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At least 811 records · Page 45Linked to original sources
PubMed2002

Boar salivary lipocalin. Three-dimensional X-ray structure and androsterol/androstenone docking simulations.

The X-ray structure of variant A of authentic boar salivary lipocalin (SAL), a pheromone-binding protein specifically expressed in the submaxillary glands of the boar, has been solved and refined at 2.1 A resolution. The structure displays a classical lipocalin fold with a nine-stranded sandwiched beta barrel and an alpha helix. A putative glycosylation site, at position 53, has been found to carry a GlcNAc sugar residue. In contrast with what was expected on the basis of mass spectroscopy reports, the internal cavity was found to be devoid of bound pheromonal compound (androstenone or androstenol). Instead, a small electron density volume could be satisfied by a glycerol molecule, a component of the cryoprotecting liquor. The internal cavity was revealed to be very small for steroid compound accommodation. Therefore, docking and molecular dynamics experiments were performed with both pheromonal compounds. These simulations clearly demonstrate a volume increase of the cavity upon steroid binding and the adaptation of the amino-acid side chains to the steroid molecules. This explains the higher affinity of SAL for both steroid molecules compared to other smaller molecules, although no specific interaction is established with either compound.

Amino Acid Sequence↗
PubMed2000

Novel carbohydrate binding site recognizing blood group A and B determinants in a hybrid of cholera toxin and Escherichia coli heat-labile enterotoxin B-subunits.

The B-subunits of cholera toxin (CTB) and Escherichia coli heat-labile enterotoxin (LTB) are structurally and functionally related. However, the carbohydrate binding specificities of the two proteins differ. While both CTB and LTB bind to the GM1 ganglioside, LTB also binds to N-acetyllactosamine-terminated glycoconjugates. The structural basis of the differences in carbohydrate recognition has been investigated by a systematic exchange of amino acids between LTB and CTB. Thereby, a CTB/LTB hybrid with a gain-of-function mutation resulting in recognition of blood group A and B determinants was obtained. Glycosphingolipid binding assays showed a specific binding of this hybrid B-subunit, but not CTB or LTB, to slowly migrating non-acid glycosphingolipids of human and animal small intestinal epithelium. A binding-active glycosphingolipid isolated from cat intestinal epithelium was characterized by mass spectrometry and proton NMR as GalNAcalpha3(Fucalpha2)Galbeta4(Fucalpha3)Glc NAcbeta3Galbeta4Glc NAcbeta3Galbeta4Glcbeta1Cer. Comparison with reference glycosphingolipids showed that the minimum binding epitope recognized by the CTB/LTB hybrid was Galalpha3(Fucalpha2)Galbeta4(Fucalpha3)GlcNAc beta. The blood group A and B determinants bind to a novel carbohydrate binding site located at the top of the B-subunit interfaces, distinct from the GM1 binding site, as found by docking and molecular dynamics simulations.

ABO Blood-Group System↗
PubMed2002

Models@Home: distributed computing in bioinformatics using a screensaver based approach.

MOTIVATION: Due to the steadily growing computational demands in bioinformatics and related scientific disciplines, one is forced to make optimal use of the available resources. A straightforward solution is to build a network of idle computers and let each of them work on a small piece of a scientific challenge, as done by Seti@Home (http://setiathome.berkeley.edu), the world's largest distributed computing project. RESULTS: We developed a generally applicable distributed computing solution that uses a screensaver system similar to Seti@Home. The software exploits the coarse-grained nature of typical bioinformatics projects. Three major considerations for the design were: (1) often, many different programs are needed, while the time is lacking to parallelize them. Models@Home can run any program in parallel without modifications to the source code; (2) in contrast to the Seti project, bioinformatics applications are normally more sensitive to lost jobs. Models@Home therefore includes stringent control over job scheduling; (3) to allow use in heterogeneous environments, Linux and Windows based workstations can be combined with dedicated PCs to build a homogeneous cluster. We present three practical applications of Models@Home, running the modeling programs WHAT IF and YASARA on 30 PCs: force field parameterization, molecular dynamics docking, and database maintenance.

Computational Biology↗
PubMed2006

N-methylpurine DNA glycosylase and 8-oxoguanine dna glycosylase metabolize the antiviral nucleoside 2-bromo-5,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole.

