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Sample records for activity molecular modeling

  1. Comparative molecular modelling of biologically active sterols

    NASA Astrophysics Data System (ADS)

    Baran, Mariusz; Mazerski, Jan

    2015-04-01

    Membrane sterols are targets for a clinically important antifungal agent - amphotericin B. The relatively specific antifungal action of the drug is based on a stronger interaction of amphotericin B with fungal ergosterol than with mammalian cholesterol. Conformational space occupied by six sterols has been defined using the molecular dynamics method to establish if the conformational features correspond to the preferential interaction of amphotericin B with ergosterol as compared with cholesterol. The compounds studied were chosen on the basis of structural features characteristic for cholesterol and ergosterol and on available experimental data on the ability to form complexes with the antibiotic. Statistical analysis of the data obtained has been performed. The results show similarity of the conformational spaces occupied by all the sterols tested. This suggests that the conformational differences of sterol molecules are not the major feature responsible for the differential sterol - drug affinity.

  2. The activation strain model and molecular orbital theory

    PubMed Central

    Wolters, Lando P; Bickelhaupt, F Matthias

    2015-01-01

    The activation strain model is a powerful tool for understanding reactivity, or inertness, of molecular species. This is done by relating the relative energy of a molecular complex along the reaction energy profile to the structural rigidity of the reactants and the strength of their mutual interactions: ΔE(ζ) = ΔEstrain(ζ) + ΔEint(ζ). We provide a detailed discussion of the model, and elaborate on its strong connection with molecular orbital theory. Using these approaches, a causal relationship is revealed between the properties of the reactants and their reactivity, e.g., reaction barriers and plausible reaction mechanisms. This methodology may reveal intriguing parallels between completely different types of chemical transformations. Thus, the activation strain model constitutes a unifying framework that furthers the development of cross-disciplinary concepts throughout various fields of chemistry. We illustrate the activation strain model in action with selected examples from literature. These examples demonstrate how the methodology is applied to different research questions, how results are interpreted, and how insights into one chemical phenomenon can lead to an improved understanding of another, seemingly completely different chemical process. WIREs Comput Mol Sci 2015, 5:324–343. doi: 10.1002/wcms.1221 PMID:26753009

  3. Molecular Modeling on Berberine Derivatives toward BuChE: An Integrated Study with Quantitative Structure-Activity Relationships Models, Molecular Docking, and Molecular Dynamics Simulations.

    PubMed

    Fang, Jiansong; Pang, Xiaocong; Wu, Ping; Yan, Rong; Gao, Li; Li, Chao; Lian, Wenwen; Wang, Qi; Liu, Ai-Lin; Du, Guan-Hua

    2016-05-01

    A dataset of 67 berberine derivatives for the inhibition of butyrylcholinesterase (BuChE) was studied based on the combination of quantitative structure-activity relationships models, molecular docking, and molecular dynamics methods. First, a series of berberine derivatives were reported, and their inhibitory activities toward butyrylcholinesterase (BuChE) were evaluated. By 2D- quantitative structure-activity relationships studies, the best model built by partial least-square had a conventional correlation coefficient of the training set (R(2) ) of 0.883, a cross-validation correlation coefficient (Qcv2) of 0.777, and a conventional correlation coefficient of the test set (Rpred2) of 0.775. The model was also confirmed by Y-randomization examination. In addition, the molecular docking and molecular dynamics simulation were performed to better elucidate the inhibitory mechanism of three typical berberine derivatives (berberine, C2, and C55) toward BuChE. The predicted binding free energy results were consistent with the experimental data and showed that the van der Waals energy term (ΔEvdw ) difference played the most important role in differentiating the activity among the three inhibitors (berberine, C2, and C55). The developed quantitative structure-activity relationships models provide details on the fine relationship linking structure and activity and offer clues for structural modifications, and the molecular simulation helps to understand the inhibitory mechanism of the three typical inhibitors. In conclusion, the results of this study provide useful clues for new drug design and discovery of BuChE inhibitors from berberine derivatives. PMID:26648584

  4. Molecular Modeling

    NASA Astrophysics Data System (ADS)

    Holmes, Jon L.

    1999-06-01

    Molecular modeling has trickled down from the realm of pharmaceutical and research laboratories into the realm of undergraduate chemistry instruction. It has opened avenues for the visualization of chemical concepts that previously were difficult or impossible to convey. I am sure that many of you have developed exercises using the various molecular modeling tools. It is the desire of this Journal to become an avenue for you to share these exercises among your colleagues. It is to this end that Ron Starkey has agreed to edit such a column and to publish not only the description of such exercises, but also the software documents they use. The WWW is the obvious medium to distribute this combination and so accepted submissions will appear online as a feature of JCE Internet. Typical molecular modeling exercise: finding conformation energies. Molecular Modeling Exercises and Experiments is the latest feature column of JCE Internet, joining Conceptual Questions and Challenge Problems, Hal's Picks, and Mathcad in the Chemistry Curriculum. JCE Internet continues to seek submissions in these areas of interest and submissions of general interest. If you have developed materials and would like to submit them, please see our Guide to Submissions for more information. The Chemical Education Resource Shelf, Equipment Buyers Guide, and WWW Site Review would also like to hear about chemistry textbooks and software, equipment, and WWW sites, respectively. Please consult JCE Internet Features to learn more about these resources at JCE Online. Email Announcements Would you like to be informed by email when the latest issue of the Journal is available online? when a new JCE Software title is shipping? when a new JCE Internet article has been published or is available for Open Review? when your subscription is about to expire? A new feature of JCE Online makes this possible. Visit our Guestbook to learn how. When

  5. [Cytotoxic activity and molecular modeling of progestins - pregna-D'-pentarans].

    PubMed

    Scherbakov, A M; Levina, I S; Kulikova, L E; Fedyushkina, I V; Skvortsov, V S; Veselovsky, A V; Kuznetsov, Y V; Zavarzin, I V

    2016-03-01

    The cytotoxic activity of synthetic progestins (pregna-D'-pentaranes) II-V full agonists of the progesterone receptor (PR) for PR-positive and PR-negative cells of human breast carcinoma was studied. These compounds were more active in the PR-positive MCF-7 cells than in the PR-negative MDA-MB-453 cells. Cytotoxic effects of tested compounds against normal epithelial MDCK cells were not found. Molecular modeling of studied steroids with PR showed that all progestins with close energy values can bind to the ligand binding domain (LBD) of PR and the magnitude of the energy exceeds the value estimated for the progesterone molecule. Thus, the studied progestins are active against different molecular subtypes of breast cancer and represent a promising class of chemical compounds for oncology. PMID:27420621

  6. Synthesis, Structural Studies and Molecular Modelling of a Novel Imidazoline Derivative with Antifungal Activity.

    PubMed

    Wróbel, Tomasz M; Kosikowska, Urszula; Kaczor, Agnieszka A; Andrzejczuk, Sylwia; Karczmarzyk, Zbigniew; Wysocki, Waldemar; Urbańczyk-Lipkowska, Zofia; Morawiak, Maja; Matosiuk, Dariusz

    2015-01-01

    Six novel imidazoline derivatives were synthesized and tested in antifungal assays. One of the compounds, N-cyclohexyl-2-imino-3-(4-nitrophenyl)imidazolidine-1-carboxamide showed moderate activity against several clinical strains of Candida albicans. Its structure was solved by X-ray crystallography and its mode of action was deduced using molecular modelling. It was found to be similar to that of fluconazole. The potential for further optimization including SAR of the compound is briefly discussed. PMID:26287137

  7. A molecular model for adsorption of water on activated carbon: Comparison of simulation and experiment

    SciTech Connect

    McCallum, C.L.; McGrother, S.C.; Bandosz, T.J.; Mueller, E.A.; Gubbins, K.E.

    1999-01-19

    Experimental and molecular simulation results are presented for the adsorption of water onto activated carbons. The pore size distribution for the carbon studied was determined from nitrogen adsorption data using density functional theory, and the density of acidic and basic surface sites was found using Boehm and potentiometric titration. The total surface site density was 0.675 site/nm{sup 2}. Water adsorption was measured for relative pressures P/P{sub 0} down to 10{sup {minus}3}. A new molecular model for the water/activated carbon system is presented, which the authors term the effective single group model, and grand canonical Monte Carlo simulations are reported for the range of pressures covered in the experiments. A comparison of these simulations with the experiments show generally good agreement, although some discrepancies are attributed to the simplification of using a single surface group species, while those at high pressure are believed to arise from uncertainties in the pore size distribution. The simulation results throw new light on the adsorption mechanism for water at low pressures. The influence of varying both the density of surface sites and the size of the graphite microcrystals is studied using molecular simulation.

  8. Molecular Modeling Analysis of the Inhibition of Mitochondrial Cytochrome BC1 Complex Activity by Tocol Derivatives

    NASA Astrophysics Data System (ADS)

    Singh, Awantika; Hauer-Jensen, Martin; Compadre, Cesar M.; Kumar, K. Sree

    2011-06-01

    The biological functions of vitamin E related compounds have been of interest in biomedical research for several decades. Among those compounds, α-, β-, δ-, and γ-tocopherols and their oxidation products, α-, β-, δ-, γ-tocopherylquinone and their analogs α-TQo, γ-TQo, TMC20 and TMC40 were recently shown to inhibit the mitochondrial cytochrome bc1 complex. In this investigation the effects of the structural variation on the inhibition of the mitochondrial cytochrome bc1 complex were analyzed using Comparative Molecular Field Analysis (CoMFA). CoMFA performed using steric and electrostatic molecular fields produced a very good correlation. The best CoMFA models were obtained using the manual alignment of 12 compounds with 5 components (q2 = 0.589, SPRESS = 0.515, r2 = 0.992, s = 0.068 and F value = 156.520). The resulting contour maps produced by the best CoMFA model were helpful in identifying the structural features required for the biological activity of compounds under study. These results would be helpful for predicting the activity of new compounds, and they could be used for guiding the design, synthesis and development of new and more effective agents.

  9. The Use of Molecular Modeling as "Pseudoexperimental" Data for Teaching VSEPR as a Hands-On General Chemistry Activity

    ERIC Educational Resources Information Center

    Martin, Christopher B.; Vandehoef, Crissie; Cook, Allison

    2015-01-01

    A hands-on activity appropriate for first-semester general chemistry students is presented that combines traditional VSEPR methods of predicting molecular geometries with introductory use of molecular modeling. Students analyze a series of previously calculated output files consisting of several molecules each in various geometries. Each structure…

  10. Homology modeling and molecular docking of human pituitary adenylate cyclase-activating polypeptide I receptor

    PubMed Central

    WU, LUSHENG; GUANG, WENHUA; CHEN, XIAOJIA; HONG, AN

    2014-01-01

    Pituitary adenylate cyclase-activating peptide I receptor (PAC1R) is member of the B class of G protein-coupled seven-transmembrane receptors, with molecular functions associated with neural cell differentiation, regeneration and the inhibition of apoptosis. However, the integrity of the protein structure is difficult to be determined in vitro. In the present study, the physicochemical properties of PAC1R were analyzed, the extracellular, transmembrane and intracellular regions were constructed and a three-dimensional structure model of PAC1R was produced using extracellular loop region optimization and the energy minimization homology modeling method. Preliminary studies on the PAC1R protein and ligand interactions used a molecular docking method. The results indicated that the interaction sites of PAC1R were at Ile63, Ser100 and Gln105. These were the sites where the PAC1R combined with a hydrazide small molecule inhibitor. This study provides a theoretical basis for further studies on the model for the development of PAC1R target drugs. PMID:25069645

  11. Molecular modeling and snake venom phospholipase A2 inhibition by phenolic compounds: Structure-activity relationship.

    PubMed

    Alam, Md Iqbal; Alam, Mohammed A; Alam, Ozair; Nargotra, Amit; Taneja, Subhash Chandra; Koul, Surrinder

    2016-05-23

    In our earlier study, we have reported that a phenolic compound 2-hydroxy-4-methoxybenzaldehyde from Janakia arayalpatra root extract was active against Viper and Cobra envenomations. Based on the structure of this natural product, libraries of synthetic structurally variant phenolic compounds were studied through molecular docking on the venom protein. To validate the activity of eight selected compounds, we have tested them in in vivo and in vitro models. The compound 21 (2-hydroxy-3-methoxy benzaldehyde), 22 (2-hydroxy-4-methoxybenzaldehyde) and 35 (2-hydroxy-3-methoxybenzylalcohol) were found to be active against venom-induced pathophysiological changes. The compounds 20, 15 and 35 displayed maximum anti-hemorrhagic, anti-lethal and PLA2 inhibitory activity respectively. In terms of SAR, the presence of a formyl group in conjunction with a phenolic group was seen as a significant contributor towards increasing the antivenom activity. The above observations confirmed the anti-venom activity of the phenolic compounds which needs to be further investigated for the development of new anti-snake venom leads. PMID:26986086

  12. Preparation, characterization and molecular modeling of PEGylated human growth hormone with agonist activity.

    PubMed

    Khameneh, Bahman; Jaafari, Mahmoud Reza; Hassanzadeh-Khayyat, Mohammad; Varasteh, AbdolReza; Chamani, JamshidKhan; Iranshahi, Mehrdad; Mohammadpanah, Hamid; Abnous, Khalil; Saberi, Mohammad Reza

    2015-09-01

    In this study, site-specific PEGylated human growth hormone (hGH) was prepared by microbial transglutaminase, modeled and characterized. To this end, the effects of different reaction parameters including reaction media, PEG:protein ratios, reaction time and pH value were investigated. PEG-hGH was purified by size exclusion chromatography method and analyzed by SDS-PAGE, BCA, peptide mapping, ESI and MALDI-TOF-TOF mass spectroscopy methods. Biophysical and biological properties of PEG-hGH were evaluated. Molecular simulation was utilized to provide molecular insight into the protein-receptor interaction. The optimum conditions that were obtained for PEGylation were phosphate buffer with pH of 7.4, 48 h of stirring and PEG:protein ratio of 40:1. By this method, mono-PEG-hGH with high reaction yield was obtained and PEGylation site was at Gln-40 residue. The circular dichroism and fluorescence spectrum indicated that PEGylation did not change the secondary structure while tertiary structure was altered. Upon enzymatic PEGylation, agonistic activity of hGH was preserved; however, Somavert(®), which is prepared by chemical PEGylation, is an antagonist form of protein. These data were confirmed by the total energy of affinity obtained by computational protein-receptor interaction. In conclusion, PEGylation of hGH was led to prepare a novel form of hormone with an agonist activity which merits further investigations. PMID:26116386

  13. Use of Molecular Models for Active Learning in Biochemistry Lecture Courses

    ERIC Educational Resources Information Center

    Hageman, James H.

    2010-01-01

    The pedagogical value of having biochemistry and organic chemistry students build and manipulate physical models of chemical species is well established in the literature. Nevertheless, for the most part, the use of molecular models is generally limited to several laboratory exercises or to demonstrations in the classroom setting. A simple…

  14. Molecular modeling and inhibitory activity of cowpea cystatin against bean bruchid pests.

    PubMed

    Aguiar, Juliana M; Franco, Octávio L; Rigden, Daniel J; Bloch, Carlos; Monteiro, Ana C S; Flores, Victor M Q; Jacinto, Tânia; Xavier-Filho, José; Oliveira, Antonia E A; Grossi-de-Sá, Maria F; Fernandes, Kátia V S

    2006-05-15

    Plant cystatins show great potential as tools to genetically engineer resistance of crop plants against pests. Two important potential targets are the bean weevils Acanthoscelides obtectus and Zabrotes subfasciatus, which display major activities of digestive cysteine proteinases in midguts. In this study a cowpea cystatin, a cysteine proteinase inhibitor found in cowpea (Vigna unguiculata) seeds, was expressed in Escherichia coli and purified with a Ni-NTA agarose column. It strongly inhibited papain and proteinases from midguts of both A. obtectus and Z. subfasciatus bruchids, as seen by in vitro assays. When the protein was incorporated into artificial seeds at concentrations as low as 0.025%, and seeds were consumed by the bruchids larva, dramatic reductions in larval weight, and increases in insect mortality were observed. Molecular modeling studies of cowpea cystatin in complex with papain revealed that five N-terminal residues responsible for a large proportion of the hydrophobic interactions involved in the stabilization of the enzyme-inhibitor complex are absent in the partial N-terminal amino acid sequencing of soybean cystatin. We suggest that this structural difference could be the reason for the much higher effectiveness of cowpea cystatin when compared to that previously tested phytocystatin. The application of this knowledge in plant protein mutation programs aiming at enhancement of plant defenses to pests is discussed. PMID:16470583

  15. Arylthioindole inhibitors of tubulin polymerization. 3. Biological evaluation, structure-activity relationships and molecular modeling studies.

    PubMed

    La Regina, Giuseppe; Edler, Michael C; Brancale, Andrea; Kandil, Sahar; Coluccia, Antonio; Piscitelli, Francesco; Hamel, Ernest; De Martino, Gabriella; Matesanz, Ruth; Díaz, José Fernando; Scovassi, Anna Ivana; Prosperi, Ennio; Lavecchia, Antonio; Novellino, Ettore; Artico, Marino; Silvestri, Romano

    2007-06-14

    The new arylthioindole (ATI) derivatives 10, 14-18, and 21-24, which bear a halogen atom or a small size ether group at position 5 of the indole moiety, were compared with the reference compounds colchicine and combretastatin A-4 for biological activity. Derivatives 10, 11, 16, and 21-24 inhibited MCF-7 cell growth with IC50 values <50 nM. A halogen atom (14-17) at position 5 caused a significant reduction in the free energy of binding of compound to tubulin, with a concomitant reduction in cytotoxicity. In contrast, methyl (21) and methoxy (22) substituents at position 5 caused an increase in cytotoxicity. Compound 16, the most potent antitubulin agent, led to a large increase (56%) in HeLa cells in the G2/M phase at 24 h, and at 48 h, 26% of the cells were hyperploid. Molecular modeling studies showed that, despite the absence of the ester moiety present in the previously examined analogues, most of the compounds bind in the colchicine site in the same orientation as the previously studied ATIs. Binding to beta-tubulin involved formation of a hydrogen bond between the indole and Thr179 and positioning of the trimethoxy phenyl group in a hydrophobic pocket near Cys241. PMID:17497841

  16. Molecular modeling studies of 1,4-dihydro-4-oxoquinoline ribonucleosides with anti-HSV-1 activity

    NASA Astrophysics Data System (ADS)

    Yoneda, Julliane Diniz; Albuquerque, Magaly Girão; Leal, Kátia Zaccur; Seidl, Peter Rudolf; de Alencastro, Ricardo Bicca

    2011-12-01

    Eight human herpes viruses ( e.g., herpes simplex, varicella-zoster, Epstein-Barr, cytomegalovirus, Kaposi's sarcoma) are responsible for several diseases from sub-clinic manifestations to fatal infections, mostly in immunocompromised patients. The major limitations of the currently available antiviral drug therapy are drug resistance, host toxicity, and narrow spectrum of activity. However, some non-nucleoside 1,4-dihydro-4-oxoquinoline derivatives ( e.g., PNU-183792) [4] shows broad spectrum antiviral activity. We have developed molecular modeling studies, including molecular docking and molecular dynamics simulations, based on a model proposed by Liu and co-workers [14] in order to understand the mechanism of action of a 6-chloro substituted 1,4-dihydro-4-oxoquinoline ribonucleoside, synthesized by the synthetic group, which showed anti-HSV-1 activity [9]. The molecular docking simulations confirmed the Liu's model showing that the ligand needs to dislocate template residues from the active site in order to interact with the viral DNA polymerase enzyme, reinforcing that the interaction with the Val823 residue is pivotal for the inhibitory activity of non-nucleoside 1,4-dihydro-4-oxoquinoline derivatives, such as PNU-183792, with the HSV-1. The molecular dynamics simulations showed that the 6-chloro-benzyl group of PNU-183792 maintains its interaction with residues of the HSV-1 DNA polymerase hydrophobic pocket, considered important according to the Liu's model, and also showed that the methyl group bounded to the nitrogen atom from PNU-183792 is probably contributing to a push-pull effect with the carbonyl group.

  17. Molecular modeling based synthesis and evaluation of in vitro anticancer activity of indolyl chalcones.

    PubMed

    Gaur, Rashmi; Yadav, Dharmendra K; Kumar, Shiv; Darokar, Mahendra P; Khan, Feroz; Bhakuni, Rajendra Singh

    2015-01-01

    A series of twenty one chalcone derivatives having indole moiety were synthesized and were evaluated against four human cancer cell lines. Indolyl chalcones 1a, 1b, 1d, 1f-1j, 2c, 2e, 2i showed good anticancer activity. Chalcones 1b and 1d were the most active and selective anticancer agents with IC50 values <1μg/ml and 1.51μg/ml, against WRL-68 cell line, respectively. Molecular mechanism was explored through in silico docking & ADMET studies. PMID:25860176

  18. Prediction of anticancer activity of diterpenes isolated from the paraiban flora through a PLS model and molecular surfaces.

    PubMed

    Scotti, Luciana; Scotti, Marcus T; Ishiki, Hamilton; Junior, Francisco J B M; dos, Santos Paula F; Tavares, Josean F; da Silva, Marcelo S

    2014-05-01

    The aim of this work was to predict the anticancer potential of 3 atisane, and 3 trachylobane diterpene compounds extracted from the roots of Xylopia langsdorffiana. The prediction of anticancer activity as expressed against PC-3 tumor cells was made using a PLS model built with 26 diterpenes in the training set. Significant statistical measures were obtained. The six investigated diterpenes were applied to the model and their activities against PC-3 cells were calculated. All the diterpenes were active, with atisane diterpenes showing the higher pICso values. In human prostate carcinoma PC-3 cells, the apoptosis mechanism is related to an inhibition of IKK/NF-KB. Antioxidant potential implies a greater electronic molecular atmosphere (increased donor electron capacity), which can reduce radical reactivity, and facilitate post donation charge accommodation. Molecular surfaces indicated a much greater electronic cloud over atisane diterpenes. PMID:25026699

  19. Synthesis, characterization, molecular modeling, and potential antimicrobial and anticancer activities of novel 2-aminoisoindoline-1,3-dione derivatives.

    PubMed

    Ahmed, Hany Emary Ali; Abdel-Salam, Hassan A; Shaker, Mohamed A

    2016-06-01

    In an effort to establish new drug candidates with improved antimicrobial and anticancer activities, we report here synthesis, molecular modeling, and in vitro biological evaluation of novel substituted N-amino phthalamide derivatives (3a-b, 4a-b, 5a-j, and 6). Structures of the newly synthesized compounds were described by IR, (1)H &(13)CNMR and LC-MS spectral data. The novel compounds were evaluated for their antibacterial activity against four types of Gm+ve and two for Gm-ve types, and antifungal activity against three fungi microorganisms by well diffusion method. Of these novel compounds, Schiff bases showed mostly promising antibacterial activity compared to reference drugs. A successful step was done for explanation of their mode of action through molecular docking of most active molecules at DNA gyrase B enzyme and further were biologically tested. Moreover, the antiproliferative activity was tested against two human carcinoma cell lines (Human colon carcinoma (HCT-116) and human breast adenocarcinoma (MCF-7)) showing promising anticancer activity compared to doxorubicin drug. The data from structure-activity relationship (SAR) analysis revealed that the lypophilic properties of these compounds might be essential parameter for their activity and suggest that 2-amino phthalamide scaffold derivatives 5g and 5h exhibited good antimicrobial and anticancer activities and might used as leads for further optimization. PMID:26986635

  20. AN EVOLUTIONARY MODEL FOR COLLAPSING MOLECULAR CLOUDS AND THEIR STAR FORMATION ACTIVITY

    SciTech Connect

    Zamora-Aviles, Manuel; Vazquez-Semadeni, Enrique; Colin, Pedro

    2012-05-20

    We present an idealized, semi-empirical model for the evolution of gravitationally contracting molecular clouds (MCs) and their star formation rate (SFR) and efficiency (SFE). The model assumes that the instantaneous SFR is given by the mass above a certain density threshold divided by its free-fall time. The instantaneous number of massive stars is computed assuming a Kroupa initial mass function. These stars feed back on the cloud through ionizing radiation, eroding it. The main controlling parameter of the evolution turns out to be the maximum cloud mass, M{sub max}. This allows us to compare various properties of the model clouds against their observational counterparts. A giant molecular cloud (GMC) model (M{sub max} {approx} 10{sup 5} M{sub Sun }) adheres very well to the evolutionary scenario recently inferred by Kawamura et al. for GMCs in the Large Magellanic Cloud. A model cloud with M{sub max} Almost-Equal-To 2000 M{sub Sun} evolves in the Kennicutt-Schmidt diagram, first passing through the locus of typical low-to-intermediate-mass star-forming clouds, and then moving toward the locus of high-mass star-forming ones over the course of {approx}10 Myr. Also, the stellar age histograms for this cloud a few Myr before its destruction agree very well with those observed in the {rho}-Oph stellar association, whose parent cloud has a similar mass, and imply that the SFR of the clouds increases with time. Our model thus agrees well with various observed properties of star-forming MCs, suggesting that the scenario of gravitationally collapsing MCs, with their SFR regulated by stellar feedback, is entirely feasible and in agreement with key observed properties of MCs.

  1. Design, synthesis, antimicrobial activity and molecular modeling studies of novel benzofuroxan derivatives against Staphylococcus aureus.

    PubMed

    Jorge, Salomão Dória; Masunari, Andrea; Rangel-Yagui, Carlota Oliveira; Pasqualoto, Kerly Fernanda Mesquita; Tavares, Leoberto Costa

    2009-04-15

    Molecular modification is a quite promising strategy in the design and development of drug analogs with better bioavailability, higher intrinsic activity and less toxicity. In the search of new leads with potential antimicrobial activity, a new series of 14 4-substituted [N'-(benzofuroxan-5-yl)methylene]benzohydrazides, nifuroxazide derivatives, were synthesized and tested against standard and multidrug-resistant Staphylococcus aureus strains. The selection of the substituent groups was based on physicochemical properties, such as hydrophobicity and electronic effect. These properties were also evaluated through the lipophilic and electrostatic potential maps, respectively, considering the compounds with better biological profile. Twelve compounds exhibited similar bacteriostatic activity against standard and multidrug-resistant strains. The most active compound was the 4-CF(3) substituted derivative, which presented a minimum inhibitory concentration (MIC) value of 14.6-13.1 microg/mL, and a ClogP value of 1.87. The results highlight the benzofuroxan derivatives as potential leads for designing new future antimicrobial drug candidates. PMID:19324556

  2. Molecular Models in Biology

    ERIC Educational Resources Information Center

    Goodman, Richard E.

    1970-01-01

    Describes types of molecular models (ball-and-stick, framework, and space-filling) and evaluates commercially available kits. Gives instructions for constructive models from polystyrene balls and pipe-cleaners. Models are useful for class demonstrations although not sufficiently accurate for research use. Illustrations show biologically important…

  3. Quantitative modeling of the molecular steps underlying shut-off of rhodopsin activity in rod phototransduction

    PubMed Central

    Kraft, Timothy W.

    2016-01-01

    Purpose To examine the predictions of alternative models for the stochastic shut-off of activated rhodopsin (R*) and their implications for the interpretation of experimentally recorded single-photon responses (SPRs) in mammalian rods. Theory We analyze the transitions that an activated R* molecule undergoes as a result of successive phosphorylation steps and arrestin binding. We consider certain simplifying cases for the relative magnitudes of the reaction rate constants and derive the probability distributions for the time to arrestin binding. In addition to the conventional model in which R* catalytic activity declines in a graded manner with successive phosphorylations, we analyze two cases in which the activity is assumed to occur not via multiple small steps upon each phosphorylation but via a single large step. We refer to these latter two cases as the binary R* shut-off and three-state R* shut-off models. Methods We simulate R*’s stochastic reactions numerically for the three models. In the simplifying cases for the ratio of rate constants in the binary and three-state models, we show that the probability distribution of the time to arrestin binding is accurately predicted. To simulate SPRs, we then integrate the differential equations for the downstream reactions using a standard model of the rod outer segment that includes longitudinal diffusion of cGMP and Ca2+. Results Our simulations of SPRs in the conventional model of graded shut-off of R* conform closely to the simulations in a recent study. However, the gain factor required to account for the observed mean SPR amplitude is higher than can be accounted for from biochemical experiments. In addition, a substantial minority of the simulated SPRs exhibit features that have not been reported in published experiments. Our simulations of SPRs using the model of binary R* shut-off appear to conform closely to experimental results for wild type (WT) mouse rods, and the required gain factor conforms to

  4. Molecular dynamics of a biophysical model for beta2-adrenergic and G protein-coupled receptor activation.

    PubMed

    Rubenstein, Lester A; Zauhar, Randy J; Lanzara, Richard G

    2006-12-01

    This study analyzes 16 molecular dynamic simulations of a biophysical model for beta(2)-adrenergic (B2AR) and G protein-coupled receptor (GPCR) activation. In this model, a highly conserved cysteine residue, C106 (C3.25 or CysIII:01), provides a free sulfhydryl or thiol group in an acid-base equilibrium between uncharged (RSH) and charged (RS(-)) states that functions as an electrostatic molecular switch for receptor activation. The transition of C106 in the B2AR between acid and base states significantly changes the helical/transmembrane (TM) domain interactions and the electrostatic interaction energy differences (DeltaDeltaE(EL)). The DeltaDeltaE(EL) changes correlate well with the experimentally observed ligand efficacies. The TM interaction energies display patterns compatible with those previously recognized as responsible for GPCR activation. Key differences between the agonist, epinephrine, and the antagonist, pindolol, are seen for the TM3 x 6, TM3 x 4, TM6 x 7 and TM1 x 7 interaction energies. Pindolol also produces a weaker DeltaDeltaE(EL) interaction and less TM interaction energy changes, which are important differences between the agonist and antagonist ligands. The D115E mutant with pindolol displays a greater DeltaDeltaE(EL) and TM interactions than for the wild-type B2AR with pindolol. This explains the higher activity of pindolol in the D115E mutant. The constitutively active D130A mutant displays TM interaction patterns similar to those for the activating ligands implying a common pattern for receptor activation. These findings support the broad concept of protean agonism and demonstrate the potential for allosteric modulation. They also demonstrate that this two-state model agrees with many previous experimental and theoretical observations of GPCRs. PMID:16574446

  5. Conformationally Constrained Peptidomimetic Inhibitors of Signal Transducer and Activator of Transcription 3: Evaluation and Molecular Modeling

    PubMed Central

    Mandal, Pijus K.; Limbrick, Donald; Coleman, David R.; Dyer, Garrett A.; Ren, Zhiyong; Birtwistle, J. Sanderson; Xiong, Chiyi; Chen, Xiaomin; Briggs, James M.; McMurray, John S.

    2009-01-01

    Signal transducer and activator of transcription 3 (Stat3) is involved in aberrant growth and survival signals in malignant tumor cells and is a validated target for anti-cancer drug design. We are targeting its SH2 domain to prevent docking to cytokine and growth factor receptors and subsequent signaling. The amino acids of our lead phosphopeptide, Ac-pTyr-Leu-Pro-Gln-Thr-Val-NH2, were replaced with conformationally constrained mimics. Structure-affinity studies led to the peptidomimetic, pCinn-Haic-Gln-NHBn (21) which had an IC50 of 162 nM (fluorescence polarization), as compared to 290 nM for the lead phosphopeptide (pCinn = 4-phosphoryloxycinnamate, Haic = (2S,5S)-5-amino-1,2,4,5,6,7-hexahydro-4-oxo-azepino[3,2,1-hi]indole-2-carboxylic acid). pCinn-Haic-Gln-OH was docked to the SH2 domain (AUTODOCK) and the two highest populated clusters were subjected to molecular dynamics simulations. Both converged to a common peptide conformation. The complex exhibits unique hydrogen bonding between Haic and Gln and Stat3 as well as hydrophobic interactions between the protein and pCinn and Haic. PMID:19334714

  6. Identification of novel peroxisome proliferator-activated receptor-gamma (PPARγ) agonists using molecular modeling method.

    PubMed

    Gee, Veronica M W; Wong, Fiona S L; Ramachandran, Lalitha; Sethi, Gautam; Kumar, Alan Prem; Yap, Chun Wei

    2014-11-01

    Peroxisome proliferator-activated receptor-gamma (PPARγ) plays a critical role in lipid and glucose homeostasis. It is the target of many drug discovery studies, because of its role in various disease states including diabetes and cancer. Thiazolidinediones, a synthetic class of agents that work by activation of PPARγ, have been used extensively as insulin-sensitizers for the management of type 2 diabetes. In this study, a combination of QSAR and docking methods were utilised to perform virtual screening of more than 25 million compounds in the ZINC library. The QSAR model was developed using 1,517 compounds and it identified 42,378 potential PPARγ agonists from the ZINC library, and 10,000 of these were selected for docking with PPARγ based on their diversity. Several steps were used to refine the docking results, and finally 30 potentially highly active ligands were identified. Four compounds were subsequently tested for their in vitro activity, and one compound was found to have a K i values of <5 μM. PMID:25168706

  7. An Expedient Synthesis, Acetylcholinesterase Inhibitory Activity, and Molecular Modeling Study of Highly Functionalized Hexahydro-1,6-naphthyridines

    PubMed Central

    Almansour, Abdulrahman I.; Suresh Kumar, Raju; Arumugam, Natarajan; Basiri, Alireza; Kia, Yalda; Ashraf Ali, Mohamed

    2015-01-01

    A series of hexahydro-1,6-naphthyridines were synthesized in good yields by the reaction of 3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones with cyanoacetamide in the presence of sodium ethoxide under simple mixing at ambient temperature for 6–10 minutes and were assayed for their acetylcholinesterase (AChE) inhibitory activity using colorimetric Ellman's method. Compound 4e with methoxy substituent at ortho-position of the phenyl rings displayed the maximum inhibitory activity with IC50 value of 2.12 μM. Molecular modeling simulation of 4e was performed using three-dimensional structure of Torpedo californica AChE (TcAChE) enzyme to disclose binding interaction and orientation of this molecule into the active site gorge of the receptor. PMID:25710037

  8. Elucidating modes of activation and herbicide resistance by sequence assembly and molecular modelling of the Acetolactate synthase complex in sugarcane.

    PubMed

    Lloyd Evans, Dyfed; Joshi, Shailesh Vinay

    2016-10-21

    Acetolactate synthase (ALS) catalyzes the first portion of the biosynthetic pathway leading to the generation of branched-chain amino acids. As such it is essential for plant health and is a major target for herbicides. ALS is a very poorly characterized molecule in sugarcane. The enzyme is activated and inhibited by a regulatory subunit (known as VAT1 in plants) whose mode of action is entirely unknown. Using Saccharum halepense as a template we have assembled the ALS gene of sugarcane (Saccharum hybrid) and have modelled the structure of ALS based on an Arabidopsis template (the first ALS model for a monocot). We have also assembled the ALS regulatory proteins (VAT1 and VAT2) from sugarcane and show that VAT2 is specific to true grasses. Employing a bacterial model, we have generated a structural model for VAT1, which explains why the separate domains of the proteins bind to either leucine or valine but not both. Using co-evolution studies we have determined molecular contacts by which we modelled the docking of VAT1 to ALS. In conclusion, we demonstrate how the binding of VAT1 to ALS activates ALS and show how VAT1 can also confer feedback inhibition to ALS. We validate our ALS model against biochemical data and employ this model to explain the function of a novel herbicide binding mutant in sugarcane. PMID:27452529

  9. Synthesis, biochemical evaluation and molecular modeling studies of novel rhodium complexes with nanomolar activity against Platelet Activating Factor.

    PubMed

    Tsoupras, Alexandros B; Papakyriakou, Athanasios; Demopoulos, Constantinos A; Philippopoulos, Athanassios I

    2013-03-01

    Two square planar Rh(I) organometallic complexes namely [Rh(L(1))(cod)]Cl (cod = cycloocta-1,5-diene, L(1)=2,2'-pyridylquinoxaline (1-Cl), [Rh(L1)(cod)](NO3) (1-NO(3)) and a series of novel octahedral rhodium(III) complexes of the general formulae mer-[Rh(L(1))Cl(3)(MeOH)] (2) and cis-[Rh(L(2))(2)Cl(2)]Cl (L(2)=4 carboxy 2 (2' pyridyl)quinoline (3), L(3)=2,2' bipyridine 4,4' dicarboxylic acid (4) were synthesized and characterized spectroscopically. All the synthesized compounds including the previously prepared cis-[Rh(L(1))(2)Cl(2)]Cl complex (5) were biologically evaluated as potential inhibitors of the Platelet Activation Factor (PAF) and thrombin induced aggregation. In particular compounds 1-Cl and 1-NO(3) were found to be strong inhibitors of PAF with IC(50) values in the range of 16 nM and 15 nM rendering them good candidates for further investigation. Their potency is comparable to that of the widely used PAF receptor antagonists WEB2170, BN52021, and Rupatadine (IC(50) of 20, 30 and 260 nM respectively). Molecular docking calculations suggest that 1-Cl, 1-NO3 and 2 can be accommodated within the ligand-binding site of PAF receptor and block the activity of PAF. On the other hand, the octahedral rhodium(III) complexes 3-5 that cannot fit the ligand-binding domain, could potentially exhibit their activity at the extracellular domain of the receptor. PMID:23318288

  10. Structure–Activity Relationships and Molecular Modeling of Sphingosine Kinase Inhibitors

    PubMed Central

    2013-01-01

    The design, synthesis, and evaluation of the potency of new isoform-selective inhibitors of sphingosine kinases 1 and 2 (SK1 and SK2), the enzyme that catalyzes the phosphorylation of d-erythro-sphingosine to produce the key signaling lipid, sphingosine 1-phosphate, are described. Recently, we reported that 1-(4-octylphenethyl)piperidin-4-ol (RB-005) is a selective inhibitor of SK1. Here we report the synthesis of 43 new analogues of RB-005, in which the lipophilic tail, polar headgroup, and linker region were modified to extend the structure–activity relationship profile for this lead compound, which we explain using modeling studies with the recently published crystal structure of SK1. We provide a basis for the key residues targeted by our profiled series and provide further evidence for the ability to discriminate between the two isoforms using pharmacological intervention. PMID:24164513

  11. Simple thermodynamic model of unassisted proton shuttle uncoupling and prediction of activity from calculated speciation, lipophilicity, and molecular geometry.

    PubMed

    Martineau, Louis C

    2012-06-21

    A mechanistic model of uncoupling of oxidative phosphorylation by lipophilic weak acids (i.e. proton shuttles) was developed for the purposes of predicting the relative activity of xenobiotics of widely varying structure and of guiding the design of optimized derivatives. The model is based on thermodynamic premises not formulated elsewhere that allow for the calculation of steady-state conditions and of rate of energy dissipation on the basis of acid-dissociation and permeability behavior, the later estimated from partitioning behavior and geometric considerations. Moreover, permeability of either the neutral or of the ionized species is proposed to be effectively enhanced under conditions of asymmetrical molecular distribution. Finally, special considerations were developed to accommodate multi-protic compounds. The comparison of predicted to measured activity for a diverse testset of 48 compounds of natural origin spanning a wide range of activity yielded a Spearman's rho of 0.90. The model was used to tentatively identify several novel proton shuttles, as well as to elucidate core structures particularly conducive to proton shuttle activity from which optimized derivatives can be designed. Principles of design were formulated and examples of derivatives projected to be active at concentrations on the order of 10(-7)M are proposed. Among these are di-protic compounds predicted to shuttle two protons per cycle iteration and proposed to maximally exploit the proton shuttle mechanism. This work promotes the design of highly active, yet easily-metabolized uncouplers for therapeutic applications, namely the indirect activation of AMP-kinase, as well as for various industrial applications where low persistence is desirable. PMID:22425608

  12. Insights into the Thiamine Diphosphate Enzyme Activation Mechanism: Computational Model for Transketolase Using a Quantum Mechanical/Molecular Mechanical Method.

    PubMed

    Nauton, Lionel; Hélaine, Virgil; Théry, Vincent; Hecquet, Laurence

    2016-04-12

    We propose the first computational model for transketolase (TK), a thiamine diphosphate (ThDP)-dependent enzyme, using a quantum mechanical/molecular mechanical method on the basis of crystallographic TK structures from yeast and Escherichia coli, together with experimental kinetic data reported in the literature with wild-type and mutant TK. This model allowed us to define a new route for ThDP activation in the enzyme environment. We evidenced a strong interaction between ThDP and Glu418B of the TK active site, itself stabilized by Glu162A. The crucial point highlighted here is that deprotonation of ThDP C2 is not performed by ThDP N4' as reported in the literature, but by His481B, involving a HOH688A molecule bridge. Thus, ThDP N4' is converted from an amino form to an iminium form, ensuring the stabilization of the C2 carbanion or carbene. Finally, ThDP activation proceeds via an intermolecular process and not by an intramolecular one as reported in the literature. More generally, this proposed ThDP activation mechanism can be applied to some other ThDP-dependent enzymes and used to define the entire TK mechanism with donor and acceptor substrates more accurately. PMID:26998737

  13. Developing sensor activity relationships for the JPL electronic nose sensors using molecular modeling and QSAR techniques

    NASA Technical Reports Server (NTRS)

    Shevade, A. V.; Ryan, M. A.; Homer, M. L.; Jewell, A. D.; Zhou, H.; Manatt, K.; Kisor, A. K.

    2005-01-01

    We report a Quantitative Structure-Activity Relationships (QSAR) study using Genetic Function Approximations (GFA) to describe the polymer-carbon composite sensor activities in the JPL Electronic Nose, when exposed to chemical vapors at parts-per-million concentration levels.

  14. Novel series of tacrine-tianeptine hybrids: Synthesis, cholinesterase inhibitory activity, S100B secretion and a molecular modeling approach.

    PubMed

    Ceschi, Marco Antonio; da Costa, Jessie Sobieski; Lopes, João Paulo Bizarro; Câmara, Viktor Saraiva; Campo, Leandra Franciscato; Borges, Antonio César de Amorim; Gonçalves, Carlos Alberto Saraiva; de Souza, Daniela Fraga; Konrath, Eduardo Luis; Karl, Ana Luiza Martins; Guedes, Isabella Alvim; Dardenne, Laurent Emmanuel

    2016-10-01

    Tianeptine was linked to various 9-aminoalkylamino-1,2,3,4-tetrahydroacridines using EDC·HCl/HOBt to afford a series of tacrine-tianeptine hybrids. The hybrids were tested for their ability to inhibit AChE and BuChE and IC50 values in the nanomolar concentration scale were obtained. AChE molecular modeling studies of these hybrids indicated that tacrine moiety interacts in the bottom of the gorge with the catalytic active site (CAS) while tianeptine binds to peripheral anionic site (PAS). Furthermore, the compounds 2g and 2e were able to reduce the in vitro basal secretion of S100B, suggesting its therapeutic action in some cases or stages of Alzheimer's disease. PMID:27392529

  15. Symbolic computation engines and molecular modeling templates: Maple-assisted point group analysis of the vibrational activity of molecules

    NASA Astrophysics Data System (ADS)

    Vail, Benjamin; Aris, Damian; Scarlete, Mihai

    The present study proposes an algorithm for point-group analysis (PGA) of the vibrational activity of molecules, adapted for the efficient utilization of the linear packages incorporated into currently available symbolic computation engines (SCE), such as Maple, Mathcad, or Mathematica. By the creation of this algorithm, we have addressed the need for a numerically friendly environment, outside the "locked" procedures within molecular modeling packages, which will preserve its flexibility, transparency, and maneuverability, regardless of the complexity of the calculation. The format of the character tables of the point groups significant to chemical species has been adapted to ensure automatic numerization, and consistent input of the alphanumeric data from the existent character tables into the SCE templates designed to perform the PGA. The two proposed templates address two complementary objectives: (i) a totally transparent and interactive file has been designed to allow access to all intermediate results at all levels of the procedure for easy implementation of potential additional modules of special interest 1-5, and (ii) for fast output and routine calculations of the IR/Raman vibrational activity of molecules based on their point groups, a totally automatic file with a highly simplified input interface has been designed. The numerical interface conveniently replaces the usual graphic user interface that is common to most commercial molecular modeling software packages, requiring minimum input determination. The structure for both templates is based on the use of the digitized forms for the character tables, for the symmetry operations, and for symmetry elements, all saved in dedicated libraries uploaded to the numerical database of the SCE.

  16. 2-Phenylbenzofuran derivatives as butyrylcholinesterase inhibitors: Synthesis, biological activity and molecular modeling.

    PubMed

    Delogu, Giovanna L; Matos, Maria J; Fanti, Maura; Era, Benedetta; Medda, Rosaria; Pieroni, Enrico; Fais, Antonella; Kumar, Amit; Pintus, Francesca

    2016-05-01

    A series of 2-phenylbenzofurans compounds was designed, synthesized and evaluated as cholinesterase inhibitors. The biological assay experiments showed that most of the compounds displayed a clearly selective inhibition for butyrylcholinesterase (BChE), while a weak or no effect towards acetylcholinesterase (AChE) was detected. Among these benzofuran derivatives, compound 16 exhibited the highest BChE inhibition with an IC50 value of 30.3μM. This compound was found to be a mixed-type inhibitor as determined by kinetic analysis. Moreover, molecular dynamics simulations revealed that compound 16 binds to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of BChE and it displayed the best interaction energy value, in agreement with our experimental data. PMID:26995529

  17. A facile ionic liquid promoted synthesis, cholinesterase inhibitory activity and molecular modeling study of novel highly functionalized spiropyrrolidines.

    PubMed

    Almansour, Abdulrahman I; Kumar, Raju Suresh; Arumugam, Natarajan; Basiri, Alireza; Kia, Yalda; Ali, Mohamed Ashraf; Farooq, Mehvish; Murugaiyah, Vikneswaran

    2015-01-01

    A series of novel dimethoxyindanone embedded spiropyrrolidines were synthesized in ionic liquid, [bmim]Br and were evaluated for their inhibitory activities towards cholinesterases. Among the spiropyrrolidines, compound 4f exhibited the most potent activity with an IC50 value of 1.57 µM against acethylcholinesterase (AChE). Molecular docking simulation for the most active compound was employed with the aim of disclosing its binding mechanism to the active site of AChE receptor. PMID:25642838

  18. Monitoring the Spatiotemporal Activities of miRNAs in Small Animal Models Using Molecular Imaging Modalities

    PubMed Central

    Baril, Patrick; Ezzine, Safia; Pichon, Chantal

    2015-01-01

    MicroRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression by binding mRNA targets via sequence complementary inducing translational repression and/or mRNA degradation. A current challenge in the field of miRNA biology is to understand the functionality of miRNAs under physiopathological conditions. Recent evidence indicates that miRNA expression is more complex than simple regulation at the transcriptional level. MiRNAs undergo complex post-transcriptional regulations such miRNA processing, editing, accumulation and re-cycling within P-bodies. They are dynamically regulated and have a well-orchestrated spatiotemporal localization pattern. Real-time and spatio-temporal analyses of miRNA expression are difficult to evaluate and often underestimated. Therefore, important information connecting miRNA expression and function can be lost. Conventional miRNA profiling methods such as Northern blot, real-time PCR, microarray, in situ hybridization and deep sequencing continue to contribute to our knowledge of miRNA biology. However, these methods can seldom shed light on the spatiotemporal organization and function of miRNAs in real-time. Non-invasive molecular imaging methods have the potential to address these issues and are thus attracting increasing attention. This paper reviews the state-of-the-art of methods used to detect miRNAs and discusses their contribution in the emerging field of miRNA biology and therapy. PMID:25749473

  19. Macrocyclic peptidomimetics with antimicrobial activity: synthesis, bioassay, and molecular modeling studies.

    PubMed

    Ibrahim, Mohamed A; Panda, Siva S; Oliferenko, Alexander A; Oliferenko, Polina V; Girgis, Adel S; Elagawany, Mohamed; Küçükbay, F Zehra; Panda, Chandramukhi S; Pillai, Girinath G; Samir, Ahmed; Tämm, Kaido; Hall, C Dennis; Katritzky, Alan R

    2015-09-28

    Novel, cyclic peptidomimetics were synthesized by facile acylation reactions using benzotriazole chemistry. Microbiological testing of the synthesized compounds revealed an exceptionally high activity against Candida albicans with a minimum inhibitory concentration (MIC) two orders of magnitude lower than the MIC of the antifungal reference drug amphotericin B. A strikingly high activity was also observed against three Gram-negative bacterial strains (Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus vulgaris), two of which are known human pathogens. Thus the discovered chemotype is a potential polypharmacological agent. The toxicity against mammalian tumor cells was found to be low, as demonstrated in five different human cell lines (HeLa, cervical; PC-3, prostate; MCF-7, breast; HepG2, liver; and HCT-116, colon). The internal consistency of the experimental data was studied using 3D-pharmacophore and 2D-QSAR. PMID:26256838

  20. Comparative modeling and molecular dynamics suggest high carboxylase activity of the Cyanobium sp. CACIAM14 RbcL protein.

