Showing papers on "Docking (molecular) published in 1997"
TL;DR: GOLD (Genetic Optimisation for Ligand Docking) is an automated ligand docking program that uses a genetic algorithm to explore the full range of ligand conformational flexibility with partial flexibility of the protein, and satisfies the fundamental requirement that the ligand must displace loosely bound water on binding.
5,882 citations
TL;DR: A protein docking study was performed for two classes of biomolecular complexes: six enzyme/inhibitor and four antibody/antigen and tested the native rather than the complexed forms of the proteins to address the more scientifically interesting problem of predictive docking.
840 citations
TL;DR: The three‐dimensional structure of stromal cell‐derived factor‐1 was determined by NMR spectroscopy and the RFFESH formed a receptor binding site, which is proposed to be an important initial docking site of SDF‐1 with its receptor.
Abstract: The three‐dimensional structure of stromal cell‐derived factor‐1 (SDF‐1) was determined by NMR spectroscopy. SDF‐1 is a monomer with a disordered N‐terminal region (residues 1–8), and differs from other chemokines in the packing of the hydrophobic core and surface charge distribution. Results with analogs showed that the N‐terminal eight residues formed an important receptor binding site; however, only Lys‐1 and Pro‐2 were directly involved in receptor activation. Modification to Lys‐1 and/or Pro‐2 resulted in loss of activity, but generated potent SDF‐1 antagonists. Residues 12–17 of the loop region, which we term the RFFESH motif, unlike the N‐terminal region, were well defined in the SDF‐1 structure. The RFFESH formed a receptor binding site, which we propose to be an important initial docking site of SDF‐1 with its receptor. The ability of the SDF‐1 analogs to block HIV‐1 entry via CXCR4, which is a HIV‐1 coreceptor for the virus in addition to being the receptor for SDF‐1, correlated with their affinity for CXCR4. Activation of the receptor is not required for HIV‐1 inhibition.
753 citations
TL;DR: Two related methods for molecular docking are described that utilize information on conformational variability from ensembles of experimental receptor structures, and it is shown that experimentally determined binding orientations and computed energies of known ligands can be reproduced accurately.
406 citations
TL;DR: Biochemical and microscopic assays for the docking step of in vitro vacuole fusion and characterized its requirements are developed and developed.
Abstract: Vacuole inheritance in yeast involves the formation of tubular and vesicular “segregation structures” which migrate into the bud and fuse there to establish the daughter cell vacuole. Vacuole fusion has been reconstituted in vitro and may be used as a model for an NSF-dependent reaction of priming, docking, and fusion. We have developed biochemical and microscopic assays for the docking step of in vitro vacuole fusion and characterized its requirements. The vacuoles must be primed for docking by the action of Sec17p (α-SNAP) and Sec18p (NSF). Priming is necessary for both fusion partners. It produces a labile state which requires rapid docking in order to lead productively to fusion. In addition to Sec17p/Sec18p, docking requires the activity of the Ras-like GTPase Ypt7p. Unlike Sec17p/Sec18p, which must act before docking, Ypt7p is directly involved in the docking process itself.
236 citations
TL;DR: This paper presents an algorithm for representing a protein's binding site in a way that is specifically suited to molecular docking applications, and tests the effectiveness of the probe representation on a number of ligand‐protein complexes.
Abstract: Molecular docking is a popular way to screen for novel drug compounds. The method involves aligning small molecules to a protein structure and estimating their binding affinity. To do this rapidly for tens of thousands of molecules requires an effective representation of the binding region of the target protein. This paper presents an algorithm for representing a protein's binding site in a way that is specifically suited to molecular docking applications. Initially the protein's surface is coated with a collection of molecular fragments that could potentially interact with the protein. Each fragment, or probe, serves as a potential alignment point for atoms in a ligand, and is scored to represent that probe's affinity for the protein. Probes are then clustered by accumulating their affinities, where high affinity clusters are identified as being the "stickiest" portions of the protein surface. The stickiest cluster is used as a computational binding "pocket" for docking. This method of site identification was tested on a number of ligand-protein complexes; in each case the pocket constructed by the algorithm coincided with the known ligand binding site. Successful docking experiments demonstrated the effectiveness of the probe representation.
