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At least 127 records · Page 7Linked to original sources

PubMed1993

DNA minor groove recognition properties of pentamidine and its analogs: a molecular modeling study.

A molecular mechanics and molecular dynamics approach has been used to examine the structure of the complex formed between pentamidine and the d(CGCGAATTCGCG)2 duplex. Similar energy calculations have also been performed on complexes with closely related pentamidine analogs, using the complex with the parent drug as the starting point. The resulting structures of the drug-DNA complexes and their energetics have been examined and are compared with the reported DNA binding affinities. These studies provide rationalizations for the differences in binding behavior of pentamidine analogs with differing linker chain lengths and aromatic ring substitutions.

Base Sequence↗

PubMed1994

RNA tertiary structure of the HIV RRE domain II containing non-Watson-Crick base pairs GG and GA: molecular modeling studies.

We have used molecular modeling techniques to model the RNA tertiary structure of the viral RNA element (referred to as domain II of Rev responsive element, RRE) bound by the Rev protein of HIV. In this study, the initial three-dimensional model was built from its established RNA secondary structure, including three non-Watson-Crick G:G, G:A and G:U base pairs. Molecular dynamics (MD) simulations were performed with hydrated or unhydrated sodium ions. Our results indicate that the non-Watson-Crick base pairs in the simulation with unhydrated sodium ions and water are more stable than those with hydrated sodium ions only. The RNA can maintain its compact double helical structure throughout the course of the MD simulations with water and unhydrated sodium ions, although the non-Watson-Crick base pairs and two bulge loops show much more flexibility and conformational distortion than the classical RNA helical region. The distinct distortion of the sugar-phosphate backbone significantly widens the RNA major groove so that the major groove is readily accessible for hydrogen bonding by specific Rev binding. This model emphasizes the importance of specific hydrogen bonding in the stabilization of the three-dimensional structure of the HIV Rev core binding element, not only between the nucleotide bases, but also among the ribose hydroxyls, phosphate anionic oxygens, base oxygens and nitrogens, and bridging water molecules. Moreover, our results suggest that sodium ions play an important role in the formation of base pairs G:G and G:A of the RRE by a manner similar to the arginine of the Rev-RRE complex.

Adenine↗

PubMed1999

Analysis of Fas-ligand interactions using a molecular model of the receptor-ligand interface.

A molecular model of the complex between Fas and its ligand was generated to better understand the location and putative effects of site-specific mutations, analyze interactions at the Fas-FasL interface, and identify contact residues. The modeling study was conservative in the sense that regions in Fas and its ligand which could not be predicted with confidence were omitted from the model to ensure accuracy of the analysis. Using the model, it was possible to map four of five N-linked glycosylation sites in Fas and FasL and to study 10 of 11 residues previously identified by mutagenesis as important for binding. Interactions involving six of these residues could be analyzed in detail and their importance for binding was rationalized based on the model. The predicted structure of the Fas-FasL interface was consistent with the experimentally established importance of these residues for binding. In addition, five previously not targeted residues were identified and predicted to contribute to binding via electrostatic interactions. Despite its limitations, the study provided a much improved basis to understand the role of Fas and FasL residues for binding compared to previous residue mapping studies using only a molecular model of Fas.

Amino Acid Sequence↗

PubMed2002

Molecular modeling as a tool to investigate molecular recognition in P2Y receptors.

Nucleotides are emerging as an ubiquitous family of extracellular signaling molecules. These effects are mediated through a specific class of plasma membrane receptors called P2 receptors that, according to the molecular structure, are further subdivided into two subfamilies: P2Y and P2X. Specifically, P2X-receptors are ligand-gated ion channels, whereas P2Y-receptors belong to the superfamily of G-protein-coupled receptors. In this review, we focus our attention to GPCRs molecular architecture, with the special emphasis on our work on the human P2Y(1) receptor. In fact, despite an enormous amount of research on the structure and function of these receptors, fundamental understanding of the molecular details of ligand/GPCR interactions remains very rudimentary. How agonist binding transforms a resting GPCR into its active form and the microscopic basis of binding site blockade by an antagonist are generally still unclear. In the absence of high-resolution structural knowledge of GPCRs, such questions only can be addressed by building models, which are tested through pharmacological and biochemical studies. In this review, we underline how different molecular modeling approaches can help the investigation of both receptor architecture and ligand/receptor molecular recognition.

Amino Acid Sequence↗

PubMed1988

Molecular modeling and dynamics of neuropeptide Y.