    PubMed

    Siqueira, Andrei Santos; Lima, Alex Ranieri Jerônimo; Dall'Agnol, Leonardo Teixeira; de Azevedo, Juliana Simão Nina; da Silva Gonçalves Vianez, João Lídio; Gonçalves, Evonnildo Costa

    2016-03-01

    Rubisco catalyzes the first step reaction in the carbon fixation pathway, bonding atmospheric CO2/O2 to ribulose 1,5-bisphosphate; it is therefore considered one of the most important enzymes in the biosphere. Genetic modifications to increase the carboxylase activity of rubisco are a subject of great interest to agronomy and biotechnology, since this could increase the productivity of biomass in plants, algae and cyanobacteria and give better yields in crops and biofuel production. Thus, the aim of this study was to characterize in silico the catalytic domain of the rubisco large subunit (rbcL gene) of Cyanobium sp. CACIAM14, and identify target sites to improve enzyme affinity for ribulose 1,5-bisphosphate. A three-dimensional model was built using MODELLER 9.14, molecular dynamics was used to generate a 100 ns trajectory by AMBER12, and the binding free energy was calculated using MM-PBSA, MM-GBSA and SIE methods with alanine scanning. The model obtained showed characteristics of form-I rubisco, with 15 beta sheets and 19 alpha helices, and maintained the highly conserved catalytic site encompassing residues Lys175, Lys177, Lys201, Asp203, and Glu204. The binding free energy of the enzyme-substrate complexation of Cyanobium sp. CACIAM14 showed values around -10 kcal mol(-1) using the SIE method. The most important residues for the interaction with ribulose 1,5-bisphosphate were Arg295 followed by Lys334. The generated model was successfully validated, remaining stable during the whole simulation, and demonstrated characteristics of enzymes with high carboxylase activity. The binding analysis revealed candidates for directed mutagenesis sites to improve rubisco's affinity. PMID:26936271

  1. Estimation of Inhibitory Effect against Tyrosinase Activity through Homology Modeling and Molecular Docking

    PubMed Central

    Nokinsee, Daungkamon; Shank, Lalida; Lee, Vannajan Sanghiran; Nimmanpipug, Piyarat

    2015-01-01

    Tyrosinase is a key enzyme in melanogenesis. Generally, mushroom tyrosinase from A. bisporus had been used as a model in skin-whitening agent tests employed in the cosmetic industry. The recently obtained crystal structure of bacterial tyrosinase from B. megaterium has high similarity (33.5%) to the human enzyme and thus it was used as a template for constructing of the human model. Binding of tyrosinase to a series of its inhibitors was simulated by automated docking calculations. Docking and MD simulation results suggested that N81, N260, H263, and M280 are involved in the binding of inhibitors to mushroom tyrosinase. E195 and H208 are important residues in bacterial tyrosinase, while E230, S245, N249, H252, V262, and S265 bind to inhibitors and are important in forming pi interaction in human tyrosinase. PMID:26788364

  2. Synthesis and molecular modeling of antimicrobial active fluoroquinolone-pyrazine conjugates with amino acid linkers.

    PubMed

    Panda, Siva S; Detistov, Oleksandr S; Girgis, Adel S; Mohapatra, Prabhu P; Samir, Ahmed; Katritzky, Alan R

    2016-05-01

    Novel fluoroquinolone-pyrazine conjugates 7a-h with amino acid linkers were synthesized in good yields utilizing benzotriazole chemistry. Antimicrobial bioassay showed that the synthesized bis-conjugates have antimicrobial properties comparable to the parent drugs. Compound 7h showed superior antibacterial activity against Staphylococcus aureus and Streptococcus pyogenes (MIC=74.6μM and 149.3μM, respectively). This matched well with the estimated values obtained from 3D-pharmacophore and 2D-QSAR studies (MIC=67μM and 92.9μM, respectively). PMID:27025339

  3. Modeling of the Nervous System: From Modulation of Glutamatergic and Gabaergic Molecular Dynamics to Neuron Spiking Activity

    PubMed Central

    Legendre, Arnaud; Allam, Sushmita L.; Ambert, Nicolas; Hu, Eric Y.; Greget, Renaud; Keller, Anne F.; Pernot, Fabien; Bischoff, Serge; Baudry, Michel; Berger, Theodore W.

    2014-01-01

    One of the fundamental characteristics of the brain is its hierarchical and temporal organization: scales in both space and time must be considered to fully grasp the system’s underlying mechanisms and their impact on brain function. Complex interactions taking place at the molecular level regulate neuronal activity that further modifies the function of millions of neurons connected by trillions of synapses, ultimately giving rise to complex function and behavior at the system level. Likewise, the spatial complexity is accompanied by a complex temporal integration of events taking place at the microsecond scale leading to slower changes occurring at the second, minute and hour scales. These integrations across hierarchies of the nervous system are sufficiently complex to have impeded the development of routine multi-level modeling methodologies. The present study describes an example of our multiscale efforts to rise from the biomolecular level to the neuron level. We more specifically describe how we integrate biomolecular mechanisms taking place at glutamatergic and gabaergic synapses and integrate them to study the impact of these modifications on spiking activity of a CA1 pyramidal cell in the hippocampus. PMID:23367445

  4. The effect of various atomic partial charge schemes to elucidate consensus activity-correlating molecular regions: a test case of diverse QSAR models.

    PubMed

    Kumar, Sivakumar Prasanth; Jha, Prakash C; Jasrai, Yogesh T; Pandya, Himanshu A

    2016-03-01

    The estimation of atomic partial charges of the small molecules to calculate molecular interaction fields (MIFs) is an important process in field-based quantitative structure-activity relationship (QSAR). Several studies showed the influence of partial charge schemes that drastically affects the prediction accuracy of the QSAR model and focused on the selection of appropriate charge models that provide highest cross-validated correlation coefficient ([Formula: see text] or q(2)) to explain the variation in chemical structures against biological endpoints. This study shift this focus in a direction to understand the molecular regions deemed to explain SAR in various charge models and recognize a consensus picture of activity-correlating molecular regions. We selected eleven diverse dataset and developed MIF-based QSAR models using various charge schemes including Gasteiger-Marsili, Del Re, Merck Molecular Force Field, Hückel, Gasteiger-Hückel, and Pullman. The generalized resultant QSAR models were then compared with Open3DQSAR model to interpret the MIF descriptors decisively. We suggest the regions of activity contribution or optimization can be effectively determined by studying various charge-based models to understand SAR precisely. PMID:25997097

  5. Assessment of Molecular Modeling & Simulation

    SciTech Connect

    2002-01-03

    This report reviews the development and applications of molecular and materials modeling in Europe and Japan in comparison to those in the United States. Topics covered include computational quantum chemistry, molecular simulations by molecular dynamics and Monte Carlo methods, mesoscale modeling of material domains, molecular-structure/macroscale property correlations like QSARs and QSPRs, and related information technologies like informatics and special-purpose molecular-modeling computers. The panel's findings include the following: The United States leads this field in many scientific areas. However, Canada has particular strengths in DFT methods and homogeneous catalysis; Europe in heterogeneous catalysis, mesoscale, and materials modeling; and Japan in materials modeling and special-purpose computing. Major government-industry initiatives are underway in Europe and Japan, notably in multi-scale materials modeling and in development of chemistry-capable ab-initio molecular dynamics codes.

  6. Conserved molecular switch interactions in modeled cardioactive RF-NH2 peptide receptors: Ligand binding and activation.

    PubMed

    Rasmussen, M; Leander, M; Ons, S; Nichols, R

    2015-09-01

    Peptides may act through G protein-coupled receptors to influence cardiovascular performance; thus, delineating mechanisms involved in signaling is a molecular-based strategy to influence health. Molecular switches, often represented by conserved motifs, maintain a receptor in an inactive state. However, once the switch is broken, the transmembrane regions move and activation occurs. The molecular switches of Drosophila melanogaster myosuppressin (MS) receptors were previously identified to include a unique ionic lock and novel 3-6 lock, as well as transmission and tyrosine toggle switches. In addition to MS, cardioactive ligands structurally related by a C-terminal RF-NH2 include sulfakinin, neuropeptide F (NPF), short NPF, and FMRF-NH2-containing peptide subfamilies. We hypothesized receptor molecular switch motifs were conserved within a RF-NH2 subfamily and across species. Thus, we investigated RF-NH2 receptor (RFa-R) molecular switches in D. melanogaster, Tribolium castaneum, Anopheles gambiae, Rhodnius prolixus, and Bombyx mori. Adipokinetic hormone (AKH), which does not contain a RF-NH2, was also examined. The tyrosine toggle switch and ionic lock showed a higher degree of conservation within a RF-NH2 subfamily than the transmission switch and 3-7 lock. AKH receptor motifs were not representative of a RF-NH2 subfamily. The motifs and interactions of switches in the RFa-Rs were consistent with receptor activation and ligand-specific binding. PMID:26211890

  7. Molecular Modeling of Heme Proteins Using MOE: Bio-Inorganic and Structure-Function Activity for Undergraduates

    ERIC Educational Resources Information Center

    Ray, Gigi B.; Cook, J. Whitney

    2005-01-01

    A biochemical molecular modeling project on heme proteins suitable for an introductory Biochemistry I class has been designed with a 2-fold objective: i) to reinforce the correlation between protein three-dimensional structure and function through a discovery oriented project, and ii) to introduce students to the fields of bioinorganic and…

  8. Benzimidazole-Based Quinazolines: In Vitro Evaluation, Quantitative Structure-Activity Relationship, and Molecular Modeling as Aurora Kinase Inhibitors.

    PubMed

    Sharma, Alka; Luxami, Vijay; Saxena, Sanjai; Paul, Kamaldeep

    2016-03-01

    A series of benzimidazole-based quinazoline derivatives with different substitutions of primary and secondary amines at the C2 position (1-12) were evaluated for their Aurora kinase inhibitory activities. All compounds except for 3 and 6 showed good activity against Aurora kinase inhibitors, with IC50 values in the range of 0.035-0.532 μM. The ligand efficiency (LE) of the compounds with Aurora A kinase was also determined. The structure-activity relationship and the quantitative structure-activity relationship revealed that the Aurora inhibitory activities of these derivatives primarily depend on the different substitutions of the amine present at the C2 position of the quinazoline core. Molecular docking studies in the active binding site also provided theoretical support for the experimental biological data acquired. The current study identifies a novel class of Aurora kinase inhibitors, which can further be used for the treatment of cancer. PMID:26773437

  9. Molecular mechanisms of microglial activation.

    PubMed

    Zielasek, J; Hartung, H P

    1996-01-01

    Microglial cells are brain macrophages which serve specific functions in the defense of the central nervous system (CNS) against microorganisms, the removal of tissue debris in neurodegenerative diseases or during normal development, and in autoimmune inflammatory disorders of the brain. In cultured microglial cells, several soluble inflammatory mediators such as cytokines and bacterial products like lipopolysaccharide (LPS) were demonstrated to induce a wide range of microglial activities, e.g. increased phagocytosis, chemotaxis, secretion of cytokines, activation of the respiratory burst and induction of nitric oxide synthase. Since heightened microglial activation was shown to play a role in the pathogenesis of experimental inflammatory CNS disorders, understanding the molecular mechanisms of microglial activation may lead to new treatment strategies for neurodegenerative disorders, multiple sclerosis and bacterial or viral infections of the nervous system. PMID:8876774

  10. Synthesis, in vitro evaluation, and molecular modeling investigation of benzenesulfonimide peroxisome proliferator-activated receptors α antagonists.

    PubMed

    Ammazzalorso, Alessandra; Carrieri, Antonio; Verginelli, Fabio; Bruno, Isabella; Carbonara, Giuseppe; D'Angelo, Alessandra; De Filippis, Barbara; Fantacuzzi, Marialuigia; Florio, Rosalba; Fracchiolla, Giuseppe; Giampietro, Letizia; Giancristofaro, Antonella; Maccallini, Cristina; Cama, Alessandro; Amoroso, Rosa

    2016-05-23

    Recent evidences suggest a moderate activation of Peroxisome Proliferator-Activated Receptors (PPARs) could be favorable in metabolic diseases, reducing side effects given from full agonists. PPAR partial agonists and antagonists represent, to date, interesting tools to better elucidate biological processes modulated by these receptors. In this work are reported new benzenesulfonimide compounds able to block PPARα, synthesized and tested by transactivation assays and gene expression analysis. Some of these compounds showed a dose-dependent antagonistic behavior on PPARα, submicromolar potency, different profiles of selectivity versus PPARγ, and a repressive effect on CPT1A expression. Dockings and molecular dynamics on properly selected benzenesulfonimide derivatives furnished fresh insights into the molecular determinant most likely responsible for PPARα antagonism. PMID:26974385

  11. The alpha-5 segment of Bacillus thuringiensis delta-endotoxin: in vitro activity, ion channel formation and molecular modelling.

    PubMed Central

    Gazit, E; Bach, D; Kerr, I D; Sansom, M S; Chejanovsky, N; Shai, Y

    1994-01-01

    A peptide with a sequence corresponding to the highly conserved alpha-5 segment of the Cry delta-endotoxin family (amino acids 193-215 of Bacillus thuringiensis CryIIIA [Gazit and Shai (1993) Biochemistry 32, 3429-3436]), was investigated with respect to its interaction with insect membranes, cytotoxicity in vitro towards Spodoptera frugiperda (Sf-9) cells, and its propensity to form ion channels in planar lipid membranes (PLMs). Selectively labelled analogues of alpha-5 at either the N-terminal amino acid or the epsilon-amine of its lysine, were used to monitor the interaction of the peptides with insect membranes. The fluorescent emission spectra of the 7-nitrobenz-2-oxa-1,3-diazole-4-yl (NBD)-labelled alpha-5 peptides displayed a blue shift upon binding to insect (Spodoptera littoralis) mid-gut membranes, reflecting the relocation of the fluorescent probes to an environment of increased apolarity, i.e. within the lipidic constituent of the membrane. Moreover, midgut membrane-bound NBD-labelled alpha-5 peptides were protected from enzymic proteolysis. Functional characterization of alpha-5 has revealed that it is cytotoxic to Sf-9 insect cells, and that it forms ion channels in PLMs with conductances ranging from 30 to 1000 pS. A proline-substituted analogue of alpha-5 is less cytolytic and slightly more exposed to enzymic digestion. Molecular modelling utilizing simulated annealing via molecular dynamics suggests that a transbilayer pore may be formed by alpha-5 monomers that assemble to form a left-handed coiled coil of approximately parallel helices. These findings further support a role for alpha-5 in the toxic mechanism of delta-endotoxins, and assign alpha-5 as one of the transmembrane helices which form the toxic pore. The suggested role is consistent with the recent finding that cleavage of CryIVB delta-endotoxin in a loop between alpha-5 and alpha-6 is highly important for its larvicidal activity [Angsuthanasombat, Crickmore and Ellar (1993) FEMS

  12. Structural and functional effects of benzimidazole/thioether-copper complexes with antitumor activity on cell membranes and molecular models.

    PubMed

    Castillo, Ivan; Suwalsky, Mario; Gallardo, María José; Troncoso, Valentina; Sánchez-Eguía, Brenda N; Santiago-Osorio, Edelmiro; Aguiñiga, Itzen; González-Ugarte, Ana K

    2016-03-01

    Two cytotoxic copper(II) complexes with N-H and N-methylated benzimidazole-derived ligands (Cu-L(2) and Cu-L(2Me)) were synthesized and made to interact with human erythrocytes and molecular models of their plasmatic membranes. The latter consisted in lipid bilayers of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE), lipids of the types present in the outer and inner monolayers of the human erythrocyte membrane, respectively. Initial assessment of the interaction of the complexes with DMPC and DMPE consisted of X-ray diffraction studies, which showed preferential interactions with the former. Scanning electron microscopy (SEM) of erythrocytes incubated with solutions of the Cu(II) complexes evidenced deformation of the cells to stomatocytes and knizocytes by Cu-L(2) and Cu-L(2Me) due to interactions with the inner and outer leaflets of the cell membranes, respectively. This was further confirmed by real-time observation of the dose-dependent effects of the complexes on live erythrocytes by defocusing microscopy (DM). The combined observations, including the increased antiproliferative activity of the N-methylated complex Cu-L(2Me) over that of Cu-L(2) is rationalized based on the higher lipophilicity of the former. This property would facilitate passive diffusion of Cu-L(2Me) through the cell membrane, particularly in the initial stages when the DMPC-rich outer leaflet is involved. In contrast, the benzimidazole N-H groups of Cu-L(2) may participate in hydrogen bonding with DMPE polar groups; this result is consistent with the formation of stomatocyte induced by the latter complex. PMID:26775279

  13. Exploring Shifts in Middle School Learners' Modeling Activity While Generating Drawings, Animations, and Computational Simulations of Molecular Diffusion

    ERIC Educational Resources Information Center

    Wilkerson-Jerde, Michelle H.; Gravel, Brian E.; Macrander, Christopher A.

    2015-01-01

    Modeling and using technology are two practices of particular interest to K-12 science educators. These practices are inextricably linked among professionals, who engage in modeling activity with and across a variety of representational technologies. In this paper, we explore the practices of five sixth-grade girls as they generated models of…

  14. Molecular characteristics versus biological activity

    USGS Publications Warehouse

    Applegate, Vernon C.; Smith, Manning A.; Willeford, Bennett R.

    1967-01-01

    The molecular characteristics of mononitrophenols containing halogens not only play a key role in their biological activity but provide a novel example of selective toxicity among vertebrate animals. It has been reported that efforts to control the parasitic sea lamprey in the Great Lakes are directed at present to the applications of a selective toxicant to streams inhabited by lamprey larvae. Since 1961, the larvicide that has been used almost exclusively in the control program has been 3-trifluoromethyl-4-nitrophenol (TFM). However, this is only one of about 15 closely related compounds, all halogen-containing mononitrophenols, that display a selectively toxic action upon lampreys. Although not all of the halogenated mononitrophenols are selectively toxic to lampreys (in fact, fewer than half of those tested), no other group of related compounds has displayed any useful larvicidal activity except for the substituted nitrosalicylanilides.

  15. Investigating Molecular Mechanisms of Activation and Mutation of the HER2 Receptor Tyrosine Kinase through Computational Modeling and Simulation

    PubMed Central

    Telesco, Shannon E.; Shih, Andrew; Liu, Yingting; Radhakrishnan, Ravi

    2011-01-01

    Human epidermal growth factor receptor 2 (HER2)/ErbB2 is a receptor tyrosine kinase belonging to the EGFR/ErbB family and is overexpressed in 20–30% of human breast cancers. Since there is a growing effort to develop pharmacological inhibitors of the HER2 kinase for the treatment of breast cancer, it is clinically valuable to rationalize how specific mutations impact the molecular mechanism of receptor activation. Although several crystal structures of the ErbB kinases have been solved, the precise mechanism of HER2 activation remains unknown, and it has been suggested that HER2 is unique in its requirement for phosphorylation of Y877, a key tyrosine residue located in the activation loop (A-loop). In our studies, discussed here, we have investigated the mechanisms that are important in HER2 kinase domain regulation and compared them with the other ErbB family members, namely EGFR and ErbB4, to determine the molecular basis for HER2’s unique mode of activation. We apply computational simulation techniques at the atomic level and at the electronic structure (quantum mechanical) level to elucidate details of the mechanisms governing the kinase domains of these ErbB members. Through analysis of our simulation results, we have discovered potential regulatory mechanisms common to EGFR, HER2, and ErbB4, including a tight coupling between the A-loop and catalytic loop that may contribute to alignment of residues required for catalysis in the active kinase. We further postulate an autoinhibitory mechanism whereby the inactive kinase is stabilized through sequestration of catalytic residues. In HER2, we also predict a role for phosphorylated Y877 in bridging a network of hydrogen bonds that fasten the A-loop in its active conformation, suggesting that HER2 may be unique among the ErbB members in requiring A-loop tyrosine phosphorylation for functionality. In EGFR, HER2, and ErbB4, we discuss the possible effects of activating mutations. Delineation of the activation

  16. Exploring Shifts in Middle School Learners' Modeling Activity While Generating Drawings, Animations, and Computational Simulations of Molecular Diffusion

    NASA Astrophysics Data System (ADS)

    Wilkerson-Jerde, Michelle H.; Gravel, Brian E.; Macrander, Christopher A.

    2015-04-01

    Modeling and using technology are two practices of particular interest to K-12 science educators. These practices are inextricably linked among professionals, who engage in modeling activity with and across a variety of representational technologies. In this paper, we explore the practices of five sixth-grade girls as they generated models of smell diffusion using drawing, stop-motion animation, and computational simulation during a multi-day workshop. We analyze video, student discourse, and artifacts to address the questions: In what ways did learners' modeling practices, reasoning about mechanism, and ideas about smell shift as they worked across this variety of representational technologies? And, what supports enabled them to persist and progress in the modeling activity? We found that the girls engaged in two distinct modeling cycles that reflected persistence and deepening engagement in the task. In the first, messing about, they focused on describing and representing many ideas related to the spread of smell at once. In the second, digging in, they focused on testing and revising specific mechanisms that underlie smell diffusion. Upon deeper analysis, we found these cycles were linked to the girls' invention of "oogtom," a representational object that encapsulated many ideas from the first cycle and allowed the girls to restart modeling with the mechanistic focus required to construct simulations. We analyze the role of activity design, facilitation, and technological infrastructure in this pattern of engagement over the course of the workshop and discuss implications for future research, curriculum design, and classroom practice.

  17. Diarylsulfonamides and their bioisosteres as dual inhibitors of alkaline phosphatase and carbonic anhydrase: Structure activity relationship and molecular modelling studies.

    PubMed

    Al-Rashida, Mariya; Ejaz, Syeda Abida; Ali, Sharafat; Shaukat, Aisha; Hamayoun, Mehwish; Ahmed, Maqsood; Iqbal, Jamshed

    2015-05-15

    The effect of bioisosteric replacement of carboxamide linking group with sulfonamide linking group, on alkaline phosphatase (AP) and carbonic anhydrase (CA) inhibition activity of aromatic benzenesulfonamides was investigated. A series of carboxamide linked aromatic benzenesulfonamides 1a-1c, 2a-2d and their sulfonamide linked bioisosteres 3a-3d, 4a-4d was synthesized and evaluated for inhibitory activity against bovine tissue non-specific alkaline phosphatase (TNAP), intestinal alkaline phosphatase (IAP) and bCA II. A significant increase in CA inhibition activity was observed upon bioisosteric replacement of carboxamide linking group with a sulfonamide group. Some of these compounds were identified as highly potent and selective AP inhibitors. Compounds 1b, 2b, 3d, 4d 5b and 5c were found to be selective bTNAP inhibitors, whereas compounds 1a, 1c, 2a, 2c, 2d, 3a, 3c, 4a, 4b, 4c, 5a were found to be selective bIAP inhibitors. For most active AP inhibitor 3b, detailed kinetic studies indicated a competitive mode of inhibition against tissue non-specific alkaline phosphatase (TNAP) and non-competitive mode of inhibition against intestinal alkaline phosphatase (IAP). Molecular docking studies were carried out to rationalize important binding site interactions. PMID:25865133

  18. γ-Benzylidene digoxin derivatives synthesis and molecular modeling: Evaluation of anticancer and the Na,K-ATPase activity effect.

    PubMed

    Alves, Silmara L G; Paixão, Natasha; Ferreira, Letícia G R; Santos, Felipe R S; Neves, Luiza D R; Oliveira, Gisele C; Cortes, Vanessa F; Salomé, Kahlil S; Barison, Andersson; Santos, Fabio V; Cenzi, Gisele; Varotti, Fernando P; Oliveira, Soraya M F; Taranto, Alex G; Comar, Moacyr; Silva, Luciana M; Noël, François; Quintas, Luis Eduardo M; Barbosa, Leandro A; Villar, José A F P

    2015-08-01

    Cardiotonic steroids (CS), natural compounds with traditional use in cardiology, have been recently suggested to exert potent anticancer effects. However, the repertoire of molecules with Na,K-ATPase activity and anticancer properties is limited. This paper describes the synthesis of 6 new digoxin derivatives substituted (on the C17-butenolide) with γ-benzylidene group and their cytotoxic effect on human fibroblast (WI-26 VA4) and cancer (HeLa and RKO) cell lines as well as their effect on Na,K-ATPase activity and expression. As digoxin, compound BD-4 was almost 100-fold more potent than the other derivatives for cytotoxicity with the three types of cells used and was also the only one able to fully inhibit the Na,K-ATPase of HeLa cells after 24h treatment. No change in the Na,K-ATPase α1 isoform protein expression was detected. On the other hand it was 30-40 fold less potent for direct Na,K-ATPase inhibition, when compared to the most potent derivatives, BD-1 and BD-3, and digoxin. The data presented here demonstrated that the anticancer effect of digoxin derivatives substituted with γ-benzylidene were not related with their inhibition of Na,K-ATPase activity or alteration of its expression, suggesting that this classical molecular mechanism of CS is not involved in the cytotoxic effect of our derivatives. PMID:26122772

  19. An Evolutionary Model for Collapsing Molecular Clouds and their Star Formation Activity. II. Mass Dependence of the Star Formation Rate

    NASA Astrophysics Data System (ADS)

    Zamora-Avilés, Manuel; Vázquez-Semadeni, Enrique

    2014-10-01

    We discuss the evolution and dependence on cloud mass of the star formation rate (SFR) and efficiency (SFE) of star-forming molecular clouds (MCs) within the scenario that clouds are undergoing global collapse and that the SFR is controlled by ionization feedback. We find that low-mass clouds (M max <~ 104 M ⊙) spend most of their evolution at low SFRs, but end their lives with a mini-burst, reaching a peak SFR ~104 M ⊙ Myr-1, although their time-averaged SFR is only langSFRrang ~ 102 M ⊙ Myr-1. The corresponding efficiencies are SFEfinal <~ 60% and langSFErang <~ 1%. For more massive clouds (M max >~ 105 M ⊙), the SFR first increases and then reaches a plateau because the clouds are influenced by stellar feedback since earlier in their evolution. As a function of cloud mass, langSFRrang and langSFErang are well represented by the fits langSFRrang ≈ 100(1 + M max/1.4 × 105 M ⊙)1.68 M ⊙ Myr-1 and langSFErang ≈ 0.03(M max/2.5 × 105 M ⊙)0.33, respectively. Moreover, the SFR of our model clouds follows closely the SFR-dense gas mass relation recently found by Lada et al. during the epoch when their instantaneous SFEs are comparable to those of the clouds considered by those authors. Collectively, a Monte Carlo integration of the model-predicted SFR(M) over a Galactic giant molecular cloud mass spectrum yields values for the total Galactic SFR that are within half an order of magnitude of the relation obtained by Gao & Solomon. Our results support the scenario that star-forming MCs may be in global gravitational collapse and that the low observed values of the SFR and SFE are a result of the interruption of each SF episode, caused primarily by the ionizing feedback from massive stars.

  20. Molecular model generator toolkit

    SciTech Connect

    Schneider, R.D.

    1994-07-01

    This report is a user manual for an ASCII file of Fortran source code which must be compiled before use. The software will assist in creating plastic models of molecules whose specifications are described in the Brookhaven Protein Databank. Other data files can be used if they are in the same format as the files in the databank. The output file is a program for a 3-D Systems Stereolithography Apparatus and the program is run on a SGI Indigo workstation.

  1. [Molecular mechanisms of niclosamide antitumor activity].

    PubMed

    Moskaleva, E Yu; Perevozchikova, V G; Zhirnik, A S; Severin, S E

    2015-01-01

    In this review the recent data regarding the antitumor activity of niclosamide and the molecular mechanisms of its antitumor activity are presented. Niclosamide has been used in the clinic for the treatment of intestinal parasite infections. In recent years in several screening investigations of various drugs and chemical compounds niclosamide was identified as a potential anticancer agent. Niclosamide not only inhibits the Wnt/β-catenin, mTORC1, STAT3, NF-κB and Notch signaling pathways, but also targets mitochondria in cancer cells to induce growth inhibition and apoptosis. A number of studies have established the anticancer activity of niclosamide in both in vitro and in vivo in xenotransplantation models using human tumors and immunodeficient mice. It is important that niclosamide is active not only against tumor cells but also cancer stem cells. Normal cells are resistant to niclosamide. The accumulated experimental data suggest niclosamide is a promising drug for the treatment of various types of cancer. PMID:26716739

  2. Activation of the molecular chaperone, sigma 1 receptor, preserves cone function in a murine model of inherited retinal degeneration.

    PubMed

    Wang, Jing; Saul, Alan; Roon, Penny; Smith, Sylvia B

    2016-06-28

    Retinal degenerative diseases are major causes of untreatable blindness, and novel approaches to treatment are being sought actively. Here we explored the activation of a unique protein, sigma 1 receptor (Sig1R), in the treatment of PRC loss because of its multifaceted role in cellular survival. We used Pde6β(rd10) (rd10) mice, which harbor a mutation in the rod-specific phosphodiesterase gene Pde6β and lose rod and cone photoreceptor cells (PRC) within the first 6 wk of life, as a model for severe retinal degeneration. Systemic administration of the high-affinity Sig1R ligand (+)-pentazocine [(+)-PTZ] to rd10 mice over several weeks led to the rescue of cone function as indicated by electroretinographic recordings using natural noise stimuli and preservation of cone cells upon spectral domain optical coherence tomography and retinal histological examination. The protective effect appears to result from the activation of Sig1R, because rd10/Sig1R(-/-) mice administered (+)-PTZ exhibited no cone preservation. (+)-PTZ treatment was associated with several beneficial cellular phenomena including attenuated reactive gliosis, reduced microglial activation, and decreased oxidative stress in mutant retinas. To our knowledge, this is the first report that activation of Sig1R attenuates inherited PRC loss. The findings may have far-reaching therapeutic implications for retinal neurodegenerative diseases. PMID:27298364

  3. An evolutionary model for collapsing molecular clouds and their star formation activity. II. Mass dependence of the star formation rate

    SciTech Connect

    Zamora-Avilés, Manuel; Vázquez-Semadeni, Enrique

    2014-10-01

    We discuss the evolution and dependence on cloud mass of the star formation rate (SFR) and efficiency (SFE) of star-forming molecular clouds (MCs) within the scenario that clouds are undergoing global collapse and that the SFR is controlled by ionization feedback. We find that low-mass clouds (M {sub max} ≲ 10{sup 4} M {sub ☉}) spend most of their evolution at low SFRs, but end their lives with a mini-burst, reaching a peak SFR ∼10{sup 4} M {sub ☉} Myr{sup –1}, although their time-averaged SFR is only (SFR) ∼ 10{sup 2} M {sub ☉} Myr{sup –1}. The corresponding efficiencies are SFE{sub final} ≲ 60% and (SFE) ≲ 1%. For more massive clouds (M {sub max} ≳ 10{sup 5} M {sub ☉}), the SFR first increases and then reaches a plateau because the clouds are influenced by stellar feedback since earlier in their evolution. As a function of cloud mass, (SFR) and (SFE) are well represented by the fits (SFR) ≈ 100(1 + M {sub max}/1.4 × 10{sup 5} M {sub ☉}){sup 1.68} M {sub ☉} Myr{sup –1} and (SFE) ≈ 0.03(M {sub max}/2.5 × 10{sup 5} M {sub ☉}){sup 0.33}, respectively. Moreover, the SFR of our model clouds follows closely the SFR-dense gas mass relation recently found by Lada et al. during the epoch when their instantaneous SFEs are comparable to those of the clouds considered by those authors. Collectively, a Monte Carlo integration of the model-predicted SFR(M) over a Galactic giant molecular cloud mass spectrum yields values for the total Galactic SFR that are within half an order of magnitude of the relation obtained by Gao and Solomon. Our results support the scenario that star-forming MCs may be in global gravitational collapse and that the low observed values of the SFR and SFE are a result of the interruption of each SF episode, caused primarily by the ionizing feedback from massive stars.

  4. A supermolecular curcumin for enhanced antiproliferative and proapoptotic activities: molecular characteristics, computer modeling and in vivo pharmacokinetics

    NASA Astrophysics Data System (ADS)

    Tan, Qunyou; Wu, Jianyong; Li, Yi; Mei, Hu; Zhao, Chunjing; Zhang, Jingqing

    2013-01-01

    The supermolecular curcumin (SMCCM) exhibiting remarkably improved solubility and release characteristics was fabricated to increase the oral bioavailability in rat as well as the antiproliferative and proapoptotic activities of curcumin (CCM) against human lung adenocarcinoma cell A549. SMCCM was characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, morphology and structure, aqueous solubility, and release behavior in vitro. Computer modeling of the supermolecular structure was performed. The pharmacokinetics, antiproliferative and proapoptotic activities of SMCCM were evaluated. The mechanisms by which SMCCM inhibited proliferation and induced apoptosis were identified. The formation of SMCCM was testified and the supermolecular structure was studied by a computer modeling technique. Compared to free CCM, SMCCM with much higher aqueous solubility exhibited obviously enhanced release and more favorable pharmacokinetic profiles, and, furthermore, SMCCM showed higher anticancer efficacy, enhanced induction of G2/M-phase arrest and apoptosis in A549 cells, which might be involved with the increases in reactive oxygen species production and intracellular Ca2+ accumulation, and a decrease in mitochondrial membrane potential. SMCCM remarkably enhanced not only the oral bioavailability but also the antiproliferative and proapoptotic activities of CCM along with improved solubility and release characteristics of CCM.

  5. Medicinal Chemistry and Molecular Modeling: An Integration to Teach Drug Structure-Activity Relationship and the Molecular Basis of Drug Action

    ERIC Educational Resources Information Center

    Carvalho, Ivone; Borges, Aurea D. L.; Bernardes, Lilian S. C.

    2005-01-01

    The use of computational chemistry and the protein data bank (PDB) to understand and predict the chemical and molecular basis involved in the drug-receptor interactions is discussed. A geometrical and chemical overview of the great structural similarity in the substrate and inhibitor is provided.

  6. Molecular Modeling of Cardiac Troponin

    NASA Astrophysics Data System (ADS)

    Manning, Edward P.

    The cardiac thin filament regulates interactions of actin and myosin, the force-generating elements of muscular contraction. Over the past several decades many details have been discovered regarding the structure and function of the cardiac thin filament and its components, including cardiac troponin (cTn). My hypothesis is that signal propagation occurs between distant ends of the cardiac troponin complex through calcium-dependent alterations in the dynamics of cTn and tropomyosin (Tm). I propose a model of the thin filament that encompasses known structures of cTn, Tm and actin to gain insight into cardiac troponin's allosteric regulation of thin filament dynamics. By performing molecular dynamics simulations of cTn in conjunction with overlapping Tm in two conditions, with and without calcium bound to site II of cardiac troponin C (cTnC), I found a combination of calcium-dependent changes in secondary structure and dynamics throughout the cTn-Tm complex. I then applied this model to investigate familial hypertrophic cardiomyopathy (FHC), a disease of the sarcomere that is one of the most commonly occurring genetic causes of heart disease. Approximately 15% of known FHC-related mutations are found in cardiac troponin T (cTnT), most of which are in or flank the alpha-helical N-tail domain TNT1. TNT1 directly interacts with overlapping Tm coiled coils. Using this model I identified effects of TNT1 mutations that propagate to the cTn core where site II of cTnC, the regulatory site of calcium binding in the thin filament, is located. Specifically, I found that mutations in TNT1 alter the flexibility of TNT1 and that the flexibility of TNT1 is inversely proportional to the cooperativity of calcium activation of the thin filament. Further, I identified a pathway of propagation of structural and dynamic changes linking TNT1 to site II of cTnC. Mutation-induced changes at site II cTnC alter calcium coordination which corresponds to biophysical measurements of calcium

  7. Ratchet models of molecular motors

    NASA Astrophysics Data System (ADS)

    Jaster, Nicole

    2003-09-01

    Transport processes in and of cells are of major importance for the survival of the organism. Muscles have to be able to contract, chromosomes have to be moved to opposing ends of the cell during mitosis, and organelles, which are compartments enclosed by membranes, have to be transported along molecular tracks. Molecular motors are proteins whose main task is moving other molecules.For that purpose they transform the chemical energy released in the hydrolysis of ATP into mechanical work. The motors of the cytoskeleton belong to the three super families myosin, kinesin and dynein. Their tracks are filaments of the cytoskeleton, namely actin and the microtubuli. Here, we examine stochastic models which are used for describing the movements of these linear molecular motors. The scale of the movements comprises the regime of single steps of a motor protein up to the directed walk along a filament. A single step bridges around 10 nm, depending on the protein, and takes about 10 ms, if there is enough ATP available. Our models comprise M states or conformations the motor can attain during its movement along a one-dimensional track. At K locations along the track transitions between the states are possible. The velocity of the protein depending on the transition rates between the single states can be determined analytically. We calculate this velocity for systems of up to four states and locations and are able to derive a number of rules which are helpful in estimating the behaviour of an arbitrary given system. Beyond that we have a look at decoupled subsystems, i.e., one or a couple of states which have no connection to the remaining system. With a certain probability a motor undergoes a cycle of conformational changes, with another probability an independent other cycle. Active elements in real transport processes by molecular motors will not be limited to the transitions between the states. In distorted networks or starting from the discrete Master equation of the

  8. Ubiquitin: molecular modeling and simulations.

    PubMed

    Ganoth, Assaf; Tsfadia, Yossi; Wiener, Reuven

    2013-11-01

    The synthesis and destruction of proteins are imperative for maintaining their cellular homeostasis. In the 1970s, Aaron Ciechanover, Avram Hershko, and Irwin Rose discovered that certain proteins are tagged by ubiquitin before degradation, a discovery that awarded them the 2004 Nobel Prize in Chemistry. Compelling data gathered during the last several decades show that ubiquitin plays a vital role not only in protein degradation but also in many cellular functions including DNA repair processes, cell cycle regulation, cell growth, immune system functionality, hormone-mediated signaling in plants, vesicular trafficking pathways, regulation of histone modification and viral budding. Due to the involvement of ubiquitin in such a large number of diverse cellular processes, flaws and impairments in the ubiquitin system were found to be linked to cancer, neurodegenerative diseases, genetic disorders, and immunological disorders. Hence, deciphering the dynamics and complexity of the ubiquitin system is of significant importance. In addition to experimental techniques, computational methodologies have been gaining increasing influence in protein research and are used to uncover the structure, stability, folding, mechanism of action and interactions of proteins. Notably, molecular modeling and molecular dynamics simulations have become powerful tools that bridge the gap between structure and function while providing dynamic insights and illustrating essential mechanistic characteristics. In this study, we present an overview of molecular modeling and simulations of ubiquitin and the ubiquitin system, evaluate the status of the field, and offer our perspective on future progress in this area of research. PMID:24113788

  9. Synthesis, characterization and molecular modelling of a novel dipyridamole supramolecule - X-ray structure, quantum mechanics and molecular dynamics study to comprehend the hydrogen bond structure-activity relationship

    NASA Astrophysics Data System (ADS)

    Vepuri, Suresh B.; Devarajegowda, H. C.; Soliman, Mahmoud E.

    2016-02-01

    Hydrochloride salt formation for Active Pharmaceutical Ingredients (APIs) is the primary choice to impart aqueous solubility and to promote dissolution. Dipyridamole (DIP) is a cardiovascular drug which is practically insoluble in water. We discovered a new form of DIP called as dipyridamole hydrochloride trihydrate (DIPHT), which was prepared by an unusual method of reacting the DIP with hydrated hydrochloric acid (HCl) that was liberated in situ by the reaction of ferric chloride with water. The liberated HCl was consumed as reagent in situ by the scavenger (API) and was converted to a hydrochloride trihydrate. The product was characterized by FTIR, mass spectroscopy, PXRD and DSC. Supramolecular structure of this novel DIPHT was revealed by single crystal XRD. A sustained intramolecular hydrogen bond alliance was found in DIP and the DIPHT. Stability of this hydrogen bond was further evaluated by means of molecular modelling studies. We performed electron calculations using quantum mechanics (QM) on both the base and salt structures to compare their geometry and molecular orbital energy levels. Molecular Dynamics (MD) simulations were also conducted in explicit solvent models to provide more insights into the hydrogen bond strength and conformational preferences of the base and salt structure. Together with QM and MD, we were able to explain the influence of hydrogen bonds on proton uptake activity of DIP and stability of DIP and DIPHT. DIPHT which can dissolve faster than DIP in water may enhance the dissolution and bioavailability of the drug. As the current drug development research is shifting to repurpose the existing drugs in order to subside the untoward risks in new drug development, we believe that DIPHT with its intrinsic aqueous solubility could bring more application for DIP and generate interest within the pharmaceutical industry.

  10. External action of di- and polyamines on maxi calcium-activated potassium channels: an electrophysiological and molecular modeling study.

    PubMed Central

    Weiger, T M; Langer, T; Hermann, A

    1998-01-01

    In this study we compared polyamines to various diamines, and we modeled flexibility as well as hydrophobicity properties of these molecules to examine possible structural differences that could explain their external effects on the channels. The natural polyamines (putrescine, cadaverine, spermidine, spermine) and diamines increasing in CH2 chain length from C2 to C12 were used to probe maxi calcium-activated potassium (BK) channels in GH3 pituitary tumor cells when applied extracellularly. In single-channel recordings we found polyamines as well as diamines up to 1,10-diaminodecane to be ineffective in altering channel current amplitudes or kinetics. In contrast, 1,12-diamino dodecane (1,12-DD) was found to be a reversible blocker, with a blocking site at an electrical distance (z delta) of 0.72 within the channel. It reduced single-channel current amplitude, mean channel open time, and channel open probability. In computer simulations structural data, such as flexibility, hydration, and log D values, were calculated. 1,12-DD showed the largest flexibility of all diamines (minimum N-N distance 9.9 A) combined with a marked hydrophobicity due to a 4-5 A hydrophobic intersegment between hydrophilic ends in the molecule, as confirmed by GRID water probe maps and a log D value of -1.82 at pH 7.2. We propose that the amount of hydration of the molecule, more than its flexibility, constitutes an essential parameter for its ability to act as a channel blocker. PMID:9533685

  11. Multiscale Modeling of Molecular Magnets

    SciTech Connect

    Ramasesha, S.; Raghunathan, Rajamani

    2007-11-29

    Here, we present an overview of methods of modeling Molecular Magnets in different length scales. First, we discuss a microscopic model to understand the nature of superexchange interaction in binuclear transition metal complexes of different geometry viz. A-B, A-B-A, B-A-B, linear A-B-A-B, and cyclic A-B-A-B systems. We obtain the quantum phase diagrams along various planes in the parameter space and identify the various model parameters which control the nature of superexchange in these systems. We also obtain contours of effective superexchange constants. In the next section we discuss the method of full symmetry adaptation in Valence Bond method to obtain the low-lying eigenstates of the Heisenberg spin Hamiltonian of large systems. The third part of this article deals with the calculation of the magnetic anisotropy parameters (D{sub M} and E{sub M}) of Single Molecule Magnets (SMMs). We use the single ion anisotropy values to obtain D{sub M} and E{sub M} values of the SMM, using a perturbative approach. We first solve the unperturbed Hamiltonian which is a simple spin Heisenberg Hamiltonian. Then we introduce the perturbing term H{sub 1} consisting of the single ion anisotropy. We then solve for the molecular anisotropy parameters by equating two different ways for computing the matrix elements of the perturbation term, from knowledge of the spin-spin correlation functions and the direction of orientation of the single ion anisotropies.

  12. Interactive Modelling of Molecular Structures

    NASA Astrophysics Data System (ADS)

    Rustad, J. R.; Kreylos, O.; Hamann, B.

    2004-12-01

    The "Nanotech Construction Kit" (NCK) [1] is a new project aimed at improving the understanding of molecular structures at a nanometer-scale level by visualization and interactive manipulation. Our very first prototype is a virtual-reality program allowing the construction of silica and carbon structures from scratch by assembling them one atom at a time. In silica crystals or glasses, the basic building block is an SiO4 unit, with the four oxygen atoms arranged around the central silicon atom in the shape of a regular tetrahedron. Two silicate units can connect to each other by their silicon atoms covalently bonding to one shared oxygen atom. Geometrically, this means that two tetrahedra can link at their vertices. Our program is based on geometric representations and uses simple force fields to simulate the interaction of building blocks, such as forming/breaking of bonds and repulsion. Together with stereoscopic visualization and direct manipulation of building blocks using wands or data gloves, this enables users to create realistic and complex molecular models in short amounts of time. The NCK can either be used as a standalone tool, to analyze or experiment with molecular structures, or it can be used in combination with "traditional" molecular dynamics (MD) simulations. In a first step, the NCK can create initial configurations for subsequent MD simulation. In a more evolved setup, the NCK can serve as a visual front-end for an ongoing MD simulation, visualizing changes in simulation state in real time. Additionally, the NCK can be used to change simulation state on-the-fly, to experiment with different simulation conditions, or force certain events, e.g., the forming of a bond, and observe the simulation's reaction. [1] http://graphics.cs.ucdavis.edu/~okreylos/ResDev/NanoTech

  13. Molecular regulation of osteoclast activity.

    PubMed

    Bruzzaniti, Angela; Baron, Roland

    2006-06-01

    Osteoclasts are multinucleated cells derived from hematopoietic precursors that are primarily responsible for the degradation of mineralized bone during bone development, homeostasis and repair. In various skeletal disorders such as osteoporosis, hypercalcemia of malignancy, tumor metastases and Paget's disease, bone resorption by osteoclasts exceeds bone formation by osteoblasts leading to decreased bone mass, skeletal fragility and bone fracture. The overall rate of osteoclastic bone resorption is regulated either at the level of differentiation of osteoclasts from their monocytic/macrophage precursor pool or through the regulation of key functional proteins whose specific activities in the mature osteoclast control its attachment, migration and resorption. Thus, reducing osteoclast numbers and/or decreasing the bone resorbing activity of osteoclasts are two common therapeutic approaches for the treatment of hyper-resorptive skeletal diseases. In this review, several of the key functional players involved in the regulation of osteoclast activity will be discussed. PMID:16951988

  14. Towards understanding the mechanism of action of antibacterial N-alkyl-3-hydroxypyridinium salts: Biological activities, molecular modeling and QSAR studies.

    PubMed

    Dolezal, Rafael; Soukup, Ondrej; Malinak, David; Savedra, Ranylson M L; Marek, Jan; Dolezalova, Marie; Pasdiorova, Marketa; Salajkova, Sarka; Korabecny, Jan; Honegr, Jan; Ramalho, Teodorico C; Kuca, Kamil

    2016-10-01

    In this study, we have carried out a combined experimental and computational investigation to elucidate several bred-in-the-bone ideas standing out in rational design of novel cationic surfactants as antibacterial agents. Five 3-hydroxypyridinium salts differing in the length of N-alkyl side chain have been synthesized, analyzed by high performance liquid chromatography, tested for in vitro activity against a panel of pathogenic bacterial and fungal strains, computationally modeled in water by a SCRF B3LYP/6-311++G(d,p) method, and evaluated by a systematic QSAR analysis. Given the results of this work, the hypothesis suggesting that higher positive charge of the quaternary nitrogen should increase antimicrobial efficacy can be rejected since 3-hydroxyl group does increase the positive charge on the nitrogen but, simultaneously, it significantly derogates the antimicrobial activity by lowering the lipophilicity and by escalating the desolvation energy of the compounds in comparison with non-hydroxylated analogues. Herein, the majority of the prepared 3-hydroxylated substances showed notably lower potency than the parent pyridinium structures, although compound 8 with C12 alkyl chain proved a distinctly better antimicrobial activity in submicromolar range. Focusing on this anomaly, we have made an effort to reveal the reason of the observed activity through a molecular dynamics simulation of the interaction between the bacterial membrane and compound 8 in GROMACS software. PMID:27341309

  15. In Silico Calculation of Infinite Dilution Activity Coefficients of Molecular Solutes in Ionic Liquids: Critical Review of Current Methods and New Models Based on Three Machine Learning Algorithms.