The rapid in vivo degradation of the potent human cytomegalovirus inhibitor 2-bromo-5,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole (BDCRB) compared with a structural L-analog, maribavir (5,6-dichloro-2-(isopropylamino)-1-beta-L-ribofuranosyl-1H-benzimidazole), has been attributed to selective glycosidic bond cleavage. An enzyme responsible for this selective BDCRB degradation, however, has not been identified. Here, we report the identification of two enzymes, 8-oxoguanine DNA glycosylase (OGG1) and N-methylpurine DNA glycosylase (MPG), that catalyze N-glycosidic bond cleavage of BDCRB and its 2-chloro homolog, 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole, but not maribavir. To our knowledge, this is the first demonstration that free nucleosides are substrates of OGG1 and MPG. To understand how these enzymes might process BDCRB, docking and molecular dynamics simulations were performed with the native human OGG1 crystal coordinates. These studies showed that OGG1 was not able to bind a negative control, guanosine, yet BDCRB and maribavir were stabilized through interactions with various binding site residues, including Phe319, His270, Ser320, and Asn149. Only BDCRB, however, achieved orientations whereby its anomeric carbon, C1', could undergo nucleophilic attack by the putative catalytic residue, Lys249. Thus, in silico observations were in perfect agreement with experimental observations. These findings implicate DNA glycosylases in drug metabolism.

Antiviral Agents↗
PubMed1996

Molecular machinery mediating vesicle budding, docking and fusion.

A general machinery buds and fuses transport vesicles which connect intracellular compartments with each other and allow communication with the extracellular environment. Cytoplasmic coat proteins deform membranes to bud vesicles and interact directly or indirectly with cargo molecules. Compartment-specific SNAREs on vesicles and target membranes dock vesicles and provide a scaffolding for the general fusion machinery to initiate lipid bilayer fusion.

Animals↗
PubMed2005

Orientational dynamics and dye-DNA interactions in a dye-labeled DNA aptamer.

We report the picosecond and nanosecond timescale rotational dynamics of a dye-labeled DNA oligonucleotide or "aptamer" designed to bind specifically to immunoglobulin E. Rotational dynamics in combination with fluorescence lifetime measurements provide information about dye-DNA interactions. Comparison of Texas Red (TR), fluorescein, and tetramethylrhodamine (TAMRA)-labeled aptamers reveals surprising differences with significant implications for biophysical studies employing such conjugates. Time-resolved anisotropy studies demonstrate that the TR- and TAMRA-aptamer anisotropy decays are dominated by the overall rotation of the aptamer, whereas the fluorescein-aptamer anisotropy decay displays a subnanosecond rotational correlation time much shorter than that expected for the overall rotation of the aptamer. Docking and molecular dynamics simulations suggest that the low mobility of TR is a result of binding in the groove of the DNA helix. Additionally, associated anisotropy analysis of the TAMRA-aptamer reveals both quenched and unquenched states that experience significant coupling to the DNA motion. Therefore, quenching of TAMRA by guanosine must depend on the configuration of the dye bound to the DNA. The strong coupling of TR to the rotational dynamics of the DNA aptamer, together with the absence of quenching of its fluorescence by DNA, makes it a good probe of DNA orientational dynamics. The understanding of the nature of dye-DNA interactions provides the basis for the development of bioconjugates optimized for specific biophysical measurements and is important for the sensitivity of anisotropy-based DNA-protein interaction studies employing such conjugates.

Anisotropy↗
PubMed2000

Nonconventional amide bond formation catalysis: programming enzyme specificity with substrate mimetics.

This article reports on the design and characteristics of substrate mimetics in protease-catalyzed reactions. Firstly, the basis of protease-catalyzed peptide synthesis and the general advantages of substrate mimetics over common acyl donor components are described. The binding behavior of these artificial substrates and the mechanism of catalysis are further discussed on the basis of hydrolysis, acyl transfer, protein-ligand docking, and molecular dynamics studies on the trypsin model. The general validity of the substrate mimetic concept is illustrated by the expansion of this strategy to trypsin-like, glutamic acid-specific, and hydrophobic amino acid-specific proteases. Finally, opportunities for the combination of the substrate mimetic strategy with the chemical solid-phase peptide synthesis and the use of substrate mimetics for non-peptide organic amide synthesis are presented.

Acyltransferases↗
PubMed2002

Substrate mimetics in protease catalysis: characteristics, kinetics, and synthetic utility.