A combination of molecular modeling and molecular dynamics (MD) is used to determine a theoretical structure for neuropeptide Y (NPY). Starting with the X-ray structure for avian pancreatic polypeptide (APP), the substituted amino acids were mutated, the side chains oriented to local potential energy minima, and the entire structure minimized and subjected to an MD simulation. Comparison of the resulting NPY structure with APP X-ray and MD results showed secondary structural elements to be maintained and RMS fluctuations to be similar, although differences in both were observed. The approach presented offers a means to study the structure-function relationships of NPY and other similar polypeptides when combined with pharmacological measurements.

Computer Simulation↗

PubMed1999

The complement regulator C4b-binding protein analyzed by molecular modeling, bioinformatics and computer-aided experimental design.

Molecular modeling and bioinformatics have gained recognition as scientific disciplines of importance in the field of biomedical research. Molecular modeling not only allows to predict the three-dimensional structure of a protein but also helps to define its function. Careful incorporation of the experimental findings in the structural/theoretical data provides means to understand molecular mechanisms for highly complex biological systems. C4b-binding protein (C4BP) is composed of one beta-chain and seven alpha-chains essentially built from three- and eight-complement control protein (CCP) modules, respectively, followed by a non-repeat carboxy-terminal region involved in polymerization of the chains. C4BP is involved in the regulation of the complement system and interacts with many molecules such as C4b, Arp, protein S and heparin. Here, we report experimental and computer data obtained for C4BP. Protein modeling together with site directed mutagenesis indicate that R39, R64 and R66 from the C4BP alpha-chain form a key binding site for heparin, suggesting that this region could be of major importance for interaction with C4b. We also propose that the first CCP of the C4BP beta-chain displays a key hydrophobic surface of major importance for the interaction with the coagulation cofactor protein S.

Complement C4b↗

PubMed2005

Homology modeling of the DNA-binding domain of human Smad5: a molecular model for inhibitor design.

Members of the Smad protein family function as signal transducers of the transforming growth factor (TGF-beta) superfamily proteins. The human Smad5 protein, a signal transducer downstream of TGF-beta/BMP receptors, is composed of N-terminal DNA binding domain (MH1) and C-terminal protein-protein interaction domain (MH2) connected together by a linker motif. We used homology-modeling techniques to generate a reliable molecular model of the Smad5 MH1 domain based on the crystal structure of Smad3 MH1 domain. Our study presents the structural features of a BMP-regulated, R-Smad subfamily member (consisting of Smad1, Smad5 and Smad8) for the first time. This model provides a structural basis for explaining both functional similarities and differences between Smad3 and Smad5. Also, the structural model of this molecular target would be useful for structure-based inhibitor design because of its high accuracy. The results of our study provide important insights into understanding the structure-function relationship of the members of the Smad protein family and can serve to guide future genetic and biochemical experiments in this area.

Amino Acid Sequence↗

PubMed1996

Molecular modelling of Staphylococcal delta-toxin ion channels by restrained molecular dynamics.

Delta-Toxin is a 26-residue channel-forming peptide from Staphylococcus aureus which forms an amphipathic alpha-helix in a membrane environment. Channel formation in planar bilayers suggests that an average of six delta-toxin helices self-assemble to form transbilayer pores. Molecular models for channels formed by delta-toxin and by a synthetic analogue have been generated using a simulated annealing protocol applied via restrained molecular dynamics. These models are analysed in terms of the predicted geometric and energetic properties of the transbilayer pores. Pore radius calculations of the models demonstrate that rings of channel-lining residues contribute a series of constrictions along the pore. Electrostatic properties of the pores are determined both by pore-lining charged side chains and by the aligned helix dipoles of the parallel helix bundle. Molecular dynamics simulations (100 ps) of delta-toxin models containing intra-pore water were performed. Analysis of the resultant dynamics trajectories further supports the proposal that alternative conformations of pore-constricting side chains may be responsible for the observed conductance heterogeneity of delta-toxin ion channels.

Amino Acid Sequence↗

PubMed2003

Developing the molecular modelling of diffusion in zeolites as a high throughput catalyst screening technique.