    PubMed

    Paduszyński, Kamil

    2016-08-22

    The aim of the paper is to address all the disadvantages of currently available models for calculating infinite dilution activity coefficients (γ(∞)) of molecular solutes in ionic liquids (ILs)-a relevant property from the point of view of many applications of ILs, particularly in separations. Three new models are proposed, each of them based on distinct machine learning algorithm: stepwise multiple linear regression (SWMLR), feed-forward artificial neural network (FFANN), and least-squares support vector machine (LSSVM). The models were established based on the most comprehensive γ(∞) data bank reported so far (>34 000 data points for 188 ILs and 128 solutes). Following the paper published previously [J. Chem. Inf. Model 2014, 54, 1311-1324], the ILs were treated in terms of group contributions, whereas the Abraham solvation parameters were used to quantify an impact of solute structure. Temperature is also included in the input data of the models so that they can be utilized to obtain temperature-dependent data and thus related thermodynamic functions. Both internal and external validation techniques were applied to assess the statistical significance and explanatory power of the final correlations. A comparative study of the overall performance of the investigated SWMLR/FFANN/LSSVM approaches is presented in terms of root-mean-square error and average absolute relative deviation between calculated and experimental γ(∞), evaluated for different families of ILs and solutes, as well as between calculated and experimental infinite dilution selectivity for separation problems benzene from n-hexane and thiophene from n-heptane. LSSVM is shown to be a method with the lowest values of both training and generalization errors. It is finally demonstrated that the established models exhibit an improved accuracy compared to the state-of-the-art model, namely, temperature-dependent group contribution linear solvation energy relationship, published in 2011 [J. Chem

  16. Molecular modeling of auxin transport inhibitors

    SciTech Connect

    Gardner, G.; Black-Schaefer, C.; Bures, M.G. )

    1990-05-01

    Molecular modeling techniques have been used to study the chemical and steric properties of auxin transport inhibitors. These bind to a specific site on the plant plasma membrane characterized by its affinity for N-1-naphthylphthalamic acid (NPA). A three-dimensional model was derived from critical features of ligands for the NPA receptor, and a suggested binding conformation is proposed. This model, along with three-dimensional structural searching techniques, was then used to search the Abbott corporate database of chemical structures. Of the 467 compounds that satisfied the search criteria, 77 representative molecules were evaluated for their ability to compete for ({sup 3}H)NPA binding 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, from chemical classes not included in the original compound set, also inhibited polar auxin transport through corn coleoptile sections.

  17. Molecular magnetic resonance imaging of activated hepatic stellate cells with ultrasmall superparamagnetic iron oxide targeting integrin αvβ3 for staging liver fibrosis in rat model

    PubMed Central

    Zhang, Caiyuan; Liu, Huanhuan; Cui, Yanfen; Li, Xiaoming; Zhang, Zhongyang; Zhang, Yong; Wang, Dengbin

    2016-01-01

    Purpose To evaluate the expression level of integrin αvβ3 on activated hepatic stellate cells (HSCs) at different stages of liver fibrosis induced by carbon tetrachloride (CCl4) in rat model and the feasibility to stage liver fibrosis by using molecular magnetic resonance imaging (MRI) with arginine-glycine-aspartic acid (RGD) peptide modified ultrasmall superparamagnetic iron oxide nanoparticle (USPIO) specifically targeting integrin αvβ3. Materials and methods All experiments received approval from our Institutional Animal Care and Use Committee. Thirty-six rats were randomly divided into three groups of 12 subjects each, and intraperitoneally injected with CCl4 for either 3, 6, or 9 weeks. Controls (n=10) received pure olive oil. The change in T2* relaxation rate (ΔR2*) pre- and postintravenous administration of RGD-USPIO or naked USPIO was measured by 3.0T clinical MRI and compared by one-way analysis of variance or the Student’s t-test. The relationship between expression level of integrin αvβ3 and liver fibrotic degree was evaluated by Spearman’s ranked correlation. Results Activated HSCs were confirmed to be the main cell types expressing integrin αvβ3 during liver fibrogenesis. The protein level of integrin αv and β3 subunit expressed on activated HSCs was upregulated and correlated well with the progression of liver fibrosis (r=0.954, P<0.001; r=0.931, P<0.001, respectively). After injection of RGD-USPIO, there is significant difference in ΔR2* among rats treated with 0, 3, 6, and 9 weeks of CCl4 (P<0.001). The accumulation of iron particles in fibrotic liver specimen is significantly greater for RGD-USPIO than naked USPIO after being injected with equal dose of iron. Conclusion Molecular MRI of integrin αvβ3 expressed on activated HSCs by using RGD-USPIO may distinguish different liver fibrotic stages in CCl4 rat model and shows promising to noninvasively monitor the progression of the liver fibrosis and therapeutic response to

  18. Modeling flexible active nematics

    NASA Astrophysics Data System (ADS)

    Varga, Michael; Selinger, Robin

    We study active nematic phases of self-propelled flexible chains in two dimensions using computer simulation, to investigate effects of chain flexibility. In a ``dry'' phase of self-propelled flexible chains, we find that increasing chain stiffness enhances orientational order and correlation length, narrows the distribution of turning angles, increases persistence length, and increases the magnitude of giant density fluctuations. We further adapt the simulation model to describe behavior of microtubules driven by kinesin molecular motors in two different environments: on a rigid substrate with kinesin immobilized on the surface; and on a lipid membrane where kinesin is bonded to lipid head groups and can diffuse. Results are compared to experiments by L. Hirst and J. Xu. Lastly, we consider active nematics of flexible particles enclosed in soft, deformable encapsulation in two dimensions, and demonstrate novel mechanisms of pattern formation that are fundamentally different from those observed in bulk. Supported by NSF-DMR 1409658.

  19. Aspergillus niger lipase: Heterologous expression in Pichia pastoris, molecular modeling prediction and the importance of the hinge domains at both sides of the lid domain to interfacial activation.

    PubMed

    Shu, Zhengyu; Duan, Mojie; Yang, Jiangke; Xu, Li; Yan, Yunjun

    2009-01-01

    Aspergillus niger lipase (ANL) is an important biocatalyst in the food processing industry. However, there is no report of its detailed three-dimensional structure because of difficulties in crystallization. In this article, based on experimental data and bioinformational analysis results, the structural features of ANL were simulated. Firstly, two recombinant ANLs expressed in Pichia pastoris were purified to homogeneity and their corresponding secondary structure compositions were determined by circular dichroism spectra. Secondly, the primary structure, the secondary structure and the three-dimensional structure of ANL were modeled by comparison with homologous lipases with known three-dimensional structures using the BioEdit software, lipase engineering database (http://www.led.uni-stuttgart.de/), PSIPRED server and SwissModel server. The predicted molecular structure of ANL presented typical features of the alpha/beta hydrolase fold including positioning of the putative catalytic triad residues and the GXSXG signature motif. Comparison of the predicted three-dimensional structure of ANL with the X-ray three-dimensional structure of A. niger feruloyl esterase showed that the functional difference of interfacial activation between lipase and esterase was concerned with the difference in position of the lid. Our three-dimensional model of ANL helps to modify lipase structure by protein engineering, which will further expand the scope of application of ANL. PMID:19248178

  20. Molecular modeling of fluoropropene refrigerants.

    PubMed

    Raabe, Gabriele

    2012-05-17

    Different fluoropropenes are currently considered as refrigerants, either as pure compounds or as components in low GWP (global warming potential) refrigerant mixtures. Due to their limited commercial production, experimental data for the thermophysical properties of fluoropropenes and their mixtures are in general rare, which hampers the exploration of their performance in technical applications. In principle, molecular simulation can be used to predict the relevant properties of refrigerants and refrigerant blends, provided that adequate intermolecular potential functions ("force fields") are available. In our earlier work (Raabe, G.; Maginn, E. J., J. Phys. Chem. B2010, 114, 10133-10142), we introduced a transferable force field for fluoropropenes comprising the compounds 3,3,3-trifluoro-1-propene (HFO-1243zf), 2,3,3,3-tetrafluoro-1-propene (HFO-1234yf), and hexafluoro-1-propene (HFO-1216). In this paper, we provide an extension of the force field model to the trans- and cis-1,3,3,3-tetrafluoro-1-propene (HFO-1234ze(E), HFO-1234ze) and the cis-1,2,3,3,3-pentafluoro-1-propene (HFO-1225ye(Z)) as well as revised simulation results for HFO-1216. We present Gibbs ensemble simulation results on the vapor pressures, saturated densities, and heats of vaporization of these compounds in comparison with experimental results. The simulation results show that the force field model enables reliable predictions of the properties of the different fluoropropenes and also reproduces well the differing vapor-liquid coexistence and vapor pressure curve of the cis- and trans-isomers of 1,3,3,3-tetrafluoro-1-propene, HFO-1234ze and HFO-1234ze(E). For these two isomers, we also present molecular dynamics simulation studies on their local structure. PMID:22519953

  1. [The oxenoid model of the mechanism of activating molecular oxygen by cytochrome p450: the role of substrate structure].

    PubMed

    Kuznetsov, A V

    1990-01-01

    The arene oxides formation energy for about 30 benzene derivatives were calculated in frames of MO LCAO method. The benzene derivatives are typical substrates of cytochrome P-450 catalyzed aromatic oxidation. The relationship between the formation energy of tetrahedral type arene oxides and the relative reactivity of substrates toward microsomal hydroxylation was found. The formation energy of arene oxides correlates also with toxicity of benzene derivatives. Some limitations of the oxenoid model are discussed. PMID:2290428

  2. Synthesis, characterization, molecular modeling and antioxidant activity of Girard's T thiosemicarbazide and its complexes with some transition metal ions.

    PubMed

    El-Gammal, O A; Mostafa, M M

    2014-06-01

    The chelation behavior of N-{[(allylamino) thiomethyl] hydrazinocarbonylmethyl} trimethylammonium chloride (H3ATHC) towards VO(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+) and UO2(2+) ions have been studied. The structures of the complexes were elucidated using elemental analyses, spectral (IR, UV-visible, (1)H NMR and ESR and mass) as well as magnetic and thermal measurements. The ligand acted as ON bidentate, ONS tridentate donor forming mononuclear complexes. A tetrahedral geometry for Co(2+), square-planar for Ni(2+) and Cu(2+), an octahedral for Zn(2+) and a square-pyramidal arrangement for VO(2+) complexes were proposed, respectively. The EPR spectra of Cu(2+) and VO(2+) complexes confirmed the suggested geometries with values of α(2) and β(2) indicating that the in-plane σ-bonding and in-plane π-bonding are appreciably covalent, and were consistent with very strong in-plane σ bonding in the complexes. Also, the bond length, bond angle, HOMO, LUMO, dipole moment and charges on the atoms have been calculated. Also, the thermal behavior and kinetic parameters were determined using Coats-Redfern and Horowitz-Metzger methods. Furthermore, the synthesized compounds were screened for their superoxide-scavenging activity in the PMS/NADH-NBT system as well as their scavenging effect on ABTS (2,2'-azino-bis(3-ethyl benzthiazoline-6-sulfonic acid) and 2,2-diphenyl-1-picrylhydrazyl(DPPH) radicals. Among these compounds, the ligand and Zn(2+) complex, exhibited the potent ABTS (2,2'-azino-bis(3-ethyl benzthiazoline-6-sulfonic acid) radical scavenging activity, comparable to that of vitamin C. PMID:24705392

  3. Antitumor agents. 1. Synthesis, biological evaluation, and molecular modeling of 5H-pyrido[3,2-a]phenoxazin-5-one, a compound with potent antiproliferative activity.

    PubMed

    Bolognese, Adele; Correale, Gaetano; Manfra, Michele; Lavecchia, Antonio; Mazzoni, Orazio; Novellino, Ettore; Barone, Vincenzo; Pani, Alessandra; Tramontano, Enzo; La Colla, Paolo; Murgioni, Chiara; Serra, Ilaria; Setzu, Giovanna; Loddo, Roberta

    2002-11-21

    The iminoquinone is an important moiety of a large number of antineoplastic drugs and plays a significant role in the nucleus of actinomycins, powerful, highly toxic, natural antibiotics that target DNA as intercalating agents. A series of polycyclic iminoquinonic compounds, 2-amino-3H-phenoxazin-3-one (1), 2-amino-1,9-diacetyl-3H-phenoxazin-3-one (2), 2-acetylamino-3H-phenoxazin-3-one (3), 3H-phenoxazin-3-one (4), 5H-pyrido[3,2-a]phenoxazin-5-one (5), and 5H-pyrido[3,2-a]phenothiazin-5-one (6), strictly related to the actinomycin chromophore, were synthesized for developing new anticancer intercalating drugs. The antiproliferative activity of these compounds, evaluated against representative human liquid and solid neoplastic cell lines, showed that 5 and its isoster 6 were the most active compounds inhibiting cell proliferation in a submicromolar range. Compound 5 was also evaluated against KB subclones (KBMDR, KB7D, and KBV20C), which overexpress the MDR1/P-glycoprotein drug efflux pump responsible for drug resistance. All the above KB subclones did not show altered sensitivity to the antiproliferative activity of 5. UV-vis and (1)H NMR spectroscopy experiments support the phenoxazinone 5/DNA binding. Molecular mechanics methods were used to build a three-dimensional model of the 5/[d(GAAGCTTC)]2 complex. Electrostatic interactions between the hydrogen of the positively charged pyridine nitrogen of 5 and the negatively charged oxygen atoms (O4' and O5') of the cytosine C5 residue together with stacking forces contribute to the high antiproliferative activity. The metal(II)-assisted synthesis procedure of 5 is described, and the formation mechanism is proposed. PMID:12431048

  4. Synthesis, spectral characterization, molecular modeling and antimicrobial activity of new potentially N2O2 Schiff base complexes

    NASA Astrophysics Data System (ADS)

    Adly, Omima M. I.; Taha, Ali; Fahmy, Shery A.

    2013-12-01

    Metal complexes of a new potentially tetradentate symmetrical Schiff base ligand (H2L) with Cu(II), Ni(II), Co(II), VO(IV), Zn(II), Cd(II), Ce(III), Fe(III) and UO2(VI) metal ions have been synthesized and characterized based on their elemental analyses, spectral (IR, UV-Vis, 1H NMR and mass spectra), magnetic and molar conductance studies as well as thermal gravimetric analysis (TGA). The synthesized complexes have the general formula [MHxL(H2O)yXn]: x = 0-1, y = 0-4 and n = 0-1; where: L = dianion of 6-hydroxy-5-[N-(2-{[(1E)-1-(6-hydroxy-2,4-dioxo-3,4-dihydro-2H-1,3-thiazin-5-yl)ethylidene]amino}ethyl) ethanimidoyl]-2H-1,3-thiazine-2,4(3H)-dione and X = nitrate or sulphate anion. The ligand behaves as diabasic tetradentate N2O2 sites, except in cases of Co(II), VO(IV) and UO2(VI) metal ions, it behaves as monobasic tetradentate Schiff base ligand. The metal complexes exhibited square planar, square-pyramidal and octahedral geometrical arrangements except for Ce(III) and UO2(VI) complexes, they are octa-coordinated. The Coats-Redfern equation was used to calculate the kinetic and thermodynamic parameters for the different thermal decomposition stages of some complexes. Structural parameters of the ligand and its metal complexes have been theoretically computed on the basis of semiemperical PM3 level, and the results were correlated with their experimental data. The antimicrobial activities of the ligand and its metal complexes were tested against some Gram-positive and Gram-negative bacteria; and fungus strain and the results were discussed.

  5. Lysostaphin: molecular changes that preserve staphylolytic activity.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Lysostaphin is a potent staphylolytic enzyme with known resistance mechanisms. To avoid resistance development, this lab is developing lysostaphin-LysK fusion proteins harboring three synergistic lytic activities in one protein. Some of the molecular changes to lysostaphin and their effects on sta...

  6. Visible-Light-Activated Molecular Switches.

    PubMed

    Bléger, David; Hecht, Stefan

    2015-09-21

    The ability to influence key properties of molecular systems by using light holds much promise for the fields of materials science and life sciences. The cornerstone of such systems is molecules that are able to reversibly photoisomerize between two states, commonly referred to as photoswitches. One serious restriction to the development of functional photodynamic systems is the necessity to trigger switching in at least one direction by UV light, which is often damaging and penetrates only partially through most media. This review provides a summary of the different conceptual strategies for addressing molecular switches in the visible and near-infrared regions of the optical spectrum. Such visible-light-activated molecular switches tremendously extend the scope of photoswitchable systems for future applications and technologies. PMID:26096635

  7. Teaching Molecular Geometry with the VSEPR Model

    ERIC Educational Resources Information Center

    Gillespie, Ronald J.

    2004-01-01

    The first introduction to molecular geometry should be through the simple and easily understood VSEPR model, as the Valence Bond Theory and MO Theory suffer from limitations as far as understanding molecular geometry is concerned. The VSEPR model gives a perfectly satisfactory description of the bonding that follows directly from the Lewis model…

  8. Molecular modeling of human alkaline sphingomyelinase.

    PubMed

    Suresh, Panneer Selvam; Olubiyi, Olujide; Thirunavukkarasu, Chinnasamy; Strodel, Birgit; Kumar, Muthuvel Suresh

    2011-01-01

    Alkaline sphingomyelinase, which is expressed in the human intestine and hydrolyses sphingomyelin, is a component of the plasma and the lysosomal membranes. Hydrolase of sphingomyelin generates ceramide, sphingosine, and sphingosine 1-phosphate that have regulatory effects on vital cellular functions such as proliferation, differentiation, and apoptosis. The enzyme belongs to the Nucleotide Pyrophosphatase/Phosphodiesterase family and it differs in structural similarity with acidic and neutral sphingomyelinase. In the present study we modeled alkaline sphingomyelinase using homology modeling based on the structure of Nucleotide Pyrophosphatase/Phosphodiesterase from Xanthomonas axonopodis with which it shares 34% identity. Homology modeling was performed using Modeller9v7. We found that Cys78 and Cys394 form a disulphide bond. Further analysis shows that Ser76 may be important for the function of this enzyme, which is supported by the findings of Wu et al. (2005), that S76F abolishes the activity completely. We found that the residues bound to Zn(2+) are conserved and geometrically similar with the template. Molecular Dynamics simulations were carried out for the modeled protein to observe the effect of Zinc metal ions. It was observed that the metal ion has little effect with regard to the stability but induces increased fluctuations in the protein. These analyses showed that Zinc ions play an important role in stabilizing the secondary structure and in maintaining the compactness of the active site. PMID:21544170

  9. Computerized molecular modeling of carbohydrates

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Computerized molecular modleing continues to increase in capability and applicability to carbohydrates. This chapter covers nomenclature and conformational aspects of carbohydrates, perhaps of greater use to carbohydrate-inexperienced computational chemists. Its comments on various methods and studi...

  10. Molecular Imaging with SERS-Active Nanoparticles

    PubMed Central

    Zhang, Yin; Hong, Hao; Myklejord, Duane V.; Cai, Weibo

    2011-01-01

    Lead-in Raman spectroscopy has been explored for various biomedical applications (e.g. cancer diagnosis) because it can provide detailed information on the chemical composition of cells and tissues. For imaging applications, several variations of Raman spectroscopy have been developed to enhance its sensitivity. To date, a wide variety of molecular targets and biological events have been investigated using surface-enhanced Raman scattering (SERS)-active nanoparticles. The superb multiplexing capability of SERS-based Raman imaging, already successfully demonstrated in live animals, can be extremely powerful in future research where different agents can be attached to different Raman tags to enable the simultaneous interrogation of multiple biological events. Over the last several years, molecular imaging with SERS-active nanoparticles has advanced significantly and many pivotal proof-of-principle experiments have been successfully carried out. It is expected that SERS-based imaging will continue to be a dynamic research field over the next decade. PMID:21932216

  11. Molecular Determinants of GS-9620-Dependent TLR7 Activation

    PubMed Central

    Rebbapragada, Indrani; Birkus, Gabriel; Perry, Jason; Xing, Weimei; Kwon, HyockJoo; Pflanz, Stefan

    2016-01-01

    GS-9620 is an orally administered agonist of Toll-like receptor (TLR)7 currently being evaluated in clinical studies for the treatment of chronic HBV and HIV patients. GS-9620 has shown antiviral efficacy in preclinical models of chronic hepadnavirus infection in woodchuck as well as chimpanzee. However, the molecular determinants of GS-9620-dependent activation of TLR7 are not well defined. The studies presented here elucidate GS-9620 subcellular distribution and characterize its molecular interactions with human TLR7 using structure-guided mutational analysis. Based on our results we present a molecular model of TLR7 bound to GS-9620. We also determine that several coding SNPs had no effect on GS-9620-dependent TLR7 activation. In addition, our studies provide evidence that TLR7 exists in a ligand-independent oligomeric state and that, TLR7 activation by GS-9620 is likely associated with compound-induced conformational changes. Finally, we demonstrate that activation of NF-κB and Akt pathways in primary plasmacytoid dendritic cells occur as immediate downstream cellular responses to GS-9620 stimulation. The data presented here further our understanding of the molecular parameters governing TLR7 activation by GS-9620, and more generally by nucleos/tide-related ligands. PMID:26784926

  12. Molecular Modeling of Estrogen Receptor Using Molecular Operating Environment

    ERIC Educational Resources Information Center

    Roy, Urmi; Luck, Linda A.

    2007-01-01

    Molecular modeling is pervasive in the pharmaceutical industry that employs many of our students from Biology, Chemistry and the interdisciplinary majors. To expose our students to this important aspect of their education we have incorporated a set of tutorials in our Biochemistry class. The present article describes one of our tutorials where…

  13. The cognitive life of mechanical molecular models.

    PubMed

    Charbonneau, Mathieu

    2013-12-01

    The use of physical models of molecular structures as research tools has been central to the development of biochemistry and molecular biology. Intriguingly, it has received little attention from scholars of science. In this paper, I argue that these physical models are not mere three-dimensional representations but that they are in fact very special research tools: they are cognitive augmentations. Despite the fact that they are external props, these models serve as cognitive tools that augment and extend the modeler's cognitive capacities and performance in molecular modeling tasks. This cognitive enhancement is obtained because of the way the modeler interacts with these models, the models' materiality contributing to the solving of the molecule's structure. Furthermore, I argue that these material models and their component parts were designed, built and used specifically to serve as cognitive facilitators and cognitive augmentations. PMID:23910718

  14. Molecular modeling of nucleic acid structure

    PubMed Central

    Galindo-Murillo, Rodrigo; Bergonzo, Christina

    2013-01-01

    This unit is the first in a series of four units covering the analysis of nucleic acid structure by molecular modeling. This unit provides an overview of computer simulation of nucleic acids. Topics include the static structure model, computational graphics and energy models, generation of an initial model, and characterization of the overall three-dimensional structure. PMID:18428873

  15. Synthesis, spectral characterization, thermal analysis, molecular modeling and antimicrobial activity of new potentially N2O2 azo-dye Schiff base complexes

    NASA Astrophysics Data System (ADS)

    Alaghaz, Abdel-Nasser M. A.; Ammar, Yousry A.; Bayoumi, Hoda A.; Aldhlmani, Sharah A.

    2014-09-01

    The azo-dye Schiff's base of N2O2 dibasic ligand, H2L [N,N‧-bis(5-(4-sulfanilamidophenylazosalicylidene)ethylenediamine] was prepared by the condensation of ethylenediamine with [5-(4-sulfanilamidophenylazo-salicylaldehyde] in ethanol. New complexes of with metal ions Cu(II), Ni(II), Co(II), Mn(II), Zn(II), Cd(II), Pt(IV), Fe(III) and Cr(III) are synthesized. Elemental, spectroscopic and thermal analyses as well as conductivity and magnetic susceptibility measurements are used to elucidate the structure of the newly prepared metal complexes. The azo-dye Schiff's base behaves as a di-negative N2O2 tetradentate ligand. The metal complexes exhibited square planar, tetrahedral and octahedral geometrical arrangements, the molar conductivity data indicates that all complexes are neutral. The thermogravimetry (TG) and differential thermoanalysis (DTA) of the Cu(II), Mn(II), Cr(III) and Co(II) complexes were carried out in the range of 30-800 °C. The complexes were decomposed in one and two stages of the Cu(II), Mn(II), Cr(III) and Co(II) complexes, respectively. Also, decomposition of the synthesized complexes is related to the Schiff's base characteristics. The thermal decomposition of the studied reactions was first order. The kinetic parameters for the decomposition steps in Cu(II), Mn(II), Cr(III) and Co(II) complexes thermograms have been calculated using Broido's method. In molecular modeling the geometries of azo-dye Schiff base ligand H2L and its metal(II/III/IV) complexes were fully optimized with respect to the energy using the 6-31G basis set. Antimicrobial activities of the azo-dye Schiff's base ligand and its corresponding metal complexes were screened against various organisms. The azo-dye Schiff's base ligand and some of its complexes were found to be biologically inactive.

  16. Modeling the Hydrogen Bond within Molecular Dynamics

    ERIC Educational Resources Information Center

    Lykos, Peter

    2004-01-01

    The structure of a hydrogen bond is elucidated within the framework of molecular dynamics based on the model of Rahman and Stillinger (R-S) liquid water treatment. Thus, undergraduates are exposed to the powerful but simple use of classical mechanics to solid objects from a molecular viewpoint.

  17. Informing Mechanistic Toxicology with Computational Molecular Models

    EPA Science Inventory

    Computational molecular models of chemicals interacting with biomolecular targets provides toxicologists a valuable, affordable, and sustainable source of in silico molecular level information that augments, enriches, and complements in vitro and in vivo effo...

  18. Molecular modeling benzo[a]pyrene N2-dG adducts in the two overlapping active sites of the Y-family DNA polymerase Dpo4.

    PubMed

    Chandani, Sushil; Loechler, Edward L

    2007-01-01

    The potent, ubiquitous environmental mutagen/carcinogen benzo[a]pyrene (B[a]P) induces a single major adduct [+ta]-B[a]P-N2-dG, whose bypass in most cases results in either no mutation (dCTP insertion) or a G-->T mutation (dATP insertion). Translesion synthesis (TLS) of [+ta]-B[a]P-N2-dG generally requires DNA polymerases (DNAPs) in the Y-family, which exist in cells to bypass DNA damage caused by chemicals and radiation. A molecular dynamics (MD) study is described with dCTP opposite [+ta]-B[a]P-N2-dG in Dpo4, which is the best studied Y-family DNAP from a structural point of view. Two orientations of B[a]P-N2-dG (BPmi5 and BPmi3) are considered, along with two orientations of the dCTP (AS1 and AS2), as outlined next. Based on NMR studies, the pyrene moiety of B[a]P-N2-dG is in the minor groove, when paired with dC, and can point toward either the base on the 5'-side (BPmi5) or the 3'-side (BPmi3). Based on published X-ray structures, Dpo4 appears to have two partially overlapping active sites. The architecture of active site 1 (AS1) is similar to all other families of DNAPs (e.g., the shape of the dNTP). Active site 2 (AS2), however, is non-canonical (e.g., the beta- and gamma-phosphates in AS2 are approximately where the alpha- and beta-phosphates are in AS1). In the Dpo4 models generated herein, using the BPmi3 orientation the pyrene moiety of [+ta]-B[a]P-N2-dG points toward the duplex region of the DNA, and is accommodated without distortions in AS1, but with distortions in AS2. Considering the BPmi5 orientation, the pyrene moiety points toward the ss-region of DNA in Dpo4, and sits in a hole defined by the fingers and little fingers domain ("chimney"); BPmi5 is accommodated in AS2 without significant distortions, but poorly in AS1. In summary, when dCTP is paired with [+ta]-B[a]P-N2-dG in the two overlapping active sites in Dpo4, the pyrene in the BPmi3 orientation is accommodated better in active site 1 (AS1), while the pyrene in the BPmi5 orientation is

  19. Molecular emission in chemically active protostellar outflows

    NASA Astrophysics Data System (ADS)

    Lefloch, B.

    2011-12-01

    Protostellar outflows play an important role in the dynamical and chemical evolution of cloud through shocks. The Herschel Space Observatory (HSO) brings new insight both on the molecular content and the physical conditions in protostellar shocks through high spectral and angular resolution studies of the emission of major gas cooling agents and hydrides. The Herschel/CHESS key-program is carrying out an in depth study of the prototypical shock region L1157-B1. Analysis of the line profiles detected allows to constrain the formation/destruction route of various molecular species, in relation with the predictions of MHD shock models. The Herschel/WISH key-program investigates the properties and origin of water emission in a broad sample of protostellar outflows and envelopes. Implications of the first results for future studies on mass-loss phenomena are discussed.

  20. Reasoning with Atomic-Scale Molecular Dynamic Models

    ERIC Educational Resources Information Center

    Pallant, Amy; Tinker, Robert F.

    2004-01-01

    The studies reported in this paper are an initial effort to explore the applicability of computational models in introductory science learning. Two instructional interventions are described that use a molecular dynamics model embedded in a set of online learning activities with middle and high school students in 10 classrooms. The studies indicate…

  1. Structure–Activity Relationships and Molecular Modeling of 3,5-Diacyl-2,4-dialkylpyridine Derivatives as Selective A3 Adenosine Receptor Antagonists

    PubMed Central

    Li, An-Hu; Moro, Stefano; Melman, Neli; Ji, Xiao-duo; Jacobson, Kenneth A.

    2012-01-01

    The structure-activity relationships of 6-phenyl-1,4-dihydropyridine derivatives as selective antagonists at human A3 adenosine receptors have been explored (Jiang et al. J. Med. Chem. 1997, 39, 4667-4675). In the present study, related pyridine derivatives have been synthesized and tested for affinity at adenosine receptors in radioligand binding assays. Ki values in the nanomolar range were observed for certain 3,5-diacyl-2,4-dialkyl-6-phenylpyridine derivatives in displacement of [125I]AB-MECA (N6-(4-amino-3-iodobenzyl)-5′-N-methylcarbamoyladenosine) at recombinant human A3 adenosine receptors. Selectivity for A3 adenosine receptors was determined vs radioligand binding at rat brain A1 and A2A receptors. Structure–activity relationships at various positions of the pyridine ring (the 3- and 5-acyl substituents and the 2- and 4-alkyl substituents) were probed. A 4-phenylethynyl group did not enhance A3 selectivity of pyridine derivatives, as it did for the 4-substituted dihydropyridines. At the 2-and 4-positions ethyl was favored over methyl. Also, unlike the dihydropyridines, a thioester group at the 3-position was favored over an ester for affinity at A3 adenosine receptors, and a 5-position benzyl ester decreased affinity. Small cycloalkyl groups at the 6-position of 4-phenylethynyl-1,4-dihydropyridines were favorable for high affinity at human A3 adenosine receptors, while in the pyridine series a 6-cyclopentyl group decreased affinity. 5-Ethyl 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 38, was highly potent at human A3 receptors, with a Ki value of 20 nM. A 4-propyl derivative, 39b, was selective and highly potent at both human and rat A3 receptors, with Ki values of 18.9 and 113 nM, respectively. A 6-(3-chlorophenyl) derivative, 44, displayed a Ki value of 7.94 nM at human A3 receptors and selectivity of 5200-fold. Molecular modeling, based on the steric and electrostatic alignment (SEAL) method, defined common pharmacophore

  2. DNA-binding affinity and anticancer activity of β-carboline-chalcone conjugates as potential DNA intercalators: Molecular modelling and synthesis.

    PubMed

    Shankaraiah, Nagula; Siraj, K P; Nekkanti, Shalini; Srinivasulu, Vunnam; Sharma, Pankaj; Senwar, Kishna Ram; Sathish, Manda; Vishnuvardhan, M V P S; Ramakrishna, Sistla; Jadala, Chetna; Nagesh, Narayana; Kamal, Ahmed

    2015-04-01

    A new series of DNA-interactive β-carboline-chalcone conjugates have been synthesized and evaluated for their in vitro cytotoxicity and DNA-binding affinity. It has been observed that most of these new hybrids have shown potent cytotoxic activities on A-549 (lung adenocarcinoma) cell lines with IC50 values lower than 10 μM. The hybrid 7b is more effective against some of the selected cancer cell lines with IC50 values less than 50 μM. In addition, compounds 7e, 7k, 7p-u has displayed significant elevation in ΔTm of DNA in comparison to Adriamycin, suggesting significant interaction and remarkable DNA stabilization. The DNA intercalation of these new hybrids has been investigated by fluorescence titration, DNA viscosity measurements, molecular docking as well as molecular dynamics and the results are in agreement with the thermal denaturation studies. PMID:25771335

  3. Mixed ligand complexation of some transition metal ions in solution and solid state: Spectral characterization, antimicrobial, antioxidant, DNA cleavage activities and molecular modeling

    NASA Astrophysics Data System (ADS)

    Shobana, Sutha; Dharmaraja, Jeyaprakash; Selvaraj, Shanmugaperumal

    2013-04-01

    Equilibrium studies of Ni(II), Cu(II) and Zn(II) mixed ligand complexes involving a primary ligand 5-fluorouracil (5-FU; A) and imidazoles viz., imidazole (him), benzimidazole (bim), histamine (hist) and L-histidine (his) as co-ligands(B) were carried out pH-metrically in aqueous medium at 310 ± 0.1 K with I = 0.15 M (NaClO4). In solution state, the stoichiometry of MABH, MAB and MAB2 species have been detected. The primary ligand(A) binds the central M(II) ions in a monodentate manner whereas him, bim, hist and his co-ligands(B) bind in mono, mono, bi and tridentate modes respectively. The calculated Δ log K, log X and log X' values indicate higher stability of the mixed ligand complexes in comparison to binary species. Stability of the mixed ligand complex equilibria follows the Irving-Williams order of stability. In vitro biological evaluations of the free ligand(A) and their metal complexes by well diffusion technique show moderate activities against common bacterial and fungal strains. Oxidative cleavage interaction of ligand(A) and their copper complexes with CT DNA is also studied by gel electrophoresis method in the presence of oxidant. In vitro antioxidant evaluations of the primary ligand(A), CuA and CuAB complexes by DPPH free radical scavenging model were carried out. In solid, the MAB type of M(II)sbnd 5-FU(A)sbnd his(B) complexes were isolated and characterized by various physico-chemical and spectral techniques. Both the magnetic susceptibility and electronic spectral analysis suggest distorted octahedral geometry. Thermal studies on the synthesized mixed ligand complexes show loss of coordinated water molecule in the first step followed by decomposition of the organic residues subsequently. XRD and SEM analysis suggest that the microcrystalline nature and homogeneous morphology of MAB complexes. Further, the 3D molecular modeling and analysis for the mixed ligand MAB complexes have also been carried out.

  4. Molecular Modeling of Fluorescent SERCA Biosensors.

    PubMed

    Svensson, Bengt; Autry, Joseph M; Thomas, David D

    2016-01-01

    Molecular modeling and simulation are useful tools in structural biology, allowing the formulation of functional hypotheses and interpretation of spectroscopy experiments. Here, we describe a method to construct in silico models of a fluorescent fusion protein construct, where a cyan fluorescent protein (CFP) is linked to the actuator domain of the Sarco/Endoplasmic Reticulum Ca(2+)-ATPase (SERCA). This CFP-SERCA construct is a biosensor that can report on structural dynamics in the cytosolic headpiece of SERCA. Molecular modeling and FRET experiments allow us to generate new structural and mechanistic models that better describe the conformational landscape and regulation of SERCA. The methods described here can be applied to the creation of models for any fusion protein constructs and also describe the steps needed to simulate FRET results using molecular models. PMID:26695057

  5. Design, synthesis, anti-tumor activity, and molecular modeling of quinazoline and pyrido[2,3-d]pyrimidine derivatives targeting epidermal growth factor receptor.

    PubMed

    Hou, Ju; Wan, Shanhe; Wang, Guangfa; Zhang, Tingting; Li, Zhonghuang; Tian, Yuanxin; Yu, Yonghuan; Wu, Xiaoyun; Zhang, Jiajie

    2016-08-01

    Three series of novel quinazoline and pyrido[2,3-d]pyrimidine derivatives were designed, synthesized and evaluated for their ability to inhibit EGFR tyrosine kinase and a panel of five human cancer cell lines (MCF-7, A549, BT-474, SK-BR-3, and MDA-MB-231). Bioassay results indicated that five of these prepared compounds (12c-12e and 13c-13d) exhibited remarkably higher inhibitory activities against EGFR and SK-BR-3 cell line. Compounds 12c and 12e displayed the most potent EGFR inhibitory activity (IC50 = 2.97 nM and 3.58 nM, respectively) and good anti-proliferative effect against SK-BR-3 cell with the IC50 values of 3.10 μM and 5.87 μM, respectively. Furthermore, molecular docking and molecular dynamics simulation studies verified that compound 12c and 12e shared similar binding pattern with gefitinib in the binding pocket of EGFR. MM-GBSA binding free energy revealed that the compound 12c and 12e have almost the same inhibitory activity against EGFR as gefitinib, and that the dominating effect of van der Waals interactions drives the binding process. PMID:27132165

  6. Structures in Molecular Clouds: Modeling

    SciTech Connect

    Kane, J O; Mizuta, A; Pound, M W; Remington, B A; Ryutov, D D

    2006-04-20

    We attempt to predict the observed morphology, column density and velocity gradient of Pillar II of the Eagle Nebula, using Rayleigh Taylor (RT) models in which growth is seeded by an initial perturbation in density or in shape of the illuminated surface, and cometary models in which structure is arises from a initially spherical cloud with a dense core. Attempting to mitigate suppression of RT growth by recombination, we use a large cylindrical model volume containing the illuminating source and the self-consistently evolving ablated outflow and the photon flux field, and use initial clouds with finite lateral extent. An RT model shows no growth, while a cometary model appears to be more successful at reproducing observations.

  7. An androgen receptor mutation in the MDA-MB-453 cell line model of molecular apocrine breast cancer compromises receptor activity.

    PubMed

    Moore, Nicole L; Buchanan, Grant; Harris, Jonathan M; Selth, Luke A; Bianco-Miotto, Tina; Hanson, Adrienne R; Birrell, Stephen N; Butler, Lisa M; Hickey, Theresa E; Tilley, Wayne D

    2012-08-01

    Recent evidence indicates that the estrogen receptor-α-negative, androgen receptor (AR)-positive molecular apocrine subtype of breast cancer is driven by AR signaling. The MDA-MB-453 cell line is the prototypical model of this breast cancer subtype; its proliferation is stimulated by androgens such as 5α-dihydrotestosterone (DHT) but inhibited by the progestin medroxyprogesterone acetate (MPA) via AR-mediated mechanisms. We report here that the AR gene in MDA-MB-453 cells contains a G-T transversion in exon 7, resulting in a receptor variant with a glutamine to histidine substitution at amino acid 865 (Q865H) in the ligand binding domain. Compared with wild-type AR, the Q865H variant exhibited reduced sensitivity to DHT and MPA in transactivation assays in MDA-MB-453 and PC-3 cells but did not respond to non-androgenic ligands or receptor antagonists. Ligand binding, molecular modeling, mammalian two-hybrid and immunoblot assays revealed effects of the Q865H mutation on ligand dissociation, AR intramolecular interactions, and receptor stability. Microarray expression profiling demonstrated that DHT and MPA regulate distinct transcriptional programs in MDA-MB-453 cells. Gene Set Enrichment Analysis revealed that DHT- but not MPA-regulated genes were associated with estrogen-responsive transcriptomes from MCF-7 cells and the Wnt signaling pathway. These findings suggest that the divergent proliferative responses of MDA-MB-453 cells to DHT and MPA result from the different genetic programs elicited by these two ligands through the AR-Q865H variant. This work highlights the necessity to characterize additional models of molecular apocrine breast cancer to determine the precise role of AR signaling in this breast cancer subtype. PMID:22719059

  8. The analysis of structure-anticancer and antiviral activity relationships for macrocyclic pyridinophanes and their analogues on the basis of 4D QSAR models (simplex representation of molecular structure).

    PubMed

    Kuz'min, Victor E; Artemenko, Anatoly G; Lozitsky, Victor P; Muratov, Eugene N; Fedtchouk, Alla S; Dyachenko, Natalia S; Nosach, Lidiya N; Gridina, Tatiyana L; Shitikova, Larisa I; Mudrik, Liubov M; Mescheriakov, Aleksey K; Chelombitko, Vladislav A; Zheltvay, Andrey I; Vanden Eynde, Jean-Jaques

    2002-01-01

    A new 4D-QSAR approach has been considered. For all investigated molecules the 3D structural models have been created and the set of conformers (fourth dimension) have been used. Each conformer is represented as a system of different simplexes (tetratomic fragments of fixed structure, chirality and symmetry). The investigation of influence of molecular structure of macrocyclic pyridinophanes, their analogues and certain other compounds on anticancer and antiviral (anti-influenza, antiherpes and antiadenovirus) activity has been carried out by means of the 4D-QSAR. Statistic characteristics for QSAR of PLS (partial least squares) models are satisfactory (R = 0.92-0.97; CVR = 0.63-0.83). Molecular fragments increasing and decreasing biological activity were defined. This information may be useful for design, and direct synthesis of novel anticancer and antiviral agents. PMID:12136936

  9. Synthesis, spectral characterization, molecular modeling and antimicrobial activity studies on 2-aminopyridine-cyclodiphosph(V)azane derivative and its homo-binuclear zinc(II) complexes

    NASA Astrophysics Data System (ADS)

    Alaghaz, Abdel-Nasser M. A.

    2014-06-01

    Complexes of zinc(II) of general composition [Zn2(L)X2(H2O)4]nH2O have been synthesized [L = 1,3-dipyridyl-2,4-dioxo-2‧,4‧-bis(2-iminopyridine)cyclodi-phosph(V)azane and X = NO3-; n = 2, OAc-; n = 1, SO42-; n = 2 and Cl-; n = 2]. The elemental analysis, molar conductance measurements, mass, IR, UV, NMR (1H and 31P), TGA, DTA, SEM and XRD spectral studies of the compounds led to the conclusion that the cyclodiphosph(V)azane ligand (H2L) acts as a bidentate manner per zinc ion. The cyclodiphosph(V)azane ligand forms hexa-coordinated complexes having octahedral geometry for Zn(II) complexes. The elemental analyses and mass spectral data have justified the [Zn2(L)X2(H2O)4]nH2O composition of complexes. Infrared spectra of the zinc complexes indicate deprotonation and coordination of the imine NH. It also confirms that nitrogen atoms of the pyridine group contribute to the complexation. The X-ray powder diffraction (XRD) was performed of [Zn2L(SO4)2(H2O)4]2H2O complex. The XRD patterns indicate crystalline nature for the [Zn2L(SO4)2(H2O)4]2H2O complex. The measured low molar conductance values in dimethylformamide indicate that the complexes are non-electrolyte nature. The surface morphology (SEM) of the cyclodiphosph(V)azane ligand and the [Zn2L(NO3)2(H2O)4]2H2O complex were studied by SEM. The thermal studies suggested that the complexes are more stable as compared to ligand. In molecular modeling the geometries of cyclodiphosph(V)azane ligand H2L and its zinc(II) complexes were fully optimized with respect to the energy using the 6-31G basis set. The cyclodiphosph(V)azane ligand and the zinc(II) complexes have been measured in vitro to judge their antibacterial (Escherichia coli and Staphylococcus aureus) and antifungal (Aspergillus niger and Pencillium chrysogenum) activities.

  10. Markov state models and molecular alchemy

    NASA Astrophysics Data System (ADS)

    Schütte, Christof; Nielsen, Adam; Weber, Marcus

    2015-01-01

    In recent years, Markov state models (MSMs) have attracted a considerable amount of attention with regard to modelling conformation changes and associated function of biomolecular systems. They have been used successfully, e.g. for peptides including time-resolved spectroscopic experiments, protein function and protein folding , DNA and RNA, and ligand-receptor interaction in drug design and more complicated multivalent scenarios. In this article, a novel reweighting scheme is introduced that allows to construct an MSM for certain molecular system out of an MSM for a similar system. This permits studying how molecular properties on long timescales differ between similar molecular systems without performing full molecular dynamics simulations for each system under consideration. The performance of the reweighting scheme is illustrated for simple test cases, including one where the main wells of the respective energy landscapes are located differently and an alchemical transformation of butane to pentane where the dimension of the state space is changed.

  11. Molecular Imaging of the ATM Kinase Activity

    SciTech Connect

    Williams, Terence M.; Nyati, Shyam; Ross, Brian D.; Rehemtulla, Alnawaz

    2013-08-01

    Purpose: Ataxia telangiectasia mutated (ATM) is a serine/threonine kinase critical to the cellular DNA-damage response, including from DNA double-strand breaks. ATM activation results in the initiation of a complex cascade of events including DNA damage repair, cell cycle checkpoint control, and survival. We sought to create a bioluminescent reporter that dynamically and noninvasively measures ATM kinase activity in living cells and subjects. Methods and Materials: Using the split luciferase technology, we constructed a hybrid cDNA, ATM-reporter (ATMR), coding for a protein that quantitatively reports on changes in ATM kinase activity through changes in bioluminescence. Results: Treatment of ATMR-expressing cells with ATM inhibitors resulted in a dose-dependent increase in bioluminescence activity. In contrast, induction of ATM kinase activity upon irradiation resulted in a decrease in reporter activity that correlated with ATM and Chk2 activation by immunoblotting in a time-dependent fashion. Nuclear targeting improved ATMR sensitivity to both ATM inhibitors and radiation, whereas a mutant ATMR (lacking the target phosphorylation site) displayed a muted response. Treatment with ATM inhibitors and small interfering (si)RNA-targeted knockdown of ATM confirm the specificity of the reporter. Using reporter expressing xenografted tumors demonstrated the ability of ATMR to report in ATM activity in mouse models that correlated in a time-dependent fashion with changes in Chk2 activity. Conclusions: We describe the development and validation of a novel, specific, noninvasive bioluminescent reporter that enables monitoring of ATM activity in real time, in vitro and in vivo. Potential applications of this reporter include the identification and development of novel ATM inhibitors or ATM-interacting partners through high-throughput screens and in vivo pharmacokinetic/pharmacodynamic studies of ATM inhibitors in preclinical models.

  12. Exploring Organic Mechanistic Puzzles with Molecular Modeling

    ERIC Educational Resources Information Center

    Horowitz, Gail; Schwartz, Gary

    2004-01-01

    The molecular modeling was used to reinforce more general skills such as deducing and drawing reaction mechanisms, analyzing reaction kinetics and thermodynamics and drawing reaction coordinate energy diagrams. This modeling was done through the design of mechanistic puzzles, involving reactions not familiar to the students.

  13. Identification of essential residues for binding and activation in the human 5-HT7(a) serotonin receptor by molecular modeling and site-directed mutagenesis.