199 citations
TL;DR: A structural perspective for the mode of collagen binding by a bacterial surface protein is presented, and recombinant proteins containing single amino acid mutations designed to disrupt the surface of the putative binding site exhibited significantly lower affinities for collagen.
Abstract: The crystal structure of the recombinant 19,000 Mr binding domain from the Staphylococcus aureus collagen adhesin has been determined at 2 A resolution. The domain fold is a jelly-roll, composed of two antiparallel β-sheets and two short α-helices. Triple-helical collagen model probes were used in a systematic docking search to identify the collagen-binding site. A groove on β-sheet I exhibited the best surface complementarity to the collagen probes. This site partially overlaps with the peptide sequence previously shown to be critical for collagen binding. Recombinant proteins containing single amino acid mutations designed to disrupt the surface of the putative binding site exhibited significantly lower affinities for collagen. Here we present a structural perspective for the mode of collagen binding by a bacterial surface protein.
156 citations
01 Jan 1997
TL;DR: It is suggested that the use of nanofiltration membranes for the recovery of phosphorous with a second type of technology is to be considered as a viable process for recovery of nitrogen in the short term.
Abstract: The hnRNP K protein is a versatile molecule that interacts with RNA, DNA, the proto-oncoprotein VaV, Src-like tyrosine and inducible serine/threonine kinases, the transcription factor TBP and a number of zinc-finger transcriptional repressors. The interaction of K protein with some of its protein partners is modulated by nucleic acids and K protein can alter the in vivo and in vitro rate of transcription . K protein can simultaneously engage several proteins and may facilitate molecular cross-talk. Taken together these diverse interactions suggest that K protein may act as a nucleic acid-regulated docking platform. © 1997 Federation of European Biochemical Societies.
150 citations
TL;DR: Gab1 is the major phosphorylation-substrate of the Met receptor and of its oncogenic variant Tpr-Met, which requires binding of Grb2 and correlates with the transforming potential of TPR-Met.
Abstract: Activation of the HGF receptor, encoded by the c-MET protooncogene (Met receptor), triggers motility, matrix-invasion and branching morphogenesis in epithelial cells. It has recently been shown that the Met receptor interacts with Gab-1, an IRS-like adaptor protein, via the docking site (Y1349VHVNATY1356VNV) known to bind Grb2 and multiple SH2-containing signal transducers. Here we show that Gab1 is the major phosphorylation-substrate of the Met receptor and of its oncogenic variant Tpr-Met. A series of point mutations in the docking site established a direct correlation between the ability to recruit and phosphorylate Gab1 and the transforming potential. Interestingly, the mutations of either Y1356 or N1358 abolished the binding of both Grb2 and Gab1 in intact cells. Furthermore, peptides designed to block either the SH2 or the SH3 domains of Grb2 interfered with the receptor-Gab1 interaction. These data indicate that Gab1 coupling to the Met receptor requires binding of Grb2 and correlates with the transforming potential of Tpr-Met.
140 citations
TL;DR: The docking section of CASP2 is reviewed, finding no single docking method seemed to consistently perform best and the predictions closest to the experimental results were not always those ranked the highest, pointing out that the evaluation of potential solutions is still an area that needs improvement.
Abstract: The docking section of CASP2 is reviewed. Seven small molecule ligand–protein targets and one protein–protein target were available for predictions. Many of the small molecule ligand complexes involved serine proteases. Overall results for the small molecule targets were good, with at least one prediction for each target being within 3 A root-mean-square deviation (RMSD) for nearly all targets and within 2 A RMSD for over half the targets. However, no single docking method seemed to consistently perform best. In addition, the predictions closest to the experimental results were not always those ranked the highest, pointing out that the evaluation (scoring) of potential solutions is still an area that needs improvement. The protein–protein target proved more difficult. None of the predictions did well in reproducing the geometry of the complex, although in many cases the interacting surfaces of the two proteins were predicted with reasonable accuracy. This target consisted of two large proteins and, therefore was a demanding target for docking methods. Proteins, Suppl. 1:198–204, 1997. © 1998 Wiley-Liss, Inc.