Molecular modelling techniques have been used to screen zeolite catalysts for their suitability for organic synthesis. For example, we have used these techniques to study the alkylation of aromatic molecules which are important in the fine-chemical and drug industries. A survey of all such efforts is reviewed in this article. The application of molecular modelling techniques in a systematic manner is an efficient first step in the design of zeolite catalysts. As a qualitative screening tool, molecular graphics is used to visualize how well the reactant and product molecules fit inside the pores of the zeolites. Using a hybrid of several molecular modelling methods, which combines molecular dynamics (MD) and Monte Carlo methods with energy minimization, it is possible to determine the minimum energy locations of the molecules inside the zeolites cages. The minimum energy configurations determined by this hybrid method are taken as a starting point for diffusion of the molecules through the zeolite channels. When a molecule is allowed to diffuse through zeolite channel, the molecule attains some maxima and minima in its diffusion energy profile. From the differences between a maximum and a minimum energy configuration, the diffusion energy barrier for the molecule can be calculated in the zeolites. By comparing the diffusion energy barriers for various isomers of a molecule in different zeolites, it is possible to find out the most suitable zeolite for achieving the required shape-selectivity. In addition, factors influencing the diffusivity of the molecules and consequently the shape selectivity are derived. The list of factors and their relative importance are analysed to derive valuable guidelines to design shape-selective zeolite catalysts for a given reaction. Thus, the ultimate aim of these studies is to develop a high throughput computational screening process for the selection of shape-selective zeolite catalysts for various reactions. The dynamic behaviour of molecules inside the pores of zeolites can be studied using MD methods. Since MD is computationally time consuming, it is more efficient to screen the possible zeolite catalysts by energy minimization methods and then perform MD in specific zeolites. More accurate values of diffusivity of the molecules can be calculated using MD methods, and these values can be correlated with the shape-selectivity observed experimentally and /or derived from diffusion energy barrier calculations.

Catalysis↗

PubMed1996

Molecular modeling of azole antifungal agents active against Candida albicans. 1. A comparative molecular field analysis study.

A series of 56 azole antifungal agents belonging to chemically diverse families related to bifonazole, one of the antimycotic drugs of clinical use, were investigated using the comparative molecular field analysis (CoMFA) paradigm. The studied compounds, which have been already synthesized and reported to be active in vitro against Candida albicans, were divided into a training set and a test set. The training set consisted of 40 molecules from all the different structural classes. Due to the lack of experimental structural data on these derivatives, molecular mechanics techniques were used to obtain putative active conformations for all the compounds. the correctness of this molecular modeling work was confirmed a posteriori by comparison with structural data of the analog 2w obtained by X-ray crystallographic analysis (Massa, S.; et al. Eur. J. Med. Chem. 1992, 27, 495-502). Two different alignment rules of the training set molecules were used in this study and are based on the assumption that according to published results on azole antifungal agents, all the studied compounds exert their inhibitory activity through the coordination of their azole moiety to the protoporphyrin iron atom of the fungal lanosterol 14alpha-demethylase enzyme. The predictive ability of each resultant CoMFA model was evaluated using a test set consisting of 16 representative compounds that belong to all the different structural classes. The best 3D-quantitative structure-activity relationship model found yields significant cross-validated, conventional, and predictive r2 values equal to 0.57, 0.95, and 0.69, respectively. The average absolute error of predictions of this model is 0.30 log units, and the structural moieties of the studied antifungal agents which are thought to contribute to the biological activity were identified. The predictive capability of this model could be exploited in further synthetic studies on antifungal azoles. Furthermore, the results obtained by using two different alignments of the inhibitors suggest that the binding mode of these molecules involves both a coordination to the iron protoporphyrin atom and an additional, likewise relevant, hydrophobic interaction with the active site.

Antifungal Agents↗

PubMed1991

Molecular modeling on the Commodore Amiga.

The Amiga 3000 is nearly ideal for desktop molecular modeling. It uses the Motorola 68030 32-bit processor, running at 16 or 25 MHz, with either the 68881 or 68882 math coprocessor and eight custom processing chips. The video system is NTSC compatible 15.75- or 31.5-KHz RGB analog or digital. The system video interface offers user selectable 320 x 200, 640 x 480, 768 x 480 or 1280 x 400 resolution with a displayable palette of 4,096 colors and interlaced, noninterlaced and overscan modes. NTSC compatibility permits simple and inexpensive video signal synchronization, so that composed monitor images can be displayed and recorded with standard video equipment. The processor, in conjunction with the custom video chips, can manipulate models mathematically at a sufficient rate to present moving or animated images in real time. Users can interact with the molecular image with mouse or joystick controls. A third-party manufacturer, Haitex Resources, has produced an inexpensive stereo image display interface for the Amiga. This stereo image display system consists of liquid crystal shutter goggles attached to a control module on one mouse/joystick port and synchronized at 60 Hz with alternating left/right screen displays. Several simple molecular graphics programs for the Amiga have been available in the public domain since 1988. The ease of video interfacing and the availability of stereo image display have stimulated several developers to begin assembling molecular modeling packages. At the National Biomedical Research Foundation the Amiga is being tested as an inexpensive stereo-image color graphics workstation for molecular modeling, biopolymer sequence analysis and medical imaging.(ABSTRACT TRUNCATED AT 250 WORDS)

Computer Graphics↗

PubMed1991

The discovery of novel auxin transport inhibitors by molecular modeling and three-dimensional pattern analysis.