    PubMed

    Impellizzeri, Agata Antonina Rita; Pappalardo, Matteo; Basile, Livia; Manfra, Ornella; Andressen, Kjetil Wessel; Krobert, Kurt Allen; Messina, Angela; Levy, Finn Olav; Guccione, Salvatore

    2015-01-01

    The human 5-HT7 receptor is expressed in both the central nervous system and peripheral tissues and is a potential drug target in behavioral and psychiatric disorders. We examined molecular determinants of ligand binding and G protein activation by the human 5-HT7(a) receptor. The role of several key residues in the 7th transmembrane domain (TMD) and helix 8 were elucidated combining in silico and experimental mutagenesis. Several single and two double point mutations of the 5-HT7(a) wild type receptor were made (W7.33V, E7.35T, E7.35R, E7.35D, E7.35A, R7.36V, Y7.43A, Y7.43F, Y7.43T, R8.52D, D8.53K; E7.35T-R7.36V, R8.52D-D8.53K), and their effects upon ligand binding were assessed by radioligand binding using a potent agonist (5-CT) and a potent antagonist (SB269970). In addition, the ability of the mutated 5-HT7(a) receptors to activate G protein after 5-HT-stimulation was determined through activation of adenylyl cyclase. In silico investigation on mutated receptors substantiated the predicted importance of TM7 and showed critical roles of residues E7.35, W7.33, R7.36 and Y7.43 in agonist and antagonist binding and conformational changes of receptor structure affecting adenylyl cyclase activation. Experimental data showed that mutants E7.35T and E7.35R were incapable of ligand binding and adenylyl cyclase activation, consistent with a requirement for a negatively charged residue at this position. The mutant R8.52D was unable to activate adenylyl cyclase, despite unaffected ligand binding, consistent with the R8.52 residue playing an important role in the receptor-G protein interface. The mutants Y7.43A and Y7.43T displayed reduced agonist binding and AC agonist potency, not seen in Y7.43F, consistent with a requirement for an aromatic residue at this position. Knowledge of the molecular interactions important in h5-HT7 receptor ligand binding and G protein activation will aid the design of selective h5-HT7 receptor ligands for potential pharmacological use. PMID

  14. Identification of essential residues for binding and activation in the human 5-HT7(a) serotonin receptor by molecular modeling and site-directed mutagenesis

    PubMed Central

    Impellizzeri, Agata Antonina Rita; Pappalardo, Matteo; Basile, Livia; Manfra, Ornella; Andressen, Kjetil Wessel; Krobert, Kurt Allen; Messina, Angela; Levy, Finn Olav; Guccione, Salvatore

    2015-01-01

    The human 5-HT7 receptor is expressed in both the central nervous system and peripheral tissues and is a potential drug target in behavioral and psychiatric disorders. We examined molecular determinants of ligand binding and G protein activation by the human 5-HT7(a) receptor. The role of several key residues in the 7th transmembrane domain (TMD) and helix 8 were elucidated combining in silico and experimental mutagenesis. Several single and two double point mutations of the 5-HT7(a) wild type receptor were made (W7.33V, E7.35T, E7.35R, E7.35D, E7.35A, R7.36V, Y7.43A, Y7.43F, Y7.43T, R8.52D, D8.53K; E7.35T-R7.36V, R8.52D-D8.53K), and their effects upon ligand binding were assessed by radioligand binding using a potent agonist (5-CT) and a potent antagonist (SB269970). In addition, the ability of the mutated 5-HT7(a) receptors to activate G protein after 5-HT-stimulation was determined through activation of adenylyl cyclase. In silico investigation on mutated receptors substantiated the predicted importance of TM7 and showed critical roles of residues E7.35, W7.33, R7.36 and Y7.43 in agonist and antagonist binding and conformational changes of receptor structure affecting adenylyl cyclase activation. Experimental data showed that mutants E7.35T and E7.35R were incapable of ligand binding and adenylyl cyclase activation, consistent with a requirement for a negatively charged residue at this position. The mutant R8.52D was unable to activate adenylyl cyclase, despite unaffected ligand binding, consistent with the R8.52 residue playing an important role in the receptor-G protein interface. The mutants Y7.43A and Y7.43T displayed reduced agonist binding and AC agonist potency, not seen in Y7.43F, consistent with a requirement for an aromatic residue at this position. Knowledge of the molecular interactions important in h5-HT7 receptor ligand binding and G protein activation will aid the design of selective h5-HT7 receptor ligands for potential pharmacological use. PMID

  15. Animal Models of Depression: Molecular Perspectives

    PubMed Central

    Krishnan, Vaishnav; Nestler, Eric J.

    2012-01-01

    Much of the current understanding about the pathogenesis of altered mood, impaired concentration and neurovegetative symptoms in major depression has come from animal models. However, because of the unique and complex features of human depression, the generation of valid and insightful depression models has been less straightforward than modeling other disabling diseases like cancer or autoimmune conditions. Today’s popular depression models creatively merge ethologically valid behavioral assays with the latest technological advances in molecular biology and automated video-tracking. This chapter reviews depression assays involving acute stress (e.g., forced swim test), models consisting of prolonged physical or social stress (e.g., social defeat), models of secondary depression, genetic models, and experiments designed to elucidate the mechanisms of antidepressant action. These paradigms are critically evaluated in relation to their ease, validity and replicability, the molecular insights that they have provided, and their capacity to offer the next generation of therapeutics for depression. PMID:21225412

  16. Hierarchical Molecular Modelling with Ellipsoids

    SciTech Connect

    Max, N

    2004-03-29

    Protein and DNA structures are represented at varying levels of details using ellipsoidal RGBA textured splats. The splat texture at each level is generated by rendering its children in a hierarchical model, from a distribution of viewing directions, and averaging the result. For rendering, the ellipsoids to be used are chosen adaptively, depending on the distance to the viewpoint. This technique is applied to visualize DNA coiling around nucleosomes in chromosomes.

  17. MODELING MOLECULAR HYPERFINE LINE EMISSION

    SciTech Connect

    Keto, Eric; Rybicki, George

    2010-06-20

    In this paper, we discuss two approximate methods previously suggested for modeling hyperfine spectral line emission for molecules whose collisional transition rates between hyperfine levels are unknown. Hyperfine structure is seen in the rotational spectra of many commonly observed molecules such as HCN, HNC, NH{sub 3}, N{sub 2}H{sup +}, and C{sup 17}O. The intensities of these spectral lines can be modeled by numerical techniques such as {Lambda}-iteration that alternately solve the equations of statistical equilibrium and the equation of radiative transfer. However, these calculations require knowledge of both the radiative and collisional rates for all transitions. For most commonly observed radio frequency spectral lines, only the net collisional rates between rotational levels are known. For such cases, two approximate methods have been suggested. The first method, hyperfine statistical equilibrium, distributes the hyperfine level populations according to their statistical weight, but allows the population of the rotational states to depart from local thermal equilibrium (LTE). The second method, the proportional method, approximates the collision rates between the hyperfine levels as fractions of the net rotational rates apportioned according to the statistical degeneracy of the final hyperfine levels. The second method is able to model non-LTE hyperfine emission. We compare simulations of N{sub 2}H{sup +} hyperfine lines made with approximate and more exact rates and find that satisfactory results are obtained.

  18. Molecular Modeling of Water Interfaces: From Molecular Spectroscopy to Thermodynamics.

    PubMed

    Nagata, Yuki; Ohto, Tatsuhiko; Backus, Ellen H G; Bonn, Mischa

    2016-04-28

    Understanding aqueous interfaces at the molecular level is not only fundamentally important, but also highly relevant for a variety of disciplines. For instance, electrode-water interfaces are relevant for electrochemistry, as are mineral-water interfaces for geochemistry and air-water interfaces for environmental chemistry; water-lipid interfaces constitute the boundaries of the cell membrane, and are thus relevant for biochemistry. One of the major challenges in these fields is to link macroscopic properties such as interfacial reactivity, solubility, and permeability as well as macroscopic thermodynamic and spectroscopic observables to the structure, structural changes, and dynamics of molecules at these interfaces. Simulations, by themselves, or in conjunction with appropriate experiments, can provide such molecular-level insights into aqueous interfaces. In this contribution, we review the current state-of-the-art of three levels of molecular dynamics (MD) simulation: ab initio, force field, and coarse-grained. We discuss the advantages, the potential, and the limitations of each approach for studying aqueous interfaces, by assessing computations of the sum-frequency generation spectra and surface tension. The comparison of experimental and simulation data provides information on the challenges of future MD simulations, such as improving the force field models and the van der Waals corrections in ab initio MD simulations. Once good agreement between experimental observables and simulation can be established, the simulation can be used to provide insights into the processes at a level of detail that is generally inaccessible to experiments. As an example we discuss the mechanism of the evaporation of water. We finish by presenting an outlook outlining four future challenges for molecular dynamics simulations of aqueous interfacial systems. PMID:27010817

  19. Mathematical modeling of molecular diffusion through mucus

    PubMed Central

    Cu, Yen; Saltzman, W. Mark

    2008-01-01

    The rate of molecular transport through the mucus gel can be an important determinant of efficacy for therapeutic agents delivered by oral, intranasal, intravaginal/rectal, and intraocular routes. Transport through mucus can be described by mathematical models based on principles of physical chemistry and known characteristics of the mucus gel, its constituents, and of the drug itself. In this paper, we review mathematical models of molecular diffusion in mucus, as well as the techniques commonly used to measure diffusion of solutes in the mucus gel, mucus gel mimics, and mucosal epithelia. PMID:19135488

  20. Molecular Models for Conductance in Junctions and Electrochemical Electron Transfer

    NASA Astrophysics Data System (ADS)

    Mazinani, Shobeir Khezr Seddigh

    This thesis develops molecular models for electron transport in molecular junctions and intra-molecular electron transfer. The goal is to identify molecular descriptors that afford a substantial simplification of these electronic processes. First, the connection between static molecular polarizability and the molecular conductance is examined. A correlation emerges whereby the measured conductance of a tunneling junction decreases as a function of the calculated molecular polarizability for several systems, a result consistent with the idea of a molecule as a polarizable dielectric. A model based on a macroscopic extension of the Clausius-Mossotti equation to the molecular domain and Simmon's tunneling model is developed to explain this correlation. Despite the simplicity of the theory, it paves the way for further experimental, conceptual and theoretical developments in the use of molecular descriptors to describe both conductance and electron transfer. Second, the conductance of several biologically relevant, weakly bonded, hydrogen-bonded systems is systematically investigated. While there is no correlation between hydrogen bond strength and conductance, the results indicate a relation between the conductance and atomic polarizability of the hydrogen bond acceptor atom. The relevance of these results to electron transfer in biological systems is discussed. Hydrogen production and oxidation using catalysts inspired by hydrogenases provides a more sustainable alternative to the use of precious metals. To understand electrochemical and spectroscopic properties of a collection of Fe and Ni mimics of hydrogenases, high-level density functional theory calculations are described. The results, based on a detailed analysis of the energies, charges and molecular orbitals of these metal complexes, indicate the importance of geometric constraints imposed by the ligand on molecular properties such as acidity and electrocatalytic activity. Based on model calculations of

  1. Potential activity of fevicordin-A from Phaleria macrocarpa (Scheff) Boerl. seeds as estrogen receptor antagonist based on cytotoxicity and molecular modelling studies.

    PubMed

    Muchtaridi, Muchtaridi; Yusuf, Muhammad; Diantini, Ajeng; Choi, Sy Bing; Al-Najjar, Belal O; Manurung, Jerry V; Subarnas, Anas; Achmad, Tri H; Wardhani, Savitri R; Wahab, Habibah A

    2014-01-01

    Fevicordin-A (FevA) isolated from Phaleria macrocarpa (Scheff) Boerl. seeds was evaluated for its potential anticancer activity by in vitro and in silico approaches. Cytotoxicity studies indicated that FevA was selective against cell lines of human breast adenocarcinoma (MCF-7) with an IC50 value of 6.4 µM. At 11.2 µM, FevA resulted in 76.8% cell death of T-47D human breast cancer cell lines. Critical pharmacophore features amongst human Estrogen Receptor-α (hERα) antagonists were conserved in FevA with regard to a hypothesis that they could make notable contributions to its pharmacological activity. The binding stability as well as the dynamic behavior of FevA towards the hERα receptor in agonist and antagonist binding sites were probed using molecular dynamics (MD) simulation approach. Analysis of MD simulation suggested that the tail of FevA was accountable for the repulsion of the C-terminal of Helix-11 (H11) in both agonist and antagonist receptor forms. The flexibility of loop-534 indicated the ability to disrupt the hydrogen bond zipper network between H3 and H11 in hERα. In addition, MM/GBSA calculation from the molecular dynamic simulations also revealed a stronger binding affinity of FevA in antagonistic action as compared to that of agonistic action. Collectively, both the experimental and computational results indicated that FevA has potential as a candidate for an anticancer agent, which is worth promoting for further preclinical evaluation. PMID:24776765

  2. Potential Activity of Fevicordin-A from Phaleria macrocarpa (Scheff) Boerl. Seeds as Estrogen Receptor Antagonist Based on Cytotoxicity and Molecular Modelling Studies

    PubMed Central

    Muchtaridi, Muchtaridi; Yusuf, Muhammad; Diantini, Ajeng; Choi, Sy Bing; Al-Najjar, Belal O.; Manurung, Jerry V.; Subarnas, Anas; Achmad, Tri H.; Wardhani, Savitri R.; Wahab, Habibah A.

    2014-01-01

    Fevicordin-A (FevA) isolated from Phaleria macrocarpa (Scheff) Boerl. seeds was evaluated for its potential anticancer activity by in vitro and in silico approaches. Cytotoxicity studies indicated that FevA was selective against cell lines of human breast adenocarcinoma (MCF-7) with an IC50 value of 6.4 μM. At 11.2 μM, FevA resulted in 76.8% cell death of T-47D human breast cancer cell lines. Critical pharmacophore features amongst human Estrogen Receptor-α (hERα) antagonists were conserved in FevA with regard to a hypothesis that they could make notable contributions to its pharmacological activity. The binding stability as well as the dynamic behavior of FevA towards the hERα receptor in agonist and antagonist binding sites were probed using molecular dynamics (MD) simulation approach. Analysis of MD simulation suggested that the tail of FevA was accountable for the repulsion of the C-terminal of Helix-11 (H11) in both agonist and antagonist receptor forms. The flexibility of loop-534 indicated the ability to disrupt the hydrogen bond zipper network between H3 and H11 in hERα. In addition, MM/GBSA calculation from the molecular dynamic simulations also revealed a stronger binding affinity of FevA in antagonistic action as compared to that of agonistic action. Collectively, both the experimental and computational results indicated that FevA has potential as a candidate for an anticancer agent, which is worth promoting for further preclinical evaluation. PMID:24776765

  3. 24-hydroxycholesterol sulfation by human cytosolic sulfotransferases: formation of monosulfates and disulfates, molecular modeling, sulfatase sensitivity, and inhibition of liver x receptor activation.

    PubMed

    Cook, Ian T; Duniec-Dmuchowski, Zofia; Kocarek, Thomas A; Runge-Morris, Melissa; Falany, Charles N

    2009-10-01

    24-Hydroxycholesterol (24-OHChol) is a major cholesterol metabolite and the form in which cholesterol is secreted from the brain. 24-OHChol is transported by apolipoprotein E to the liver and converted into bile acids or excreted. In both brain and liver, 24-OHChol is a liver X receptor (LXR) agonist and has an important role in cholesterol homeostasis. 24-OHChol sulfation was examined to understand its role in 24-OHChol metabolism and its effect on LXR activation. 24-OHChol was conjugated by three isoforms of human cytosolic sulfotransferase (SULT). SULT2A1 and SULT1E1 sulfated both the 3- and 24-hydroxyls to form the 24-OHChol-3, 24-disulfate. SULT2B1b formed only 24-OHChol-3-sulfate. The 3-sulfate as a monosulfate or as the disulfate was hydrolyzed by human placental steroid sulfatase, whereas the 24-sulfate was resistant. At physiological 24-OHChol concentrations, SULT2A1 formed the 3-monosulfate and the 3, 24-disulfate as a result of a high affinity for sulfation of the 3-OH in 24-OHChol-24-sulfate. Molecular docking simulations indicate that 24-OHChol-24-sulfate binds in an active configuration in the SULT2A1 substrate binding site with high affinity only when the SULT2A1 homodimer structure was used. 24-OHChol is an LXR activator. In contrast, the 24-OHChol monosulfates were not LXR agonists in a fluorescence resonance energy transfer coactivator recruitment assay. However, both the 24-OHChol-3-sulfate and 24-sulfate were antagonists of LXR activation by N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trif-luoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide (T0901317) with an IC(50) of 0.15 and 0.31 muM, respectively. Inhibition of LXR activation by the 24-OHChol monosulfates at low nanomolar concentrations indicates that sulfation has a role in LXR regulation by oxysterols. PMID:19589875

  4. An Integrated Biochemistry Laboratory, Including Molecular Modeling

    NASA Astrophysics Data System (ADS)

    Hall, Adele J. Wolfson Mona L.; Branham, Thomas R.

    1996-11-01

    ) experience with methods of protein purification; (iii) incorporation of appropriate controls into experiments; (iv) use of basic statistics in data analysis; (v) writing papers and grant proposals in accepted scientific style; (vi) peer review; (vii) oral presentation of results and proposals; and (viii) introduction to molecular modeling. Figure 1 illustrates the modular nature of the lab curriculum. Elements from each of the exercises can be separated and treated as stand-alone exercises, or combined into short or long projects. We have been able to offer the opportunity to use sophisticated molecular modeling in the final module through funding from an NSF-ILI grant. However, many of the benefits of the research proposal can be achieved with other computer programs, or even by literature survey alone. Figure 1.Design of project-based biochemistry laboratory. Modules (projects, or portions of projects) are indicated as boxes. Each of these can be treated independently, or used as part of a larger project. Solid lines indicate some suggested paths from one module to the next. The skills and knowledge required for protein purification and design are developed in three units: (i) an introduction to critical assays needed to monitor degree of purification, including an evaluation of assay parameters; (ii) partial purification by ion-exchange techniques; and (iii) preparation of a grant proposal on protein design by mutagenesis. Brief descriptions of each of these units follow, with experimental details of each project at the end of this paper. Assays for Lysozyme Activity and Protein Concentration (4 weeks) The assays mastered during the first unit are a necessary tool for determining the purity of the enzyme during the second unit on purification by ion exchange. These assays allow an introduction to the concept of specific activity (units of enzyme activity per milligram of total protein) as a measure of purity. In this first sequence, students learn a turbidimetric assay

  5. Regioselective synthesis and molecular modeling study of vasorelaxant active 7,9-dioxa-1,2-diaza-spiro[4.5]dec-2-ene-6,10-diones.

    PubMed

    Girgis, Adel S; Ismail, Nasser S M; Farag, Hanaa; el-Eraky, Wafaa I; Saleh, Dalia O; Tala, Srinivasa R; Katritzky, Alan R

    2010-09-01

    Nitrilimines (PhC(-):N(+):NR') generated in situ from hydrazonoyl chlorides 2a,b reacted regioselectively with 5-arylidene-2,2-dimethyl[1,3]dioxane-4,6-diones 1a-f to afford 1,3,4-triaryl-8,8-dimethyl-7,9-dioxa-1,2-diaza-spiro[4.5]dec-2-ene-6,10-diones 3a-l. In vitro vasodilation activity screening of the synthesized compounds using isolated thoracic aortic rings of male Wister rats pre-contracted with norepinephrine hydrochloride revealed considerable vasodilation activity; compounds 3f and 3j had IC(50) (concentration necessary for 50% reduction of maximal norepinephrine hydrochloride induced contracture) of 0.325, 0.321 mM, respectively. Molecular modeling, including fitting to a 3D-pharmacophore model using Discovery studio 2.1 programs and their docking into optimized alpha(1)-AR homology models as alpha(1)-AR antagonist showed high-docking score and fit values. The experimental in vitro vasodilation activity of compounds 3a-l was consistent with the molecular modeling. PMID:20615586

  6. Molecular Ice Nucleation Activity of Birch Pollen

    NASA Astrophysics Data System (ADS)

    Felgitsch, Laura; Bichler, Magdalena; Häusler, Thomas; Weiss, Victor U.; Marchetti-Deschmann, Martina; Allmaier, Günter; Grothe, Hinrich

    2015-04-01

    Heterogeneous ice nucleation plays a major part in ecosystem and climate. Due to the triggering of ice cloud formation it influences the radiation balance of the earth, but also on the ground it can be found to be important in many processes of nature. So far the process of heterogeneous ice nucleation is not fully understood and many questions remain to be answered. Biological ice nucleation is hereby from great interest, because it shows the highest freezing temperatures. Several bacteria and fungi act as ice nuclei. A famous example is Pseudomonas syringae, a bacterium in commercial use (Snomax®), which increases the freezing from homogeneous freezing temperatures of approx. -40° C (for small volumes as in cloud droplets) to temperatures up to -2° C. In 2001 it was found that birch pollen can trigger ice nucleation (Diehl et al. 2001; Diehl et al. 2002). For a long time it was believed that this is due to macroscopic features of the pollen surface. Recent findings of Bernhard Pummer (2012) show a different picture. The ice nuclei are not attached on the pollen surface directly, but on surface material which can be easily washed off. This shows that not only the surface morphology, but also specific molecules or molecular structures are responsible for the ice nucleation activity of birch pollen. With various analytic methods we work on elucidating the structure of these molecules as well as the mechanism with which they trigger ice nucleation. To solve this we use various instrumental analytic techniques like Nuclear Magnetic Resonance spectroscopy (NMR), Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry (MALDI-MS), and Gas-phase Electrophoretic Mobility Molecular Analysis (GEMMA). Also standard techniques like various chromatographic separation techniques and solvent extraction are in use. We state here that this feature might be due to the aggregation of small molecules, with agglomerates showing a specific surface structure. Our results

  7. Trends in substitution models of molecular evolution

    PubMed Central

    Arenas, Miguel

    2015-01-01

    Substitution models of evolution describe the process of genetic variation through fixed mutations and constitute the basis of the evolutionary analysis at the molecular level. Almost 40 years after the development of first substitution models, highly sophisticated, and data-specific substitution models continue emerging with the aim of better mimicking real evolutionary processes. Here I describe current trends in substitution models of DNA, codon and amino acid sequence evolution, including advantages and pitfalls of the most popular models. The perspective concludes that despite the large number of currently available substitution models, further research is required for more realistic modeling, especially for DNA coding and amino acid data. Additionally, the development of more accurate complex models should be coupled with new implementations and improvements of methods and frameworks for substitution model selection and downstream evolutionary analysis. PMID:26579193

  8. Trends in substitution models of molecular evolution.

    PubMed

    Arenas, Miguel

    2015-01-01

    Substitution models of evolution describe the process of genetic variation through fixed mutations and constitute the basis of the evolutionary analysis at the molecular level. Almost 40 years after the development of first substitution models, highly sophisticated, and data-specific substitution models continue emerging with the aim of better mimicking real evolutionary processes. Here I describe current trends in substitution models of DNA, codon and amino acid sequence evolution, including advantages and pitfalls of the most popular models. The perspective concludes that despite the large number of currently available substitution models, further research is required for more realistic modeling, especially for DNA coding and amino acid data. Additionally, the development of more accurate complex models should be coupled with new implementations and improvements of methods and frameworks for substitution model selection and downstream evolutionary analysis. PMID:26579193

  9. Mobile modeling in the molecular sciences

    EPA Science Inventory

    The art of modeling in the molecular sciences is highly dependent on both the available computational technology, underlying data, and ability to collaborate. With the ever increasing market share of mobile devices, it is assumed by many that tablets will overtake laptops as the...

  10. Molecular mechanisms of asymmetric RAF dimer activation.

    PubMed

    Jambrina, Pablo G; Bohuszewicz, Olga; Buchete, Nicolae-Viorel; Kolch, Walter; Rosta, Edina

    2014-08-01

    Protein phosphorylation is one of the most common post-translational modifications in cell regulatory mechanisms. Dimerization plays also a crucial role in the kinase activity of many kinases, including RAF, CDK2 (cyclin-dependent kinase 2) and EGFR (epidermal growth factor receptor), with heterodimers often being the most active forms. However, the structural and mechanistic details of how phosphorylation affects the activity of homo- and hetero-dimers are largely unknown. Experimentally, synthesizing protein samples with fully specified and homogeneous phosphorylation states remains a challenge for structural biology and biochemical studies. Typically, multiple changes in phosphorylation lead to activation of the same protein, which makes structural determination methods particularly difficult. It is also not well understood how the occurrence of phosphorylation and dimerization processes synergize to affect kinase activities. In the present article, we review available structural data and discuss how MD simulations can be used to model conformational transitions of RAF kinase dimers, in both their phosphorylated and unphosphorylated forms. PMID:25109958

  11. Synthesis, characterization, molecular modeling and antibacterial activity of N1‧, N2‧-bis[1-(pyridin-2-yl)ethylidene]oxalohydrazide and its metal complexes

    NASA Astrophysics Data System (ADS)

    El-Gammal, O. A.; El-Shazly, R. M.; El-Morsy, F. E.; El-Asmy, A. A.

    2011-07-01

    New complexes of N 1',N 2'-bis[1-(pyridin-2-yl)ethylidene]oxalohydrazide (H 2L) with Cr 3+, Mn 2+, Fe 3+, Co 2+, Ni 2+, Cu 2+, Cd 2+, VO 2+ and Ag + have been prepared and characterized. The ligand has 10-12 buffering range and pK's of 4.62, 7.78 and 9.45. The IR spectra showed the neutral, (mono- or dibasic) bidentate, tridentate or tetradentate of H 2L. The molar conductance values, in DMSO, are in the range of nonelectrolytes. An octahedral geometry is proposed for the Cr 3+, Mn 2+, Fe 3+, Ni 2+; VO 2+ complexes and square-planar for the Co 2+ and Cu 2+ complexes. The ESR spectra support the mononuclear species for [VO(H 2L)SO 4-(H 2O) 2]·H 2O and [Cu(H 2L)(OAc) 2]·H 2O. The molecular parameters have been calculated to confirm the geometry of the ligand and its complexes. The ligand and some complexes were screened against Bacillus thuringiensis (Bt) as Gram positive and Pseudomonas aeuroginosa (Pa) as Gram negative bacteria using the inhibitory zone diameter. The data showed no effect for the complexes on Pa bacteria growth except [Ag(H 2L)(NO 3)]H 2O which had a high activity. Cu 2+, VO 2+ and Ag + complexes exhibit activity against BT; Cu 2+complex is the highest one.

  12. Molecular simulation and modeling of complex I.

    PubMed

    Hummer, Gerhard; Wikström, Mårten

    2016-07-01

    Molecular modeling and molecular dynamics simulations play an important role in the functional characterization of complex I. With its large size and complicated function, linking quinone reduction to proton pumping across a membrane, complex I poses unique modeling challenges. Nonetheless, simulations have already helped in the identification of possible proton transfer pathways. Simulations have also shed light on the coupling between electron and proton transfer, thus pointing the way in the search for the mechanistic principles underlying the proton pump. In addition to reviewing what has already been achieved in complex I modeling, we aim here to identify pressing issues and to provide guidance for future research to harness the power of modeling in the functional characterization of complex I. This article is part of a Special Issue entitled Respiratory complex I, edited by Volker Zickermann and Ulrich Brandt. PMID:26780586

  13. The role of molecular modeling in bionanotechnology

    PubMed Central

    Lu, Deyu; Aksimentiev, Aleksei; Shih, Amy Y.; Cruz-Chu, Eduardo; Freddolino, Peter L.; Arkhipov, Anton; Schulten, Klaus

    2008-01-01

    Molecular modeling is advocated here as a key methodology for research and development in bionanotechnology. Molecular modeling provides nanoscale images at atomic and even electronic resolution, predicts the nanoscale interaction of yet unfamiliar combinations of biological and inorganic materials, and can evaluate strategies for redesigning biopolymers for nanotechnological uses. The methodology is illustrated in this paper through three case studies. The first involves the use of single-walled carbon nanotubes as biomedical sensors where a computationally efficient, yet accurate description of the influence of biomolecules on nanotube electronic properties and a description of nanotube - biomolecule interactions were developed; this development furnishes the ability to test nanotube electronic properties in realistic biological environments. The second case study involves the use of nanopores manufactured into electronic nanodevices based on silicon compounds for single molecule electrical recording, in particular, for DNA sequencing. Here, modeling combining classical molecular dynamics, material science, and device physics, describes the interaction of biopolymers, e.g., DNA, with silicon nitrate and silicon oxide pores, furnishes accurate dynamic images of pore translocation processes, and predicts signals. The third case study involves the development of nanoscale lipid bilayers for the study of embedded membrane proteins and cholesterol. Molecular modeling tested scaffold proteins, redesigned lipoproteins found in mammalian plasma that hold the discoidal membranes in shape, and predicted the assembly as well as final structure of the nanodiscs. In entirely new technological areas like bionanotechnology qualitative concepts, pictures, and suggestions are sorely needed; these three case studies document that molecular modeling can serve a critical role in this respect, even though it may still fall short on quantitative precision. PMID:16582464

  14. The role of molecular modeling in bionanotechnology

    NASA Astrophysics Data System (ADS)

    Lu, Deyu; Aksimentiev, Aleksei; Shih, Amy Y.; Cruz-Chu, Eduardo; Freddolino, Peter L.; Arkhipov, Anton; Schulten, Klaus

    2006-03-01

    Molecular modeling is advocated here as a key methodology for research and development in bionanotechnology. Molecular modeling provides nanoscale images at atomic and even electronic resolution, predicts the nanoscale interaction of unfamiliar combinations of biological and inorganic materials, and evaluates strategies for redesigning biopolymers for nanotechnological uses. The methodology is illustrated in this paper through reviewing three case studies. The first one involves the use of single-walled carbon nanotubes as biomedical sensors where a computationally efficient, yet accurate, description of the influence of biomolecules on nanotube electronic properties through nanotube-biomolecule interactions was developed; this development furnishes the ability to test nanotube electronic properties in realistic biological environments. The second case study involves the use of nanopores manufactured into electronic nanodevices based on silicon compounds for single molecule electrical recording, in particular, for DNA sequencing. Here, modeling combining classical molecular dynamics, material science and device physics, described the interaction of biopolymers, e.g., DNA, with silicon nitrate and silicon oxide pores, furnished accurate dynamic images of pore translocation processes, and predicted signals. The third case study involves the development of nanoscale lipid bilayers for the study of embedded membrane proteins and cholesterol. Molecular modeling tested scaffold proteins, redesigned apolipoproteins found in mammalian plasma that hold the discoidal membranes in the proper shape, and predicted the assembly as well as final structure of the nanodiscs. In entirely new technological areas such as bionanotechnology, qualitative concepts, pictures and suggestions are sorely needed; these three case studies document that molecular modeling can serve a critical role in this respect, even though it may still fall short on quantitative precision.

  15. Molecular Modeling of Solid Fluid Phase Behavior

    SciTech Connect

    Peter A. Monson

    2007-12-20

    This report gives a summary of the achievements under DOE contract No. DOE/ER/14150 during the period September 1, 1990 to December 31, 2007. This project was concerned with the molecular modeling of solid-fluid equilibrium. The focus was on understanding how solid-fluid and solid-solid phase behavior are related to molecular structure, and the research program made a seminal contribution in this area. The project led to 34 journal articles, including a comprehensive review article published in Advances in Chemical Physics. The DOE funding supported the work of 5 Ph.D. students, 2 M.S. students and 5 postdoctoral researchers.

  16. Simple model of a coherent molecular photocell

    NASA Astrophysics Data System (ADS)

    Ernzerhof, Matthias; Bélanger, Marc-André; Mayou, Didier; Nemati Aram, Tahereh

    2016-04-01

    Electron transport in molecular electronic devices is often dominated by a coherent mechanism in which the wave function extends from the left contact over the molecule to the right contact. If the device is exposed to light, photon absorption in the molecule might occur, turning the device into a molecular photocell. The photon absorption promotes an electron to higher energy levels and thus modifies the electron transmission probability through the device. A model for such a molecular photocell is presented that minimizes the complexity of the problem while providing a non-trivial description of the device mechanism. In particular, the role of the molecule in the photocell is investigated. It is described within the Hückel method and the source-sink potential approach [F. Goyer, M. Ernzerhof, and M. Zhuang, J. Chem. Phys. 126, 144104 (2007)] is used to eliminate the contacts in favor of complex-valued potentials. Furthermore, the photons are explicitly incorporated into the model through a second-quantized field. This facilitates the description of the photon absorption process with a stationary state calculation, where eigenvalues and eigenvectors are determined. The model developed is applied to various generic molecular photocells.

  17. Chemistry in the Molecular Disks of Active Galactic Nuclei

    NASA Astrophysics Data System (ADS)

    Harada, Nanase; Herbst, Eric

    2010-06-01

    Active galactic nuclei (AGNs) are the centers of galaxies with supermassive blackholes whose accretion of mass causes very high luminosities of L˜1044-46erg s-1. An accretion disk has a molecular component that extends to hundreds of pc from the central AGN core. The question of how much central illumination affects the disk and how much star formation is present near the core have been astrophysical interests. Rotational lines from these disks at a sub-kpc scale have been observed for molecules such as CO, HCO+, HCN, and HNC. When ALMA becomes fully operational, it will be able to resolve these disks at much higher resolution than currently. Molecular observations at higher resolution may give some hints on the physics in the molecular disk. We modeled the chemical composition of a molecular disk in an AGN on a scale of tens of pc. To do this, we extended our standard gas-phase OSU network to include important processes at much higher temperatures, approaching 1000 K. We used the density model of Thompson et al., and determined the temperature by the blackbody approximation from the luminosity of the AGN core. The ionization by X-rays from the AGN core, by cosmic-rays from the AGN core, supernovae and stellar winds, and by UV-photons from OB stars are considered. We will briefly mention the effects from other factors that may change the molecular abundances such as shock waves and inhomogeneity of the density of the disk. T. Thompson, E. Quataert, and N. Murray, Astrophysical J. 630, 167 (2005)

  18. Realistic molecular model of kerogen's nanostructure

    NASA Astrophysics Data System (ADS)

    Bousige, Colin; Ghimbeu, Camélia Matei; Vix-Guterl, Cathie; Pomerantz, Andrew E.; Suleimenova, Assiya; Vaughan, Gavin; Garbarino, Gaston; Feygenson, Mikhail; Wildgruber, Christoph; Ulm, Franz-Josef; Pellenq, Roland J.-M.; Coasne, Benoit

    2016-05-01

    Despite kerogen's importance as the organic backbone for hydrocarbon production from source rocks such as gas shale, the interplay between kerogen's chemistry, morphology and mechanics remains unexplored. As the environmental impact of shale gas rises, identifying functional relations between its geochemical, transport, elastic and fracture properties from realistic molecular models of kerogens becomes all the more important. Here, by using a hybrid experimental-simulation method, we propose a panel of realistic molecular models of mature and immature kerogens that provide a detailed picture of kerogen's nanostructure without considering the presence of clays and other minerals in shales. We probe the models' strengths and limitations, and show that they predict essential features amenable to experimental validation, including pore distribution, vibrational density of states and stiffness. We also show that kerogen's maturation, which manifests itself as an increase in the sp2/sp3 hybridization ratio, entails a crossover from plastic-to-brittle rupture mechanisms.

  19. Realistic molecular model of kerogen's nanostructure.

    PubMed

    Bousige, Colin; Ghimbeu, Camélia Matei; Vix-Guterl, Cathie; Pomerantz, Andrew E; Suleimenova, Assiya; Vaughan, Gavin; Garbarino, Gaston; Feygenson, Mikhail; Wildgruber, Christoph; Ulm, Franz-Josef; Pellenq, Roland J-M; Coasne, Benoit

    2016-05-01

    Despite kerogen's importance as the organic backbone for hydrocarbon production from source rocks such as gas shale, the interplay between kerogen's chemistry, morphology and mechanics remains unexplored. As the environmental impact of shale gas rises, identifying functional relations between its geochemical, transport, elastic and fracture properties from realistic molecular models of kerogens becomes all the more important. Here, by using a hybrid experimental-simulation method, we propose a panel of realistic molecular models of mature and immature kerogens that provide a detailed picture of kerogen's nanostructure without considering the presence of clays and other minerals in shales. We probe the models' strengths and limitations, and show that they predict essential features amenable to experimental validation, including pore distribution, vibrational density of states and stiffness. We also show that kerogen's maturation, which manifests itself as an increase in the sp(2)/sp(3) hybridization ratio, entails a crossover from plastic-to-brittle rupture mechanisms. PMID:26828313

  20. Molecular simulation of receptors of physiologically active compounds for purposes of medical chemistry

    NASA Astrophysics Data System (ADS)

    Baskin, Igor I.; Palyulin, Vladimir A.; Zefirov, Nikolai S.

    2009-06-01

    The general strategy of the molecular simulation of biological receptors and their interaction with ligands is considered. The procedures for construction of 3D protein models, molecular docking, evaluation of model quality, determination of the free energy of protein binding with ligands are discussed. The methods of molecular design of new medicaments based on molecular models of biological targets: virtual screening and de novo design, are presented. Examples of the above-listed approaches for the simulation of a number of pharmacologically significant receptors, analysis of receptor-ligand interactions and design of new biologically active organic compounds are given.

  1. An approach towards molecular imaging of activated platelets allows imaging of symptomatic human carotid plaques in a new model of a tissue flow chamber.

    PubMed

    von Elverfeldt, Dominik; Meissner, Mirko; Peter, Karlheinz; Paul, Dominik; Meixner, Fabian; Neudorfer, Irene; Merkle, Annette; Harloff, Andreas; Zirlik, Andreas; Schöllhorn, Joachim; Markl, Michael; Hennig, Jürgen; Bode, Christoph; von zur Muhlen, Constantin

    2012-01-01

    The development of magnetic resonance imaging (MRI) contrast agents targeting epitopes in atherosclerosis is of general interest. In particular, early detection of activated platelets as key players in plaque rupture could provide improved triage of patients. However, so far the efficiency of contrast agents targeting human pathologies can only be examined in animal experiments, which do not necessarily reflect human in vivo conditions. We therefore describe application of a contrast agent targeting activated human platelets in an MRI tissue flow chamber, allowing detection and characterization of contrast agent binding. Microparticles of iron oxide (MPIO) were conjugated to an antibody targeting ligand-induced binding sites (LIBS) on the activated platelet glycoprotein IIb/IIIa-receptor or to control antibody, resulting in LIBS-MPIO or control-MPIO contrast agent. Human endarterectomy specimens from patients with acute stroke or transient ischemic attack were imaged ex vivo before and after contrast agent perfusion using a 9.4 T MRI system. Specimens were measured under static (n = 18) or flow conditions (n = 18) in a specially designed flow chamber setup, simulating physiological conditions in a stenosed vessel. A significant MPIO-induced negative contrast was achieved in MRI by LIBS-MPIO in specimens under static and flow conditions (LIBS-MPIO vs control-MPIO: p < 0.01), and the location of LIBS-MPIO binding corresponded well between histology and MRI (p < 0.05). The number of MPIOs per platelet area on endarterectomy specimens in histology was significantly higher with LIBS-MPIO (p < 0.001). Furthermore, the intensity of contrast agent binding and signal change showed the potential to reflect the severity of clinical symptoms. LIBS-MPIO allows the detection of activated platelets on the surface of symptomatic atherosclerotic human plaques using molecular MRI. Furthermore, the MRI tissue flow chamber setup described could help to evaluate

  2. Optical models of the molecular atmosphere

    NASA Technical Reports Server (NTRS)

    Zuev, V. E.; Makushkin, Y. S.; Mitsel, A. A.; Ponomarev, Y. N.; Rudenko, V. P.; Firsov, K. M.

    1986-01-01

    The use of optical and laser methods for performing atmospheric investigations has stimulated the development of the optical models of the atmosphere. The principles of constructing the optical models of molecular atmosphere for radiation with different spectral composition (wideband, narrowband, and monochromatic) are considered in the case of linear and nonlinear absorptions. The example of the development of a system which provides for the modeling of the processes of optical-wave energy transfer in the atmosphere is presented. Its physical foundations, structure, programming software, and functioning were considered.

  3. Molecular modelling on small molecular CDK2 inhibitors: an integrated approach using a combination of molecular docking, 3D-QSAR and pharmacophore modelling.

    PubMed

    Yuan, H; Liu, H; Tai, W; Wang, F; Zhang, Y; Yao, S; Ran, T; Lu, S; Ke, Z; Xiong, X; Xu, J; Chen, Y; Lu, T

    2013-10-01

    Cyclin-dependent kinase 2 (CDK2) has been identified as an important target for developing novel anticancer agents. Molecular docking, three-dimensional quantitative structure-activity relationship (3D-QSAR) and pharmacophore modelling were combined with the ultimate goal of studying the structure-activity relationship of CDK2 inhibitors. The comparative molecular similarity indices analysis (CoMSIA) model constructed based on a set of 3-aminopyrazole derivatives as CDK2 inhibitors gave statistically significant results (q (2) = 0.700; r (2) = 0.982). A HypoGen pharmacophore model, constructed using diverse CDK2 inhibitors, also showed significant statistics ([Formula: see text]Cost = 61.483; RMSD = 0.53; Correlation coefficient = 0.98). The small residues and error values between the estimated and experimental activities of the training and test set compounds proved their strong capability of activity prediction. The structural insights obtained from these two models were consistent with each other. The pharmacophore model summarized the important pharmacophoric features required for protein-ligand binding. The 3D contour maps in combination with the comprehensive pharmacophoric features helped to better interpret the structure-activity relationship. The results will be beneficial for the discovery and design of novel CDK2 inhibitors. The simplicity of this approach provides expansion to its applicability in optimizing other classes of small molecular CDK2 inhibitors. PMID:23941641

  4. Molecular models and simulations of layered materials.

    SciTech Connect

    Kalinichev, Andrey G.; Cygan, Randall Timothy; Heinz, Hendrik; Greathouse, Jeffery A.

    2008-11-01

    The micro- to nano-sized nature of layered materials, particularly characteristic of naturally occurring clay minerals, limits our ability to fully interrogate their atomic dispositions and crystal structures. The low symmetry, multicomponent compositions, defects, and disorder phenomena of clays and related phases necessitate the use of molecular models and modern simulation methods. Computational chemistry tools based on classical force fields and quantum-chemical methods of electronic structure calculations provide a practical approach to evaluate structure and dynamics of the materials on an atomic scale. Combined with classical energy minimization, molecular dynamics, and Monte Carlo techniques, quantum methods provide accurate models of layered materials such as clay minerals, layered double hydroxides, and clay-polymer nanocomposites.

  5. Molecular model and ReaxFF molecular dynamics simulation of coal vitrinite pyrolysis.

    PubMed

    Li, Wu; Zhu, Yan-ming; Wang, Geoff; Wang, Yang; Liu, Yu

    2015-08-01

    Vitrinite in coal, the mainly generating methane maceral, plays an important role in hydrocarbon generation of coal. This study aims at obtaining products formation mechanism of vitrinite pyrolysis, and hence determining the chemical bond, molecular liquefaction activity, and reactions mechanism of methane and C2-4 during pyrolysis. The ReaxFF molecular dynamics (MD) simulation was carried out at temperature of 1500 K in order to investigate the mechanism of vitrinite pyrolysis. Initially, a minimum energy conformational structure model was constrained by a combination of elemental and carbon-13 nuclear magnetic resonance ((13)C NMR) literature data. The model analysis shows the chemical and physical parameters of vitrinite pyrolysis are broadly consistent with the experimental data. Based on the molecular model, ReaxFF MD simulations further provide information of unimolecule such as bond length, and chemical shift, and hence the total population and energy of main products. Molecules bond and pyrolysis fragments, based on active bond analyzed, revealed pyrolysis products of single vitrinite molecule with aliphatic C-C bond, especially ring and chain aliphatic as liquefaction activity. The molecular cell whose density is 0.9 g/cm(3) with lowest energy accords with the experimental density 1.33 g/cm(3). The content of main products after pyrolysis, classifying as CH4, H2O, and H2, was changed along with the increasing temperature. The gas molecule, fragments and generation pathways of CO2, H2, CH4, and C2H6 were also elucidated. These results show agreement with experimental observations, implying that MD simulation can provide reasonable explanation for the reaction processes involved in coal vitrinite pyrolysis. Thus the mechanism of coal hydrocarbon generation was revealed at the molecular level. PMID:26149754

  6. Molecular dynamics modelling of solidification in metals

    SciTech Connect

    Boercker, D.B.; Belak, J.; Glosli, J.

    1997-12-31

    Molecular dynamics modeling is used to study the solidification of metals at high pressure and temperature. Constant pressure MD is applied to a simulation cell initially filled with both solid and molten metal. The solid/liquid interface is tracked as a function of time, and the data are used to estimate growth rates of crystallites at high pressure and temperature in Ta and Mg.

  7. Synthesis, spectroscopic studies, molecular modeling and antimicrobial activity of binuclear Co(II) and Cu(II) complexes of 4,6-diacetylresorcinol

    NASA Astrophysics Data System (ADS)

    Shebl, Magdy; Khalil, Saied M. E.; Taha, A.; Mahdi, M. A. N.

    2013-09-01

    Reactions of 4,6-diacetylresorcinol with different cobalt(II) and copper(II) salts viz., OAc-, Cl-, NO3- and SO42-, yielded a new series of binuclear metal complexes. Reactions of the ligand with these metal ions in the presence of a secondary ligand (L‧) [O,O-donor; acetylacetone, N,O-donor; 8-hydroxyquinoline or N,N-donor; 1,10-phenanthroline and N,N,N‧,N‧-tetramethylethylenediamine] in 1:2:2 (L:M:L‧) molar ratio yielded mixed-ligand complexes with different molar ratios. The metal complexes were characterized by elemental and thermal analyses, IR, electronic, ESR and mass spectra as well as conductivity and magnetic susceptibility measurements. The analytical and spectroscopic data suggested that the H2L ligand behaves as a neutral, monobasic or dibasic tetradentate ligand, depending on the type of the anion and secondary ligand used, through the two phenolic and two carbonyl groups. Electronic spectra, magnetic and conductivity measurements showed that all complexes are octahedral with non-electrolytic nature. The profile of ESR spectra of copper(II) complexes suggested the octahedral geometry and the spin Hamiltonian parameters of the complexes were calculated and discussed. Molecular orbital calculations were performed for metal complexes using Hyperchem 7.52 program on the bases of PM3 level and the results correlated with the experimental data. The free ligand and some of its metal complexes showed antimicrobial activity towards some of Gram-positive and Gram-negative bacteria, yeast (Candida albicans) and fungus (Aspergillus fumigatus).

  8. Synthesis, spectroscopic studies, molecular modeling and antimicrobial activity of binuclear Co(II) and Cu(II) complexes of 4,6-diacetylresorcinol.

    PubMed

    Shebl, Magdy; Khalil, Saied M E; Taha, A; Mahdi, M A N

    2013-09-01

    Reactions of 4,6-diacetylresorcinol with different cobalt(II) and copper(II) salts viz., OAc(-), Cl(-), NO3(-) and SO4(2-), yielded a new series of binuclear metal complexes. Reactions of the ligand with these metal ions in the presence of a secondary ligand (L') [O,O-donor; acetylacetone, N,O-donor; 8-hydroxyquinoline or N,N-donor; 1,10-phenanthroline and N,N,N',N'-tetramethylethylenediamine] in 1:2:2 (L:M:L') molar ratio yielded mixed-ligand complexes with different molar ratios. The metal complexes were characterized by elemental and thermal analyses, IR, electronic, ESR and mass spectra as well as conductivity and magnetic susceptibility measurements. The analytical and spectroscopic data suggested that the H2L ligand behaves as a neutral, monobasic or dibasic tetradentate ligand, depending on the type of the anion and secondary ligand used, through the two phenolic and two carbonyl groups. Electronic spectra, magnetic and conductivity measurements showed that all complexes are octahedral with non-electrolytic nature. The profile of ESR spectra of copper(II) complexes suggested the octahedral geometry and the spin Hamiltonian parameters of the complexes were calculated and discussed. Molecular orbital calculations were performed for metal complexes using Hyperchem 7.52 program on the bases of PM3 level and the results correlated with the experimental data. The free ligand and some of its metal complexes showed antimicrobial activity towards some of Gram-positive and Gram-negative bacteria, yeast (Candida albicans) and fungus (Aspergillus fumigatus). PMID:23743042

  9. Applications of molecular modeling in coal research

    SciTech Connect

    Carlson, G.A.; Faulon, J.L.

    1994-01-01

    Over the past several years, molecular modeling has been applied to study various characteristics of coal molecular structures. Powerful workstations coupled with molecular force-field-based software packages have been used to study coal and coal-related molecules. Early work involved determination of the minimum-energy three-dimensional conformations of various published coal structures (Given, Wiser, Solomon and Shinn), and the dominant role of van der Waals and hydrogen bonding forces in defining the energy-minimized structures. These studies have been extended to explore various physical properties of coal structures, including density, microporosity, surface area, and fractal dimension. Other studies have related structural characteristics to cross-link density and have explored small molecule interactions with coal. Finally, recent studies using a structural elucidation (molecular builder) technique have constructed statistically diverse coal structures based on quantitative and qualitative data on coal and its decomposition products. This technique is also being applied to study coalification processes based on postulated coalification chemistry.