This article reviews the latest developments in protease-catalyzed peptide synthesis focusing on the use of substrate mimetics. The substrate mimetics approach takes advantage of the characteristic of this novel type of substrates to direct the enzyme to recognize an alternative site on the acyl donor, i.e. the site-specific ester leaving group, mediating the acceptance of originally poorly reactive acyl moieties. At first the kinetics and catalytic mechanism of substrate mimetics-mediated reactions are discussed on the basis of hydrolysis, peptide synthesis, protein-ligand docking, and molecular dynamics studies. By the example of the Glu-specific V8 protease and the aromatic amino acid-specific chymotrypsin both the empirical and computer-aided design of specific substrate mimetics is described. The influence of the leaving group specifically recognized by the enzyme is also considered. The benefits of these artificial substrates over common acyl donor components are illustrated by selected synthesis reactions of small peptides, peptide isosteres, non-peptidic carboxylic acid amides, and the coupling of peptide fragments at non-specific ligation sites resulting in biologically active peptide products. Finally, this review focuses on critical syntheses that uses specific-amino acid-containing peptides as the reactants of ligation. Based on these, the restrictions of the substrate mimetics approach is critically discussed and techniques to their overcoming are presented.

Acylation↗
PubMed2004

Using bradykinin-potentiating peptide structures to develop new antihypertensive drugs.

Angiotensin I-converting enzyme (ACE) is a dipeptidyl-carboxypeptidase expressed in endothelial, epithelial and neuroepithelial cells. It is composed of two domains, known as N- and C-domains, and it is primarily involved in blood pressure regulation. Although the physiological functions of ACE are not limited to its cardiovascular role, it has been an attractive target for drug design due to its critical role in cardiovascular and renal disease. We examined natural structures based on bradykinin-potentiating peptides (BPPs) extracted from Bothrops jararaca venom for ACE inhibition. Modeling, docking and molecular dynamics were used to study the conserved residues in the S2', S1' and S1 positions that allow enzyme-substrate/inhibitor contacts. These positions are conserved in other oligopeptidases, and they form tight and non-specific contacts with lisinopril, enalapril and BPP9a inhibitors. The only specific inhibitor for human somatic ACE (sACE) was BPP9a, which is instable in the N-sACE-BPP9a complex due to repulsive electrostatic interactions between Arg P4-Arg 412 residues. Specificity for the C-terminal domain in human sACE inhibition was confirmed by electrostatic interaction with the Asp 1008 residue. Peptide-like BPP structures, naturally developed by snakes across millions of years of evolution, appear to be good candidates for the development of domain-selective ACE inhibitors with high stability and improved pharmacological profiles.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1993

Proposed atomic structure of a truncated human immunodeficiency virus glycoprotein gp120 derived by molecular modeling: target CD4 recognition and docking mechanism.

The atomic structure of a truncated glycoprotein gp120 from human immunodeficiency virus 1 (HIV-1) that contains the principal neutralizing antigenic sites and the CD4 binding domain has been derived by molecular dynamics and calculation of potential energy using the DREIDING force field. The resultant N-glycosylated molecular model is consistent with known properties of gp120 and docks with CD4 with a substantial reduction in the sum of the internal potential energies of the individual proteins (delta E = -200 kcal/mol). The primary mechanism of recognition and binding is the insertion of the solvent-accessible Phe-43 of CD4 into a gp120 solvent-accessible acceptor pit formed by Trp-427, Tyr-435, and the high-mannose oligosaccharide N-linked to Asn-230. delta E for the nonglycosylated complex is reduced significantly (-75 kcal/mol). Binding is by pi-pi* interactions of the aromatic groups forming a hydrophobic, thermodynamically stable environment for these functional noncovalent bonding participants. This model for gp120 provides a theoretical basis for the evaluation of HIV molecular pathogenesis involving the env proteins, the analysis of conformation on functional immune response of the host, and the design of nonproteinaceous inhibitors specific for the CD4 binding site on gp120.

Amino Acid Sequence↗
PubMed1999

Efficient computational algorithms for docking and for generating and matching a library of functional epitopes I. Rigid and flexible hinge-bending docking algorithms.

In this, and the next review article (1), we present highly efficient, computer-vision and robotics based algorithms for docking and for the generation and matching of epitopes on molecular surfaces. We start with descriptions of molecular surfaces, and proceed to utilize these in both rigid-body and flexible matching routines. These algorithms originate in the computer vision and robotics disciplines. Frequently used approaches, both in searches for molecular similarity and for docking, i.e., molecular complementarity, strive to obtain highly accurate correspondence of respective molecular surfaces. However, owing to molecular surface variability in solution, to mutational events, and to the need to use modeled structures in addition to high resolution ones, utilization of epitopes might prove to be a judicious approach to follow. Furthermore, through the deployment of libraries of epitopes which represent recurring features, or motifs in a given family of receptors or of enzymes, in principle we a priori focus on the more critical groups of atoms, or amino acids, essential for the binding of the two molecules. Utilization of recurring motifs may prove more robust than single molecule matchings. In addition, via utilization of epitopes one can make use of information derived from evolutionary related molecules. All of the above combine to represent an approach which may be highly advantageous. Combinatorial approaches have proven their immense utility in the wet laboratory. The combination of efficient computational approaches and the utilization of such libraries may well be particularly profitable. Our highly efficient techniques are amenable to such a task. In this review we focus on rigid and flexible docking algorithms. In the second review (1) we address the generation of epitopes in families of molecules. These may be used by the docking algorithms to identify the more likely bound interfaces.