103 citations
TL;DR: A new method for flexible docking by multicanonical molecular dynamics simulation is presented, applied to the binding of a short proline-rich peptide to a Src homology 3 (SH3) domain, which resulted in only a few predominant binding modes.
TL;DR: A new, combinatorial method for flexible docking of peptides to proteins that allows full rotation around all single bonds of the peptide ligand and around those of a large set of receptor side chains is described.
Abstract: Docking algorithms play an important role in the process of rational drug design and in understanding the mechanism of molecular recognition. An important determinant for successful docking is the extent to which the configurational space (including conformational changes) of the ligand/receptor system is searched. Here we describe a new, combinatorial method for flexible docking of peptides to proteins that allows full rotation around all single bonds of the peptide ligand and around those of a large set of receptor side chains. We have simulated the binding of several viral peptides to murine major histocompatibility complex class I H-2Kb. In addition, we have explored the limits of our method by simulating a complex between calmodulin and an 18-residue long helical peptide from calmodulin-dependent protein kinase IIalpha. The calculated peptide conformations generally matched well with the X-ray structures. Essential information about local flexibility and about residues that are responsible for strong...
TL;DR: The modeling of the CCK-A receptor and the docking of the peptide agonists indicated that their N terminus was connected to the receptor through a strong bond network involving Trp-39 and Gln-40 thus confirming experimental data, an important step toward the complete delineation of the agonist binding site.
TL;DR: Deletion studies show that the N‐terminal half of Sly1p rather than the C‐terminus (harbouring the E532K substitution in Sly1‐20p) is most critical for its binding to Sed5p, which appears to argue for an active rather than an inhibitory role of Sly 1p in vesicle docking.
TL;DR: In this article, a Monte Carlo docking procedure that combines random displacements of the substrate and protein side chains with minimization of the enzyme substrate complex is described and applied to finding the binding mode of the blocked tetrapeptide N-acetyl-Leu-Pro-Phe-methylamide to the FK506 binding protein.
Abstract: A Monte Carlo docking procedure that combines random displacements of the substrate and protein side chains with minimization of the enzyme)substrate complex is described and applied to finding the binding mode of the blocked tetrapeptide N-acetyl-Leu-Pro-Phe-methylamide to the FK506 binding protein .FKBP . The tetrapeptide, an analog of the preferred FKBP substrate, and the FKBP binding site are flexible during the docking procedure. The twisted-imide transition-state form of the substrate is used during docking. The enzyme charges are scaled individually to account for solvent screening of specific binding site residues during the Monte Carlo sampling. To evaluate the relative binding free energies of the resulting structures, a rapid method for calculating polar and nonpolar solvation effects is introduced. Accurate electrostatic solute)solvent energies are calculated by solving the finite-difference linearized Poisson)Boltzmann equation; nonpolar contributions to the stability of the different conformers are estimated by the free energy of cavity formation, which is obtained from the molecular surface, and the solute)solvent van der Waals energy, which is calculated with a continuum approach. In the conformation of the enzyme)substrate complex with the lowest free energy, the tetrapeptide is bound as a type VIa proline turn with solvent accessible ends to permit longer polypeptide chains to act as substrates. Except for the imide carbonyl, which is involved in polar interactions with aromatic side chains of the FKBP binding
01 Jan 1997
TL;DR: A comparison of the use of the genetic algorithm with lo cal search in Autodock and the results are done in terms of optimization success and absolute success in nding the true physical docked con guration.