  10. Molecular model for hydrated biological tissues.

    PubMed

    Sato, Erika Tiemi; Rocha, Alexandre Reily; de Carvalho, Luis Felipe das Chagas e Silva; Almeida, Janete Dias; Martinho, Herculano

    2015-06-01

    A density-functional microscopic model for soft tissues (STmod) is presented. The model was based on a prototype molecular structure from experimentally resolved type I collagen peptide residues and water clusters treated in periodic boundary conditions. We obtained the optimized geometry, binding and coupling energies, dipole moments, and vibrational frequencies. The results concerning the stability of the confined water clusters, the water-water, and water-collagen interactions were successfully correlated to some important experimental trends of normal and inflammatory tissues. PMID:26172825

  11. Molecular hydrogen suppresses activated Wnt/β-catenin signaling.

    PubMed

    Lin, Yingni; Ohkawara, Bisei; Ito, Mikako; Misawa, Nobuaki; Miyamoto, Kentaro; Takegami, Yasuhiko; Masuda, Akio; Toyokuni, Shinya; Ohno, Kinji

    2016-01-01

    Molecular hydrogen (H2) is effective for many diseases. However, molecular bases of H2 have not been fully elucidated. Cumulative evidence indicates that H2 acts as a gaseous signal modulator. We found that H2 suppresses activated Wnt/β-catenin signaling by promoting phosphorylation and degradation οf β-catenin. Either complete inhibition of GSK3 or mutations at CK1- and GSK3-phosphorylation sites of β-catenin abolished the suppressive effect of H2. H2 did not increase GSK3-mediated phosphorylation of glycogen synthase, indicating that H2 has no direct effect on GSK3 itself. Knock-down of adenomatous polyposis coli (APC) or Axin1, which form the β-catenin degradation complex, minimized the suppressive effect of H2 on β-catenin accumulation. Accordingly, the effect of H2 requires CK1/GSK3-phosphorylation sites of β-catenin, as well as the β-catenin degradation complex comprised of CK1, GSK3, APC, and Axin1. We additionally found that H2 reduces the activation of Wnt/β-catenin signaling in human osteoarthritis chondrocytes. Oral intake of H2 water tended to ameliorate cartilage degradation in a surgery-induced rat osteoarthritis model through attenuating β-catenin accumulation. We first demonstrate that H2 suppresses abnormally activated Wnt/β-catenin signaling, which accounts for the protective roles of H2 in a fraction of diseases. PMID:27558955

  12. Molecular hydrogen suppresses activated Wnt/β-catenin signaling

    PubMed Central

    Lin, Yingni; Ohkawara, Bisei; Ito, Mikako; Misawa, Nobuaki; Miyamoto, Kentaro; Takegami, Yasuhiko; Masuda, Akio; Toyokuni, Shinya; Ohno, Kinji

    2016-01-01

    Molecular hydrogen (H2) is effective for many diseases. However, molecular bases of H2 have not been fully elucidated. Cumulative evidence indicates that H2 acts as a gaseous signal modulator. We found that H2 suppresses activated Wnt/β-catenin signaling by promoting phosphorylation and degradation οf β-catenin. Either complete inhibition of GSK3 or mutations at CK1- and GSK3-phosphorylation sites of β-catenin abolished the suppressive effect of H2. H2 did not increase GSK3-mediated phosphorylation of glycogen synthase, indicating that H2 has no direct effect on GSK3 itself. Knock-down of adenomatous polyposis coli (APC) or Axin1, which form the β-catenin degradation complex, minimized the suppressive effect of H2 on β-catenin accumulation. Accordingly, the effect of H2 requires CK1/GSK3-phosphorylation sites of β-catenin, as well as the β-catenin degradation complex comprised of CK1, GSK3, APC, and Axin1. We additionally found that H2 reduces the activation of Wnt/β-catenin signaling in human osteoarthritis chondrocytes. Oral intake of H2 water tended to ameliorate cartilage degradation in a surgery-induced rat osteoarthritis model through attenuating β-catenin accumulation. We first demonstrate that H2 suppresses abnormally activated Wnt/β-catenin signaling, which accounts for the protective roles of H2 in a fraction of diseases. PMID:27558955

  13. X-Ray Spectral Model of Reprocess by Smooth and Clumpy Molecular Tori in Active Galactic Nuclei with the Framework MONACO

    NASA Astrophysics Data System (ADS)

    Furui, Shun'ya; Fukazawa, Yasushi; Odaka, Hirokazu; Kawaguchi, Toshihiro; Ohno, Masanori; Hayashi, Kazuma

    2016-02-01

    We construct an X-ray spectral model of reprocessing by a torus in an active galactic nucleus (AGN) with the Monte Carlo simulation framework MONACO. Two torus geometries of smooth and clumpy cases are considered and compared. In order to reproduce a Compton shoulder accurately, MONACO includes not only free electron scattering but also bound electron scattering. Raman and Rayleigh scattering are also treated, and scattering cross sections dependent on chemical states of hydrogen and helium are included. Doppler broadening by turbulence velocity can be implemented. Our model gives results consistent with other available models, such as MYTorus, except for differences due to different physical parameters and assumptions. We studied the dependence on torus parameters for a Compton shoulder, and found that a intensity ratio of a Compton shoulder to the line core mainly depends on column density, inclination angle, and metal abundance. For instance, an increase of metal abundance makes a Compton shoulder relatively weak. Also, the shape of a Compton shoulder depends on the column density. Furthermore, these dependences become different between smooth and clumpy cases. Then, we discuss the possibility of ASTRO-H/SXS spectroscopy of Compton shoulders in AGN reflection spectra.

  14. Modeling anti-allergic natural compounds by molecular topology.

    PubMed

    García-Domenech, Ramón; Zanni, Riccardo; Galvez-Llompart, María; de Julián-Ortiz, J Vicente

    2013-09-01

    Molecular topology has been applied to the search of QSAR models able to identify the anti-allergic activity of a wide group of heterogeneous compounds. Through the linear discriminant analysis and artificial neural networks, correct classification percentages above 85% for both the training set and the test set have been obtained. After carrying out a virtual screening with a natural product library, about thirty compounds with theoretical anti-allergic activity have been selected. Among them, hesperidin, naringin, salinomycin, sorbitol, curcumol, myricitrin, diosmin and kinetin stand out. Some of these compounds have already been referenced as having anti-allergic activity. PMID:23597273

  15. Activation of molecular catalysts using semiconductor quantum dots

    DOEpatents

    Meyer, Thomas J.; Sykora, Milan; Klimov, Victor I.

    2011-10-04

    Photocatalytic materials based on coupling of semiconductor nanocrystalline quantum dots (NQD) and molecular catalysts. These materials have capability to drive or catalyze non-spontaneous chemical reactions in the presence of visible radiation, ultraviolet radiation, or both. The NQD functions in these materials as a light absorber and charge generator. Following light absorption, the NQD activates a molecular catalyst adsorbed on the surface of the NQD via transfer of one or more charges (either electrons or electron-holes) from the NQD to the molecular catalyst. The activated molecular catalyst can then drive a chemical reaction. A photoelectrolytic device that includes such photocatalytic materials is also described.

  16. Electronic continuum model for molecular dynamics simulations.

    PubMed

    Leontyev, I V; Stuchebrukhov, A A

    2009-02-28

    A simple model for accounting for electronic polarization in molecular dynamics (MD) simulations is discussed. In this model, called molecular dynamics electronic continuum (MDEC), the electronic polarization is treated explicitly in terms of the electronic continuum (EC) approximation, while the nuclear dynamics is described with a fixed-charge force field. In such a force-field all atomic charges are scaled to reflect the screening effect by the electronic continuum. The MDEC model is rather similar but not equivalent to the standard nonpolarizable force-fields; the differences are discussed. Of our particular interest is the calculation of the electrostatic part of solvation energy using standard nonpolarizable MD simulations. In a low-dielectric environment, such as protein, the standard MD approach produces qualitatively wrong results. The difficulty is in mistreatment of the electronic polarizability. We show how the results can be much improved using the MDEC approach. We also show how the dielectric constant of the medium obtained in a MD simulation with nonpolarizable force-field is related to the static (total) dielectric constant, which includes both the nuclear and electronic relaxation effects. Using the MDEC model, we discuss recent calculations of dielectric constants of alcohols and alkanes, and show that the MDEC results are comparable with those obtained with the polarizable Drude oscillator model. The applicability of the method to calculations of dielectric properties of proteins is discussed. PMID:19256627

  17. Molecular modelling of miraculin: Structural analyses and functional hypotheses.

    PubMed

    Paladino, Antonella; Costantini, Susan; Colonna, Giovanni; Facchiano, Angelo M

    2008-02-29

    Miraculin is a plant protein that displays the peculiar property of modifying taste by swiching sour into a sweet taste. Its monomer is flavourless at all pH as well as at high concentration; the dimer form elicits its taste-modifying activity at acidic pH; a tetrameric form is also reported as active. Two histidine residues, located in exposed regions, are the main responsible of miraculin activity, as demonstrated by mutagenesis studies. Since structural data of miraculin are not available, we have predicted its three-dimensional structure and simulated both its dimer and tetramer forms by comparative modelling and molecular docking techniques. Finally, molecular dynamics simulations at different pH conditions have indicated that at acidic pH the dimer assumes a widely open conformation, in agreement with the hypotheses coming from other studies. PMID:18158914

  18. Powerful Molecular Outflows in Nearby Active Galaxies

    NASA Astrophysics Data System (ADS)

    Veilleux, Sylvain; Meléndez, Marcio

    2014-07-01

    We report the results from a systematic search for molecular (OH 119 μm) outflows with Herschel-PACS† in a sample of 43 nearby (z < 0.3) galaxy mergers, mostly ultraluminous infrared galaxies (ULIRGs) and QSOs. We find that the character of the OH feature (strength of the absorption relative to the emission) correlates with that of the 9.7-μm silicate feature, a measure of obscuration in ULIRGs. Unambiguous evidence for molecular outflows, based on the detection of OH absorption profiles with median velocities more blueshifted than -50 km s-1, is seen in 26 (70%) of the 37 OH-detected targets, suggesting a wide-angle (~ 145°) outflow geometry. Conversely, unambiguous evidence for molecular inflows, based on the detection of OH absorption profiles with median velocities more redshifted than +50 km s-1, is seen in only 4 objects, suggesting a planar or filamentary geometry for the inflowing gas. Terminal outflow velocities of ~ -1000 km s-1 are measured in several objects, but median outflow velocities are typically ~ -200 km s-1. While the outflow velocities show no statistically significant dependence on the star formation rate, they are distinctly more blueshifted among systems with large AGN fractions and luminosities [log (L AGN/L ⊙) >= 11.8 +/- 0.3]. The quasars in these systems play a dominant role in driving the molecular outflows. In contrast, the most AGN dominated systems, where OH is seen purely in emission, show relatively modest OH line widths, despite their large AGN luminosities, perhaps indicating that molecular outflows subside once the quasar has cleared a path through the obscuring material.

  19. An Integrated Biochemistry Laboratory, Including Molecular Modeling

    NASA Astrophysics Data System (ADS)

    Hall, Adele J. Wolfson Mona L.; Branham, Thomas R.

    1996-11-01

    ) experience with methods of protein purification; (iii) incorporation of appropriate controls into experiments; (iv) use of basic statistics in data analysis; (v) writing papers and grant proposals in accepted scientific style; (vi) peer review; (vii) oral presentation of results and proposals; and (viii) introduction to molecular modeling. Figure 1 illustrates the modular nature of the lab curriculum. Elements from each of the exercises can be separated and treated as stand-alone exercises, or combined into short or long projects. We have been able to offer the opportunity to use sophisticated molecular modeling in the final module through funding from an NSF-ILI grant. However, many of the benefits of the research proposal can be achieved with other computer programs, or even by literature survey alone. Figure 1.Design of project-based biochemistry laboratory. Modules (projects, or portions of projects) are indicated as boxes. Each of these can be treated independently, or used as part of a larger project. Solid lines indicate some suggested paths from one module to the next. The skills and knowledge required for protein purification and design are developed in three units: (i) an introduction to critical assays needed to monitor degree of purification, including an evaluation of assay parameters; (ii) partial purification by ion-exchange techniques; and (iii) preparation of a grant proposal on protein design by mutagenesis. Brief descriptions of each of these units follow, with experimental details of each project at the end of this paper. Assays for Lysozyme Activity and Protein Concentration (4 weeks) The assays mastered during the first unit are a necessary tool for determining the purity of the enzyme during the second unit on purification by ion exchange. These assays allow an introduction to the concept of specific activity (units of enzyme activity per milligram of total protein) as a measure of purity. In this first sequence, students learn a turbidimetric assay

  20. A Series of Molecular Dynamics and Homology Modeling Computer Labs for an Undergraduate Molecular Modeling Course

    ERIC Educational Resources Information Center

    Elmore, Donald E.; Guayasamin, Ryann C.; Kieffer, Madeleine E.

    2010-01-01

    As computational modeling plays an increasingly central role in biochemical research, it is important to provide students with exposure to common modeling methods in their undergraduate curriculum. This article describes a series of computer labs designed to introduce undergraduate students to energy minimization, molecular dynamics simulations,…

  1. A realistic molecular model of cement hydrates

    PubMed Central

    Pellenq, Roland J.-M.; Kushima, Akihiro; Shahsavari, Rouzbeh; Van Vliet, Krystyn J.; Buehler, Markus J.; Yip, Sidney; Ulm, Franz-Josef

    2009-01-01

    Despite decades of studies of calcium-silicate-hydrate (C-S-H), the structurally complex binder phase of concrete, the interplay between chemical composition and density remains essentially unexplored. Together these characteristics of C-S-H define and modulate the physical and mechanical properties of this “liquid stone” gel phase. With the recent determination of the calcium/silicon (C/S = 1.7) ratio and the density of the C-S-H particle (2.6 g/cm3) by neutron scattering measurements, there is new urgency to the challenge of explaining these essential properties. Here we propose a molecular model of C-S-H based on a bottom-up atomistic simulation approach that considers only the chemical specificity of the system as the overriding constraint. By allowing for short silica chains distributed as monomers, dimers, and pentamers, this C-S-H archetype of a molecular description of interacting CaO, SiO2, and H2O units provides not only realistic values of the C/S ratio and the density computed by grand canonical Monte Carlo simulation of water adsorption at 300 K. The model, with a chemical composition of (CaO)1.65(SiO2)(H2O)1.75, also predicts other essential structural features and fundamental physical properties amenable to experimental validation, which suggest that the C-S-H gel structure includes both glass-like short-range order and crystalline features of the mineral tobermorite. Additionally, we probe the mechanical stiffness, strength, and hydrolytic shear response of our molecular model, as compared to experimentally measured properties of C-S-H. The latter results illustrate the prospect of treating cement on equal footing with metals and ceramics in the current application of mechanism-based models and multiscale simulations to study inelastic deformation and cracking. PMID:19805265

  2. An undergraduate laboratory activity on molecular dynamics simulations.

    PubMed

    Spitznagel, Benjamin; Pritchett, Paige R; Messina, Troy C; Goadrich, Mark; Rodriguez, Juan

    2016-01-01

    Vision and Change [AAAS, 2011] outlines a blueprint for modernizing biology education by addressing conceptual understanding of key concepts, such as the relationship between structure and function. The document also highlights skills necessary for student success in 21st century Biology, such as the use of modeling and simulation. Here we describe a laboratory activity that allows students to investigate the dynamic nature of protein structure and function through the use of a modeling technique known as molecular dynamics (MD). The activity takes place over two lab periods that are 3 hr each. The first lab period unpacks the basic approach behind MD simulations, beginning with the kinematic equations that all bioscience students learn in an introductory physics course. During this period students are taught rudimentary programming skills in Python while guided through simple modeling exercises that lead up to the simulation of the motion of a single atom. In the second lab period students extend concepts learned in the first period to develop skills in the use of expert MD software. Here students simulate and analyze changes in protein conformation resulting from temperature change, solvation, and phosphorylation. The article will describe how these activities can be carried out using free software packages, including Abalone and VMD/NAMD. PMID:26751047

  3. Interfacial activation-based molecular bioimprinting of lipolytic enzymes.

    PubMed Central

    Mingarro, I; Abad, C; Braco, L

    1995-01-01

    Interfacial activation-based molecular (bio)-imprinting (IAMI) has been developed to rationally improve the performance of lipolytic enzymes in nonaqueous environments. The strategy combinedly exploits (i) the known dramatic enhancement of the protein conformational rigidity in a water-restricted milieu and (ii) the reported conformational changes associated with the activation of these enzymes at lipid-water interfaces, which basically involves an increased substrate accessibility to the active site and/or an induction of a more competent catalytic machinery. Six model enzymes have been assayed in several model reactions in nonaqueous media. The results, rationalized in light of the present biochemical and structural knowledge, show that the IAMI approach represents a straightforward, versatile method to generate manageable, activated (kinetically trapped) forms of lipolytic enzymes, providing under optimal conditions nonaqueous rate enhancements of up to two orders of magnitude. It is also shown that imprintability of lipolytic enzymes depends not only on the nature of the enzyme but also on the "quality" of the interface used as the template. PMID:7724558

  4. Glycolic acid inhibits enzymatic, hemorrhagic and edema-inducing activities of BaP1, a P-I metalloproteinase from Bothrops asper snake venom: insights from docking and molecular modeling.

    PubMed

    Pereañez, Jaime Andrés; Patiño, Arley Camilo; Rey-Suarez, Paola; Núñez, Vitelbina; Henao Castañeda, Isabel Cristina; Rucavado, Alexandra

    2013-09-01

    Glycolic acid (GA) (2-Hydroxyethanoic acid) is widely used as chemical peeling agent in Dermatology and, more recently, as a therapeutic and cosmetic compound in the field of skin care and disease treatment. In this work we tested the inhibitory ability of glycolic acid on the enzymatic, hemorrhagic and edema-inducing activities of BaP1, a P-I metalloproteinase from Bothrops asper venom, which induces a variety of toxic actions. Glycolic acid inhibited the proteolytic activity of BaP1 on azocasein, with an IC₅₀ of 1.67 mM. The compound was also effective at inhibiting the hemorrhagic activity of BaP1 in skin and muscle in experiments involving preincubation of enzyme and inhibitor prior to injection. When BaP1 was injected i.m. and then, at the same site, different concentrations of glycolic acid were administered at either 0 or 5 min, 7 mM solutions of the inhibitor partially abrogated hemorrhagic activity when administered at 0 min. Moreover, glycolic acid inhibited, in a concentration-dependent manner, edema-forming activity of BaP1 in the footpad. In order to have insights on the mode of action of glycolic acid, UV-vis and intrinsic fluorescence studies were performed. Results of these assays suggest that glycolic acid interacts directly with BaP1 and chelates the Zn²⁺ ion at the active site. These findings were supported by molecular docking results, which suggested that glycolic acid forms hydrogen bonds with residues Glu143, Arg110 and Ala111 of the enzyme. Additionally, molecular modeling results suggest that the inhibitor chelates Zn²⁺, with a distance of 3.58 Å, and may occupy part of substrate binding cleft of BaP1. Our results suggest that glycolic acid is a candidate for the development of inhibitors to be used in snakebite envenomation. PMID:23726855

  5. Molecular Models of Liquid Crystal Elastomers

    NASA Astrophysics Data System (ADS)

    Rajshekhar

    Liquid crystal elastomers combine the elastic properties of conventional rubbers with the optical properties of liquid crystals. This dual nature gives rise to unusual physical properties, including the stress induced transition from a polydomain state, consisting of multiple nematic regions with independent orientations, to a monodomain state consisting of a single nematic region with a uniform director. We propose several molecular-scale coarse-grained models of liquid crystal elastomers with varying degrees of resolution. The models employ the Gay-Berne soft potential, and exhibit the chain connectivity of a diamond network. Simulation results show that these models are able to capture the polydomain state exhibited by liquid crystal elastomers in the absence of any external stress. When subjected to uniaxial stress, our models exhibit a polydomain to monodomain transition. We explain that the polydomain state occurs through the aggregation of liquid crystal molecules assisted by crosslinking sites, and conclude that the transition mechanism to the monodomain state is based on the reorientation of nematic domains along the direction of applied stress. Our modeling efforts are primarily focused on three models. The first two models consider the effects of rigid and flexible crosslinkers in liquid crystal elastomers with a diamond topology for chain connectivity. The third model deviates from the diamond network topology and adopts a random network topology.

  6. Molecular Abundances in the Disk of AN Active Galactic Nucleus

    NASA Astrophysics Data System (ADS)

    Harada, N.; Thompson, T. A.; Herbst, E.

    2011-06-01

    There are galactic nuclei that emit high luminosities L˜1044-46 erg S-1 including luminosity produced by X-rays from high mass accretion onto the central black holes. These nuclei are called active galactic nuclei (AGNs), and they are accompanied by molecular disks. Observations show high abundances of CN and HCN in the disks; the molecules are proposed to be probes of X-ray dominated regions (XDRs) created by the X-rays from AGNs. We have constructed a spatially-dependent chemical-abundance model of the molecular disk in NGC 1068, a typical AGN-dominated galaxy. Recently, new observations of CN and HCN have been made at much higher spatial resolution, and there are also detections of polyatomic molecules such as HC3N, c-C3H2, and C2H. We discuss how these observations and our simulations can help us to better understand the physical conditions, the disk structure, and conditions for star formation within molecular disks, which are still uncertain. We also include a comparison with other types of galaxies such as (ultra-) luminous infrared galaxies. Usero et al.Astronomy and Astrophysics. 419 (897), 2004. Initial results were presented at the International Symposium on Molecular Spectroscopy 2010, RF05 Garcia-Burillo et al. Astronomy and Astrophysics. 519 (2), 2010. Garcia-Burillo et al. Journal of Physics Conference Series, 131 (12031), 2008. Costagliola et al. ArXiv e-print arXiv:1101.2122, 2011. Nakajima et al. Astrophysical Journal Letters 728 (L38), 2008.

  7. Molecular Sieve Bench Testing and Computer Modeling

    NASA Technical Reports Server (NTRS)

    Mohamadinejad, Habib; DaLee, Robert C.; Blackmon, James B.

    1995-01-01

    The design of an efficient four-bed molecular sieve (4BMS) CO2 removal system for the International Space Station depends on many mission parameters, such as duration, crew size, cost of power, volume, fluid interface properties, etc. A need for space vehicle CO2 removal system models capable of accurately performing extrapolated hardware predictions is inevitable due to the change of the parameters which influences the CO2 removal system capacity. The purpose is to investigate the mathematical techniques required for a model capable of accurate extrapolated performance predictions and to obtain test data required to estimate mass transfer coefficients and verify the computer model. Models have been developed to demonstrate that the finite difference technique can be successfully applied to sorbents and conditions used in spacecraft CO2 removal systems. The nonisothermal, axially dispersed, plug flow model with linear driving force for 5X sorbent and pore diffusion for silica gel are then applied to test data. A more complex model, a non-darcian model (two dimensional), has also been developed for simulation of the test data. This model takes into account the channeling effect on column breakthrough. Four FORTRAN computer programs are presented: a two-dimensional model of flow adsorption/desorption in a packed bed; a one-dimensional model of flow adsorption/desorption in a packed bed; a model of thermal vacuum desorption; and a model of a tri-sectional packed bed with two different sorbent materials. The programs are capable of simulating up to four gas constituents for each process, which can be increased with a few minor changes.

  8. Modelling Molecular Emission from Young Embedded Disks

    NASA Astrophysics Data System (ADS)

    Harsono, D.; Visser, R.; van Dishoeck, E. F.; Kristensen, L.; Bruderer, S.; Brinch, C. Hogerheijde, M.

    2011-05-01

    Circumstellar disks play an important role in the formation of stars and planets. Recent observations and models have placed strong constraints on the later stages of their evolution (the T Tauri or Herbig Ae/Be phase), when an envelope is no longer present. However, little is known of the disk structure and evolution during the embedded phase of star formation. With Herschel and the VLT, and soon ALMA, we will be able to detect and characterize the early stages of disk formation. Sophisticated modeling including both physical and chemical structure of the system would be needed to interpret the high quality of data. We present a two-dimensional, semi-analytical model of disk formation as also used in Visser et al. (2009) and Visser and Dullemond (2010). The dust temperature is determined using a three-dimensional dust continuum radiative transfer code (RADMC-3D). Molecular abundances are calculated by following freeze-out and evaporation from the pre-stellar core up to the formation of the circumstellar disk. Synthetic spectra of CO and H2O within the wavelength ranges observable with Herschel and VLT-CRIRES are then produced at a series of time steps, tracing the different stages of disk formation. We also present simulated ALMA images. We discuss the evolution of the molecular emission and the possibility of identifying the presence of embedded disks.

  9. Application of Molecular Modeling to Urokinase Inhibitors Development

    PubMed Central

    Sulimov, V. B.; Katkova, E. V.; Oferkin, I. V.; Sulimov, A. V.; Romanov, A. N.; Roschin, A. I.; Beloglazova, I. B.; Plekhanova, O. S.; Tkachuk, V. A.; Sadovnichiy, V. A.

    2014-01-01

    Urokinase-type plasminogen activator (uPA) plays an important role in the regulation of diverse physiologic and pathologic processes. Experimental research has shown that elevated uPA expression is associated with cancer progression, metastasis, and shortened survival in patients, whereas suppression of proteolytic activity of uPA leads to evident decrease of metastasis. Therefore, uPA has been considered as a promising molecular target for development of anticancer drugs. The present study sets out to develop the new selective uPA inhibitors using computer-aided structural based drug design methods. Investigation involves the following stages: computer modeling of the protein active site, development and validation of computer molecular modeling methods: docking (SOL program), postprocessing (DISCORE program), direct generalized docking (FLM program), and the application of the quantum chemical calculations (MOPAC package), search of uPA inhibitors among molecules from databases of ready-made compounds to find new uPA inhibitors, and design of new chemical structures and their optimization and experimental examination. On the basis of known uPA inhibitors and modeling results, 18 new compounds have been designed, calculated using programs mentioned above, synthesized, and tested in vitro. Eight of them display inhibitory activity and two of them display activity about 10 μM. PMID:24967388

  10. Homology modeling, molecular docking, and molecular dynamics simulations elucidated α-fetoprotein binding modes

    PubMed Central

    2013-01-01

    Background An important mechanism of endocrine activity is chemicals entering target cells via transport proteins and then interacting with hormone receptors such as the estrogen receptor (ER). α-Fetoprotein (AFP) is a major transport protein in rodent serum that can bind and sequester estrogens, thus preventing entry to the target cell and where they could otherwise induce ER-mediated endocrine activity. Recently, we reported rat AFP binding affinities for a large set of structurally diverse chemicals, including 53 binders and 72 non-binders. However, the lack of three-dimensional (3D) structures of rat AFP hinders further understanding of the structural dependence for binding. Therefore, a 3D structure of rat AFP was built using homology modeling in order to elucidate rat AFP-ligand binding modes through docking analyses and molecular dynamics (MD) simulations. Methods Homology modeling was first applied to build a 3D structure of rat AFP. Molecular docking and Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) scoring were then used to examine potential rat AFP ligand binding modes. MD simulations and free energy calculations were performed to refine models of binding modes. Results A rat AFP tertiary structure was first obtained using homology modeling and MD simulations. The rat AFP-ligand binding modes of 13 structurally diverse, representative binders were calculated using molecular docking, (MM-GBSA) ranking and MD simulations. The key residues for rat AFP-ligand binding were postulated through analyzing the binding modes. Conclusion The optimized 3D rat AFP structure and associated ligand binding modes shed light on rat AFP-ligand binding interactions that, in turn, provide a means to estimate binding affinity of unknown chemicals. Our results will assist in the evaluation of the endocrine disruption potential of chemicals. PMID:24266910

  11. Many-Body Models for Molecular Nanomagnets

    NASA Astrophysics Data System (ADS)

    Chiesa, A.; Carretta, S.; Santini, P.; Amoretti, G.; Pavarini, E.

    2013-04-01

    We present a flexible and effective ab initio scheme to build many-body models for molecular nanomagnets, and to calculate magnetic exchange couplings and zero-field splittings. It is based on using localized Foster-Boys orbitals as a one-electron basis. We apply this scheme to three paradigmatic systems, the antiferromagnetic rings Cr8 and Cr7Ni, and the single-molecule magnet Fe4. In all cases we identify the essential magnetic interactions and find excellent agreement with experiments.

  12. Kinetic modelling of molecular hydrogen transport in microporous carbon materials.

    SciTech Connect

    Hankel, M.; Zhang, H.; Nguyen, T. X.; Bhatia, S. K.; Gray, S. K.; Smith, S. C.

    2011-01-01

    The proposal of kinetic molecular sieving of hydrogen isotopes is explored by employing statistical rate theory methods to describe the kinetics of molecular hydrogen transport in model microporous carbon structures. A Lennard-Jones atom-atom interaction potential is utilized for the description of the interactions between H{sub 2}/D{sub 2} and the carbon framework, while the requisite partition functions describing the thermal flux of molecules through the transition state are calculated quantum mechanically in view of the low temperatures involved in the proposed kinetic molecular sieving application. Predicted kinetic isotope effects for initial passage from the gas phase into the first pore mouth are consistent with expectations from previous modeling studies, namely, that at sufficiently low temperatures and for sufficiently narrow pore mouths D{sub 2} transport is dramatically favored over H{sub 2}. However, in contrast to expectations from previous modeling, the absence of any potential barrier along the minimum energy pathway from the gas phase into the first pore mouth yields a negative temperature dependence in the predicted absolute rate coefficients - implying a negative activation energy. In pursuit of the effective activation barrier, we find that the minimum potential in the cavity is significantly higher than in the pore mouth for nanotube-shaped models, throwing into question the common assumption that passage through the pore mouths should be the rate-determining step. Our results suggest a new mechanism that, depending on the size and shape of the cavity, the thermal activation barrier may lie in the cavity rather than at the pore mouth. As a consequence, design strategies for achieving quantum-mediated kinetic molecular sieving of H{sub 2}/D{sub 2} in a microporous membrane will need, at the very least, to take careful account of cavity shape and size in addition to pore-mouth size in order to ensure that the selective step, namely passage

  13. Modeling the Molecular Gas in NGC 6240

    NASA Astrophysics Data System (ADS)

    Tunnard, R.; Greve, T. R.; Garcia-Burillo, S.; Graciá Carpio, J.; Fuente, A.; Tacconi, L.; Neri, R.; Usero, A.

    2015-12-01

    We present the first observations of H13CN (1-0), H13CO+(1-0), and SiO (2-1)in NGC 6240, obtained with the IRAM Plateau de Bure Interferometer. Combining a Markov Chain Monte Carlo code with Large Velocity Gradient (LVG) modeling, and with additional data from the literature, we simultaneously fit three gas phases and six molecular species to constrain the physical condition of the molecular gas, including mass-luminosity conversion factors. We find ˜ {10}10{M}⊙ of dense molecular gas in cold, dense clouds ({T}{{k}}˜ 10 K, {n}{{{H}}2}˜ {10}6 cm-3) with a volume filling factor \\lt 0.002, embedded in a shock heated molecular medium ({T}{{k}}˜ 2000 K, {n}{{{H}}2}˜ {10}3.6 cm-3), both surrounded by an extended diffuse phase ({T}{{k}}˜ 200 K, {n}{{{H}}2}˜ {10}2.5 cm-3). We derive a global {α }{{CO}}={1.5}1.17.1 with gas masses {{log}}10≤ft(M/[{M}⊙ ]\\right)={10.1}10.010.8, dominated by the dense gas. We also find {α }{{HCN}}={32}1389, which traces the cold, dense gas. The [12C]/[13C] ratio is only slightly elevated ({98}65230), contrary to the very high [CO]/[13CO] ratio (300-500) reported in the literature. However, we find very high [HCN]/[H13CN] and [HCO+]/[H13CO+] abundance ratios ({300}200500) which we attribute to isotope fractionation in the cold, dense clouds.

  14. Molecular aspects of vitamin D anticancer activity.

    PubMed

    Picotto, Gabriela; Liaudat, Ana C; Bohl, Luciana; Tolosa de Talamoni, Nori

    2012-10-01

    Environment may influence the development and prevention of cancer. Calcitriol has been associated with calcium homeostasis regulation. Many epidemiological, biochemical, and genetic studies have shown non-classic effects of vitamin D, such as its involvement in the progression of different cancers. Although vitamin D induces cellular arrest, triggers apoptotic pathways, inhibits angiogenesis, and alters cellular adhesion, the precise mechanisms of its action are still not completely established. This article will present a revision about the molecular aspects proposed to be involved in the anticancer action of calcitriol. Adequate levels of vitamin D to prevent cancer development will also be discussed. PMID:22963190

  15. A Comparative Study of Successful Central Nervous System Drugs Using Molecular Modeling

    ERIC Educational Resources Information Center

    Kim, Hyosub; Sulaimon, Segun; Menezes, Sandra; Son, Anne; Menezes, Warren J. C.

    2011-01-01

    Molecular modeling is a powerful tool used for three-dimensional visualization and for exploring electrostatic forces involved in drug transport. This tool enhances student understanding of structure-property relationships, as well as actively engaging them in class. Molecular modeling of several central nervous system (CNS) drugs is used to…

  16. Modeling ion sensing in molecular electronics

    NASA Astrophysics Data System (ADS)

    Chen, Caroline J.; Smeu, Manuel; Ratner, Mark A.

    2014-02-01

    We examine the ability of molecules to sense ions by measuring the change in molecular conductance in the presence of such charged species. The detection of protons (H+), alkali metal cations (M+), calcium ions (Ca2+), and hydronium ions (H3O+) is considered. Density functional theory (DFT) is used within the Keldysh non-equilibrium Green's function framework (NEGF) to model electron transport properties of quinolinedithiol (QDT, C9H7NS2), bridging Al electrodes. The geometry of the transport region is relaxed with DFT. The transport properties of the device are modeled with NEGF-DFT to determine if this device can distinguish among the M+ + QDT species containing monovalent cations, where M+ = H+, Li+, Na+, or K+. Because of the asymmetry of QDT in between the two electrodes, both positive and negative biases are considered. The electron transmission function and conductance properties are simulated for electrode biases in the range from -0.5 V to 0.5 V at increments of 0.1 V. Scattering state analysis is used to determine the molecular orbitals that are the main contributors to the peaks in the transmission function near the Fermi level of the electrodes, and current-voltage relationships are obtained. The results show that QDT can be used as a proton detector by measuring transport through it and can conceivably act as a pH sensor in solutions. In addition, QDT may be able to distinguish among different monovalent species. This work suggests an approach to design modern molecular electronic conductance sensors with high sensitivity and specificity using well-established quantum chemistry.

  17. Modeling ion sensing in molecular electronics

    SciTech Connect

    Chen, Caroline J.; Smeu, Manuel Ratner, Mark A.

    2014-02-07

    We examine the ability of molecules to sense ions by measuring the change in molecular conductance in the presence of such charged species. The detection of protons (H{sup +}), alkali metal cations (M{sup +}), calcium ions (Ca{sup 2+}), and hydronium ions (H{sub 3}O{sup +}) is considered. Density functional theory (DFT) is used within the Keldysh non-equilibrium Green's function framework (NEGF) to model electron transport properties of quinolinedithiol (QDT, C{sub 9}H{sub 7}NS{sub 2}), bridging Al electrodes. The geometry of the transport region is relaxed with DFT. The transport properties of the device are modeled with NEGF-DFT to determine if this device can distinguish among the M{sup +} + QDT species containing monovalent cations, where M{sup +} = H{sup +}, Li{sup +}, Na{sup +}, or K{sup +}. Because of the asymmetry of QDT in between the two electrodes, both positive and negative biases are considered. The electron transmission function and conductance properties are simulated for electrode biases in the range from −0.5 V to 0.5 V at increments of 0.1 V. Scattering state analysis is used to determine the molecular orbitals that are the main contributors to the peaks in the transmission function near the Fermi level of the electrodes, and current-voltage relationships are obtained. The results show that QDT can be used as a proton detector by measuring transport through it and can conceivably act as a pH sensor in solutions. In addition, QDT may be able to distinguish among different monovalent species. This work suggests an approach to design modern molecular electronic conductance sensors with high sensitivity and specificity using well-established quantum chemistry.

  18. Deterministic Modelling of BAK Activation Kinetics

    NASA Astrophysics Data System (ADS)

    Grills, C.; Chacko, A.; Crawford, N.; Johnston, P. G.; Fennell, D. A.; O'Rourke, S. F. C.

    2009-08-01

    The molecular mechanism underlying mitochondrial BAK activation during apoptosis remains highly controversial. Two seemingly conflicting models have been proposed. In the activation model, BAK requires so-called activating BH3 only proteins (aBH3) to initiate its conformation change. In the other, displacement from inhibitory pro-survival BCL-2 proteins (PBPs) and monomerization of BAK by PBP restricted dissociator BH3-only proteins (dBH3) is sufficient. To better understand the kinetic implications of these models and reconcile these conflicting but highly evidence-based models, we have employed dynamical systems analysis to explore the kinetics underlying BAK activation as a non-linear reaction system. Our findings accommodate both pure agonism and dissociation as mutually exclusive mechanisms capable of initiating BAK activation. In addition we find our work supports a modelling based approach for predicting resistance to therapeutically relevant small molecules BH3 mimetics.

  19. A Molecular Communications Model for Drug Delivery.

    PubMed

    Femminella, Mauro; Reali, Gianluca; Vasilakos, Athanasios V

    2015-12-01

    This paper considers the scenario of a targeted drug delivery system, which consists of deploying a number of biological nanomachines close to a biological target (e.g., a tumor), able to deliver drug molecules in the diseased area. Suitably located transmitters are designed to release a continuous flow of drug molecules in the surrounding environment, where they diffuse and reach the target. These molecules are received when they chemically react with compliant receptors deployed on the receiver surface. In these conditions, if the release rate is relatively high and the drug absorption time is significant, congestion may happen, essentially at the receiver site. This phenomenon limits the drug absorption rate and makes the signal transmission ineffective, with an undesired diffusion of drug molecules elsewhere in the body. The original contribution of this paper consists of a theoretical analysis of the causes of congestion in diffusion-based molecular communications. For this purpose, it is proposed a reception model consisting of a set of pure loss queuing systems. The proposed model exhibits an excellent agreement with the results of a simulation campaign made by using the Biological and Nano-Scale communication simulator version 2 (BiNS2), a well-known simulator for molecular communications, whose reliability has been assessed through in vitro experiments. The obtained results can be used in rate control algorithms to optimally determine the optimal release rate of molecules in drug delivery applications. PMID:26529770

  20. A Molecular Model for Chiral Symmetry Breaking

    NASA Astrophysics Data System (ADS)

    Latinwo, Folarin; Stillinger, Frank; Debenedetti, Pablo

    In this work, we present a new class of molecular models for chiral phenomena in condensed matter systems. A key feature of these models is the ability of the four-site (tetramer) ``molecules'' to inter-convert between two distinct chiral forms (enantiomers). Given this feature, we use analytical theory and computer simulations to investigate the emergent chiral properties (including symmetry breaking) over a range of conditions. In particular, we consider the single-molecule level and condensed-phase behavior of our model system. Interestingly, we find that our liquid-phase predictions are in excellent agreement with recent experimental reports on chiral self-sorting in isotropic liquids. From this perspective, our model demonstrates accurate predictive capabilities, as well as a platform for understanding the microscopic origins of a variety of chiral phenomena. In a broader context, we anticipate that this class of models will be relevant to chirality-dominated areas such as the pharmaceutical industry and pre-biotic geochemistry.

  1. Molecular mechanisms regulating NLRP3 inflammasome activation

    PubMed Central

    Jo, Eun-Kyeong; Kim, Jin Kyung; Shin, Dong-Min; Sasakawa, Chihiro

    2016-01-01

    Inflammasomes are multi-protein signaling complexes that trigger the activation of inflammatory caspases and the maturation of interleukin-1β. Among various inflammasome complexes, the NLRP3 inflammasome is best characterized and has been linked with various human autoinflammatory and autoimmune diseases. Thus, the NLRP3 inflammasome may be a promising target for anti-inflammatory therapies. In this review, we summarize the current understanding of the mechanisms by which the NLRP3 inflammasome is activated in the cytosol. We also describe the binding partners of NLRP3 inflammasome complexes activating or inhibiting the inflammasome assembly. Our knowledge of the mechanisms regulating NLRP3 inflammasome signaling and how these influence inflammatory responses offers further insight into potential therapeutic strategies to treat inflammatory diseases associated with dysregulation of the NLRP3 inflammasome. PMID:26549800

  2. Molecular modeling of conformational properties of oligodepsipeptides.

    PubMed

    Zhang, Jiajing; King, Michael; Suggs, Laura; Ren, Pengyu

    2007-10-01

    A depsipeptide is a chemical structure consisting of both ester and amide bonds. Quantum mechanics calculations have been performed to investigate the conformational properties of a depsidipeptide in the gas and solution phases. Similar to an alanine dipeptide, the depsidipeptide exhibits a strong preference for the polyproline II (PPII) helical conformation. Meanwhile, due to the changes in the intramolecular interaction, the propensity for beta-sheets and alpha-helices diminishes while an unusual inclination for the (phi,psi) = (-150 degrees ,0 degrees ) conformation was observed. A molecular mechanics model has been developed for polydepsipeptides based on the quantum mechanical study. Both simulated annealing and replica exchange molecular dynamics simulations have been carried out on oligodepsipeptide sequences with alternating depsi and natural residues in solution. Novel helical structures have been indicated from the simulations. When glycine is used as the alternating natural amino acid residue, the PPII conformation of a depsi residue stabilizes the peptide into a right-handed helical structure while the alpha-helical conformation of the depsi residue favors an overall left-handed helical structure. The free energy analysis indicates that both the left- and the right-handed helices are equally likely to exist. When charged lysine is introduced as the alternating natural residue, however, it is found that the depsipeptide sequence prefers an extended conformation as in PPII. Our results indicate that the depsipeptide is potentially useful in designing protein mimetics with controllable structure, function, and chemistry. PMID:17877396

  3. Some Reflections on the Use and Abuse of Molecular Models

    ERIC Educational Resources Information Center

    Petersen, Quentin R.

    1970-01-01

    Describes the historical applications of molecular models and the controversies which they produced. The author discusses types of molecular models from the van't Hoff and Kekule models to the more recently developed ones. He presents a new model which was constructed to overcome the disadvantages of (1) falling apart, (2) inaccurate angles, (3)…

  4. Assessing Molecular Dynamics Simulations with Solvatochromism Modeling.

    PubMed

    Schwabe, Tobias

    2015-08-20

    For the modeling of solvatochromism with an explicit representation of the solvent molecules, the quality of preceding molecular dynamics simulations is crucial. Therefore, the possibility to apply force fields which are derived with as little empiricism as possible seems desirable. Such an approach is tested here by exploiting the sensitive solvatochromism of p-nitroaniline, and the use of reliable excitation energies based on approximate second-order coupled cluster results within a polarizable embedding scheme. The quality of the various MD settings for four different solvents, water, methanol, ethanol, and dichloromethane, is assessed. In general, good agreement with the experiment is observed when polarizable force fields and special treatment of hydrogen bonding are applied. PMID:26220273

  5. Ab Initio Modeling of Molecular Radiation

    NASA Technical Reports Server (NTRS)

    Jaffe, Richard; Schwenke, David

    2014-01-01

    Radiative emission from excited states of atoms and molecules can comprise a significant fraction of the total heat flux experienced by spacecraft during atmospheric entry at hypersonic speeds. For spacecraft with ablating heat shields, some of this radiative flux can be absorbed by molecular constituents in the boundary layer that are formed by the ablation process. Ab initio quantum mechanical calculations are carried out to predict the strengths of these emission and absorption processes. This talk will describe the methods used in these calculations using, as examples, the 4th positive emission bands of CO and the 1g+ 1u+ absorption in C3. The results of these calculations are being used as input to NASA radiation modeling codes like NeqAir, HARA and HyperRad.

  6. Bioinformatics and molecular modeling in glycobiology

    PubMed Central

    Schloissnig, Siegfried

    2010-01-01

    The field of glycobiology is concerned with the study of the structure, properties, and biological functions of the family of biomolecules called carbohydrates. Bioinformatics for glycobiology is a particularly challenging field, because carbohydrates exhibit a high structural diversity and their chains are often branched. Significant improvements in experimental analytical methods over recent years have led to a tremendous increase in the amount of carbohydrate structure data generated. Consequently, the availability of databases and tools to store, retrieve and analyze these data in an efficient way is of fundamental importance to progress in glycobiology. In this review, the various graphical representations and sequence formats of carbohydrates are introduced, and an overview of newly developed databases, the latest developments in sequence alignment and data mining, and tools to support experimental glycan analysis are presented. Finally, the field of structural glycoinformatics and molecular modeling of carbohydrates, glycoproteins, and protein–carbohydrate interaction are reviewed. PMID:20364395

  7. First Principles Quantitative Modeling of Molecular Devices

    NASA Astrophysics Data System (ADS)

    Ning, Zhanyu

    In this thesis, we report theoretical investigations of nonlinear and nonequilibrium quantum electronic transport properties of molecular transport junctions from atomistic first principles. The aim is to seek not only qualitative but also quantitative understanding of the corresponding experimental data. At present, the challenges to quantitative theoretical work in molecular electronics include two most important questions: (i) what is the proper atomic model for the experimental devices? (ii) how to accurately determine quantum transport properties without any phenomenological parameters? Our research is centered on these questions. We have systematically calculated atomic structures of the molecular transport junctions by performing total energy structural relaxation using density functional theory (DFT). Our quantum transport calculations were carried out by implementing DFT within the framework of Keldysh non-equilibrium Green's functions (NEGF). The calculated data are directly compared with the corresponding experimental measurements. Our general conclusion is that quantitative comparison with experimental data can be made if the device contacts are correctly determined. We calculated properties of nonequilibrium spin injection from Ni contacts to octane-thiolate films which form a molecular spintronic system. The first principles results allow us to establish a clear physical picture of how spins are injected from the Ni contacts through the Ni-molecule linkage to the molecule, why tunnel magnetoresistance is rapidly reduced by the applied bias in an asymmetric manner, and to what extent ab initio transport theory can make quantitative comparisons to the corresponding experimental data. We found that extremely careful sampling of the two-dimensional Brillouin zone of the Ni surface is crucial for accurate results in such a spintronic system. We investigated the role of contact formation and its resulting structures to quantum transport in several molecular

  8. Oriented active shape models.

    PubMed

    Liu, Jiamin; Udupa, Jayaram K

    2009-04-01

    Active shape models (ASM) are widely employed for recognizing anatomic structures and for delineating them in medical images. In this paper, a novel strategy called oriented active shape models (OASM) is presented in an attempt to overcome the following five limitations of ASM: 1) lower delineation accuracy, 2) the requirement of a large number of landmarks, 3) sensitivity to search range, 4) sensitivity to initialization, and 5) inability to fully exploit the specific information present in the given image to be segmented. OASM effectively combines the rich statistical shape information embodied in ASM with the boundary orientedness property and the globally optimal delineation capability of the live wire methodology of boundary segmentation. The latter characteristics allow live wire to effectively separate an object boundary from other nonobject boundaries with similar properties especially when they come very close in the image domain. The approach leads to a two-level dynamic programming method, wherein the first level corresponds to boundary recognition and the second level corresponds to boundary delineation, and to an effective automatic initialization method. The method outputs a globally optimal boundary that agrees with the shape model if the recognition step is successful in bringing the model close to the boundary in the image. Extensive evaluation experiments have been conducted by utilizing 40 image (magnetic resonance and computed tomography) data sets in each of five different application areas for segmenting breast, liver, bones of the foot, and cervical vertebrae of the spine. Comparisons are made between OASM and ASM based on precision, accuracy, and efficiency of segmentation. Accuracy is assessed using both region-based false positive and false negative measures and boundary-based distance measures. The results indicate the following: 1) The accuracy of segmentation via OASM is considerably better than that of ASM; 2) The number of landmarks

  9. Molecular Modeling, Synthesis, and Anti-HIV Activity of Novel Isoindolinedione Analogues as Potent Non-nucleoside Reverse Transcriptase Inhibitors.

    PubMed

    Kumari, Garima; Singh, Ramendra K

    2016-02-01

    Different isoindolinedione derivatives bearing imine, amide, thioamide, and sulfonamide linkages have been designed in silico using discovery studio software (BIOVIA, San Diego, CA, USA), synthesized, and evaluated for their anti-HIV activity. SAR studies revealed that the linkages in these molecules did affect their anti-HIV activity and the molecules having sulfonamide linkages were the most potent HIV-RT inhibitors as the S=O bonds of the sulfonamide moiety interacted with Lys103 (NH or carbonyl or both) and Pro236; the NH part of the sulfonamide linkage formed bond with carbonyl of Lys101. blood-brain barrier (BBB) plots were also studied, and it was found that all the designed molecules have potential to cross BBB, a very vital criteria for anti-HIV drugs. In vitro screening was performed using HIV-1 strain IIIB in MT-4 cells using the MTT assay, and it was seen that some of these molecules were effective inhibitors of HIV-1 replication at nanomolar concentration with selectivity indices ranging from 33.75 to 73.33 under in vitro conditions. Some of these molecules have shown good anti-HIV activity at 3-4 nm concentrations. These derivatives have potential to be developed as lead molecules effective against HIV-1. Novel isoindolinedione derivatives as probable NNRTIs have been synthesized and characterized. Some of these molecules have shown good anti-HIV activity at 3-4 nm concentrations. PMID:26212217

  10. Model For Dense Molecular Cloud Cores

    NASA Technical Reports Server (NTRS)

    Doty, Steven D.; Neufeld, David A.