Algorithms↗
PubMed2000

A method for including protein flexibility in protein-ligand docking: improving tools for database mining and virtual screening.

Second-generation methods for docking ligands into their biological receptors, such as FLOG, provide for flexibility of the ligand but not of the receptor. Molecular dynamics based methods, such as free energy perturbation, account for flexibility, solvent effects, etc., but are very time consuming. We combined the use of statistical analysis of conformational samples from short-run protein molecular dynamics with grid-based docking protocols and demonstrated improved performance in two test cases. Our statistical analysis explores the importance of the average strength of a potential interaction with the biological target and optionally applies a weighting depending on the variability in the strength of the interaction seen during dynamics simulation. Using these methods, we improved the num-top-ranked 10% of a database of drug-like molecules, in searches based on the three-dimensional structure of the protein. These methods are able to match the ability of manual docking to assess likely inactivity on steric grounds and indeed to rank order ligands from a homologous series of cyclooxygenase-2 inhibitors with good correlation to their true activity. Furthermore, these methods reduce the need for human intervention in setting up molecular docking experiments.

Combinatorial Chemistry Techniques↗
PubMedDate not supplied

Modeling the structural basis of human CCR5 chemokine receptor function: from homology model building and molecular dynamics validation to agonist and antagonist docking.

This article describes the construction and validation of a three-dimensional model of the human CCR5 receptor using a homology-based approach starting from the X-ray structure of the bovine rhodopsin receptor. The reliability of the model is assessed through molecular dynamics and docking simulations using both natural agonists and a synthetic antagonist. Some important structural and functional features of the receptor cavity and the extracellular loops are identified, in agreement with data available from site-directed mutagenesis. The results of this study help to explain the structural basis for the recognition, activation, and inhibition processes of CCR5 and may provide fresh insights for the design of HIV-1 entry blockers.

CCR5 Receptor Antagonists↗
PubMed1995

Conformational analysis of molecular chains using nano-kinematics.

We present algorithms for 3-D manipulation and conformational analysis of molecular chains, when bond lengths, bond angles and related dihedral angles remain fixed. These algorithms are useful for local deformations of linear molecules, exact ring closure in cyclic molecules and molecular embedding for short chains. Other possible applications include structure prediction, protein folding, conformation energy analysis and 3D molecular matching and docking. The algorithms are applicable to all serial molecular chains and make no assumptions about their geometry. We make use of results on direct and inverse kinematics from robotics and mechanics literature and show the correspondence between kinematics and conformational analysis of molecules. In particular, we pose these problems algebraically and compute all the solutions making use of the structure of these equations and matrix computations. The algorithms have been implemented and perform well in practice. In particular, they take tens of milliseconds on current workstations for local deformations and chain closures on molecular chains consisting of six or fewer rotatable dihedral angles.

Algorithms↗
PubMed2004

Molecular determinants of thapsigargin binding by SERCA Ca2+-ATPase: a computational docking study.

Thapsigargin (TG) is a potent and commonly used inhibitor of the ion transport activity of sarco/endoplasmic reticulum Ca2+-ATPases (SERCA). Based on the recently published crystal structures of rabbit muscle SERCA1a in the Ca2+/E1 (E1) and TG/E2 (E2) conformations, we performed computational docking studies to characterize the molecular interactions that govern binding of TG and TG-analogs by the enzyme. Using the program GOLD (genetic optimization for ligand docking) in combination with the scoring function ChemScore, TG was docked into the binding site of the E1 and E2 conformations of SERCA1a. The docking results revealed a consensus ligand-binding mode consistent with the crystal structure and showed that hydrophobic interactions are the primary driving force of TG binding by SERCA. Moreover, it was shown that the conformational changes accompanying the E2 to E1 transition in the enzyme likely displace TG from its favored orientation in the binding site, thereby substantially reducing its binding affinity. This finding illustrates on the molecular level how TG may exert its inhibitory effect in binding tightly to the E2 form and preventing it from converting into its E1 form, a requirement for catalytic function. We also docked 9 TG analogs into the E2 conformation of the enzyme. Eight of the analogs adopted a binding mode very similar to that of TG, whereas one compound preferred a different orientation in the binding site. Analysis of the predicted binding affinities showed a good correlation with the experimentally observed inhibitory potencies of the analogs. Docking was also performed with several modeled mutants of SERCA1a, whose phenylalanine residue in position 256 (Phe256) had been modified. The experimentally observed declines in TG sensitivity in most of the Phe256 mutants was qualitatively accounted for and appears, at least in part, be due to a slightly altered TG-binding mode.