Molecular modeling techniques and three-dimensional (3D) pattern analysis have been used to investigate the chemical and steric properties of compounds that inhibit transport of the plant hormone auxin. These compounds bind to a specific site on the plant plasma membrane characterized by its affinity for the herbicide N-1-naphthylphthalamic acid (NPA). A 3D model was derived from critical features of a set of ligands for the NPA receptor, a suggested binding conformation is proposed, and implications for the topographical features of the NPA receptor are discussed. This model, along with 3D structural analysis techniques, was then used to search the Abbott corporate database of chemical structures. Of the 467 compounds that satisfied the criteria of the model, 77 representative molecules were evaluated for their ability to compete for the binding of [3H]NPA to corn microsomal membranes. Nineteen showed activity that ranged from 16 to 85% of the maximum NPA binding. Four of the most active of these, representing chemical classes not included in the original compound set, were also found to inhibit polar auxin transport through corn coleoptile sections. Thus, this study demonstrates that 3D analysis techniques can identify active, novel ligands for biochemical target sites with concomitant physiological activity.

Binding Sites↗

PubMed1993

Stability of triple helices containing RNA and DNA strands: experimental and molecular modeling studies.

UV-absorption spectrophotometry and molecular modeling have been used to study the influence of the chemical nature of sugars (ribose or deoxyribose) on triple helix stability. For the Pyrimidine.purine* Pyrimidine motif, all eight combinations were tested with each of the three strands composed of either DNA or RNA. The chemical nature of sugars has a dramatic influence on triple helix stability. For each double helix composition, a more stable triple helix was formed when the third strand was RNA rather than DNA. No stable triple helix was detected when the polypurine sequence was made of RNA with a third strand made of DNA. Energy minimization studies using the JUMNA program suggested that interactions between the 2'-hydroxyl group of the third strand and the phosphates of the polypurine strand play an important role in determining the relative stabilities of triple-helical structures in which the polypyrimidine third strand is oriented parallel to the polypurine sequence. These interactions are not allowed when the third strand adopts an antiparallel orientation with respect to the target polypurine sequence, as observed when the third strand contains G and A or G and T/U. We show by footprinting and gel retardation experiments that an oligoribonucleotide containing G and A or G and U fails to bind double helical DNA, while the corresponding DNA oligomers form stable triple-helical complexes.

Base Sequence↗

PubMed1984

The molecular weights of UDP-glucuronyltransferase determined with radiation-inactivation analysis. A molecular model of bilirubin UDP-glucuronyltransferase.

The molecular masses of the UDP-glucuronyltransferases were determined by means of radiation-inactivation analysis of sodium dodecyl sulfate-treated lyophilized rat liver microsomal preparations using a calibrated 60Co source. Bilirubin glucuronidation with formation of bilirubin monoglucuronide is catalyzed by a 41,500-Da enzyme; conversion of bilirubin mono- to diglucuronide is catalyzed by a 175,000-Da enzyme. The glucuronidation of estrone and testosterone is mediated by enzymes with molecular masses of 73,500 and 142,000 Da, respectively, and the glucuronidation of p-nitrophenol and phenolphthalein is mediated by enzymes with molecular masses of 109,000 and 159,000 Da, respectively. Our results show that UDP-glucuronyltransferase consists of a heterogenous group of enzymes with strikingly different molecular masses. Our data furthermore suggest that these enzymes may be oligomers composed of one to four subunits with similar molecular masses. Based on these findings, a molecular model of bilirubin UDP-glucuronyltransferase is proposed, consisting of four subunits. For bilirubin diglucuronide formation, the complete tetrameric enzyme is required, whereas formation of monoglucuronide can be mediated by a single subunit. The monomeric monoglucuronide-forming enzyme is resistant to sodium dodecyl sulfate, treatment whereas the tetrameric diglucuronide-forming enzyme is labile, but once inactivated, the diglucuronide-forming enzyme can be reconstituted by decreasing the sodium dodecyl sulfate concentration by means of dialysis.

Animals↗

PubMed1990

Molecular modeling studies on the urease active site and the enzyme-catalyzed urea hydrolysis.