    1997-01-01

    We present a detailed theoretical model for the thermal balance, chemistry, and radiative transfer within quiescent dense molecular cloud cores that contain a central protostar. In the interior of such cores, we expect the dust and gas temperatures to be well coupled, while in the outer regions CO rotational emissions dominate the gas cooling and the predicted gas temperature lies significantly below the dust temperature. Large spatial variations in the gas temperature are expected to affect the gas phase chemistry dramatically; in particular, the predicted water abundance varies by more than a factor of 1000 within cloud cores that contain luminous protostars. Based upon our predictions for the thermal and chemical structure of cloud cores, we have constructed self-consistent radiative transfer models to compute the line strengths and line profiles for transitions of (12)CO, (13)CO, C(18)O, ortho- and para-H2(16)O, ortho- and para-H2(18)O, and O I. We carried out a general parameter study to determine the dependence of the model predictions upon the parameters assumed for the source. We expect many of the far-infrared and submillimeter rotational transitions of water to be detectable either in emission or absorption with the use of the Infrared Space Observatory (ISO) and the Submillimeter Wave Astronomy Satellite. Quiescent, radiatively heated hot cores are expected to show low-gain maser emission in the 183 GHz 3(sub 13)-2(sub 20) water line, such as has been observed toward several hot core regions using ground-based telescopes. We predict the (3)P(sub l) - (3)P(sub 2) fine-structure transition of atomic oxygen near 63 micron to be in strong absorption against the continuum for many sources. Our model can also account successfully for recent ISO observations of absorption in rovibrational transitions of water toward the source AFGL 2591.

  11. Modelling spin Hamiltonian parameters of molecular nanomagnets.

    PubMed

    Gupta, Tulika; Rajaraman, Gopalan

    2016-07-12

    Molecular nanomagnets encompass a wide range of coordination complexes possessing several potential applications. A formidable challenge in realizing these potential applications lies in controlling the magnetic properties of these clusters. Microscopic spin Hamiltonian (SH) parameters describe the magnetic properties of these clusters, and viable ways to control these SH parameters are highly desirable. Computational tools play a proactive role in this area, where SH parameters such as isotropic exchange interaction (J), anisotropic exchange interaction (Jx, Jy, Jz), double exchange interaction (B), zero-field splitting parameters (D, E) and g-tensors can be computed reliably using X-ray structures. In this feature article, we have attempted to provide a holistic view of the modelling of these SH parameters of molecular magnets. The determination of J includes various class of molecules, from di- and polynuclear Mn complexes to the {3d-Gd}, {Gd-Gd} and {Gd-2p} class of complexes. The estimation of anisotropic exchange coupling includes the exchange between an isotropic metal ion and an orbitally degenerate 3d/4d/5d metal ion. The double-exchange section contains some illustrative examples of mixed valance systems, and the section on the estimation of zfs parameters covers some mononuclear transition metal complexes possessing very large axial zfs parameters. The section on the computation of g-anisotropy exclusively covers studies on mononuclear Dy(III) and Er(III) single-ion magnets. The examples depicted in this article clearly illustrate that computational tools not only aid in interpreting and rationalizing the observed magnetic properties but possess the potential to predict new generation MNMs. PMID:27366794

  12. Integrated Multiscale Modeling of Molecular Computing Devices

    SciTech Connect

    Weinan E

    2012-03-29

    The main bottleneck in modeling transport in molecular devices is to develop the correct formulation of the problem and efficient algorithms for analyzing the electronic structure and dynamics using, for example, the time-dependent density functional theory. We have divided this task into several steps. The first step is to developing the right mathematical formulation and numerical algorithms for analyzing the electronic structure using density functional theory. The second step is to study time-dependent density functional theory, particularly the far-field boundary conditions. The third step is to study electronic transport in molecular devices. We are now at the end of the first step. Under DOE support, we have made subtantial progress in developing linear scaling and sub-linear scaling algorithms for electronic structure analysis. Although there has been a huge amount of effort in the past on developing linear scaling algorithms, most of the algorithms developed suffer from the lack of robustness and controllable accuracy. We have made the following progress: (1) We have analyzed thoroughly the localization properties of the wave-functions. We have developed a clear understanding of the physical as well as mathematical origin of the decay properties. One important conclusion is that even for metals, one can choose wavefunctions that decay faster than any algebraic power. (2) We have developed algorithms that make use of these localization properties. Our algorithms are based on non-orthogonal formulations of the density functional theory. Our key contribution is to add a localization step into the algorithm. The addition of this localization step makes the algorithm quite robust and much more accurate. Moreover, we can control the accuracy of these algorithms by changing the numerical parameters. (3) We have considerably improved the Fermi operator expansion (FOE) approach. Through pole expansion, we have developed the optimal scaling FOE algorithm.

  13. Final Report for Integrated Multiscale Modeling of Molecular Computing Devices

    SciTech Connect

    Glotzer, Sharon C.

    2013-08-28

    In collaboration with researchers at Vanderbilt University, North Carolina State University, Princeton and Oakridge National Laboratory we developed multiscale modeling and simulation methods capable of modeling the synthesis, assembly, and operation of molecular electronics devices. Our role in this project included the development of coarse-grained molecular and mesoscale models and simulation methods capable of simulating the assembly of millions of organic conducting molecules and other molecular components into nanowires, crossbars, and other organized patterns.

  14. Detection of DNA methyltransferase activity using allosteric molecular beacons.

    PubMed

    Zhang, Weiting; Zu, Xiaolong; Song, Yanling; Zhu, Zhi; Yang, Chaoyong James

    2016-01-21

    Abnormal DNA methylation patterns caused by altered DNA methyltransferase (MTase) activity are closely associated with cancer. Herein, using DNA adenine methylation methyltransferase (Dam MTase) as a model analyte, we designed an allosteric molecular beacon (aMB) for sensitive detection of Dam MTase activity. When the specific site in an aMB is methylated by Dam MTase, the probe can be cut by the restriction nuclease DpnI to release a fluorophore labeled aptamer specific for streptavidin (SA) which will bind to SA beads to generate highly fluorescent beads for easy signal readout by a microscope or flow cytometer. However, aMBs maintain a hairpin structure without the binding ability to SA beads in the absence of Dam MTase, leading to weakly fluorescent SA beads. Unlike the existing signal amplified assays, our method is simpler and more convenient. The high performance of the aptamer and the easy bead separation process make this probe superior to other methods for the detection of MTase in complex biological systems. Overall, the proposed method with a detection limit of 0.57 U mL(-1) for Dam MTase shows great potential for further applications in the detection of other MTases, screening of MTase inhibitors, and early diagnosis of cancer. PMID:26478921

  15. Fluctuation driven active molecular transport in passive channel proteins

    NASA Astrophysics Data System (ADS)

    Kosztin, Ioan

    2006-03-01

    Living cells interact with their extracellular environment through the cell membrane, which acts as a protective permeability barrier for preserving the internal integrity of the cell. However, cell metabolism requires controlled molecular transport across the cell membrane, a function that is fulfilled by a wide variety of transmembrane proteins, acting as either passive or active transporters. In this talk it is argued that, contrary to the general belief, in active cell membranes passive and spatially asymmetric channel proteins can act as active transporters by consuming energy from nonequilibrium fluctuations fueled by cell metabolism. This assertion is demonstrated in the case of the E. coli aquaglyceroporin GlpF channel protein, whose high resolution crystal structure is manifestly asymmetric. By calculating the glycerol flux through GlpF within the framework of a stochastic model, it is found that, as a result of channel asymmetry, glycerol uptake driven by a concentration gradient is enhanced significantly in the presence of non-equilibrium fluctuations. Furthermore, the enhancement caused by a ratchet-like mechanism is larger for the outward, i.e., from the cytoplasm to the periplasm, flux than for the inward one, suggesting that the same non-equilibrium fluctuations also play an important role in protecting the interior of the cell against poisoning by excess uptake of glycerol. Preliminary data on water and sugar transport through aquaporin and maltoporin channels, respectively, are indicative of the universality of the proposed nonequilibrium-fluctuation-driven active transport mechanism. This work was supported by grants from the Univ. of Missouri Research Board, the Institute for Theoretical Sciences and the Department of Energy (DOE Contract W-7405-ENG-36), and the National Science Foundation (FIBR-0526854).

  16. Integrated Multiscale Modeling of Molecular Computing Devices

    SciTech Connect

    Jerzy Bernholc

    2011-02-03

    will some day reach a miniaturization limit, forcing designers of Si-based electronics to pursue increased performance by other means. Any other alternative approach would have the unenviable task of matching the ability of Si technology to pack more than a billion interconnected and addressable devices on a chip the size of a thumbnail. Nevertheless, the prospects of developing alternative approaches to fabricate electronic devices have spurred an ever-increasing pace of fundamental research. One of the promising possibilities is molecular electronics (ME), self-assembled molecular-based electronic systems composed of single-molecule devices in ultra dense, ultra fast molecular-sized components. This project focused on developing accurate, reliable theoretical modeling capabilities for describing molecular electronics devices. The participants in the project are given in Table 1. The primary outcomes of this fundamental computational science grant are publications in the open scientific literature. As listed below, 62 papers have been published from this project. In addition, the research has also been the subject of more than 100 invited talks at conferences, including several plenary or keynote lectures. Many of the goals of the original proposal were completed. Specifically, the multi-disciplinary group developed a unique set of capabilities and tools for investigating electron transport in fabricated and self-assembled nanostructures at multiple length and time scales.

  17. Phase Behavior of Active Swimmers in Depletants: Molecular Dynamics and Integral Equation Theory

    NASA Astrophysics Data System (ADS)

    Das, Subir K.; Egorov, Sergei A.; Trefz, Benjamin; Virnau, Peter; Binder, Kurt

    2014-05-01

    We study the structure and phase behavior of a binary mixture where one of the components is self-propelling in nature. The interparticle interactions in the system are taken from the Asakura-Oosawa model for colloid-polymer mixtures for which the phase diagram is known. In the current model version, the colloid particles are made active using the Vicsek model for self-propelling particles. The resultant active system is studied by molecular dynamics methods and integral equation theory. Both methods produce results consistent with each other and demonstrate that the Vicsek model-based activity facilitates phase separation, thus, broadening the coexistence region.

  18. Phase behavior of active swimmers in depletants: molecular dynamics and integral equation theory.

    PubMed

    Das, Subir K; Egorov, Sergei A; Trefz, Benjamin; Virnau, Peter; Binder, Kurt

    2014-05-16

    We study the structure and phase behavior of a binary mixture where one of the components is self-propelling in nature. The interparticle interactions in the system are taken from the Asakura-Oosawa model for colloid-polymer mixtures for which the phase diagram is known. In the current model version, the colloid particles are made active using the Vicsek model for self-propelling particles. The resultant active system is studied by molecular dynamics methods and integral equation theory. Both methods produce results consistent with each other and demonstrate that the Vicsek model-based activity facilitates phase separation, thus, broadening the coexistence region. PMID:24877969

  19. Synthesis, spectral characterization, molecular modeling, biological activity and potentiometric studies of 4-amino-5-mercapto-3-methyl-S-triazole Schiff's base complexes

    NASA Astrophysics Data System (ADS)

    Alaghaz, Abdel-Nasser M. A.; Zayed, Mohamed E.; Alharbi, Suliman A.

    2015-03-01

    The Schiff's base derived from condensation of s-triazole (4-amino-5-mercapto-3-methyl-S-triazole) with pyridine-2-aldehyde and their corresponding Mn(II), Co(II), Ni(II), Cu(II) and Zn(II) complexes have been synthesized. The isolated solid complexes were characterized by elemental analyses, molar conductance, spectral (IR, UV-Vis, 1H NMR, mass), magnetic moment and thermal measurements. The IR spectral data suggest that the ligand coordinate in a tridentate manner (SNN) via the one thiol (SH), one pyridine ring and the azomethine (Cdbnd N) groups. The data show that the complexes have composition of ML2 type. The activation of thermodynamic parameters are calculated using Coats-Redfern, Horowitz-Metzger (HM), and Piloyan-Novikova (PN). The octahedral geometry of the complexes is confirmed using DFT method from DMOL3 calculations and ligand field parameters. Protonation constants of Schiff base and stability constants of their binary metal complexes have been determined potentiometrically in 50% DMSO-water media at 25 °C and ionic strength 0.10 M potassium nitrate. The biological activity of these compounds against various fungi has been investigated.

  20. Molecular modeling of nucleic Acid structure: setup and analysis.

    PubMed

    Galindo-Murillo, Rodrigo; Bergonzo, Christina; Cheatham, Thomas E

    2014-01-01

    The last in a set of units by the same authors, this unit addresses some important remaining questions about molecular modeling of nucleic acids. The unit describes how to choose an appropriate molecular mechanics force field; how to set up and equilibrate the system for accurate simulation of a nucleic acid in an explicit solvent by molecular dynamics or Monte Carlo simulation; and how to analyze molecular dynamics trajectories. PMID:25606980

  1. Tubulin inhibitors: pharmacophore modeling, virtual screening and molecular docking

    PubMed Central

    Niu, Miao-miao; Qin, Jing-yi; Tian, Cai-ping; Yan, Xia-fei; Dong, Feng-gong; Cheng, Zheng-qi; Fida, Guissi; Yang, Man; Chen, Haiyan; Gu, Yue-qing

    2014-01-01

    Aim: To construct a quantitative pharmacophore model of tubulin inhibitors and to discovery new leads with potent antitumor activities. Methods: Ligand-based pharmacophore modeling was used to identify the chemical features responsible for inhibiting tubulin polymerization. A set of 26 training compounds was used to generate hypothetical pharmacophores using the HypoGen algorithm. The structures were further validated using the test set, Fischer randomization method, leave-one-out method and a decoy set, and the best model was chosen to screen the Specs database. Hit compounds were subjected to molecular docking study using a Molecular Operating Environment (MOE) software and to biological evaluation in vitro. Results: Hypo1 was demonstrated to be the best pharmacophore model that exhibited the highest correlation coefficient (0.9582), largest cost difference (70.905) and lowest RMSD value (0.6977). Hypo1 consisted of one hydrogen-bond acceptor, a hydrogen-bond donor, a hydrophobic feature, a ring aromatic feature and three excluded volumes. Hypo1 was validated with four different methods and had a goodness-of-hit score of 0.81. When Hypo1 was used in virtual screening of the Specs database, 952 drug-like compounds were revealed. After docking into the colchicine-binding site of tubulin, 5 drug-like compounds with the required interaction with the critical amino acid residues and the binding free energies <-4 kcal/mol were selected as representative leads. Compounds 1 and 3 exhibited inhibitory activity against MCF-7 human breast cancer cells in vitro. Conclusion: Hypo1 is a quantitative pharmacophore model for tubulin inhibitors, which not only provides a better understanding of their interaction with tubulin, but also assists in discovering new potential leads with antitumor activities. PMID:24909516

  2. A Molecular Model for Lithium's Bioactive Form.

    PubMed

    Briggs, Katharine T; Giulian, Gary G; Li, Gong; Kao, Joseph P Y; Marino, John P

    2016-07-26

    Lithium carbonate, a drug for the treatment of bipolar disorder, provides mood stability to mitigate recurrent episodes of mania and/or depression. Despite its long-term and widespread use, the mechanism by which lithium acts to elicit these psychological changes has remained unknown. Using nuclear magnetic resonance (NMR) methods, in this study we characterized the association of lithium with adenosine triphosphate (ATP) and identified a bimetallic (Mg·Li) ATP complex. Lithium's affinity to form this complex was found to be relatively high (Kd ∼1.6 mM) compared with other monovalent cations and relevant, considering lithium dosing and physiological concentrations of Mg(2+) and ATP. The ATP·Mg·Li complex reveals, for the first time, to the best of our knowledge, that lithium can associate with magnesium-bound phosphate sites and then act to modulate purine receptor activity in neuronal cells, suggesting a molecular mode for in vivo lithium action. PMID:27463132

  3. Synthesis, characterization, molecular modeling and antioxidant activity of Girard‧s T thiosemicarbazide and its complexes with some transition metal ions

    NASA Astrophysics Data System (ADS)

    El-Gammal, O. A.; Mostafa, M. M.

    2014-06-01

    The chelation behavior of N-{[(allylamino) thiomethyl] hydrazinocarbonylmethyl} trimethylammonium chloride (H3ATHC) towards VO2+, Co2+, Ni2+, Cu2+, Zn2+ and UO22+ ions have been studied. The structures of the complexes were elucidated using elemental analyses, spectral (IR, UV-visible, 1H NMR and ESR and mass) as well as magnetic and thermal measurements. The ligand acted as ON bidentate, ONS tridentate donor forming mononuclear complexes. A tetrahedral geometry for Co2+, square-planar for Ni2+ and Cu2+, an octahedral for Zn2+ and a square-pyramidal arrangement for VO2+ complexes were proposed, respectively. The EPR spectra of Cu2+ and VO2+ complexes confirmed the suggested geometries with values of α2 and β2 indicating that the in-plane σ-bonding and in-plane π-bonding are appreciably covalent, and were consistent with very strong in-plane σ bonding in the complexes. Also, the bond length, bond angle, HOMO, LUMO, dipole moment and charges on the atoms have been calculated. Also, the thermal behavior and kinetic parameters were determined using Coats-Redfern and Horowitz-Metzger methods. Furthermore, the synthesized compounds were screened for their superoxide-scavenging activity in the PMS/NADH-NBT system as well as their scavenging effect on ABTS (2,2‧-azino-bis(3-ethyl benzthiazoline-6-sulfonic acid) and 2,2-diphenyl-1-picrylhydrazyl(DPPH) radicals. Among these compounds, the ligand and Zn2+ complex, exhibited the potent ABTS (2,2‧-azino-bis(3-ethyl benzthiazoline-6-sulfonic acid) radical scavenging activity, comparable to that of vitamin C.

  4. Insights from the Molecular Dynamics Simulation of Cellobiohydrolase Cel6A Molecular Structural Model from Aspergillus fumigatus NITDGPKA3.

    PubMed

    Dodda, Subba Reddy; Sarkar, Nibedita; Aikat, Kaustav; Krishnaraj, Navanietha R; Bhattacharjee, Sanchari; Bagchi, Angshuman; Mukhopadhyay, Sudit S

    2016-01-01

    Global demand for bioethanol is increasing tremendously as it could help to replace the conventional fossil fuel and at the same time supporting the bioremediation of huge volume of cellulosic wastes generated from different sources. Ideal genetic engineering approaches are essential to improve the efficacy of the bioethanol production processes for real time applications. A locally isolated fungal strain Aspergillus fumigatus NITDGPKA3 was used in our laboratory for the hydrolysis of lignocellulose with good cellulolytic activity when compared with other contemporary fungal strains. An attempt is made to sequence the cellobiohydrolases (CBHs) of A. fumigatus NITDGPKA3, model its structure to predict its catalytic activity towards improving the protein by genetic engineering approaches. Herein, the structure of the sequenced Cellobiohydrolases (CBHs) of A. fumigatus NITDGPKA3, modelled by homology modelling and its validation is reported. Further the catalytic activity of the modelled CBH enzyme was assessed by molecular docking analysis. Phylogenetic analysis showed that CBH from A. fumigatus NITDGPKA3 belongs to the Glycohydro 6 (Cel6A) super family. Molecular modeling and molecular dynamics simulation suggest the structural and functional mechanism of the enzyme. The structures of both the cellulose binding (CBD) and catalytic domain (CD) have been compared with most widely studied CBH of Trichoderma reesei. The molecular docking with cellulose suggests that Gln 248, Pro 287, Val236, Asn284, and Ala288 are the main amino acids involved in the hydrolysis of the β, 1-4, glycosidic bonds of cellulose. PMID:27109185

  5. A molecular-thermodynamic model for polyelectrolyte solutions

    SciTech Connect

    Jiang, J.; Liu, H.; Hu, Y.; Prausnitz, J.M.

    1998-01-01

    Polyelectrolyte solutions are modeled as freely tangent-jointed, charged hard-sphere chains and corresponding counterions in a continuum medium with permitivity {var_epsilon}. By adopting the sticky-point model, the Helmholtz function for polyelectrolyte solutions is derived through the r-particle cavity-correlation function (CCF) for chains of sticky, charged hard spheres. The r-CCF is approximated by a product of effective nearest-neighbor two-particle CCFs; these are determined from the hypernetted-chain and mean-spherical closures (HNC/MSA) inside and outside the hard core, respectively, for the integral equation theory for electrolytes. The colligative properties are given as explicit functions of a scaling parameter {Gamma} that can be estimated by a simple iteration procedure. Osmotic pressures, osmotic coefficients, and activity coefficients are calculated for model solutions with various chain lengths. They are in good agreement with molecular simulation and experimental results. {copyright} {ital 1998 American Institute of Physics.}

  6. Molecular modeling studies of HIV-1 reverse transcriptase nonnucleoside inhibitors: total energy of complexation as a predictor of drug placement and activity.

    PubMed Central

    Kroeger Smith, M. B.; Rouzer, C. A.; Taneyhill, L. A.; Smith, N. A.; Hughes, S. H.; Boyer, P. L.; Janssen, P. A.; Moereels, H.; Koymans, L.; Arnold, E.

    1995-01-01

    Computer modeling studies have been carried out on three nonnucleoside inhibitors complexed with human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), using crystal coordinate data from a subset of the protein surrounding the binding pocket region. Results from the minimizations of solvated complexes of 2-cyclopropyl-4-methyl-5,11-dihydro-5H-dipyrido[3,2-b :2',3'-e][1,4] diazepin-6-one (nevirapine), alpha-anilino-2, 6-dibromophenylacetamide (alpha-APA), and 8-chloro-tetrahydro-imidazo(4,5,1-jk)(1,4)-benzodiazepin-2(1H)-thi one (TIBO) show that all three inhibitors maintain a very similar conformational shape, roughly overlay each other in the binding pocket, and appear to function as pi-electron donors to aromatic side-chain residues surrounding the pocket. However, side-chain residues adapt to each bound inhibitor in a highly specific manner, closing down around the surface of the drug to make tight van der Waals contacts. Consequently, the results from the calculated minimizations reveal that only when the inhibitors are modeled in a site constructed from coordinate data obtained from their particular RT complex can the calculated binding energies be relied upon to predict the correct orientation of the drug in the pocket. In the correct site, these binding energies correlate with EC50 values determined for all three inhibitors in our laboratory. Analysis of the components of the binding energy reveals that, for all three inhibitors, solvation of the drug is endothermic, but solvation of the protein is exothermic, and the sum favors complex formation. In general, the protein is energetically more stable and the drug less stable in their complexes as compared to the reactant conformations. For all three inhibitors, interaction with the protein in the complex is highly favorable. Interactions of the inhibitors with individual residues correlate with crystallographic and site-specific mutational data. pi-Stacking interactions are important in

  7. 4,6-Diphenylpyridines as Promising Novel Anti-Influenza Agents Targeting the PA-PB1 Protein-Protein Interaction: Structure-Activity Relationships Exploration with the Aid of Molecular Modeling.

    PubMed

    Trist, Iuni M L; Nannetti, Giulio; Tintori, Cristina; Fallacara, Anna Lucia; Deodato, Davide; Mercorelli, Beatrice; Palù, Giorgio; Wijtmans, Maikel; Gospodova, Tzveta; Edink, Ewald; Verheij, Mark; de Esch, Iwan; Viteva, Lilia; Loregian, Arianna; Botta, Maurizio

    2016-03-24

    Influenza is an infectious disease that represents an important public health burden, with high impact on the global morbidity, mortality, and economy. The poor protection and the need of annual updating of the anti-influenza vaccine, added to the rapid emergence of viral strains resistant to current therapy make the need for antiviral drugs with novel mechanisms of action compelling. In this regard, the viral RNA polymerase is an attractive target that allows the design of selective compounds with reduced risk of resistance. In previous studies we showed that the inhibition of the polymerase acidic protein-basic protein 1 (PA-PB1) interaction is a promising strategy for the development of anti-influenza agents. Starting from the previously identified 3-cyano-4,6-diphenyl-pyridines, we chemically modified this scaffold and explored its structure-activity relationships. Noncytotoxic compounds with both the ability of disrupting the PA-PB1 interaction and antiviral activity were identified, and their mechanism of target binding was clarified with molecular modeling simulations. PMID:26924568

  8. New models and molecular markers in evaluation of developmental toxicity

    SciTech Connect

    Huuskonen, Hannele . E-mail: hannele.huuskonen@sttv.fi

    2005-09-01

    Mammalian and non-mammalian embryos and embryonic stem cells may be used as models in mechanistic studies and in testing embryotoxicity of compounds. In addition to conventional culture methods, genetic modifications and use of molecular markers offer significant advantages in mechanistic studies as well as in developing new test methods for embryotoxicity. Zebrafish model has been used for a long time and at present several applications are available. It is an easy vertebral non-mammalian model, whose genome is largely known and several genetic modifications are easily constructed to study gene expression or knocked down genes. Fluorescent marker proteins can be used also in zebrafish to indicate gene activation in transgenic models. Chemical genetics approach has been developed using zebrafish model. This is a new approach to screen small molecules that regulate signaling pathways. Embryonic stem cells have been used in mechanistic studies and mouse embryonic stem cell test has been validated to study embryotoxicity in vitro. This method has been improved using quantitative measurements of molecular endpoints by real-time RT-PCR or fluorescent activated cell sorting methods (FACS). Methods facilitating differentiation to several different cell types are available. We have studied preimplantation mouse embryos as a possible model for in vitro testing. In this method, superovulated and in vivo fertilized preimplantation embryos were collected at morula stage and cultured up to blastocysts. The mouse preimplantation culture test was improved by quantitative gene expression measurement using two-step real-time RT-PCR methods. New endpoints improve the tests of in vitro embryotoxicity because subjective assessments are replaced by objective measurements. In addition, automation is possible and less time is needed for analysis. Thus, high throughput screening will come possible to test large numbers of compounds.

  9. Model calculations for diffuse molecular clouds. [interstellar hydrogen cloud model

    NASA Technical Reports Server (NTRS)

    Glassgold, A. E.; Langer, W. D.

    1974-01-01

    A steady state isobaric cloud model is developed. The pressure, thermal, electrical, and chemical balance equations are solved simultaneously with a simple one dimensional approximation to the equation of radiative transfer appropriate to diffuse clouds. Cooling is mainly by CII fine structure transitions, and a variety of heating mechanisms are considered. Particular attention is given to the abundance variation of H2. Inhomogeneous density distributions are obtained because of the attenuation of the interstellar UV field and the conversion from atomic to molecular hyrodgen. The effects of changing the model parameters are described and the applicability of the model to OAO-3 observations is discussed. Good qualitative agreement with the fractional H2 abundance determinations has been obtained. The observed kinetic temperatures near 80 K can also be achieved by grain photoelectron heating. The problem of the electron density is solved taking special account of the various hydrogen ions as well as heavier ones.

  10. Spectral, magnetic, thermal, molecular modelling, ESR studies and antimicrobial activity of ( E )-3-(2-(2-hydroxybenzylidene) hydrazinyl)-3-oxo- n (thiazole-2-yl)propanamide complexes

    NASA Astrophysics Data System (ADS)

    Zaky, R. R.; Yousef, T. A.

    2011-09-01

    ( E)-3-(2-(2-hydroxybenzylidene)hydrazinyl)-3-oxo- n(thiazole-2-yl) propane-mide (H 2L) has been prepared and its structure confirmed by elemental analysis, IR and 1HNMR spectroscopy. It has been used to produce diverse complexes with Ni(II), Co(II) and Cu(II) ions. The complexes obtained have been investigated by thermal analysis, spectral studies (IR, UV-visible, ESR), and magnetic measurements. IR spectra suggest that the H 2L acts as a bidentate ligand coordinating via (C dbnd N) 1 and (OH) phenolic or deprotonated enolized carbonyl oxygen ( dbnd C sbnd O sbnd ) 1. The electronic spectra of the complexes and their magnetic moments provide information about geometries. The room temperature solid state ESR spectra of the Cu(II) complexes show d x2-y2 as a ground state, suggesting tetragonally distorted octahedral or square-planar geometries around Cu(II) centre. The molar conductance measurements proved that the complexes are non-electrolytes. The bond length, bond angle, HOMO, LUMO, dipole moment and charges on the atoms have been calculated to confirm the geometry of the ligand and the investigated complexes. Also, thermal properties and decomposition kinetics of all compounds are investigated. The interpretation, mathematical analysis and evaluation of kinetic parameters ( Ea, A, Δ H, Δ S and Δ G) of all thermal decomposition stages have been evaluated using Coats-Redfern and Horowitz-Metzger methods. Finally, the antimicrobial activity has been tested.

  11. Synthesis, spectral characterization, molecular modeling and in vitro antibacterial activity of complexes designed from O2, NO and NO donor Schiff-base ligand

    NASA Astrophysics Data System (ADS)

    El-Gammal, Ola A.; Abu El-Reash, G.; Ahmed, S. F.

    2015-01-01

    A new chelating agent, N‧-(4-methoxybenzylidene)-2-oxo-2-(phenylamino)acetohydrazide (H2OMPH) and its complexes with Mn(II), Co(II), Ni(II), Cu(II), Zn(II), Hg(II) and U(IV)O22+ ions have been prepared and characterized by conventional techniques. The spectral data indicated that the ligand coordinates as neutral bidentate with Cu(II), Mn(II), U(IV)O22+ and Hg(II), neutral tridentate with Ni(II), mononegative tridentate with Co(II) and binegative tetradentate with Zn(II) ions. On basis of magnetic and electronic spectral data an octahedral geometry for Mn(II), Co(II) and Ni(II) complexes and a square planar geometry for Cu(II) complex have been proposed and confirmed by applying geometry optimization and conformational analysis. The protonation constants of H2OMPH and the stepwise stability constants of its complexes are calculated at 298, 308 and 318 k as well as their thermodynamic parameters. Also, the Kinetic parameters (Ea, A, ΔH*, ΔS* and ΔG*) were determined for each thermal degradation stage of some complexes using Coats-Redfern and Horowitz-Metzger methods. Moreover, the ligand and some complexes were screened for in vitro antibacterial activity against Staphylococcus epidermalies (St. epid); Streptococcus pyagenies (Strp. py.) as Gram +ve bacteria and Escherichia coli (E. coli); Klebsiella spp. (kleb. spp.) as Gram -ve bacteria using inhibition zone diameter.

  12. Molecular Modeling and Design of Arylthioindole Derivatives as Tubulin Inhibitors

    NASA Astrophysics Data System (ADS)

    Liao, Si-yan; Miao, Ti-fang; Chen, Jin-can; Lu, Hai-liang; Zheng, Kang-cheng

    2009-10-01

    Three-dimensional quantitative structure activity relationship (3D-QSAR) and docking studies of a series of arylthioindole derivatives as tubulin inhibitors against human breast cancer cell line MCF-7 have been carried out. An optimal 3D-QSAR model from the comparative molecular field analysis (CoMFA) for training set with significant statistical quality (R2 = 0.898) and predictive ability (q2 = 0.654) was established. The same model was further applied to predict pIC50 values of the compounds in test set, and the resulting predictive correlation coefficient R2(pred) reaches 0.816, further showing that this CoMFA model has high predictive ability. Moreover, the appropriate binding orientations and conformations of these compounds interacting with tubulin are located by docking study, and it is very interesting to find the consistency between the CoMFA field distribution and the 3D topology structure of active site of tubulin. Based on CoMFA along with docking results, some important factors improving the activities of these compounds were discussed in detail and were summarized as follows: the substituents R3-R5 (on the phenyl ring) with higher electronegativity, the substituent R6 with higher electropositivity and bigger bulk, the substituent R7 with smaller bulk, and so on. In addition, five new compounds with higher activities have been designed. Such results can offer useful theoretical references for experimental works.

  13. Metal based pharmacologically active agents: Synthesis, structural characterization, molecular modeling, CT-DNA binding studies and in vitro antimicrobial screening of iron(II) bromosalicylidene amino acid chelates

    NASA Astrophysics Data System (ADS)

    Abdel-Rahman, Laila H.; El-Khatib, Rafat M.; Nassr, Lobna A. E.; Abu-Dief, Ahmed M.; Ismael, Mohamed; Seleem, Amin Abdou

    2014-01-01

    In recent years, great interest has been focused on Fe(II) Schiff base amino acid complexes as cytotoxic and antitumor drugs. Thus a series of new iron(II) complexes based on Schiff bases amino acids ligands have been designed and synthesized from condensation of 5-bromosalicylaldehyde (bs) and α-amino acids (L-alanine (ala), L-phenylalanine (phala), L-aspartic acid (aspa), L-histidine (his) and L-arginine (arg)). The structure of the investigated iron(II) complexes was elucidated using elemental analyses, infrared, ultraviolet-visible, thermogravimetric analysis, as well as conductivity and magnetic susceptibility measurements. Moreover, the stoichiometry and the stability constants of the prepared complexes have been determined spectrophotometrically. The results suggest that 5-bromosalicylaldehyde amino acid Schiff bases (bs:aa) behave as dibasic tridentate ONO ligands and coordinate to Fe(II) in octahedral geometry according to the general formula [Fe(bs:aa)2]ṡnH2O. The conductivity values between 37 and 64 ohm-1 mol-1 cm2 in ethanol imply the presence of nonelectrolyte species. The structure of the complexes was validated using quantum mechanics calculations based on accurate DFT methods. Geometry optimization of the Fe-Schiff base amino acid complexes showed that all complexes had octahedral coordination. In addition, the interaction of these complexes with (CT-DNA) was investigated at pH = 7.2, by using UV-vis absorption, viscosity and agarose gel electrophoresis measurements. Results indicated that the investigated complexes strongly bind to calf thymus DNA via intercalative mode and showed a different DNA binding according to the sequence: bsari > bshi > bsali > bsasi > bsphali. Moreover, the prepared compounds are screened for their in vitro antibacterial and antifungal activity against three types of bacteria, Escherichia coli, Pseudomonas aeruginosa and Bacillus cereus and three types of anti fungal cultures, Penicillium purpurogenium, Aspergillus

  14. Decolorization / deodorization of zein via activated carbons and molecular sieves

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The objective is to evaluate a series of granular media consisting of activated carbons and molecular sieves in a batch process for the purpose of clarifying and removal of color and odor components from yellow zein dispersed in an aqueous alcohol medium. The major contributors of yellow zein is du...

  15. Digital Learning Material for Model Building in Molecular Biology

    ERIC Educational Resources Information Center

    Aegerter-Wilmsen, Tinri; Janssen, Fred; Hartog, Rob; Bisseling, Ton

    2005-01-01

    Building models to describe processes forms an essential part of molecular biology research. However, in molecular biology curricula little attention is generally being paid to the development of this skill. In order to provide students the opportunity to improve their model building skills, we decided to develop a number of digital cases about…

  16. Model of turbulent destruction of molecular clouds

    NASA Astrophysics Data System (ADS)

    Rybakin, B. P.; Betelin, V. B.; Dushin, V. R.; Mikhalchenko, E. V.; Moiseenko, S. G.; Stamov, L. I.; Tyurenkova, V. V.

    2016-02-01

    We represent numerical simulation results of interaction process of supernova strong shock with interstellar molecular cloud in 3D. In the paper we neglect gravitation, heat conductivity and radiative losses. We analyze in detail processes of deformation and fragmentation of molecular cloud (MC). Formation of passed by and reflected shocks system, contraction and ablation of the matter is investigated in detail. The post-processor treatment and the results of calculations made it possible to find the following features of the molecular cloud matter - the vortexes formation, erosion and ablation.

  17. Modeling propagation of coherent optical pulses through molecular vapor

    SciTech Connect

    Shore, B.W.; Eberly, J.H.

    1982-01-01

    Results of modeling the mutual coupling of coherent molecular response and coherent optical pulses during propagation are described. The propagation is treated numerically, with particular emphasis on both continuum and discrete behavior associated with the quasicontinuum model.

  18. Modeling Natural Anti-Inflammatory Compounds by Molecular Topology

    PubMed Central

    Galvez-Llompart, María; Zanni, Riccardo; García-Domenech, Ramón

    2011-01-01

    One of the main pharmacological problems today in the treatment of chronic inflammation diseases consists of the fact that anti-inflammatory drugs usually exhibit side effects. The natural products offer a great hope in the identification of bioactive lead compounds and their development into drugs for treating inflammatory diseases. Computer-aided drug design has proved to be a very useful tool for discovering new drugs and, specifically, Molecular Topology has become a good technique for such a goal. A topological-mathematical model, obtained by linear discriminant analysis, has been developed for the search of new anti-inflammatory natural compounds. An external validation obtained with the remaining compounds (those not used in building up the model), has been carried out. Finally, a virtual screening on natural products was performed and 74 compounds showed actual anti-inflammatory activity. From them, 54 had been previously described as anti-inflammatory in the literature. This can be seen as a plus in the model validation and as a reinforcement of the role of Molecular Topology as an efficient tool for the discovery of new anti-inflammatory natural compounds. PMID:22272145

  19. Modeling Complex Workflow in Molecular Diagnostics

    PubMed Central

    Gomah, Mohamed E.; Turley, James P.; Lu, Huimin; Jones, Dan

    2010-01-01

    One of the hurdles to achieving personalized medicine has been implementing the laboratory processes for performing and reporting complex molecular tests. The rapidly changing test rosters and complex analysis platforms in molecular diagnostics have meant that many clinical laboratories still use labor-intensive manual processing and testing without the level of automation seen in high-volume chemistry and hematology testing. We provide here a discussion of design requirements and the results of implementation of a suite of lab management tools that incorporate the many elements required for use of molecular diagnostics in personalized medicine, particularly in cancer. These applications provide the functionality required for sample accessioning and tracking, material generation, and testing that are particular to the evolving needs of individualized molecular diagnostics. On implementation, the applications described here resulted in improvements in the turn-around time for reporting of more complex molecular test sets, and significant changes in the workflow. Therefore, careful mapping of workflow can permit design of software applications that simplify even the complex demands of specialized molecular testing. By incorporating design features for order review, software tools can permit a more personalized approach to sample handling and test selection without compromising efficiency. PMID:20007844

  20. Molecular modeling of enzyme attachment on AFM probes.

    PubMed

    Oliveira, Guedmiller S; Leite, Fabio L; Amarante, Adriano M; Franca, Eduardo F; Cunha, Richard A; Briggs, James M; Freitas, Luiz C G

    2013-09-01

    The immobilization of enzymes on atomic force microscope tip (AFM tip) surface is a crucial step in the development of nanobiosensors to be used in detection process. In this work, an atomistic modeling of the attachment of the acetyl coenzyme A carboxylase (ACC enzyme) on a functionalized AFM tip surface is proposed. Using electrostatic considerations, suitable enzyme-surface orientations with the active sites of the ACC enzyme available for interactions with bulk molecules were found. A 50 ns molecular dynamics trajectory in aqueous solution was obtained and surface contact area, hydrogen bonding and protein stability were analyzed. The enzyme-surface model proposed here with minor adjustment can be applied to study antigen-antibody interactions as well as enzyme immobilization on silica for chromatography applications. PMID:24029365

  1. Molecular Mechanism of Active Zone Organization at Vertebrate Neuromuscular Junctions

    PubMed Central

    Nishimune, Hiroshi

    2013-01-01

    Organization of presynaptic active zones is essential for development, plasticity, and pathology of the nervous system. Recent studies indicate a trans-synaptic molecular mechanism that organizes the active zones by connecting the pre- and the postsynaptic specialization. The presynaptic component of this trans-synaptic mechanism is comprised of cytosolic active zone proteins bound to the cytosolic domains of voltage-dependent calcium channels (P/Q-, N-, and L-type) on the presynaptic membrane. The postsynaptic component of this mechanism is the synapse organizer (laminin β2) that is expressed by the postsynaptic cell and accumulates specifically on top of the postsynaptic specialization. The pre- and the postsynaptic components interact directly between the extracellular domains of calcium channels and laminin β2 to anchor the presynaptic protein complex in front of the postsynaptic specialization. Hence, the presynaptic calcium channel functions as a scaffolding protein for active zone organization and as an ion-conducting channel for synaptic transmission. In contrast to the requirement of calcium influx for synaptic transmission, the formation of the active zone does not require the calcium influx through the calcium channels. Importantly, the active zones of adult synapses are not stable structures and require maintenance for their integrity. Furthermore, aging or diseases of the central and peripheral nervous system impair the active zones. This review will focus on the molecular mechanisms that organize the presynaptic active zones and summarize recent findings at the neuromuscular junctions and other synapses. PMID:22135013

  2. A comparative molecular field analysis and molecular modelling studies on pyridylimidazole type of angiotensin II antagonists.

    PubMed

    Yoo, S E; Kim, S K; Lee, S H; Yi, K Y; Lee, D W

    1999-12-01

    A large number of compounds known as "AII (Angiotensin II) antagonists" have been developed for the treatment of various heart diseases such as hypertension, congestive heart failure, and chronic renal failure. Most of the currently known AII receptor antagonists share a similar chemical structure, consisting of nitrogen atoms, a lipophilic alkyl side chain and an acidic group. As a new series, we have designed and synthesized various pyridylimidazole derivatives. In this report we would like to discuss the structure-activity relationship of these series of compounds using the comparative molecular field analysis (CoMFA) methods. We could come up with a good CoMFA model (cross-validated and conventional r2 values equal to 0.702 and 0.991, respectively) and the validity of the model was confirmed by synthesizing and measuring their biological activity of additional 6 compounds suggested by the model. This result provides additional information on the structural requirement for structurally diverse group of AII receptor antagonists. PMID:10658603

  3. New tungstenocenes containing 3-hydroxy-4-pyrone ligands: antiproliferative activity on HT-29 and MCF-7 cell lines and binding to human serum albumin studied by fluorescence spectroscopy and molecular modeling methods

    PubMed Central

    Domínguez-García, Moralba; Ortega-Zúñiga, Carlos; Meléndez, Enrique

    2012-01-01

    Three new water-soluble tungstenocene derivatives were synthesized and characterized using 3-hydroxy-4-pyrone ligands, which provide aqueous stability to the complexes. The antiproliferative activities of the complexes on HT-29 colon cancer and MCF-7 breast cancer cell lines were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and showed the new tungstenocene derivatives have higher antiproliferative action than tungstenocene dichloride (Cp2WCl2, where Cp is cyclopentadienyl). The binding interactions of the tungstenocenes with human serum albumin (HSA) were investigated using fluorescence spectroscopy and molecular modeling methods. Analysis of the fluorescence quenching spectra indicates that the tungstenocene complexes bind HSA by hydrophobic interactions and hydrogen bonding at fatty acid binding site 6 and drug binding site II. Docking studies provided a description of the hydrophobic interactions and hydrogen bonding by which the tungstenocenes become engaged with HSA. It was determined that the binding affinity of the tungstenoecenes for HSA is in the order Cp2WCl2 < [Cp2W(ethyl maltolato)]Cl < [Cp2W (maltolato)]Cl < [Cp2W(kojato)]Cl, consistent with the hydrophobic interactions and the number of hydrogen bonds involved. PMID:23212785

  4. Nucleolar protein B23 has molecular chaperone activities.

    PubMed Central

    Szebeni, A.; Olson, M. O.

    1999-01-01

    Protein B23 is an abundant, multifunctional nucleolar phosphoprotein whose activities are proposed to play a role in ribosome assembly. Szebeni et al. (1997) showed stimulation of nuclear import in vitro by protein B23 and suggested that this effect was due to a molecular chaperone-like activity. Protein B23 was tested for chaperone activities using several protein substrates. The temperature-dependent and -independent aggregation of the HIV-1 Rev protein was measured using a zero angle light scattering (turbidity) assay. Protein B23 inhibited the aggregation of the Rev protein, with the amount of inhibition proportional to the concentration of B23 added. This activity was saturable with nearly complete inhibition when the molar ratio of B23:Rev was slightly above one. Protein B23 also protected liver alcohol dehydrogenase (LADH), carboxypeptidase A, citrate synthase, and rhodanese from aggregation during thermal denaturation and preserved the enzyme activity of LADH under these conditions. In addition, protein B23 was able to promote the restoration of activity of LADH previously denatured with guanidine-HCl. Protein B23 preferentially bound denatured substrates and exposed hydrophobic regions when complexed with denatured proteins. Thus, by several criteria, protein B23 behaves like a molecular chaperone; these activities may be related to its role in ribosome biogenesis. PMID:10211837

  5. Network-Based Models in Molecular Biology

    NASA Astrophysics Data System (ADS)

    Beyer, Andreas

    Biological systems are characterized by a large number of diverse interactions. Interaction maps have been used to abstract those interactions at all biological scales ranging from food webs at the ecosystem level down to protein interaction networks at the molecular scale.

  6. Cellular and Molecular Mechanisms Underpinning Macrophage Activation during Remyelination

    PubMed Central

    Lloyd, Amy F.; Miron, Veronique E.

    2016-01-01

    Remyelination is an example of central nervous system (CNS) regeneration, whereby myelin is restored around demyelinated axons, re-establishing saltatory conduction and trophic/metabolic support. In progressive multiple sclerosis, remyelination is limited or fails altogether which is considered to contribute to axonal damage/loss and consequent disability. Macrophages have critical roles in both CNS damage and regeneration, such as remyelination. This diverse range in functions reflects the ability of macrophages to acquire tissue microenvironment-specific activation states. This activation is dynamically regulated during efficient regeneration, with a switch from pro-inflammatory to inflammation-resolution/pro-regenerative phenotypes. Although, some molecules and pathways have been implicated in the dynamic activation of macrophages, such as NFκB, the cellular and molecular mechanisms underpinning plasticity of macrophage activation are unclear. Identifying mechanisms regulating macrophage activation to pro-regenerative phenotypes may lead to novel therapeutic strategies to promote remyelination in multiple sclerosis. PMID:27446913

  7. GPU-Accelerated Molecular Modeling Coming Of Age

    PubMed Central

    Stone, John E.; Hardy, David J.; Ufimtsev, Ivan S.

    2010-01-01

    Graphics processing units (GPUs) have traditionally been used in molecular modeling solely for visualization of molecular structures and animation of trajectories resulting from molecular dynamics simulations. Modern GPUs have evolved into fully programmable, massively parallel co-processors that can now be exploited to accelerate many scientific computations, typically providing about one order of magnitude speedup over CPU code and in special cases providing speedups of two orders of magnitude. This paper surveys the development of molecular modeling algorithms that leverage GPU computing, the advances already made and remaining issues to be resolved, and the continuing evolution of GPU technology that promises to become even more useful to molecular modeling. Hardware acceleration with commodity GPUs is expected to benefit the overall computational biology community by bringing teraflops performance to desktop workstations and in some cases potentially changing what were formerly batch-mode computational jobs into interactive tasks. PMID:20675161

  8. Molecular Modeling and Computational Chemistry at Humboldt State University.

    ERIC Educational Resources Information Center

    Paselk, Richard A.; Zoellner, Robert W.

    2002-01-01

    Describes a molecular modeling and computational chemistry (MM&CC) facility for undergraduate instruction and research at Humboldt State University. This facility complex allows the introduction of MM&CC throughout the chemistry curriculum with tailored experiments in general, organic, and inorganic courses as well as a new molecular modeling…

  9. Nanoindentation of virus capsids in a molecular model

    NASA Astrophysics Data System (ADS)

    Cieplak, Marek; Robbins, Mark O.

    2010-01-01

    A molecular-level model is used to study the mechanical response of empty cowpea chlorotic mottle virus (CCMV) and cowpea mosaic virus (CPMV) capsids. The model is based on the native structure of the proteins that constitute the capsids and is described in terms of the Cα atoms. Nanoindentation by a large tip is modeled as compression between parallel plates. Plots of the compressive force versus plate separation for CCMV are qualitatively consistent with continuum models and experiments, showing an elastic region followed by an irreversible drop in force. The mechanical response of CPMV has not been studied, but the molecular model predicts an order of magnitude higher stiffness and a much shorter elastic region than for CCMV. These large changes result from small structural changes that increase the number of bonds by only 30% and would be difficult to capture in continuum models. Direct comparison of local deformations in continuum and molecular models of CCMV shows that the molecular model undergoes a gradual symmetry breaking rotation and accommodates more strain near the walls than the continuum model. The irreversible drop in force at small separations is associated with rupturing nearly all of the bonds between capsid proteins in the molecular model, while a buckling transition is observed in continuum models.

