides bind to the same PDZ domain, and different PDZ domains can bind the same peptides. A detailed understanding of the PDZ-peptide recognition is needed to elucidate this complexity. To this end, we have designed a family of docking protocols for PDZ domains (termed PDZ-DocScheme) that is based on simulated annealing molecular dynamics and rotamer optimization, and is applicable to the docking of long peptides (20-40 rotatable bonds) to both known PDZ structures and to the more complicated problem of homology models of these domains. The resulting protocol reproduces the structures of PDZ complexes with peptides 4-8 amino acids long within 1-2 A from the experimental structure when the docking is performed to the original structure. If the structure of the target PDZ domain is an apo structure or a homology model, the docking protocol yields structures within 3 A in 9 out of 12 test cases. The automated docking procedure PDZ-DocScheme can serve in the generation of a structural context for validation of PDZ domain specificity from mutagenesis and ligand binding data.

Models, Molecular↗
PubMed2003

Surflex: fully automatic flexible molecular docking using a molecular similarity-based search engine.

Surflex is a fully automatic flexible molecular docking algorithm that combines the scoring function from the Hammerhead docking system with a search engine that relies on a surface-based molecular similarity method as a means to rapidly generate suitable putative poses for molecular fragments. Results are presented evaluating reliability and accuracy of dockings compared with crystallographic experimental results on 81 protein/ligand pairs of substantial structural diversity. In over 80% of the complexes, Surflex's highest scoring docked pose was within 2.5 A root-mean-square deviation (rmsd), with over 90% of the complexes having one of the top ranked poses within 2.5 A rmsd. Results are also presented assessing Surflex's utility as a screening tool on two protein targets (thymidine kinase and estrogen receptor) using data sets on which competing methods were run. Performance of Surflex was significantly better, with true positive rates of greater than 80% at false positive rates of less than 1%. Docking time was roughly linear in number of rotatable bonds, beginning with a few seconds for rigid molecules and adding approximately 10 s per rotatable bond.

Algorithms↗
PubMed2004

Virtual screening with flexible docking and COMBINE-based models. Application to a series of factor Xa inhibitors.

A two-step, fully automatic virtual screening procedure consisting of flexible docking followed by activity prediction by COMparative BINding Energy (COMBINE) analysis is presented. This novel approach has been successfully applied, as an example with medicinal chemistry interest, to a recently reported series of 133 factor Xa (fXa)(1) inhibitors whose activities encompass 4 orders of magnitude. The docking algorithm is linked to the COMBINE analysis program and used to derive independent regression models of the 133 inhibitors docked within three different fXa structures (PDB entries 1fjs, 1f0r, and 1xka), so as to explore the effect of receptor conformation on the overall results. Reliable docking conformations and predictive regression models requiring eight latent variables could be derived for two of the fXa structures, with the best model achieving a Q(2) of 0.63 and a standard deviation of errors of prediction (SDEP) of 0.51 (leave-one-out). The two-step procedure was then employed to screen a designed virtual library of 112 ligands, containing both active and inactive compounds. While docking energies alone could show a good performance for selecting hits, including structurally diverse ones, inclusion of COMBINE analysis regression models provided improved rankings for the identification of structurally related molecules in external sets. In our best case, a recognition rate of approximately 80% of known binders at approximately 15% false positives rate was achieved, corresponding to an enrichment factor of approximately 450% over random.

Algorithms↗