Abstract: Molecular docking software makes compu tational predictions of the interaction of molecules This can be useful for example in evaluating the binding of candidate drug molecules to a target molecule from a virus In the Autodock docking software a phys ical model is used to evaluate the energy of candidate docked con gurations and heuristic search is used to minimize this energy Pre vious versions of Autodock used simulated an nealing to do this heuristic search We eval uate the use of the genetic algorithm with lo cal search in Autodock We investigate several GA local search GA LS hybrids and compare results with those obtained from simulated an nealing This comparison is done in terms of optimization success and absolute success in nding the true physical docked con guration We use these results to test the energy function and evaluate the success of the application
TL;DR: A simulation procedure based on molecular dynamics has been developed for modeling the interaction of peptides with n-alkylsilica reversed phase chromatographic sorbents and it is demonstrated that the partial helical chara...
Abstract: A simulation procedure based on molecular dynamics has been developed for modeling the interaction of peptides with n-alkylsilica reversed phase chromatographic sorbents. A four-step docking procedure was used which included the following stages: (1) interactive rigid-body docking of the peptide with an n-butylsilica sorbent using amino acid hydrophobicity coefficients to direct the orientation; (2) automated rigid-body docking by a Monte Carlo simulated annealing procedure in the space of six orientational parameters; (3) solvation of the peptide−sorbent complex with water, and (4) automated docking by molecular dynamics simulated annealing in the full Cartesian coordinate space. The procedure has been validated with the simulation of the binding of the peptide bombesin to an n-butylsilica C4 sorbent. The results were analyzed in terms of the change in conformation of both the n-butyl ligand chains and the peptide solute following peptide docking. These studies demonstrate that the partial helical chara...
TL;DR: The antimalarial activity of a series of synthetic 1,2,4-trioxanes is correlated with molecular structure by using a pharmacophore search method (CATALYST), and docking between an active trioxane and the receptor, heme, is the crucial step for drug action.
Abstract: The antimalarial activity of a series of synthetic 1,2,4-trioxanes is correlated with molecular structure by using a pharmacophore search method (CATALYST). The technique is shown to have predictive accuracy and confirms that docking between an active trioxane and the receptor, heme, is the crucial step for drug action.
TL;DR: It snows that there may be a calcium-binding site in the extracellular N terminus of this receptor, and the results of modeling agree well with experimental QSAR studies.
Abstract: A three-dimensional model of human cannabinoid receptor is constructed using computer-aided molecular modeling techniques. The helices of bacteriorhodopsin were used as the initial template to construct the transmembrane helices. The extracellular and intracellular loops were added using the SYBYL molecular modeling package. The extracellular N terminus was modeled on the basis of its similarity to rat oncomodulin. Similarly, the C terminus was constructed on the basis of similarity to bovine prothrombin fragment J. The final structure was refined by several runs of minimization and dynamics calculation using the CHARMm package. Δ9-Tetra hydrocannabinol was docked into the int'mal cavity using the AUTODOCK program. Our study snows that there may be a calcium-binding site in the extracellular N terminus of this receptor. The ligand binds mainly to a hydrophobic site, which consists of residues Met-240, Trp-241 (TMH-4), Trp-356, Leu-359, Leu-360 (TMH-6), and Ala-283 (TMH-5). Its phenolic hydroxyl group forms a hydrogen bond with the carboxy group of Ala-198 (TMH-3). The results of modeling agree well with experimental QSAR studies.
TL;DR: The study has provided insights into structure-activity relationships for use in the design of modified inhibitors of DHFR, and binding affinities of the different ligands in each binding site have been correlated with experimental dissociation constants.
Abstract: Orientations of the deazapterin ring and the conformational preferences of groups appended to the deazapterin ring in a set of 8-substituted deazapterin cations docked into the dihydrofolate reductase (DHFR) binding site have been investigated using a methodology based on the simulated annealing technique within molecular dynamics (MD) simulations. Of five possible binding pockets for the 8-substituents, identified from a preliminary manual docking study, one has been definitively eliminated after an analysis of MD trajectories, while another remains uncertain. Using a new method based on standard thermodynamic cycles and a linear approximation of polar and non-polar free energy contributions from MD averages, binding affinities of the different ligands in each binding site have been correlated with experimental dissociation constants. The study has provided insights into structure-activity relationships for use in the design of modified inhibitors of DHFR.