  10. Nanoindentation of virus capsids in a molecular model.

    PubMed

    Cieplak, Marek; Robbins, Mark O

    2010-01-01

    A molecular-level model is used to study the mechanical response of empty cowpea chlorotic mottle virus (CCMV) and cowpea mosaic virus (CPMV) capsids. The model is based on the native structure of the proteins that constitute the capsids and is described in terms of the C(alpha) atoms. Nanoindentation by a large tip is modeled as compression between parallel plates. Plots of the compressive force versus plate separation for CCMV are qualitatively consistent with continuum models and experiments, showing an elastic region followed by an irreversible drop in force. The mechanical response of CPMV has not been studied, but the molecular model predicts an order of magnitude higher stiffness and a much shorter elastic region than for CCMV. These large changes result from small structural changes that increase the number of bonds by only 30% and would be difficult to capture in continuum models. Direct comparison of local deformations in continuum and molecular models of CCMV shows that the molecular model undergoes a gradual symmetry breaking rotation and accommodates more strain near the walls than the continuum model. The irreversible drop in force at small separations is associated with rupturing nearly all of the bonds between capsid proteins in the molecular model, while a buckling transition is observed in continuum models. PMID:20078182

  11. Insights from molecular modeling and dynamics simulation of pathogen resistance (R) protein from brinjal.

    PubMed

    Shrivastava, Dipty; Nain, Vikrant; Sahi, Shakti; Verma, Anju; Sharma, Priyanka; Sharma, Prakash Chand; Kumar, Polumetla Ananda

    2011-01-01

    Resistance (R) protein recognizes molecular signature of pathogen infection and activates downstream hypersensitive response signalling in plants. R protein works as a molecular switch for pathogen defence signalling and represent one of the largest plant gene family. Hence, understanding molecular structure and function of R proteins has been of paramount importance for plant biologists. The present study is aimed at predicting structure of R proteins signalling domains (CC-NBS) by creating a homology model, refining and optimising the model by molecular dynamics simulation and comparing ADP and ATP binding. Based on sequence similarity with proteins of known structures, CC-NBS domains were initially modelled using CED- 4 (cell death abnormality protein) and APAF-1 (apoptotic protease activating factor) as multiple templates. The final CC-NBS structural model was built and optimized by molecular dynamic simulation for 5 nanoseconds (ns). Docking of ADP and ATP at active site shows that both ligand bind specifically with same residues and with minor difference (1 Kcal/mol) in binding energy. Sharing of binding site by ADP and ATP and low difference in their binding site makes CC-NBS suitable for working as molecular switch. Furthermore, structural superimposition elucidate that CC-NBS and CARD (caspase recruitment domains) domain of CED-4 have low RMSD value of 0.9 A° Availability of 3D structural model for both CC and NBS domains will . help in getting deeper insight in these pathogen defence genes. PMID:21383919

  12. Insights from molecular modeling and dynamics simulation of pathogen resistance (R) protein from brinjal

    PubMed Central

    Shrivastava, Dipty; Nain, Vikrant; Sahi, Shakti; Verma, Anju; Sharma, Priyanka; Sharma, Prakash Chand; Kumar, Polumetla Ananda

    2011-01-01

    Resistance (R) protein recognizes molecular signature of pathogen infection and activates downstream hypersensitive response signalling in plants. R protein works as a molecular switch for pathogen defence signalling and represent one of the largest plant gene family. Hence, understanding molecular structure and function of R proteins has been of paramount importance for plant biologists. The present study is aimed at predicting structure of R proteins signalling domains (CC-NBS) by creating a homology model, refining and optimising the model by molecular dynamics simulation and comparing ADP and ATP binding. Based on sequence similarity with proteins of known structures, CC-NBS domains were initially modelled using CED- 4 (cell death abnormality protein) and APAF-1 (apoptotic protease activating factor) as multiple templates. The final CC-NBS structural model was built and optimized by molecular dynamic simulation for 5 nanoseconds (ns). Docking of ADP and ATP at active site shows that both ligand bind specifically with same residues and with minor difference (1 Kcal/mol) in binding energy. Sharing of binding site by ADP and ATP and low difference in their binding site makes CC-NBS suitable for working as molecular switch. Furthermore, structural superimposition elucidate that CC-NBS and CARD (caspase recruitment domains) domain of CED-4 have low RMSD value of 0.9 A° Availability of 3D structural model for both CC and NBS domains will . help in getting deeper insight in these pathogen defence genes. PMID:21383919

  13. Meet the Molecules in Chocolate: Informal Opportunities for Building Thematic Molecular Models with Children

    ERIC Educational Resources Information Center

    Amey, Jennifer R.; Fletcher, Matthew D.; Fletcher, Rachael V.; Jones, Alison; Roberts, Erica W.; Roberts, Ieuan O.

    2008-01-01

    We describe the development and use of a molecular model building activity with a chocolate theme, suitable for a public presentation of chemistry through interaction with visitors to science festivals and museums, and as a special classroom activity during science weeks, and so forth. (Contains 3 figures.)

  14. Antibacterial kaolinite/urea/chlorhexidine nanocomposites: Experiment and molecular modelling

    NASA Astrophysics Data System (ADS)

    Holešová, Sylva; Valášková, Marta; Hlaváč, Dominik; Madejová, Jana; Samlíková, Magda; Tokarský, Jonáš; Pazdziora, Erich

    2014-06-01

    Clay minerals are commonly used materials in pharmaceutical production both as inorganic carriers or active agents. The purpose of this study is the preparation and characterization of clay/antibacterial drug hybrids which can be further included in drug delivery systems for treatment oral infections. Novel nanocomposites with antibacterial properties were successfully prepared by ion exchange reaction from two types of kaolinite/urea intercalates and chlorhexidine diacetate. Intercalation compounds of kaolinite were prepared by reaction with solid urea in the absence of solvents (dry method) as well as with urea aqueous solution (wet method). The antibacterial activity of two prepared samples against Enterococcus faecalis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa was evaluated by finding the minimum inhibitory concentration (MIC). Antibacterial studies of both samples showed the lowest MIC values (0.01%, w/v) after 1 day against E. faecalis, E. coli and S. aureus. A slightly worse antibacterial activity was observed against P. aeruginosa (MIC 0.12%, w/v) after 1 day. Since samples showed very good antibacterial activity, especially after 1 day of action, this means that these samples can be used as long-acting antibacterial materials. Prepared samples were characterized by X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR). The experimental data are supported by results of molecular modelling.

  15. Model results for graphene electrodes in molecular junctions

    NASA Astrophysics Data System (ADS)

    Motta, Carlo; Italo Trioni, Mario; Brivio, Gian Paolo; Lukose Sebastian, Kizhakeyil; Sánchez Portal, Daniel

    2012-02-01

    Graphene is a material with a high potential for nanoelectronic applications as transparent conductive electrode. In view of a graphene-based electronics, a possible way to bridge graphene electrodes is by molecular linkers either organic molecules or graphene-derived systems such as graphene nanoribbons (GNR). In the present work, we investigated the electronic and conductive properties of such junctions for two different devices. First we modeled a photochromic switch based on diarylethene molecules, which can be activated/deactivated by light. We found a large on/off current ratio, which can be improved by modifying the functional groups of the molecule. We then investigated the properties of graphene/GNR/graphene junctions, showing that their conductive properties can be tailored by changing the length and width of the GNR. The calculations have been carried out by using the non-equilibrium Green's function method combined with density functional theory.

  16. Noninvasive Molecular Imaging of Disease Activity in Atherosclerosis.

    PubMed

    Dweck, Marc R; Aikawa, Elena; Newby, David E; Tarkin, Jason M; Rudd, James H F; Narula, Jagat; Fayad, Zahi A

    2016-07-01

    Major focus has been placed on the identification of vulnerable plaques as a means of improving the prediction of myocardial infarction. However, this strategy has recently been questioned on the basis that the majority of these individual coronary lesions do not in fact go on to cause clinical events. Attention is, therefore, shifting to alternative imaging modalities that might provide a more complete pan-coronary assessment of the atherosclerotic disease process. These include markers of disease activity with the potential to discriminate between patients with stable burnt-out disease that is no longer metabolically active and those with active atheroma, faster disease progression, and increased risk of infarction. This review will examine how novel molecular imaging approaches can provide such assessments, focusing on inflammation and microcalcification activity, the importance of these processes to coronary atherosclerosis, and the advantages and challenges posed by these techniques. PMID:27390335

  17. Molecular profiling of activated neurons by phosphorylated ribosome capture.

    PubMed

    Knight, Zachary A; Tan, Keith; Birsoy, Kivanc; Schmidt, Sarah; Garrison, Jennifer L; Wysocki, Robert W; Emiliano, Ana; Ekstrand, Mats I; Friedman, Jeffrey M

    2012-11-21

    The mammalian brain is composed of thousands of interacting neural cell types. Systematic approaches to establish the molecular identity of functional populations of neurons would advance our understanding of neural mechanisms controlling behavior. Here, we show that ribosomal protein S6, a structural component of the ribosome, becomes phosphorylated in neurons activated by a wide range of stimuli. We show that these phosphorylated ribosomes can be captured from mouse brain homogenates, thereby enriching directly for the mRNAs expressed in discrete subpopulations of activated cells. We use this approach to identify neurons in the hypothalamus regulated by changes in salt balance or food availability. We show that galanin neurons are activated by fasting and that prodynorphin neurons restrain food intake during scheduled feeding. These studies identify elements of the neural circuit that controls food intake and illustrate how the activity-dependent capture of cell-type-specific transcripts can elucidate the functional organization of a complex tissue. PMID:23178128

  18. Determination of structure parameters in molecular tunnelling ionisation model

    NASA Astrophysics Data System (ADS)

    Wang, Jun-Ping; Zhao, Song-Feng; Zhang, Cai-Rong; Li, Wei; Zhou, Xiao-Xin

    2014-04-01

    We extracted the accurate structure parameters in a molecular tunnelling ionisation model (the so-called MO-ADK model) for 23 selected linear molecules including some inner orbitals. The molecular wave functions with the correct asymptotic behaviour are obtained by solving the time-independent Schrödinger equation with B-spline functions and molecular potentials numerically constructed using the modified Leeuwen-Baerends (LBα) model. We show that the orientation-dependent ionisation rate reflects the shape of the ionising orbitals in general. The influences of the Stark shifts of the energy levels on the orientation-dependent ionisation rates of the polar molecules are studied. We also examine the angle-dependent ionisation rates (or probabilities) based on the MO-ADK model by comparing with the molecular strong-field approximation calculations and with recent experimental measurements.

  19. Cellular automata with object-oriented features for parallel molecular network modeling.

    PubMed

    Zhu, Hao; Wu, Yinghui; Huang, Sui; Sun, Yan; Dhar, Pawan

    2005-06-01

    Cellular automata are an important modeling paradigm for studying the dynamics of large, parallel systems composed of multiple, interacting components. However, to model biological systems, cellular automata need to be extended beyond the large-scale parallelism and intensive communication in order to capture two fundamental properties characteristic of complex biological systems: hierarchy and heterogeneity. This paper proposes extensions to a cellular automata language, Cellang, to meet this purpose. The extended language, with object-oriented features, can be used to describe the structure and activity of parallel molecular networks within cells. Capabilities of this new programming language include object structure to define molecular programs within a cell, floating-point data type and mathematical functions to perform quantitative computation, message passing capability to describe molecular interactions, as well as new operators, statements, and built-in functions. We discuss relevant programming issues of these features, including the object-oriented description of molecular interactions with molecule encapsulation, message passing, and the description of heterogeneity and anisotropy at the cell and molecule levels. By enabling the integration of modeling at the molecular level with system behavior at cell, tissue, organ, or even organism levels, the program will help improve our understanding of how complex and dynamic biological activities are generated and controlled by parallel functioning of molecular networks. Index Terms-Cellular automata, modeling, molecular network, object-oriented. PMID:16117022

  20. A dynamic styrofoam-ball model for simulating molecular motion

    NASA Astrophysics Data System (ADS)

    Mak, Se-yuen; Cheung, Derek

    2001-01-01

    In this paper we introduce a simple styrofoam-ball model that can be used for simulating molecular motion in all three states. As the foam balls are driven by a vibrator that is in turn driven by a signal generator, the frequency and the amplitude of vibration can be adjusted independently. Thus, the model is appropriate for simulating molecular motion in the liquid state, which is a combination of vibration and meandering motion.

  1. Constructing Molecular Models with Low-Cost Toy Beads

    ERIC Educational Resources Information Center

    Ng, Pun-hon; Wong, Siu-ling; Mak, Se-yuen

    2012-01-01

    In teaching the science of the nano world, ball-and-stick molecular models are frequently used as 3D representations of molecules. Unlike a chemical formula, a molecular model allows us to visualise the 3D shape of the molecule and the relative positions of its atoms, the bonds between atoms and why a pair of mirror isomers with the same atoms,…

  2. [Comparison study on adsorption of middle molecular substances with multiwalled carbon nanotubes and activated carbon].

    PubMed

    Li, Guifeng; Wan, Jianxin; Huang, Xiangqian; Zeng, Qiao; Tang, Jing

    2011-08-01

    In recent years, multi-walled carbon nanotubes (MWCTs) are very favorable to the adsorption of middle molecular substances in the hemoperfusion because of their multiporous structure, large surface area and high reactivity, which are beneficial to the excellent absorption properties. The purpose of this study was to study the MWCTs on the adsorption capacity of the middle molecular substances. Vitamin B12 (VB12) was selected as a model of the middle molecular substances. The morphologies of MWCTs and activated carbon from commercial "carbon kidney" were observed with scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The adsorption behavior of VB12 was compared to each other with UV-visible absorption spectra. The MWCTs formed a sophistaicate gap structure, and compared to the activated carbon, MWCTs had a larger surface area. By Langmuir equation and Freundlich equation fitting analysis, VB12 adsorption on MWCTs is fit for multi-molecular layer adsorption, and the adsorption type of activated carbon is more inclined to the model corresponding to Langmuir monolayer adsorption. The adsorption rate of MWCTs is faster than that of the activated carbon and the adsorption capacity is greater, which could be expected to become the new adsorbent in the hemoperfusion. PMID:21936376

  3. A Cooperative Molecular Modeling Exercise--The Hypersurface as Classroom

    NASA Astrophysics Data System (ADS)

    Cramer, Christopher J.; Kormos, Bethany L.; Winget, Paul; Audette, Vanessa M.; Beebe, Jeremy M.; Brauer, Carolyn S.; Burdick, W. Russ; Cochran, Eric W.; Eklov, Brian L.; Giese, Timothy J.; Jun, Yongseok; Kesavan, Lakshmi S. D.; Kinsinger, Christopher R.; Minyaev, Mickail E.; Rajamani, Ramkumar; Salsbury, Jonathon S.; Stubbs, John M.; Surek, Jack T.; Thompson, Jason D.; Voelz, Vincent A.; Wick, Collin D.; Zhang, Ling

    2001-09-01

    A molecular modeling exercise and an associated exam that have both competitive and cooperative learning aspects are described. Collaborative efforts are facilitated by Web-based information management. The exercise/exam is appropriate for use in undergraduate or graduate quantum chemistry or molecular modeling courses that have access to modest computational resources. Students develop a molecular potential energy surface, identify multiple minima and transition-state structures, repeat the process at two or more levels of theory, and then analyze the data looking for interesting chemical or computational phenomena.

  4. Free volume model for molecular weights of polymers

    NASA Technical Reports Server (NTRS)

    Singh, J. J.; Eftekhari, A.

    1992-01-01

    A free volume model has been developed for determining molecular weights of linear polymers. It is based on the size of free volume cells in two geometries of poly(arylene ether ketone)s. Free volume cell sizes in test samples were measured using positron lifetime spectroscopy. The molecular weights computed from free volume cell sizes are in good agreement with the values measured by gel permeation chromatography, with a low angle laser light scattering photometer as the detector. The model has been further tested on two atactic polystyrene samples, where it predicted the ratio of their molecular weights with reasonable accuracy.

  5. Global Modeling Activities and NAME

    NASA Technical Reports Server (NTRS)

    Schubert, Siegfried; Atlas, Robert (Technical Monitor)

    2002-01-01

    In this talk I will review global modeling activities in the United States that could contribute to and benefit from NAME activities. I will present some preliminary results from several global atmospheric general circulation model simulation experiments for the initial NAME model intercomparison project period of May-Oct 1990. These include an ensemble of medium resolution simulations, and a high resolution (one half degree) simulation. I will also discuss possible high resolution global data assimilation experiments that could be used to help validate the model simulations and assimilate planned NAME observations.

  6. Mean ionic activity coefficients in aqueous NaCl solutions from molecular dynamics simulations.

    PubMed

    Mester, Zoltan; Panagiotopoulos, Athanassios Z

    2015-01-28

    The mean ionic activity coefficients of aqueous NaCl solutions of varying concentrations at 298.15 K and 1 bar have been obtained from molecular dynamics simulations by gradually turning on the interactions of an ion pair inserted into the solution. Several common non-polarizable water and ion models have been used in the simulations. Gibbs-Duhem equation calculations of the thermodynamic activity of water are used to confirm the thermodynamic consistency of the mean ionic activity coefficients. While the majority of model combinations predict the correct trends in mean ionic activity coefficients, they overestimate their values at high salt concentrations. The solubility predictions also suffer from inaccuracies, with all models underpredicting the experimental values, some by large factors. These results point to the need for further ion and water model development. PMID:25637995

  7. Mean ionic activity coefficients in aqueous NaCl solutions from molecular dynamics simulations

    SciTech Connect

    Mester, Zoltan; Panagiotopoulos, Athanassios Z.

    2015-01-28

    The mean ionic activity coefficients of aqueous NaCl solutions of varying concentrations at 298.15 K and 1 bar have been obtained from molecular dynamics simulations by gradually turning on the interactions of an ion pair inserted into the solution. Several common non-polarizable water and ion models have been used in the simulations. Gibbs-Duhem equation calculations of the thermodynamic activity of water are used to confirm the thermodynamic consistency of the mean ionic activity coefficients. While the majority of model combinations predict the correct trends in mean ionic activity coefficients, they overestimate their values at high salt concentrations. The solubility predictions also suffer from inaccuracies, with all models underpredicting the experimental values, some by large factors. These results point to the need for further ion and water model development.

  8. Molecular candidates for cardiac stretch-activated ion channels

    PubMed Central

    Reed, Alistair; Kohl, Peter; Peyronnet, Rémi

    2014-01-01

    The heart is a mechanically-active organ that dynamically senses its own mechanical environment. This environment is constantly changing, on a beat-by-beat basis, with additional modulation by respiratory activity and changes in posture or physical activity, and further overlaid with more slowly occurring physiological (e.g. pregnancy, endurance training) or pathological challenges (e.g. pressure or volume overload). Far from being a simple pump, the heart detects changes in mechanical demand and adjusts its performance accordingly, both via heart rate and stroke volume alteration. Many of the underlying regulatory processes are encoded intracardially, and are thus maintained even in heart transplant recipients. Over the last three decades, molecular substrates of cardiac mechanosensitivity have gained increasing recognition in the scientific and clinical communities. Nonetheless, the processes underlying this phenomenon are still poorly understood. Stretch-activated ion channels (SAC) have been identified as one contributor to mechanosensitive autoregulation of the heartbeat. They also appear to play important roles in the development of cardiac pathologies – most notably stretch-induced arrhythmias. As recently discovered, some established cardiac drugs act, in part at least, via mechanotransduction pathways suggesting SAC as potential therapeutic targets. Clearly, identification of the molecular substrate of cardiac SAC is of clinical importance and a number of candidate proteins have been identified. At the same time, experimental studies have revealed variable–and at times contrasting–results regarding their function. Further complication arises from the fact that many ion channels that are not classically defined as SAC, including voltage and ligand-gated ion channels, can respond to mechanical stimulation. Here, we summarise what is known about the molecular substrate of the main candidates for cardiac SAC, before identifying potential further

  9. Modeling approaches for active systems

    NASA Astrophysics Data System (ADS)

    Herold, Sven; Atzrodt, Heiko; Mayer, Dirk; Thomaier, Martin

    2006-03-01

    To solve a wide range of vibration problems with the active structures technology, different simulation approaches for several models are needed. The selection of an appropriate modeling strategy is depending, amongst others, on the frequency range, the modal density and the control target. An active system consists of several components: the mechanical structure, at least one sensor and actuator, signal conditioning electronics and the controller. For each individual part of the active system the simulation approaches can be different. To integrate the several modeling approaches into an active system simulation and to ensure a highly efficient and accurate calculation, all sub models must harmonize. For this purpose, structural models considered in this article are modal state-space formulations for the lower frequency range and transfer function based models for the higher frequency range. The modal state-space formulations are derived from finite element models and/or experimental modal analyses. Consequently, the structure models which are based on transfer functions are directly derived from measurements. The transfer functions are identified with the Steiglitz-McBride iteration method. To convert them from the z-domain to the s-domain a least squares solution is implemented. An analytical approach is used to derive models of active interfaces. These models are transferred into impedance formulations. To couple mechanical and electrical sub-systems with the active materials, the concept of impedance modeling was successfully tested. The impedance models are enhanced by adapting them to adequate measurements. The controller design strongly depends on the frequency range and the number of modes to be controlled. To control systems with a small number of modes, techniques such as active damping or independent modal space control may be used, whereas in the case of systems with a large number of modes or with modes that are not well separated, other control

  10. Molecular modeling of responsive polymer films

    SciTech Connect

    Tagliazucchi, Mario; Calvo, Ernesto J; Szleifer, Igal

    2010-06-29

    In this perspective, we have shown three different cases of responsive polymers at surfaces where the properties of the surface can be varied in response to cues from the bulk solution or in the presence of an external field. The most important conclusion in all three cases is that the chemical reaction equilibrium, physical interactions and molecular organization are strongly coupled, and it is imperative to consider the global and local changes that occur to the surface structure and properties due to this coupling. In particular acid-base and redox equilibrium are very different in polymer-modified surfaces than in the corresponding bulk solutions. Moreover, the definition of ‘‘apparent redox potentials’’ and ‘‘apparent pKa’’results from the averaging over highly inhomogeneous values,and, therefore, they do not necessarily represent the state of the layer and the local values and their variation are very important for the design of functional surfaces. The very large variation on chemical equilibrium results from the optimization of all the interactions. The picture that emerges is that trying to deduce what the final state of the system is by looking at the individual optimization of each contribution leads to qualitative incorrect assumptions and only the minimization of the complete free energy leads to the proper behavior in these complex systems.In the cases where domain formation is possible in grafted weak polyacid layers charge regulation may lead to regimes of coexistence between aggregates with relatively low fraction of charged polymer segments surrounded by highly stretched chains that have a relatively high fraction of charged groups.Therefore, one can control the state of charge, local electrostatic potential and local pH in all three dimensions with im-portant gradients on length scales of nanometers. For hydrophobic redox polymers we show how the application of an electrode potential can lead to changes in the structure

  11. A Home Production Activity Model.

    ERIC Educational Resources Information Center

    Beutler, Ivan F.; Owen, Alma J.

    1980-01-01

    The family is examined as a focal unit of production and a home production activity model is developed. An interdisciplinary approach is used which puts the broad range of family activities on a continuum from production to consumption. (Author/SK)

  12. Linking neural activity and molecular oscillations in the SCN

    PubMed Central

    Colwell, Christopher S.

    2015-01-01

    Neurons in the suprachiasmatic nucleus (SCN) function as part of a central timing circuit that drives daily changes in our behaviour and underlying physiology. A hallmark feature of SCN neuronal populations is that they are mostly electrically silent during the night, start to fire action potentials near dawn and then continue to generate action potentials with a slow and steady pace all day long. Sets of currents are responsible for this daily rhythm, with the strongest evidence for persistent Na+ currents, L-type Ca2+ currents, hyperpolarization-activated currents (IH), large-conductance Ca2+ activated K+ (BK) currents and fast delayed rectifier (FDR) K+ currents. These rhythms in electrical activity are crucial for the function of the circadian timing system, including the expression of clock genes, and decline with ageing and disease. This article reviews our current understanding of the ionic and molecular mechanisms that drive the rhythmic firing patterns in the SCN. PMID:21886186

  13. Unveiling the molecular mechanism of brassinosteroids: Insights from structure-based molecular modeling studies.

    PubMed

    Lei, Beilei; Liu, Jiyuan; Yao, Xiaojun

    2015-12-01

    Brassinosteroid (BR) phytohormones play indispensable roles in plant growth and development. Brassinolide (BL) and 24-epibrassinolide (24-epiBL) are the most active ones among the BRs reported thus far. Unfortunately, the extremely low natural content and intricate synthesis process limit their popularization in agricultural production. Earlier reports to discover alternative compounds have resulted in molecules with nearly same scaffold structure and without diversity in chemical space. In the present study, receptors structure based BRs regulation mechanism was analyzed. First, we examined the detailed binding interactions and their dynamic stability between BL and its receptor BRI1 and co-receptor BAK1. Then, the binding modes and binding free energies for 24-epiBL and a series of representative BRs binding with BRI1 and BRI1-BAK1 were carried out by molecular docking, energy minimization and MM-PBSA free energy calculation. The obtained binding structures and energetic results provided vital insights into the structural factors affecting the activity from both receptors and BRs aspects. Subsequently, the obtained knowledge will serve as valuable guidance to build pharmacophore models for rational screening of new scaffold alternative BRs. PMID:26362600

  14. Quantitative and logic modelling of gene and molecular networks

    PubMed Central

    Le Novère, Nicolas

    2015-01-01

    Behaviours of complex biomolecular systems are often irreducible to the elementary properties of their individual components. Explanatory and predictive mathematical models are therefore useful for fully understanding and precisely engineering cellular functions. The development and analyses of these models require their adaptation to the problems that need to be solved and the type and amount of available genetic or molecular data. Quantitative and logic modelling are among the main methods currently used to model molecular and gene networks. Each approach comes with inherent advantages and weaknesses. Recent developments show that hybrid approaches will become essential for further progress in synthetic biology and in the development of virtual organisms. PMID:25645874

  15. Molecular modeling studies, synthesis and biological evaluation of dabigatran analogues as thrombin inhibitors.

    PubMed

    Dong, Ming-Hui; Chen, Hai-Feng; Ren, Yu-Jie; Shao, Fang-Ming

    2016-01-15

    In this work, 48 thrombin inhibitors based on the structural scaffold of dabigatran were analyzed using a combination of molecular modeling techniques. We generated three-dimensional quantitative structure-activity relationship (3D-QSAR) models based on three alignments for both comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) to highlight the structural requirements for thrombin protein inhibition. In addition to the 3D-QSAR study, Topomer CoMFA model also was established with a higher leave-one-out cross-validation q(2) and a non-cross-validation r(2), which suggest that the three models have good predictive ability. The results indicated that the steric, hydrophobic and electrostatic fields play key roles in QSAR model. Furthermore, we employed molecular docking and re-docking simulation explored the binding relationship of the ligand and the receptor protein in detail. Molecular docking simulations identified several key interactions that were also indicated through 3D-QSAR analysis. On the basis of the obtained results, two compounds were designed and predicted by three models, the biological evaluation in vitro (IC50) demonstrated that these molecular models were effective for the development of novel potent thrombin inhibitors. PMID:26690913

  16. A Novel Network Model for Molecular Prognosis

    PubMed Central

    Wan, Ying-Wooi; Bose, Swetha; Denvir, James; Guo, Nancy Lan

    2015-01-01

    Network-based genome-wide association studies (NWAS) utilize the molecular interactions between genes and functional pathways in biomarker identification. This study presents a novel network-based methodology for identifying prognostic gene signatures to predict cancer recurrence. The methodology contains the following steps: 1) Constructing genome-wide coexpression networks for different disease states (metastatic vs. non-metastatic). Prediction logic is used to induct valid implication relations between each pair of gene expression profiles in terms of formal logic rules. 2) Identifying differential components associated with specific disease states from the genome-wide coexpression networks. 3) Dissecting network modules that are tightly connected with major disease signal hallmarks from the disease specific differential components. 4) Identifying most significant genes/probes associated with clinical outcome from the pathway connected network modules. Using this methodology, a 14-gene prognostic signature was identified for accurate patient stratification in early stage lung cancer. PMID:26005718

  17. Nanoplasmonic molecular ruler for nuclease activity and DNA footprinting

    DOEpatents

    Chen, Fanqing Frank; Liu, Gang L; Lee, Luke P

    2013-10-29

    This invention provides a nanoplasmonic molecular ruler, which can perform label-free and real-time monitoring of nucleic acid (e.g., DNA) length changes and perform nucleic acid footprinting. In various embodiments the ruler comprises a nucleic acid attached to a nanoparticle, such that changes in the nucleic acid length are detectable using surface plasmon resonance. The nanoplasmonic ruler provides a fast and convenient platform for mapping nucleic acid-protein interactions, for nuclease activity monitoring, and for other footprinting related methods.

  18. Molecular Imprint of Enzyme Active Site by Camel Nanobodies

    PubMed Central

    Li, Jiang-Wei; Xia, Lijie; Su, Youhong; Liu, Hongchun; Xia, Xueqing; Lu, Qinxia; Yang, Chunjin; Reheman, Kalbinur

    2012-01-01

    Screening of inhibitory Ab1 antibodies is a critical step for producing catalytic antibodies in the anti-idiotypic approach. However, the incompatible surface of the active site of the enzyme and the antigen-binding site of heterotetrameric conventional antibodies become the limiting step. Because camelid-derived nanobodies possess the potential to preferentially bind to the active site of enzymes due to their small size and long CDR3, we have developed a novel approach to produce antibodies with alliinase activities by exploiting the molecular mimicry of camel nanobodies. By screening the camelid-derived variable region of the heavy chain cDNA phage display library with alliinase, we obtained an inhibitory nanobody VHHA4 that recognizes the active site. Further screening with VHHA4 from the same variable domain of the heavy chain of a heavy-chain antibody library led to a higher incidence of anti-idiotypic Ab2 abzymes with alliinase activities. One of the abzymes, VHHC10, showed the highest activity that can be inhibited by Ab1 VHHA4 and alliinase competitive inhibitor penicillamine and significantly suppressed the B16 tumor cell growth in the presence of alliin in vitro. The results highlight the feasibility of producing abzymes via anti-idiotypic nanobody approach. PMID:22374998

  19. Molecular Modeling on the PC (by Matthew F. Schlecht)

    NASA Astrophysics Data System (ADS)

    Rioux, Reviewed Frank

    2000-06-01

    "Computeraided molecular modeling doesn't exist for its own sake, but to contribute to scientific endeavor, and enable the scientist to work smarter." This is the last sentence of Schlecht's preface and it says something very important about contemporary scientific research in the academic and industrial venues. Owing to the accelerating improvement in computer technology (hardware and software) and its widespread availability, molecular modeling has become a reliable and important tool in chemical research. Consequently, experimentalists have incorporated molecular modeling techniques in their research, and partnerships with computational chemists have become common. This is a wellorganized and thorough monograph that devotes its attention to one type of molecular modeling, molecular mechanics, and one molecular modeling software package, PCMODEL. Schlecht targets two reader-user groups, the novice and the journeyman modeler, and articulates three goals. He wants to provide the novice with an introduction to molecular mechanics, and after that with some practical examples of the use of empirical force field calculations. His third goal is to provide the journeyman modeler with a reference work that will aid "further study and practice". These are potentially conflicting goals, but Schlecht is, in my opinion, successful because of the way his book is organized. A comprehensive treatment such as this one is not meant to be read from cover to cover, because it is both an exposition of basic principles and a user's manual. Therefore, the novice and the experienced modeler will undoubtedly use this book in different ways. For example, a novice modeler might be advised to read the Preface and Chapter 1, which together provide a broad introduction to the historical development and goals of molecular mechanics. From there the novice could go to Chapter 5 and read section 5.1 on the components of the molecular mechanics force field, which is presented in 22 pages with

  20. Generalized Mixture Models for Molecular Phylogenetic Estimation

    PubMed Central

    Evans, Jason; Sullivan, Jack

    2012-01-01

    The rapidly growing availability of multigene sequence data during the past decade has enabled phylogeny estimation at phylogenomic scales. However, dealing with evolutionary process heterogeneity across the genome becomes increasingly challenging. Here we develop a mixture model approach that uses reversible jump Markov chain Monte Carlo (MCMC) estimation to permit as many distinct models as the data require. Each additional model considered may be a fully parametrized general time-reversible model or any of its special cases. Furthermore, we expand the usual proposal mechanisms for topology changes to permit hard polytomies (i.e., zero-length internal branches). This new approach is implemented in the Crux software toolkit. We demonstrate the feasibility of using reversible jump MCMC on mixture models by reexamining a well-known 44-taxon mammalian data set comprising 22 concatenated genes. We are able to reproduce the results of the original analysis (with respect to bipartition support) when we make identical assumptions, but when we allow for polytomies and/or use data-driven mixture model estimation, we infer much lower bipartition support values for several key bipartitions. PMID:21873377

  1. Adaptive modelling of structured molecular representations for toxicity prediction

    NASA Astrophysics Data System (ADS)

    Bertinetto, Carlo; Duce, Celia; Micheli, Alessio; Solaro, Roberto; Tiné, Maria Rosaria

    2012-12-01

    We investigated the possibility of modelling structure-toxicity relationships by direct treatment of the molecular structure (without using descriptors) through an adaptive model able to retain the appropriate structural information. With respect to traditional descriptor-based approaches, this provides a more general and flexible way to tackle prediction problems that is particularly suitable when little or no background knowledge is available. Our method employs a tree-structured molecular representation, which is processed by a recursive neural network (RNN). To explore the realization of RNN modelling in toxicological problems, we employed a data set containing growth impairment concentrations (IGC50) for Tetrahymena pyriformis.

  2. Recent insights into the molecular mechanisms of the NLRP3 inflammasome activation

    PubMed Central

    Próchnicki, Tomasz; Mangan, Matthew S.; Latz, Eicke

    2016-01-01

    Inflammasomes are high-molecular-weight protein complexes that are formed in the cytosolic compartment in response to danger- or pathogen-associated molecular patterns. These complexes enable activation of an inflammatory protease caspase-1, leading to a cell death process called pyroptosis and to proteolytic cleavage and release of pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Along with caspase-1, inflammasome components include an adaptor protein, ASC, and a sensor protein, which triggers the inflammasome assembly in response to a danger signal. The inflammasome sensor proteins are pattern recognition receptors belonging either to the NOD-like receptor (NLR) or to the AIM2-like receptor family. While the molecular agonists that induce inflammasome formation by AIM2 and by several other NLRs have been identified, it is not well understood how the NLR family member NLRP3 is activated. Given that NLRP3 activation is relevant to a range of human pathological conditions, significant attempts are being made to elucidate the molecular mechanism of this process. In this review, we summarize the current knowledge on the molecular events that lead to activation of the NLRP3 inflammasome in response to a range of K + efflux-inducing danger signals. We also comment on the reported involvement of cytosolic Ca 2+ fluxes on NLRP3 activation. We outline the recent advances in research on the physiological and pharmacological mechanisms of regulation of NLRP3 responses, and we point to several open questions regarding the current model of NLRP3 activation. PMID:27508077

  3. Recent insights into the molecular mechanisms of the NLRP3 inflammasome activation.

    PubMed

    Próchnicki, Tomasz; Mangan, Matthew S; Latz, Eicke

    2016-01-01

    Inflammasomes are high-molecular-weight protein complexes that are formed in the cytosolic compartment in response to danger- or pathogen-associated molecular patterns. These complexes enable activation of an inflammatory protease caspase-1, leading to a cell death process called pyroptosis and to proteolytic cleavage and release of pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Along with caspase-1, inflammasome components include an adaptor protein, ASC, and a sensor protein, which triggers the inflammasome assembly in response to a danger signal. The inflammasome sensor proteins are pattern recognition receptors belonging either to the NOD-like receptor (NLR) or to the AIM2-like receptor family. While the molecular agonists that induce inflammasome formation by AIM2 and by several other NLRs have been identified, it is not well understood how the NLR family member NLRP3 is activated. Given that NLRP3 activation is relevant to a range of human pathological conditions, significant attempts are being made to elucidate the molecular mechanism of this process. In this review, we summarize the current knowledge on the molecular events that lead to activation of the NLRP3 inflammasome in response to a range of K (+) efflux-inducing danger signals. We also comment on the reported involvement of cytosolic Ca (2+) fluxes on NLRP3 activation. We outline the recent advances in research on the physiological and pharmacological mechanisms of regulation of NLRP3 responses, and we point to several open questions regarding the current model of NLRP3 activation. PMID:27508077

  4. Data-mining of potential antitubercular activities from molecular ingredients of traditional Chinese medicines

    PubMed Central

    Jamal, Salma

    2014-01-01

    Background. Traditional Chinese medicine encompasses a well established alternate system of medicine based on a broad range of herbal formulations and is practiced extensively in the region for the treatment of a wide variety of diseases. In recent years, several reports describe in depth studies of the molecular ingredients of traditional Chinese medicines on the biological activities including anti-bacterial activities. The availability of a well-curated dataset of molecular ingredients of traditional Chinese medicines and accurate in-silico cheminformatics models for data mining for antitubercular agents and computational filters to prioritize molecules has prompted us to search for potential hits from these datasets. Results. We used a consensus approach to predict molecules with potential antitubercular activities from a large dataset of molecular ingredients of traditional Chinese medicines available in the public domain. We further prioritized 160 molecules based on five computational filters (SMARTSfilter) so as to avoid potentially undesirable molecules. We further examined the molecules for permeability across Mycobacterial cell wall and for potential activities against non-replicating and drug tolerant Mycobacteria. Additional in-depth literature surveys for the reported antitubercular activities of the molecular ingredients and their sources were considered for drawing support to prioritization. Conclusions. Our analysis suggests that datasets of molecular ingredients of traditional Chinese medicines offer a new opportunity to mine for potential biological activities. In this report, we suggest a proof-of-concept methodology to prioritize molecules for further experimental assays using a variety of computational tools. We also additionally suggest that a subset of prioritized molecules could be used for evaluation for tuberculosis due to their additional effect against non-replicating tuberculosis as well as the additional hepato-protection offered by

  5. Molecular Modeling of Nucleic Acid Structure: Electrostatics and Solvation

    PubMed Central

    Bergonzo, Christina; Galindo-Murillo, Rodrigo; Cheatham, Thomas E.

    2014-01-01

    This unit presents an overview of computer simulation techniques as applied to nucleic acid systems, ranging from simple in vacuo molecular modeling techniques to more complete all-atom molecular dynamics treatments that include an explicit representation of the environment. The third in a series of four units, this unit focuses on critical issues in solvation and the treatment of electrostatics. UNITS 7.5 & 7.8 introduced the modeling of nucleic acid structure at the molecular level. This included a discussion of how to generate an initial model, how to evaluate the utility or reliability of a given model, and ultimately how to manipulate this model to better understand the structure, dynamics, and interactions. Subject to an appropriate representation of the energy, such as a specifically parameterized empirical force field, the techniques of minimization and Monte Carlo simulation, as well as molecular dynamics (MD) methods, were introduced as means to sample conformational space for a better understanding of the relevance of a given model. From this discussion, the major limitations with modeling, in general, were highlighted. These are the difficult issues in sampling conformational space effectively—the multiple minima or conformational sampling problems—and accurately representing the underlying energy of interaction. In order to provide a realistic model of the underlying energetics for nucleic acids in their native environments, it is crucial to include some representation of solvation (by water) and also to properly treat the electrostatic interactions. These are discussed in detail in this unit. PMID:18428877

  6. Molecular modeling of nucleic Acid structure: electrostatics and solvation.

    PubMed

    Bergonzo, Christina; Galindo-Murillo, Rodrigo; Cheatham, Thomas E

    2014-01-01

    This unit presents an overview of computer simulation techniques as applied to nucleic acid systems, ranging from simple in vacuo molecular modeling techniques to more complete all-atom molecular dynamics treatments that include an explicit representation of the environment. The third in a series of four units, this unit focuses on critical issues in solvation and the treatment of electrostatics. UNITS 7.5 & 7.8 introduced the modeling of nucleic acid structure at the molecular level. This included a discussion of how to generate an initial model, how to evaluate the utility or reliability of a given model, and ultimately how to manipulate this model to better understand its structure, dynamics, and interactions. Subject to an appropriate representation of the energy, such as a specifically parameterized empirical force field, the techniques of minimization and Monte Carlo simulation, as well as molecular dynamics (MD) methods, were introduced as a way of sampling conformational space for a better understanding of the relevance of a given model. This discussion highlighted the major limitations with modeling in general. When sampling conformational space effectively, difficult issues are encountered, such as multiple minima or conformational sampling problems, and accurately representing the underlying energy of interaction. In order to provide a realistic model of the underlying energetics for nucleic acids in their native environments, it is crucial to include some representation of solvation (by water) and also to properly treat the electrostatic interactions. These subjects are discussed in detail in this unit. PMID:25631536

  7. The Electron-Pair Repulsion Model for Molecular Geometry

    ERIC Educational Resources Information Center

    Gillespie, R. J.

    1970-01-01

    Describes how the electron-pair repulsion model qualitatively explains the size and shape of molecular orbitals. Briefly discusses trigonal bipyramidal molecules, three-center bonds, and transition elements. Describes cluster compounds and finishes with a discussion of the exceptions to the model and effects of ligand-ligand repulsions. (RR)

  8. Study on the active mechanism of β-secretase inhibitors by molecular simulations.

    PubMed

    Tian, Yue Li; Lv, Min; Li, Jiao Jiao; Xu, Tao; Zhai, Hong Lin; Zhang, Xiao Yun

    2015-08-30

    The proteolytic enzyme β-secretase (BACE-1) is one of potential drug targets for treating Alzheimers's disease. First, the reliable and accurate models of three-dimensional quantitative structure-activity relationship for the BACE-1 inhibitors were established, and the several important structural factors that mainly influence the inhibitory activity were obtained. Second, the results of molecular docking presented the binding mode between BACE-1 and its inhibitors, and molecular dynamic simulations provided the details of the receptor-ligand interactions. Furthermore, several new derivatives were designed and validated based on these theoretical analyses. Our studies revealed the binding mechanism between BACE-1 and its inhibitors, and provide some insights into the further structural modification and the design of new inhibitors with higher activity. PMID:25965961

  9. Modelling refractive index changes due to molecular interactions

    NASA Astrophysics Data System (ADS)

    Varma, Manoj

    2016-03-01

    There are a large number of sensing techniques which use optical changes to monitor interactions between molecules. In the absence of fluorophores or other labels, the basic signal transduction mechanism relies on refractive index changes arising from the interactions of the molecules involved. A quantitative model incorporating molecular transport, reaction kinetics and optical mixing is presented which reveals important insights concerning the optimal detection of molecular interactions optically. Although conceptually simple, a comprehensive model such as this has not been reported anywhere. Specifically, we investigate the pros and cons of detecting molecular interactions in free solution relative to detecting molecular interactions on surfaces using surface bound receptor molecules such as antibodies. The model reveals that the refractive index change produced in surface based sensors is 2-3 orders of magnitude higher than that from interactions in free solution. On the other hand, the model also reveals that it is indeed possible to distinguish specific molecular interactions from non-specific ones based on free-solution bulk refractometry without any washing step necessary in surface based sensors. However, the refractive index change for free solution interactions predicted by the model is smaller than 10-7 RIU, even for large proteins such as IgG in sufficiently high concentrations. This value is smaller than the typical 10-6 RIU detection limit of most state of the art optical sensing techniques therefore requiring techniques with substantially higher index sensitivity such as Back Scattering Interferometry.

  10. Emerging Models for the Molecular Basis of Mammalian Circadian Timing

    PubMed Central

    2015-01-01

    Mammalian circadian timekeeping arises from a transcription-based feedback loop driven by a set of dedicated clock proteins. At its core, the heterodimeric transcription factor CLOCK:BMAL1 activates expression of Period, Cryptochrome, and Rev-Erb genes, which feed back to repress transcription and create oscillations in gene expression that confer circadian timing cues to cellular processes. The formation of different clock protein complexes throughout this transcriptional cycle helps to establish the intrinsic ∼24 h periodicity of the clock; however, current models of circadian timekeeping lack the explanatory power to fully describe this process. Recent studies confirm the presence of at least three distinct regulatory complexes: a transcriptionally active state comprising the CLOCK:BMAL1 heterodimer with its coactivator CBP/p300, an early repressive state containing PER:CRY complexes, and a late repressive state marked by a poised but inactive, DNA-bound CLOCK:BMAL1:CRY1 complex. In this review, we analyze high-resolution structures of core circadian transcriptional regulators and integrate biochemical data to suggest how remodeling of clock protein complexes may be achieved throughout the 24 h cycle. Defining these detailed mechanisms will provide a foundation for understanding the molecular basis of circadian timing and help to establish new platforms for the discovery of therapeutics to manipulate the clock. PMID:25303119

  11. Extracting Structure Parameters of Dimers for Molecular Tunneling Ionization Model

    NASA Astrophysics Data System (ADS)

    Song-Feng, Zhao; Fang, Huang; Guo-Li, Wang; Xiao-Xin, Zhou

    2016-03-01

    We determine structure parameters of the highest occupied molecular orbital (HOMO) of 27 dimers for the molecular tunneling ionization (so called MO-ADK) model of Tong et al. [Phys. Rev. A 66 (2002) 033402]. The molecular wave functions with correct asymptotic behavior are obtained by solving the time-independent Schrödinger equation with B-spline functions and molecular potentials which are numerically created using the density functional theory. We examine the alignment-dependent tunneling ionization probabilities from MO-ADK model for several molecules by comparing with the molecular strong-field approximation (MO-SFA) calculations. We show the molecular Perelomov–Popov–Terent'ev (MO-PPT) can successfully give the laser wavelength dependence of ionization rates (or probabilities). Based on the MO-PPT model, two diatomic molecules having valence orbital with antibonding systems (i.e., Cl2, Ne2) show strong ionization suppression when compared with their corresponding closest companion atoms. Supported by National Natural Science Foundation of China under Grant Nos. 11164025, 11264036, 11465016, 11364038, the Specialized Research Fund for the Doctoral Program of Higher Education of China under Grant No. 20116203120001, and the Basic Scientific Research Foundation for Institution of Higher Learning of Gansu Province

  12. Extracting Structure Parameters of Dimers for Molecular Tunneling Ionization Model

    NASA Astrophysics Data System (ADS)

    Zhao, Song-Feng; Huang, Fang; Wang, Guo-Li; Zhou, Xiao-Xin

    2016-03-01

    We determine structure parameters of the highest occupied molecular orbital (HOMO) of 27 dimers for the molecular tunneling ionization (so called MO-ADK) model of Tong et al. [Phys. Rev. A 66 (2002) 033402]. The molecular wave functions with correct asymptotic behavior are obtained by solving the time-independent Schrödinger equation with B-spline functions and molecular potentials which are numerically created using the density functional theory. We examine the alignment-dependent tunneling ionization probabilities from MO-ADK model for several molecules by comparing with the molecular strong-field approximation (MO-SFA) calculations. We show the molecular Perelomov-Popov-Terent'ev (MO-PPT) can successfully give the laser wavelength dependence of ionization rates (or probabilities). Based on the MO-PPT model, two diatomic molecules having valence orbital with antibonding systems (i.e., Cl2, Ne2) show strong ionization suppression when compared with their corresponding closest companion atoms. Supported by National Natural Science Foundation of China under Grant Nos. 11164025, 11264036, 11465016, 11364038, the Specialized Research Fund for the Doctoral Program of Higher Education of China under Grant No. 20116203120001, and the Basic Scientific Research Foundation for Institution of Higher Learning of Gansu Province

  13. Corn Storage Protein - A Molecular Genetic Model

    SciTech Connect

    Messing, Joachim

    2013-05-31

    Corn is the highest yielding crop on earth and probably the most valuable agricultural product of the United States. Because it converts sun energy through photosynthesis into starch and proteins, we addressed energy savings by focusing on protein quality. People and animals require essential amino acids derived from the digestion of proteins. If proteins are relatively low in certain essential amino acids, the crop becomes nutritionally defective and has to be supplemented. Such deficiency affects meat and fish production and countries where corn is a staple. Because corn seed proteins have relatively low levels of lysine and methionine, a diet has to be supplemented with soybeans for the missing lysine and with chemically synthesized methionine. We therefore have studied genes expressed during maize seed development and their chromosomal organization. A critical technical requirement for the understanding of the molecular structure of genes and their positional information was DNA sequencing. Because of the length of sequences, DNA sequencing methods themselves were insufficient for this type of analysis. We therefore developed the so-called “DNA shotgun sequencing” strategy, where overlapping DNA fragments were sequenced in parallel and used to reconstruct large DNA molecules via overlaps. Our publications became the most frequently cited ones during the decade of 1981-1990 and former Associate Director of Science for the Office of Basic Energy Sciences Patricia M. Dehmer presented our work as one of the great successes of this program. A major component of the sequencing strategy was the development of bacterial strains and vectors, which were also used to develop the first biotechnology crops. These crops possessed new traits thanks to the expression of foreign genes in plants. To enable such expression, chimeric genes had to be constructed using our materials and methods by the industry. Because we made our materials and methods freely available to

  14. Computational models of epileptiform activity.

    PubMed

    Wendling, Fabrice; Benquet, Pascal; Bartolomei, Fabrice; Jirsa, Viktor

    2016-02-15

    We reviewed computer models that have been developed to reproduce and explain epileptiform activity. Unlike other already-published reviews on computer models of epilepsy, the proposed overview starts from the various types of epileptiform activity encountered during both interictal and ictal periods. Computational models proposed so far in the context of partial and generalized epilepsies are classified according to the following taxonomy: neural mass, neural field, detailed network and formal mathematical models. Insights gained about interictal epileptic spikes and high-frequency oscillations, about fast oscillations at seizure onset, about seizure initiation and propagation, about spike-wave discharges and about status epilepticus are described. This review shows the richness and complementarity of the various modeling approaches as well as the fruitful contribution of the computational neuroscience community in the field of epilepsy research. It shows that models have progressively gained acceptance and are now considered as an efficient way of integrating structural, functional and pathophysiological data about neural systems into "coherent and interpretable views". The advantages, limitations and future of modeling approaches are discussed. Perspectives in epilepsy research and clinical epileptology indicate that very promising directions are foreseen, like model-guided experiments or model-guided therapeutic strategy, among others. PMID:25843066

  15. Energetics of molecular-beam epitaxy models

    NASA Technical Reports Server (NTRS)

    Krishnamurthy, Srinivasan; Berding, M. A.; Sher, A.; Chen, A.-B.