These studies are an attempt to gain better insight into the pharmacophore requirements of urease. On the basis of published information on this enzyme (EXAFS, amino acid sequence, essential groups at the active site) a hypothetical nickel-tripeptide complex, as preliminary substitute for the urease active site was modeled using computer-aided molecular modeling techniques. The results suggest two alternative docking modes of urea and reaction intermediates, corresponding to two different reaction mechanisms. Both binding modes are compatible with the docking of known potent inhibitors such as selected hydroxamic acids and phosphorodiamides. The results can be used to help in the design of new potential inhibitors of urease.

Binding Sites↗

PubMed1989

The different influences of ether and ester phospholipids on the conformation of gramicidin A. A molecular modelling study.

With AMBER (assisted model building with energy refinement) molecular modelling techniques, the interactions between lipids which differ in the type of chain linkage (e.g., ether or ester) and gramicidin were approximated. It was found, theoretically, that replacement of the ester function in dipalmitoylphosphatidylcholine (DPPC) by an ether moiety induces a shift in the rotameric distribution of the Trp-15 side-chain in gramicidin A. Concomitantly, the channel entrance is contracted by approx. 0.4 A. The perturbation can be related to the strong hydrogen-bond formed between the lipid carbonyl group and the indole proton of the Trp-15 residue of gramicidin. In the ether lipid-gramicidin assembly a weaker H-bond is formed between Trp-15 and the phosphate moiety. To obtain a first indication of the influence of the strength of this H-bond on gramicidin A, a preliminary experimental study was set up. The transport properties of gramicidin A were studied using efflux measurements through vesicle walls containing ether and ester lipids, respectively. A change in the permeability of gramicidin A was found when ether lipids were added to a bilayer composed of the ester lipid dioleoylphosphatidylcholine (DOPC).

1,2-Dipalmitoylphosphatidylcholine↗

PubMed2005

Structural features of the glutamate binding site in recombinant NR1/NR2A N-methyl-D-aspartate receptors determined by site-directed mutagenesis and molecular modeling.

We have used site-directed mutagenesis of amino acids located within the S1 and S2 ligand binding domains of the NR2A N-methyl-D-aspartate (NMDA) receptor subunit to explore the nature of ligand binding. Wild-type or mutated NR1/NR2A NMDA receptors were expressed in Xenopus laevis oocytes and studied using two electrode voltage clamp. We investigated the effects of mutations in the S1 and S2 regions on the potencies of the agonists L-glutamate, L-aspartate, (R,S)-tetrazol-5yl-glycine, and NMDA. Mutation of each of the corresponding residues found in the NR2A receptor subunit, suggested to be contact residues in the GluR2 alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit, caused a rightward shift in the concentration-response curve for each agonist examined. None of the mutations examined altered the efficacy of glutamate as assessed by methanethiosulfonate ethylammonium potentiation of agonist-evoked currents. In addition, none of the mutations altered the potency of glycine. Homology modeling and molecular dynamics were used to evaluate molecular details of ligand binding of both wild-type and mutant receptors, as well as to explore potential explanations for agonist selectivity between glutamate receptor subtypes. The modeling studies support our interpretation of the mutagenesis data and indicate a similar binding strategy for L-glutamate and NMDA when they occupy the binding site in NMDA receptors, as has been proposed for glutamate binding to the GluR2 AMPA receptor subunit. Furthermore, we offer an explanation as to why "charge conserving" mutations of two residues in the binding pocket result in nonfunctional receptor channels and suggest a contributing molecular determinant for why NMDA is not an agonist at AMPA receptors.

Amino Acid Sequence↗

PubMed1992

A molecular model of the complete three-dimensional structure of the Klenow fragment of Escherichia coli DNA polymerase I: binding of the dNTP substrate and template-primer.

A complete three-dimensional structure of the Klenow fragment of Escherichia coli DNA polymerase I (pol I) has been proposed on the basis of molecular modeling and molecular mechanics studies using available C alpha coordinates. The structure seems quite reliable because the overall surface of electrostatic potentials calculated for the molecularly modeled enzyme closely resembles that reported for the X-ray structure. The modeled structure is then used in developing a ternary complex of dTTP and (dA)25-(dT)14 poised in its active site. The orientation of both substrates in the ternary complex was primarily guided by the amino acid residues which had been known to interact with dNTP and DNA substrates from earlier studies. The proposed model (a) explains the geometrical and physicochemical relationship of the two substrates with the various critical amino acid residues involved in the binding process and (b) suggests possible roles for additional residues in the binding and/or polymerization reaction. Furthermore, the ternary complex appears to satisfy many biochemical and genetic data concerning catalytic requirements known to exist for the polymerization reaction.

Amino Acid Sequence↗