Algorithms↗
PubMed1999

A proposed molecular model for the interaction of calcineurin with the cyclosporin A-cyclophilin A complex.

Cyclosporin A (CsA) and FK506 are potent natural product immunosuppressants that induce their biological effects by forming an initial complex with cytosolic proteins termed immunophilins. These drug immunophilin complexes then bind to and inhibit the serine/threonine protein phosphatase calcineurin (CN). Two classes of immunophilin have been identified with cyclophilins (CyP's) being proteins specifically binding CsA and FKBPs specifically binding FK506. Solution and crystal structures of various CsA-CyP and FK506-FKBP complexes have been determined and show no apparent structural similarity between the two classes of drug protein complexes. These findings raise the question as to how, given their structural differences, these two complexes can both inhibit CN. While the crystal structure of the FK506-FKBP12-CN complex has been reported, no structure for a CsA-CyP CN complex has been determined. Here are reported studies that use various modelling strategies to construct a model for the interaction of the cyclosporin A- cyclophilin A complex with calcineurin. The first stage of constructing this model consisted of using conformational comparison of CsA and FK506, GRID and GROUP analysis and restrained molecular dynamics to dock CsA into the FK506 binding site of the FK506-FKBP12-CN structure. An initial model for the CsA-CyPA-CN complex was then constructed by superimposing the structure of the CsA-CyPA complex onto the docked CsA molecule. This model was then optimised with molecular dynamics simulations run on sterically clashing regions. The validity of the model for the CsA-CyPA-CN complex was then examined with respect to the effect of chemical modifications to CsA and amino acid substitutions within CyPA on the ability of the drug-immunophilin complex to inhibit calcineurin.

Amino Acid Substitution↗
PubMed2026

In silico analysis based on network pharmacology and biomolecular informatics to explore the mechanism of action of Erjing Pills (from Shengji Zonglu) in the treatment of leukotrichia.

This study aimed to explore the core active ingredients and potential molecular mechanisms of Erjing Pills, a prescription in the classic work of Traditional Chinese Medicine, "Shengji Zonglu," in the treatment of leukotrichia by utilizing network pharmacology and biomolecular docking techniques. The chemical components and potential targets of Chinese herbal medicines were analyzed through databases such as the Traditional Chinese Medicine Systems Pharmacology Database. The targets related to leukotrichia were collected using GeneCards. The intersection targets were obtained using RStudio. The protein-protein interaction (PPI) network map and the "drug-component-target-disease" visualization network were generated using Cytoscape and STRING to screen the core components and key targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were carried out using the Database for Annotation, Visualization and Integrated Discovery and RStudio. Finally, molecular docking verification was performed by AutoDock and PyMOL (Schrödinger LLC). The key active ingredients of Erjing Pills in the treatment of leukotrichia are β-sitosterol, quercetin, baicalein, and stigmasterol. The top 5 PPI core target proteins, in order, are AKT serine/threonine kinase 1, interleukin 6, tumor protein p53, cysteine-aspartic acid protease 3, and interleukin 1 beta. The Gene Ontology enrichment analysis suggests that the biological processes mainly include responses to exogenous stimuli, membrane rafts, and DNA-binding transcription factor binding. The Kyoto Encyclopedia of Genes and Genomes pathways involve signal pathways such as lipid and atherosclerosis, hepatitis B, Kaposi sarcoma virus infection, chemical carcinogenesis, and human cytomegalovirus infection. The molecular docking results indicate that most of the main active ingredients in Erjing Pills have relatively stable binding activities with the key targets, such as AKT serine/threonine kinase 1, interleukin 6, tumor protein p53, cysteine-aspartic acid protease 3, and interleukin 1 beta, in the PPI network. The active ingredients of Erjing Pills may interfere with the pathological process of leukotrichia by regulating key targets and signal pathways. This study provides a theoretical basis for the clinical application of Erjing Pills and indicates the direction for subsequent experimental research.

Drugs, Chinese Herbal↗