TL;DR: To investigate glucoamylase interaction with the monosaccharides D‐glucose, D‐mannose, and D‐galactose and with the substrate analogues 1‐deoxynojirimycin,D‐glucono‐1,5‐lactone, and methyl αacarviosinide, MM3(92)‐optimized structures were docked into its active site using AutoDock 2.1.
Abstract: Glucoamylase is an important industrial glucohydrolase with a large specificity range. To investigate its interaction with the monosaccharides D-glucose, D-mannose, and D-galactose and with the substrate analogues 1-deoxynojirimycin, D-glucono-1,5-lactone, and methyl alpha-acarviosinide, MM3(92)-optimized structures were docked into its active site using AutoDock 2.1. The results were compared to structures of glucoamylase complexes obtained by protein crystallography. Charged forms of some substrate analogues were also docked to assess the degree of protonation possessed by glucoamylase inhibitors. Many forms of methyl alpha-acarviosinide were conformationally mapped by using MM3(92), characterizing the conformational pH dependence found for the acarbose family of glucosidase inhibitors. Their significant conformers, representing the most common states of the inhibitor, were used as initial structures for docking. This constitutes a new approach for the exploration of binding modes of carbohydrate chains. Docking results differ slightly from x-ray crystallographic data, the difference being of the order of the crystallographic error. The estimated energetic interactions, even though agreeing in some cases with experimental binding kinetics, are only qualitative due to the large approximations made by AutoDock force field.
TL;DR: It is suggested that binding site shape and lipophilic character are key determinants of GST isozyme selectivity for close GSH analogues for close glutathione S‐transferases.
Abstract: Glutathione S-transferases (GST, E.C.2.5.1.18) comprise a family of detoxification enzymes. Elevated levels of specific GST isozymes in tumor cells are thought responsible for resistance to chemotherapeutics, which renders selective GST inhibitors potentially useful pharmaceutical agents. We discuss the development of a structure activity model that rationalizes the isozyme selectivity observed in a series of 12 glutathione (GSH) analogues. Enzymatic activity data was determined for human P1-1, A1-1, and M2-2 isozymes, and these data were then considered in light of structural features of these three GST proteins. A survey of all GST structures in the PDB revealed that GSH binds to these proteins in a single “bioactive” conformation. To focus on differences between binding sites, we exploited our finding of a common GSH conformation and aligned the GST x-ray structures using bound ligands rather than the backbones of the different proteins. Once aligned, binding site lipophilicity and electrostatic potentials were computed, visualized, and compared. Docking and energy minimization exercises provided additional refinements to a model of selectivity developed initially by visual analysis. Our results suggest that binding site shape and lipophilic character are key determinants of GST isozyme selectivity for close GSH analogues. Proteins 28:202–216, 1997. © 1997 Wiley-Liss Inc.
TL;DR: A mutation at the surface of the substrate access channel which dramatically decreases the affinity for some fatty acids in P450BM‐3 was discovered by random mutagenesis and the P25Q mutant displays an affinity for palmitate which is approximately 100‐fold weaker than the wild‐type enzyme.
TL;DR: It is hoped that a proper account of the most important enzyme-inhibitor interactions revealed by this study will allow, in the future, the design of new lead compounds having structures unrelated to carboxylic acids.
TL;DR: An anti-estradiol antibody with improved specificity is searched for by combining steroid analog binding studies, mutant antibodies obtained from a phage-display library and structural modeling.
TL;DR: In this article, low energy conformers of analogues of the disaccharide isomaltose were determined with MM3(92) and were then flexibly docked into the glucoamylase active site using AutoDock 2.1.
TL;DR: The predicted conformations of recognition tripeptide and tetrapeptide sequences are also in structural harmony and composed of peptide fragments that are individually unfrustrated in their bound conformation, resulting in a minimally frustrated energy landscape for recognition peptides.
Abstract: Computational structure prediction of streptavidin-peptide complexes for known recognition sequences and a number of random di-, tri-, and tetrapeptides has been conducted, and mechanisms of peptide recognition with streptavidin have been investigated by a new computational protocol. The structural consensus criterion, which is computed from multiple docking simulations and measures the accessibility of the dominant binding mode, identifies recognition motifs from a set of random peptide sequences, whereas energetic analysis is less discriminatory. The predicted conformations of recognition tripeptide and tetrapeptide sequences are also in structural harmony and composed of peptide fragments that are individually unfrustrated in their bound conformation, resulting in a minimally frustrated energy landscape for recognition peptides.
TL;DR: The kinetic mechanism for the binding of NAD+ and NADH to the EE and SS isozymes of alcohol dehydrogenase (LADH) was studied between pH 7 and pH 10 by monitoring the quenching of tryptophan fluorescence and a pH dependence for NADH binding is observed.
Abstract: The kinetic mechanism for the binding of NAD+ and NADH to the EE and SS isozymes of alcohol dehydrogenase (LADH) was studied between pH 7 and pH 10 by monitoring the quenching of tryptophan fluorescence. A consistent interpretation of all data was only possible by introducing a two-step binding mechanism. The first binding step is related to docking of the adenosine part of the coenzymes and the subsequent isomerization to the binding of the nicotinamide part. At high NADH concentrations an additional slow isomerization was identified as a conformational transition of the protein. A pH dependence for NADH binding is observed which is restricted to changes in the binding kinetics of the adenosine moiety going from pH 7 to pH 10, a tendency which is similar also for NAD+. This is attributed to pH-dependent variations in electrostatic attractions acting as a steering force of the docking process. The nicotinamide docking of NADH is equally fast for both isozymes and pH-independent over the measured range, whereas this docking equilibrium for NAD+ is pH-dependent for EE- and SS-LADH alike and the rate of association comparable. Presumably, a GluEE-366-LysSS substitution results in a stronger binding and faster association of both oxidized and reduced cofactor to the SS isozyme. A structural proof is presented for coenzyme-competitive binding of a sulfate ion, resulting in electrostatic shielding.
TL;DR: It was found for both superantigens that docking the HLA‐DR1 surface complementary with the SEB and TSST‐1 contact regions containing a homologous hydrophobic surface loop provided sufficient recognition for the reconstitution of native‐like conformers exhibiting the highest‐scoring free energies.
Abstract: The molecular recognition of two superantigens with class II major histocompatibility complex molecules was simulated by using protein– protein docking. Superantigens studied were staphylococcal enterotoxin B (SEB) and toxic shock syndrome toxin-1 (TSST-1) in their crystallographic assemblies with HLA-DR1. Rigid-body docking was performed sampling configurational space of the interfacial surfaces by employing a strategy of partitioning the contact regions on HLA-DR1 into separate molecular recognition units. Scoring of docked conformations was based on an electrostatic continuum model evaluated with the finite-difference Poisson– Boltzmann method. Estimates of nonpolar contributions were derived from the buried molecular surface areas. We found for both superantigens that docking the HLA-DR1 surface complementary with the SEB and TSST-1 contact regions containing a homologous hydrophobic surface loop provided sufficient recognition for the reconstitution of native-like conformers exhibiting the highest-scoring free energies. For the SEB complex, the calculations were successful in reproducing the total association free energy. A comparison of the free-energy determinants of the conserved hydrophobic contact residue indicates functional similarity between the two proteins for this interface. Though both superantigens share a common global association mode, differences in binding topology distinguish the conformational specificities underlying recognition. © 1998 John Wiley & Sons, Ltd.
TL;DR: Structure Activity Relationship and docking studies focused on the role of the non-aromatic ° address in a novel class of potent and selective ligands, pyrrolooctahydroisoquinolines, are discussed in this paper.