    1990-01-01

    The removal energies of constituent atoms from various unreconstructed semiconductor surfaces are calculated using a Green function method. An efficient difference-equation approach within the second-neighbor tight-binding model is employed. For a compound AB, binding energies for the A and B atoms on the (111), (-1 -1 -1), (100), and (110) surfaces are calculated. Analyses are made of the energy to remove an atom from the nearly full surface and from the nearly empty surface. Results are presented for Si, GaAs, CdTe, and HgTe; and the surface sublimation energies are found to depend on surface coverage and do not display a simple linear relationship to the number of bonds broken, as is often assumed in modeling growth by MBE.

  16. Energetics of molecular-beam epitaxy models

    NASA Astrophysics Data System (ADS)

    Krishnamurthy, Srinivasan; Berding, M. A.; Sher, A.; Chen, A.-B.

    1990-10-01

    The removal energies of constituent atoms from various unreconstructed semiconductor surfaces are calculated using a Green function method. An efficient difference-equation approach within the second-neighbor tight-binding model is employed. For a compound AB, binding energies for the A and B atoms on the (111), (-1 -1 -1), (100), and (110) surfaces are calculated. Analyses are made of the energy to remove an atom from the nearly full surface and from the nearly empty surface. Results are presented for Si, GaAs, CdTe, and HgTe; and the surface sublimation energies are found to depend on surface coverage and do not display a simple linear relationship to the number of bonds broken, as is often assumed in modeling growth by MBE.

  17. Modeling Cytoskeletal Active Matter Systems

    NASA Astrophysics Data System (ADS)

    Blackwell, Robert

    Active networks of filamentous proteins and crosslinking motor proteins play a critical role in many important cellular processes. One of the most important microtubule-motor protein assemblies is the mitotic spindle, a self-organized active liquid-crystalline structure that forms during cell division and that ultimately separates chromosomes into two daughter cells. Although the spindle has been intensively studied for decades, the physical principles that govern its self-organization and function remain mysterious. To evolve a better understanding of spindle formation, structure, and dynamics, I investigate course-grained models of active liquid-crystalline networks composed of microtubules, modeled as hard spherocylinders, in diffusive equilibrium with a reservoir of active crosslinks, modeled as hookean springs that can adsorb to microtubules and and translocate at finite velocity along the microtubule axis. This model is investigated using a combination of brownian dynamics and kinetic monte carlo simulation. I have further refined this model to simulate spindle formation and kinetochore capture in the fission yeast S. pombe. I then make predictions for experimentally realizable perturbations in motor protein presence and function in S. pombe.

  18. 1-[(3-Aryloxy-3-aryl)propyl]-1H-imidazoles, new imidazoles with potent activity against Candida albicans and dermatophytes. Synthesis, structure-activity relationship, and molecular modeling studies.

    PubMed

    La Regina, Giuseppe; D'Auria, Felicia Diodata; Tafi, Andrea; Piscitelli, Francesco; Olla, Stefania; Caporuscio, Fabiana; Nencioni, Lucia; Cirilli, Roberto; La Torre, Francesco; De Melo, Nadja Rodrigues; Kelly, Steven L; Lamb, David C; Artico, Marino; Botta, Maurizio; Palamara, Anna Teresa; Silvestri, Romano

    2008-07-10

    New 1-[(3-aryloxy-3-aryl)propyl]-1 H-imidazoles were synthesized and evaluated against Candida albicans and dermatophytes in order to develop structure-activity relationships (SARs). Against C. albicans the new imidazoles showed minimal inhibitory concentrations (MICs) comparable to those of ketoconazole, miconazole, and econazole, and were more potent than fluconazole. Several derivatives ( 10, 12, 14, 18- 20, 24, 28, 29, 30, and 34) turned out to be potent inhibitors of C. albicans strains resistant to fluconazole, with MIC values less than 10 microg/mL. Against dermatophytes strains, compounds 20, 25, and 33 (MIC

  19. Modeling Polymorphic Molecular Crystals with Electronic Structure Theory.

    PubMed

    Beran, Gregory J O

    2016-05-11

    Interest in molecular crystals has grown thanks to their relevance to pharmaceuticals, organic semiconductor materials, foods, and many other applications. Electronic structure methods have become an increasingly important tool for modeling molecular crystals and polymorphism. This article reviews electronic structure techniques used to model molecular crystals, including periodic density functional theory, periodic second-order Møller-Plesset perturbation theory, fragment-based electronic structure methods, and diffusion Monte Carlo. It also discusses the use of these models for predicting a variety of crystal properties that are relevant to the study of polymorphism, including lattice energies, structures, crystal structure prediction, polymorphism, phase diagrams, vibrational spectroscopies, and nuclear magnetic resonance spectroscopy. Finally, tools for analyzing crystal structures and intermolecular interactions are briefly discussed. PMID:27008426

  20. The molecular regulation of Janus kinase (JAK) activation.

    PubMed

    Babon, Jeffrey J; Lucet, Isabelle S; Murphy, James M; Nicola, Nicos A; Varghese, Leila N

    2014-08-15

    The JAK (Janus kinase) family members serve essential roles as the intracellular signalling effectors of cytokine receptors. This family, comprising JAK1, JAK2, JAK3 and TYK2 (tyrosine kinase 2), was first described more than 20 years ago, but the complexities underlying their activation, regulation and pleiotropic signalling functions are still being explored. Here, we review the current knowledge of their physiological functions and the causative role of activating and inactivating JAK mutations in human diseases, including haemopoietic malignancies, immunodeficiency and inflammatory diseases. At the molecular level, recent studies have greatly advanced our knowledge of the structures and organization of the component FERM (4.1/ezrin/radixin/moesin)-SH2 (Src homology 2), pseudokinase and kinase domains within the JAKs, the mechanism of JAK activation and, in particular, the role of the pseudokinase domain as a suppressor of the adjacent tyrosine kinase domain's catalytic activity. We also review recent advances in our understanding of the mechanisms of negative regulation exerted by the SH2 domain-containing proteins, SOCS (suppressors of cytokine signalling) proteins and LNK. These recent studies highlight the diversity of regulatory mechanisms utilized by the JAK family to maintain signalling fidelity, and suggest alternative therapeutic strategies to complement existing ATP-competitive kinase inhibitors. PMID:25057888

  1. The Molecular Mechanism of P2Y1 Receptor Activation.

    PubMed

    Yuan, Shuguang; Chan, H C Stephen; Vogel, Horst; Filipek, Slawomir; Stevens, Raymond C; Palczewski, Krzysztof

    2016-08-22

    Human purinergic G protein-coupled receptor P2Y1 (P2Y1 R) is activated by adenosine 5'-diphosphate (ADP) to induce platelet activation and thereby serves as an important antithrombotic drug target. Crystal structures of P2Y1 R revealed that one ligand (MRS2500) binds to the extracellular vestibule of this GPCR, whereas another (BPTU) occupies the surface between transmembrane (TM) helices TM2 and TM3. We introduced a total of 20 μs all-atom long-timescale molecular dynamic (MD) simulations to inquire why two molecules in completely different locations both serve as antagonists while ADP activates the receptor. Our results indicate that BPTU acts as an antagonist by stabilizing extracellular helix bundles leading to an increase of the lipid order, whereas MRS2500 blocks signaling by occupying the ligand binding site. Both antagonists stabilize an ionic lock within the receptor. However, binding of ADP breaks this ionic lock, forming a continuous water channel that leads to P2Y1 R activation. PMID:27460867

  2. The molecular regulation of Janus kinase (JAK) activation

    PubMed Central

    2014-01-01

    The Janus Kinase (JAK) family members serve essential roles as the intracellular signalling effectors of cytokine receptors. This family, comprising JAK1, JAK2, JAK3 and TYK2, was first described more than 20 years ago, but the complexities underlying their activation, regulation and pleiotropic signalling functions are still being explored. Here, we review the current knowledge of their physiological functions and the causative role of activating and inactivating JAK mutations in human diseases, including haematopoietic malignancies, immunodeficiency and inflammatory diseases. At the molecular level, recent studies have greatly advanced our knowledge of the structures and organisation of the component FERM-SH2, pseudokinase and kinase domains within the JAKs, the mechanism of JAK activation and, in particular, the role of the pseudokinase domain as a suppressor of the adjacent tyrosine kinase domain's catalytic activity. We also review recent advances in our understanding of the mechanisms of negative regulation exerted by the SH2 domain containing proteins, SOCS (Suppressors of Cytokine Signalling) proteins and Lnk. These recent advances highlight the diversity of regulatory mechanisms utilised by the JAK family to maintain signalling fidelity, and suggest alternative therapeutic strategies to complement existing ATP-competitive kinase inhibitors. PMID:25057888

  3. The Molecular Mechanism of P2Y1 Receptor Activation

    PubMed Central

    Chan, H. C. Stephen; Vogel, Horst; Filipek, Slawomir

    2016-01-01

    Human purinergic G protein-coupled receptor P2Y1 (P2Y1R) is activated by adenosine 5’-diphosphate (ADP) to induce platelet activation and thereby serves as an important antithrombotic drug target. Crystal structures of P2Y1R revealed that one ligand (MRS2500) binds to the extracellular vestibule of this GPCR, whereas another (BPTU) occupies the surface between transmembrane (TM) helices TM2 and TM3. We introduced a total of 20 µs all-atom long-timescale molecular dynamic (MD) simulations to inquire why two molecules in completely different locations both serve as antagonists while ADP activates the receptor. Our results indicate that BPTU acts as an antagonist by stabilizing extracellular helix bundles leading to an increase of the lipid order, whereas MRS2500 blocks signaling by occupying the ligand binding site. Both antagonists stabilize an ionic lock within the receptor. However, binding of ADP breaks this ionic lock, forming a continuous water channel that leads to P2Y1R activation. PMID:27460867

  4. Nondynamical correlation energy in model molecular systems

    NASA Astrophysics Data System (ADS)

    Chojnacki, Henryk

    The hypersurfaces for the deprotonation processes have been studied at the nonempirical level for H3O+, NH+4, PH+4, and H3S+ cations within their correlation consistent basis set. The potential energy curves were calculated and nondynamical correlation energies analyzed. We have found that the restricted Hartree-Fock wavefunction leads to the improper dissociation limit and, in the three latest cases requires multireference description. We conclude that these systems may be treated as a good models for interpretation of the proton transfer mechanism as well as for testing one-determinantal or multireference cases.

  5. Stochastic Interaction between Neural Activity and Molecular Cues in the Formation of Topographic Maps.

    PubMed

    Owens, Melinda T; Feldheim, David A; Stryker, Michael P; Triplett, Jason W

    2015-09-23

    Topographic maps in visual processing areas maintain the spatial order of the visual world. Molecular cues and neuronal activity both play critical roles in map formation, but their interaction remains unclear. Here, we demonstrate that when molecular- and activity-dependent cues are rendered nearly equal in force, they drive topographic mapping stochastically. The functional and anatomical representation of azimuth in the superior colliculus of heterozygous Islet2-EphA3 knockin (Isl2(EphA3/+)) mice is variable: maps may be single, duplicated, or a combination of the two. This heterogeneity is not due to genetic differences, since map organizations in individual mutant animals often differ between colliculi. Disruption of spontaneous waves of retinal activity resulted in uniform map organization in Isl2(EphA3/+) mice, demonstrating that correlated spontaneous activity is required for map heterogeneity. Computational modeling replicates this heterogeneity, revealing that molecular- and activity-dependent forces interact simultaneously and stochastically during topographic map formation. PMID:26402608

  6. Decarboxylation of Δ 9-tetrahydrocannabinol: Kinetics and molecular modeling

    NASA Astrophysics Data System (ADS)

    Perrotin-Brunel, Helene; Buijs, Wim; van Spronsen, Jaap; van Roosmalen, Maaike J. E.; Peters, Cor J.; Verpoorte, Rob; Witkamp, Geert-Jan

    2011-02-01

    Efficient tetrahydrocannabinol (Δ 9-THC) production from cannabis is important for its medical application and as basis for the development of production routes of other drugs from plants. This work presents one of the steps of Δ 9-THC production from cannabis plant material, the decarboxylation reaction, transforming the Δ 9-THC-acid naturally present in the plant into the psychoactive Δ 9-THC. Results of experiments showed pseudo-first order reaction kinetics, with an activation barrier of 85 kJ mol -1 and a pre-exponential factor of 3.7 × 10 8 s -1. Using molecular modeling, two options were identified for an acid catalyzed β-keto acid type mechanism for the decarboxylation of Δ 9-THC-acid. Each of these mechanisms might play a role, depending on the actual process conditions. Formic acid proved to be a good model for a catalyst of such a reaction. Also, the computational idea of catalysis by water to catalysis by an acid, put forward by Li and Brill, and Churchev and Belbruno was extended, and a new direct keto-enol route was found. A direct keto-enol mechanism catalyzed by formic acid seems to be the best explanation for the observed activation barrier and the pre-exponential factor of the decarboxylation of Δ 9-THC-acid. Evidence for this was found by performing an extraction experiment with Cannabis Flos. It revealed the presence of short chain carboxylic acids supporting this hypothesis. The presented approach is important for the development of a sustainable production of Δ 9-THC from the plant.

  7. Molecular Modeling of Prion Transmission to Humans

    PubMed Central

    Levavasseur, Etienne; Privat, Nicolas; Martin, Juan-Carlos Espinosa; Simoneau, Steve; Baron, Thierry; Flan, Benoit; Torres, Juan-Maria; Haïk, Stéphane

    2014-01-01

    Using different prion strains, such as the variant Creutzfeldt-Jakob disease agent and the atypical bovine spongiform encephalopathy agents, and using transgenic mice expressing human or bovine prion protein, we assessed the reliability of protein misfolding cyclic amplification (PMCA) to model interspecies and genetic barriers to prion transmission. We compared our PMCA results with in vivo transmission data characterized by attack rates, i.e., the percentage of inoculated mice that developed the disease. Using 19 seed/substrate combinations, we observed that a significant PMCA amplification was only obtained when the mouse line used as substrate is susceptible to the corresponding strain. Our results suggest that PMCA provides a useful tool to study genetic barriers to transmission and to study the zoonotic potential of emerging prion strains. PMID:25279820

  8. A molecular model for neurodevelopmental disorders

    PubMed Central

    Gigek, C O; Chen, E S; Ota, V K; Maussion, G; Peng, H; Vaillancourt, K; Diallo, A B; Lopez, J P; Crapper, L; Vasuta, C; Chen, G G; Ernst, C

    2015-01-01

    Genes implicated in neurodevelopmental disorders (NDDs) important in cognition and behavior may have convergent function and several cellular pathways have been implicated, including protein translational control, chromatin modification, and synapse assembly and maintenance. Here, we test the convergent effects of methyl-CpG binding domain 5 (MBD5) and special AT-rich binding protein 2 (SATB2) reduced dosage in human neural stem cells (NSCs), two genes implicated in 2q23.1 and 2q33.1 deletion syndromes, respectively, to develop a generalized model for NDDs. We used short hairpin RNA stably incorporated into healthy neural stem cells to supress MBD5 and SATB2 expression, and massively parallel RNA sequencing, DNA methylation sequencing and microRNA arrays to test the hypothesis that a primary etiology of NDDs is the disruption of the balance of NSC proliferation and differentiation. We show that reduced dosage of either gene leads to significant overlap of gene-expression patterns, microRNA patterns and DNA methylation states with control NSCs in a differentiating state, suggesting that a unifying feature of 2q23.1 and 2q33.1 deletion syndrome may be a lack of regulation between proliferation and differentiation in NSCs, as we observed previously for TCF4 and EHMT1 suppression following a similar experimental paradigm. We propose a model of NDDs whereby the balance of NSC proliferation and differentiation is affected, but where the molecules that drive this effect are largely specific to disease-causing genetic variation. NDDs are diverse, complex and unique, but the optimal balance of factors that determine when and where neural stem cells differentiate may be a major feature underlying the diverse phenotypic spectrum of NDDs. PMID:25966365

  9. Quantum interference in thermoelectric molecular junctions: A toy model perspective

    SciTech Connect

    Nozaki, Daijiro E-mail: research@nano.tu-dresden.de; Avdoshenko, Stas M.; Sevinçli, Hâldun; Cuniberti, Gianaurelio

    2014-08-21

    Quantum interference (QI) phenomena between electronic states in molecular circuits offer a new opportunity to design new types of molecular devices such as molecular sensors, interferometers, and thermoelectric devices. Controlling the QI effect is a key challenge for such applications. For the development of single molecular devices employing QI effects, a systematic study of the relationship between electronic structure and the quantum interference is needed. In order to uncover the essential topological requirements for the appearance of QI effects and the relationship between the QI-affected line shape of the transmission spectra and the electronic structures, we consider a homogeneous toy model where all on-site energies are identical and model four types of molecular junctions due to their topological connectivities. We systematically analyze their transmission spectra, density of states, and thermoelectric properties. Even without the degree of freedom for on-site energies an asymmetric Fano peak could be realized in the homogeneous systems with the cyclic configuration. We also calculate the thermoelectric properties of the model systems with and without fluctuation of on-site energies. Even under the fluctuation of the on-site energies, the finite thermoelectrics are preserved for the Fano resonance, thus cyclic configuration is promising for thermoelectric applications. This result also suggests the possibility to detect the cyclic configuration in the homogeneous systems and the presence of the QI features from thermoelectric measurements.

  10. Quantum interference in thermoelectric molecular junctions: A toy model perspective

    NASA Astrophysics Data System (ADS)

    Nozaki, Daijiro; Avdoshenko, Stas M.; Sevinçli, Hâldun; Cuniberti, Gianaurelio

    2014-08-01

    Quantum interference (QI) phenomena between electronic states in molecular circuits offer a new opportunity to design new types of molecular devices such as molecular sensors, interferometers, and thermoelectric devices. Controlling the QI effect is a key challenge for such applications. For the development of single molecular devices employing QI effects, a systematic study of the relationship between electronic structure and the quantum interference is needed. In order to uncover the essential topological requirements for the appearance of QI effects and the relationship between the QI-affected line shape of the transmission spectra and the electronic structures, we consider a homogeneous toy model where all on-site energies are identical and model four types of molecular junctions due to their topological connectivities. We systematically analyze their transmission spectra, density of states, and thermoelectric properties. Even without the degree of freedom for on-site energies an asymmetric Fano peak could be realized in the homogeneous systems with the cyclic configuration. We also calculate the thermoelectric properties of the model systems with and without fluctuation of on-site energies. Even under the fluctuation of the on-site energies, the finite thermoelectrics are preserved for the Fano resonance, thus cyclic configuration is promising for thermoelectric applications. This result also suggests the possibility to detect the cyclic configuration in the homogeneous systems and the presence of the QI features from thermoelectric measurements.

  11. Molecular mechanism of L-DNase II activation and function as a molecular switch in apoptosis.

    PubMed

    Torriglia, Alicia; Leprêtre, Chloé; Padrón-Barthe, Laura; Chahory, Sabine; Martin, Elisabeth

    2008-12-01

    The discovery of caspase activation counts as one of the most important finds in the biochemistry of apoptosis. However, targeted disruption of caspases does not impair every type of apoptosis. Other proteases can replace caspases and several so called "caspase independent" pathways are now described. Here we review our current knowledge on one of these pathways, the LEI/L-DNase II. It is a serine protease-dependent pathway and its key event is the transformation of LEI (leukocyte elastase inhibitor, a serine protease inhibitor) into L-DNase II (an endonuclease). The molecular events leading to this change of enzymatic function as well as the cross-talk and interactions of this molecule with other apoptotic pathway, including caspases, are discussed. PMID:18761000

  12. Antituberculosis Activity of the Molecular Libraries Screening Center Network Library

    PubMed Central

    MADDRY, JOSEPH A.; ANANTHAN, SUBRAMANIAM; GOLDMAN, ROBERT C.; HOBRATH, JUDITH V.; KWONG, CECIL D.; MADDOX, CLINTON; RASMUSSEN, LYNN; REYNOLDS, ROBERT C.; SECRIST, JOHN A.; SOSA, MELINDA I.; WHITE, E. LUCILE; ZHANG, WEI

    2009-01-01

    SUMMARY There is an urgent need for the discovery and development of new antitubercular agents that target novel biochemical pathways and treat drug-resistant forms of the disease. One approach to addressing this need is through high-throughput screening of drug-like small molecule libraries against the whole bacterium in order to identify a variety of new, active scaffolds that will stimulate additional biological research and drug discovery. Through the Molecular Libraries Screening Center Network, the NIAID Tuberculosis Antimicrobial Acquisition and Coordinating Facility tested a 215,110-compound library against M. tuberculosis strain H37Rv. A medicinal chemistry survey of the results from the screening campaign is reported herein. PMID:19783214

  13. MEK1/2 Inhibitors: Molecular Activity and Resistance Mechanisms.

    PubMed

    Wu, Pui-Kei; Park, Jong-In

    2015-12-01

    Aberrant activation of the three-layered protein kinase cascade, Raf/MEK/ERK, is often detected in human cancer, which is mainly attributed to the oncogenic alterations of RAF, or its upstream activators RAS or cell surface receptor tyrosine kinases. Deregulated activity of the Raf/MEK/ERK pathway drives uncontrolled tumor cell proliferation and survival, thus providing a rational therapeutic target for the treatment of many cancers. While Raf, MEK1/2, and ERK1/2 are equally important targets for the design of therapeutic small molecular weight inhibitors, the effort to develop MEK1/2-specific inhibitors has been greatly successful. Particularly, MEK1/2 have been relatively advantageous for the design of highly selective adenosine triphosphate (ATP)-noncompetitive inhibitors. Indeed, a plethora of highly selective and potent MEK1/2 inhibitors are now available and many of those inhibitors have been evaluated for their therapeutic potential. Herein, we review different MEK1/2 inhibitors that have been studied for their inhibitory mechanisms and therapeutic potential in cancer. Some of the key structural features of MEK1/2 that are important for the efficacy of these inhibitors are also discussed. In addition, we discuss current challenges and future prospective in using these advanced MEK1/2 inhibitors for cancer therapy. PMID:26615130

  14. Restricted dynamics of molecular hydrogen confined in activated carbon nanopores

    SciTech Connect

    Contescu, Cristian I; Saha, Dipendu; Gallego, Nidia C; Mamontov, Eugene; Kolesnikov, Alexander I; Bhat, Vinay V

    2012-01-01

    Quasi-elastic neutron scattering was used for characterization of dynamics of molecular hydrogen confined in narrow nanopores of two activated carbon materials: PFAC (derived from polyfurfuryl alcohol) and UMC (ultramicroporous carbon). Fast, but incomplete ortho-para conversion was observed at 10 K, suggesting that scattering originates from the fraction of unconverted ortho isomer which is rotation-hindered because of confinement in nanopores. Hydrogen molecules entrapped in narrow nanopores (<7 ) were immobile below 22-25 K. Mobility increased rapidly with temperature above this threshold, which is 8 K higher than the melting point of bulk hydrogen. Diffusion obeyed fixed-jump length mechanism, indistinguishable between 2D and 3D processes. Thermal activation of diffusion was characterized between ~22 and 37 K, and structure-dependent differences were found between the two carbons. Activation energy of diffusion was higher than that of bulk solid hydrogen. Classical notions of liquid and solid do not longer apply for H2 confined in narrow nanopores.

  15. Chemical and thermal modulation of molecular motor activities

    NASA Astrophysics Data System (ADS)

    Hong, Weili

    Molecular motors of kinesin and dynein families are responsible for various intracellular activities, from long distance movement of organelles, vesicles, protein complexes, and mRNAs to powering mitotic processes. They can take nanometer steps using chemical energy from the hydrolysis of ATP (adenosine triphosphate), and their dysfunction is involved in many neurodegenerative diseases that require long distance transport of cargos. Here I report on the study of the properties of molecular motors at a single-molecule level using optical trappings. I first studied the inhibition properties of kinesin motors by marine natural compound adociasulfates. I showed that adociasulfates compete with microtubules for binding to kinesins and thus inhibit kinesins' activity. Although adociasulfates are a strong inhibitor for all kinesin members, they show a much higher inhibition effect for conventional kinesins than for mitotic kinesins. Thus adociasulfates can be used to specifically inhibit conventional kinesins. By comparing the inhibition of kinesins by two structurally similar adociasulfates, one can see that the negatively charged sulfate residue of adociasulfates can be replaced by other negative residues and thus make it possible for adociasulfate-derived compounds to be more cell permeable. Kinesins and dyneins move cargos towards opposite directions along a microtubule. Cargos with both kinesins and dyneins attached often move bidirectionally due to undergoing a tug-of-war between the oppositely moving kinesin and dynein motors. Here I studied the effect of temperature on microtubule-based kinesin and dynein motor transport. While kinesins' and dyneins' velocities are closely matched above 15 °C, below this temperature the dyneins' velocity decreases much faster than the kinesins'. The kinesins' and dyneins' forces do not measurably change with temperature. The results suggest that temperature has significant effects on bidirectional transport and can be used to

  16. Kinetic modeling of molecular motors: pause model and parameter determination from single-molecule experiments

    NASA Astrophysics Data System (ADS)

    Morin, José A.; Ibarra, Borja; Cao, Francisco J.

    2016-05-01

    Single-molecule manipulation experiments of molecular motors provide essential information about the rate and conformational changes of the steps of the reaction located along the manipulation coordinate. This information is not always sufficient to define a particular kinetic cycle. Recent single-molecule experiments with optical tweezers showed that the DNA unwinding activity of a Phi29 DNA polymerase mutant presents a complex pause behavior, which includes short and long pauses. Here we show that different kinetic models, considering different connections between the active and the pause states, can explain the experimental pause behavior. Both the two independent pause model and the two connected pause model are able to describe the pause behavior of a mutated Phi29 DNA polymerase observed in an optical tweezers single-molecule experiment. For the two independent pause model all parameters are fixed by the observed data, while for the more general two connected pause model there is a range of values of the parameters compatible with the observed data (which can be expressed in terms of two of the rates and their force dependencies). This general model includes models with indirect entry and exit to the long-pause state, and also models with cycling in both directions. Additionally, assuming that detailed balance is verified, which forbids cycling, this reduces the ranges of the values of the parameters (which can then be expressed in terms of one rate and its force dependency). The resulting model interpolates between the independent pause model and the indirect entry and exit to the long-pause state model

  17. How Cells Feel: Stochastic Model for a Molecular Mechanosensor

    PubMed Central

    Escudé, Matteo; Rigozzi, Michelle K.; Terentjev, Eugene M.

    2014-01-01

    Understanding mechanosensitivity (i.e., how cells sense the stiffness of their environment) is very important, yet there is a fundamental difficulty in understanding its mechanism: to measure an elastic modulus one requires two points of application of force—a measuring and a reference point. The cell in contact with substrate has only one (adhesion) point to work with, and thus a new method of measurement needs to be invented. The aim of this theoretical work is to develop a self-consistent physical model for mechanosensitivity, a process by which a cell detects the mechanical stiffness of its environment (e.g., a substrate it is attached to via adhesion points) and generates an appropriate chemical signaling to remodel itself in response to this environment. The model uses the molecular mechanosensing complex of latent TGF-β attached to the adhesion point as the biomarker. We show that the underlying Brownian motion in the substrate is the reference element in the measuring process. The model produces a closed expression for the rate of release of active TGF-β, which depends on the substrate stiffness and the pulling force coming from the cell in a subtle and nontrivial way. It is consistent with basic experimental data showing an increase in signal for stiffer substrates and higher pulling forces. In addition, we find that for each cell there is a range of stiffness where a homeostatic configuration of the cell can be achieved, outside of which the cell either relaxes its cytoskeletal forces and detaches from the very weak substrate, or generates an increasingly strong pulling force through stress fibers with a positive feedback loop on very stiff substrates. In this way, the theory offers the underlying mechanism for the myofibroblast conversion in wound healing and smooth muscle cell dysfunction in cardiac disease. PMID:24411244

  18. How cells feel: stochastic model for a molecular mechanosensor.

    PubMed

    Escudé, Matteo; Rigozzi, Michelle K; Terentjev, Eugene M

    2014-01-01

    Understanding mechanosensitivity (i.e., how cells sense the stiffness of their environment) is very important, yet there is a fundamental difficulty in understanding its mechanism: to measure an elastic modulus one requires two points of application of force-a measuring and a reference point. The cell in contact with substrate has only one (adhesion) point to work with, and thus a new method of measurement needs to be invented. The aim of this theoretical work is to develop a self-consistent physical model for mechanosensitivity, a process by which a cell detects the mechanical stiffness of its environment (e.g., a substrate it is attached to via adhesion points) and generates an appropriate chemical signaling to remodel itself in response to this environment. The model uses the molecular mechanosensing complex of latent TGF-β attached to the adhesion point as the biomarker. We show that the underlying Brownian motion in the substrate is the reference element in the measuring process. The model produces a closed expression for the rate of release of active TGF-β, which depends on the substrate stiffness and the pulling force coming from the cell in a subtle and nontrivial way. It is consistent with basic experimental data showing an increase in signal for stiffer substrates and higher pulling forces. In addition, we find that for each cell there is a range of stiffness where a homeostatic configuration of the cell can be achieved, outside of which the cell either relaxes its cytoskeletal forces and detaches from the very weak substrate, or generates an increasingly strong pulling force through stress fibers with a positive feedback loop on very stiff substrates. In this way, the theory offers the underlying mechanism for the myofibroblast conversion in wound healing and smooth muscle cell dysfunction in cardiac disease. PMID:24411244

  19. Atomic and molecular physics and data activities for astrophysics at Oak Ridge National Laboratory

    SciTech Connect

    Jeffery, D.J.; Kristic, P.S.; Liu, W.; Schultz, D.R.; Stancil, P.C.

    1998-04-01

    The atomic astrophysics group at ORNL produces, collects, evaluates, and disseminates atomic and molecular data relevant to astrophysics and actively models various astrophysical environments utilizing this information. With the advent of the World Wide Web, these data are also being placed on-line to facilitate their use by end-users. In this brief report, the group`s recent activities in data production and in modeling are highlighted. For example, the authors describe recent calculations of elastic and transport cross sections relevant to ionospheric and heliospheric studies, charge transfer between metal ions and metal atoms and novel supernova nebular spectra modeling, ion-molecule collision data relevant to planetary atmospheres and comets, and data for early universe modeling.

  20. SPECTRAFACTORY.NET: A DATABASE OF MOLECULAR MODEL SPECTRA

    SciTech Connect

    Cami, J.; Van Malderen, R.; Markwick, A. J. E-mail: Andrew.Markwick@manchester.ac.uk

    2010-04-01

    We present a homogeneous database of synthetic molecular absorption and emission spectra from the optical to mm wavelengths for a large range of temperatures and column densities relevant for various astrophysical purposes, but in particular for the analysis, identification, and first-order analysis of molecular bands in spectroscopic observations. All spectra are calculated in the LTE limit from several molecular line lists, and are presented at various spectral resolving powers corresponding to several specific instrument simulations. The database is available online at http://www.spectrafactory.net, where users can freely browse, search, display, and download the spectra. We describe how additional model spectra can be requested for (automatic) calculation and inclusion. The database already contains over half a million model spectra for 39 molecules (96 different isotopologues) over the wavelength range 350 nm-3 mm ({approx}3-30000 cm{sup -1})

  1. Interaction of methotrexate with trypsin analyzed by spectroscopic and molecular modeling methods

    NASA Astrophysics Data System (ADS)

    Wang, Yanqing; Zhang, Hongmei; Cao, Jian; Zhou, Qiuhua

    2013-11-01

    Trypsin is one of important digestive enzymes that have intimate correlation with human health and illness. In this work, the interaction of trypsin with methotrexate was investigated by spectroscopic and molecular modeling methods. The results revealed that methotrexate could interact with trypsin with about one binding site. Methotrexate molecule could enter into the primary substrate-binding pocket, resulting in inhibition of trypsin activity. Furthermore, the thermodynamic analysis implied that electrostatic force, hydrogen bonding, van der Waals and hydrophobic interactions were the main interactions for stabilizing the trypsin-methotrexate system, which agreed well with the results from the molecular modeling study.

  2. Modeling Activities in Earth Science

    NASA Astrophysics Data System (ADS)

    Malone, Kathy

    2014-05-01

    Students usually find science to be quite abstract. This is especially true of disciplines like Earth Science where it is difficult for the students to conduct and design hands-on experiments in areas such as Plate Tectonics that would allow them to develop predictive models. In the United States the new Next Generation Science Standards explicitly requires students to experience the science disciplines via modeling based activities. This poster presentation will discuss an activity that demonstrates how modeling, plate tectonics and student discourse converge in the earth science classroom. The activities featured on the poster will include using cardboard and shaving cream to demonstrate convergent plate boundaries, a Milky Way candy bar to demonstrate divergent boundaries and silly putty to demonstrate a strike slip boundary. I will discuss how students report back to the group about the findings from the lab and the techniques that can be used to heighten the student discourse. The activities outlined in this poster were originally designed for a middle school Earth Science class by Suzi Shoemaker for a graduate thesis at Arizona State University.

  3. Pomegranate Extracts and Cancer Prevention: Molecular and Cellular Activities

    PubMed Central

    Syed, Deeba N.; Chamcheu, Jean-Christopher; Adhami, Vaqar M.; Mukhtar, Hasan

    2014-01-01

    There is increased appreciation by the scientific community that dietary phytochemicals can be potential weapons in the fight against cancer. Emerging data has provided new insights into the molecular and cellular framework needed to establish novel mechanism-based strategies for cancer prevention by selective bioactive food components. The unique chemical composition of the pomegranate fruit, rich in antioxidant tannins and flavonoids has drawn the attention of many investigators. Polyphenol rich fractions derived from the pomegranate fruit have been studied for their potential chemopreventive and/or cancer therapeutic effects in several animal models. Although data from in vitro and in vivo studies look convincing, well designed clinical trials in humans are needed to ascertain whether pomegranate can become part of our armamentarium against cancer. This review summarizes the available literature on the effects of pomegranate against various cancers. PMID:23094914

  4. A binary ant colony optimization classifier for molecular activities.

    PubMed

    Hammann, Felix; Suenderhauf, Claudia; Huwyler, Jörg

    2011-10-24

    Chemical fingerprints encode the presence or absence of molecular features and are available in many large databases. Using a variation of the Ant Colony Optimization (ACO) paradigm, we describe a binary classifier based on feature selection from fingerprints. We discuss the algorithm and possible cross-validation procedures. As a real-world example, we use our algorithm to analyze a Plasmodium falciparum inhibition assay and contrast its performance with other machine learning paradigms in use today (decision tree induction, random forests, support vector machines, artificial neural networks). Our algorithm matches established paradigms in predictive power, yet supplies the medicinal chemist and basic researcher with easily interpretable results. Furthermore, models generated with our paradigm are easy to implement and can complement virtual screenings by additionally exploiting the precalculated fingerprint information. PMID:21854036

  5. United polarizable multipole water model for molecular mechanics simulation

    NASA Astrophysics Data System (ADS)

    Qi, Rui; Wang, Lee-Ping; Wang, Qiantao; Pande, Vijay S.; Ren, Pengyu

    2015-07-01

    We report the development of a united AMOEBA (uAMOEBA) polarizable water model, which is computationally 3-5 times more efficient than the three-site AMOEBA03 model in molecular dynamics simulations while providing comparable accuracy for gas-phase and liquid properties. In this coarse-grained polarizable water model, both electrostatic (permanent and induced) and van der Waals representations have been reduced to a single site located at the oxygen atom. The permanent charge distribution is described via the molecular dipole and quadrupole moments and the many-body polarization via an isotropic molecular polarizability, all located at the oxygen center. Similarly, a single van der Waals interaction site is used for each water molecule. Hydrogen atoms are retained only for the purpose of defining local frames for the molecular multipole moments and intramolecular vibrational modes. The parameters have been derived based on a combination of ab initio quantum mechanical and experimental data set containing gas-phase cluster structures and energies, and liquid thermodynamic properties. For validation, additional properties including dimer interaction energy, liquid structures, self-diffusion coefficient, and shear viscosity have been evaluated. The results demonstrate good transferability from the gas to the liquid phase over a wide range of temperatures, and from nonpolar to polar environments, due to the presence of molecular polarizability. The water coordination, hydrogen-bonding structure, and dynamic properties given by uAMOEBA are similar to those derived from the all-atom AMOEBA03 model and experiments. Thus, the current model is an accurate and efficient alternative for modeling water.

  6. United polarizable multipole water model for molecular mechanics simulation

    PubMed Central

    Qi, Rui; Wang, Lee-Ping; Wang, Qiantao; Pande, Vijay S.; Ren, Pengyu

    2015-01-01

    We report the development of a united AMOEBA (uAMOEBA) polarizable water model, which is computationally 3–5 times more efficient than the three-site AMOEBA03 model in molecular dynamics simulations while providing comparable accuracy for gas-phase and liquid properties. In this coarse-grained polarizable water model, both electrostatic (permanent and induced) and van der Waals representations have been reduced to a single site located at the oxygen atom. The permanent charge distribution is described via the molecular dipole and quadrupole moments and the many-body polarization via an isotropic molecular polarizability, all located at the oxygen center. Similarly, a single van der Waals interaction site is used for each water molecule. Hydrogen atoms are retained only for the purpose of defining local frames for the molecular multipole moments and intramolecular vibrational modes. The parameters have been derived based on a combination of ab initio quantum mechanical and experimental data set containing gas-phase cluster structures and energies, and liquid thermodynamic properties. For validation, additional properties including dimer interaction energy, liquid structures, self-diffusion coefficient, and shear viscosity have been evaluated. The results demonstrate good transferability from the gas to the liquid phase over a wide range of temperatures, and from nonpolar to polar environments, due to the presence of molecular polarizability. The water coordination, hydrogen-bonding structure, and dynamic properties given by uAMOEBA are similar to those derived from the all-atom AMOEBA03 model and experiments. Thus, the current model is an accurate and efficient alternative for modeling water. PMID:26156485

  7. United polarizable multipole water model for molecular mechanics simulation.

    PubMed

    Qi, Rui; Wang, Lee-Ping; Wang, Qiantao; Pande, Vijay S; Ren, Pengyu

    2015-07-01

    We report the development of a united AMOEBA (uAMOEBA) polarizable water model, which is computationally 3-5 times more efficient than the three-site AMOEBA03 model in molecular dynamics simulations while providing comparable accuracy for gas-phase and liquid properties. In this coarse-grained polarizable water model, both electrostatic (permanent and induced) and van der Waals representations have been reduced to a single site located at the oxygen atom. The permanent charge distribution is described via the molecular dipole and quadrupole moments and the many-body polarization via an isotropic molecular polarizability, all located at the oxygen center. Similarly, a single van der Waals interaction site is used for each water molecule. Hydrogen atoms are retained only for the purpose of defining local frames for the molecular multipole moments and intramolecular vibrational modes. The parameters have been derived based on a combination of ab initio quantum mechanical and experimental data set containing gas-phase cluster structures and energies, and liquid thermodynamic properties. For validation, additional properties including dimer interaction energy, liquid structures, self-diffusion coefficient, and shear viscosity have been evaluated. The results demonstrate good transferability from the gas to the liquid phase over a wide range of temperatures, and from nonpolar to polar environments, due to the presence of molecular polarizability. The water coordination, hydrogen-bonding structure, and dynamic properties given by uAMOEBA are similar to those derived from the all-atom AMOEBA03 model and experiments. Thus, the current model is an accurate and efficient alternative for modeling water. PMID:26156485

  8. United polarizable multipole water model for molecular mechanics simulation

    SciTech Connect

    Qi, Rui; Wang, Qiantao; Ren, Pengyu; Wang, Lee-Ping; Pande, Vijay S.

    2015-07-07

    We report the development of a united AMOEBA (uAMOEBA) polarizable water model, which is computationally 3–5 times more efficient than the three-site AMOEBA03 model in molecular dynamics simulations while providing comparable accuracy for gas-phase and liquid properties. In this coarse-grained polarizable water model, both electrostatic (permanent and induced) and van der Waals representations have been reduced to a single site located at the oxygen atom. The permanent charge distribution is described via the molecular dipole and quadrupole moments and the many-body polarization via an isotropic molecular polarizability, all located at the oxygen center. Similarly, a single van der Waals interaction site is used for each water molecule. Hydrogen atoms are retained only for the purpose of defining local frames for the molecular multipole moments and intramolecular vibrational modes. The parameters have been derived based on a combination of ab initio quantum mechanical and experimental data set containing gas-phase cluster structures and energies, and liquid thermodynamic properties. For validation, additional properties including dimer interaction energy, liquid structures, self-diffusion coefficient, and shear viscosity have been evaluated. The results demonstrate good transferability from the gas to the liquid phase over a wide range of temperatures, and from nonpolar to polar environments, due to the presence of molecular polarizability. The water coordination, hydrogen-bonding structure, and dynamic properties given by uAMOEBA are similar to those derived from the all-atom AMOEBA03 model and experiments. Thus, the current model is an accurate and efficient alternative for modeling water.

  9. The Use of Molecular Modeling Programs in Medicinal Chemistry Instruction.

    ERIC Educational Resources Information Center

    Harrold, Marc W.

    1992-01-01

    This paper describes and evaluates the use of a molecular modeling computer program (Alchemy II) in a pharmaceutical education program. Provided are the hardware requirements and basic program features as well as several examples of how this program and its features have been applied in the classroom. (GLR)

  10. Fischer and Schrock Carbene Complexes: A Molecular Modeling Exercise

    ERIC Educational Resources Information Center

    Montgomery, Craig D.

    2015-01-01

    An exercise in molecular modeling that demonstrates the distinctive features of Fischer and Schrock carbene complexes is presented. Semi-empirical calculations (PM3) demonstrate the singlet ground electronic state, restricted rotation about the C-Y bond, the positive charge on the carbon atom, and hence, the electrophilic nature of the Fischer…

  11. Comparative validated molecular modeling of p53-HDM2 inhibitors as antiproliferative agents.

    PubMed

    Mondal, Chanchal; Halder, Amit Kumar; Adhikari, Nilanjan; Saha, Achintya; Saha, Krishna Das; Gayen, Shovanlal; Jha, Tarun

    2015-01-27

    Tumor suppressor protein p53 regulates the cell cycle and inhibits tumor growth. It is inactivated by mutation or binding with human double minute 2 (HDM2) protein. The HDM2 is a promising target for treatment of p53 protein related cancers. Molecular modeling techniques such as 2D-QSAR, pharmacophore mapping and 3D-QSAR analyses were performed on 155 structurally diverse HDM2 inhibitors to understand structural and physicochemical requirements for higher activity. The linear and spline 2D-QSAR models were developed through multiple linear regression and genetic functional algorithm methods. The 2D-QSAR models suggested that number of fluorine, chlorine, tertiary nitrogen atoms as well as donor feature, stereogenic centers and higher value of solvent accessible surface area are important features in defining activity. Monte Carlo method was applied to generate QSAR models that determined structural indicators (alerts) for increase or decrease of the biological activity. Ligand-based pharmacophore mapping showed importance of two hydrophobic, one hydrophobic aromatic, one ring aromatic and one donor features. The structure-based pharmacophore model demonstrated significance of two hydrophobic, one ring aromatic and two acceptor features. The pharmacophore (ligand) aligned structures were subjected to 3D-QSAR analyses. The structure-based pharmacophore was also used for pharmacophore restraint molecular docking to analyze ligand-receptor interactions and for adjudging predictability as well as validation of different modeling techniques. These comparative molecular modeling techniques may help to design novel HDM2 inhibitors. PMID:25535952

  12. Derivatives of Ergot-alkaloids: Molecular structure, physical properties, and structure-activity relationships

    NASA Astrophysics Data System (ADS)

    Ivanova, Bojidarka B.; Spiteller, Michael

    2012-09-01

    A comprehensive screening of fifteen functionalized Ergot-alkaloids, containing bulk aliphatic cyclic substituents at D-ring of the ergoline molecular skeleton was performed, studying their structure-active relationships and model interactions with α2A-adreno-, serotonin (5HT2A) and dopamine D3 (D3A) receptors. The accounted high affinity to the receptors binding loops and unusual bonding situations, joined with the molecular flexibility of the substituents and the presence of proton accepting/donating functional groups in the studied alkaloids, may contribute to further understanding the mechanisms of biological activity in vivo and in predicting their therapeutic potential in central nervous system (CNS), including those related the Schizophrenia. Since the presented correlation between the molecular structure and properties, was based on the comprehensively theoretical computational and experimental physical study on the successfully isolated derivatives, through using routine synthetic pathways in a relatively high yields, marked these derivatives as 'treasure' for further experimental and theoretical studied in areas such as: (a) pharmacological and clinical testing; (b) molecular-drugs design of novel psychoactive substances; (c) development of the analytical protocols for determination of Ergot-alkaloids through a functionalization of the ergoline-skeleton, and more.

  13. Gradient models in molecular biophysics: progress, challenges, opportunities

    NASA Astrophysics Data System (ADS)

    Bardhan, Jaydeep P.

    2013-12-01

    In the interest of developing a bridge between researchers modeling materials and those modeling biological molecules, we survey recent progress in developing nonlocal-dielectric continuum models for studying the behavior of proteins and nucleic acids. As in other areas of science, continuum models are essential tools when atomistic simulations (e.g., molecular dynamics) are too expensive. Because biological molecules are essentially all nanoscale systems, the standard continuum model, involving local dielectric response, has basically always been dubious at best. The advanced continuum theories discussed here aim to remedy these shortcomings by adding nonlocal dielectric response. We begin by describing the central role of electrostatic interactions in biology at the molecular scale, and motivate the development of computationally tractable continuum models using applications in science and engineering. For context, we highlight some of the most important challenges that remain, and survey the diverse theoretical formalisms for their treatment, highlighting the rigorous statistical mechanics that support the use and improvement of continuum models. We then address the development and implementation of nonlocal dielectric models, an approach pioneered by Dogonadze, Kornyshev, and their collaborators almost 40 years ago. The simplest of these models is just a scalar form of gradient elasticity, and here we use ideas from gradient-based modeling to extend the electrostatic model to include additional length scales. The review concludes with a discussion of open questions for model development, highlighting the many opportunities for the materials community to leverage its physical, mathematical, and computational expertise to help solve one of the most challenging questions in molecular biology and biophysics.

  14. Gradient Models in Molecular Biophysics: Progress, Challenges, Opportunities

    PubMed Central

    Bardhan, Jaydeep P.

    2014-01-01

    In the interest of developing a bridge between researchers modeling materials and those modeling biological molecules, we survey recent progress in developing nonlocal-dielectric continuum models for studying the behavior of proteins and nucleic acids. As in other areas of science, continuum models are essential tools when atomistic simulations (e.g. molecular dynamics) are too expensive. Because biological molecules are essentially all nanoscale systems, the standard continuum model, involving local dielectric response, has basically always been dubious at best. The advanced continuum theories discussed here aim to remedy these shortcomings by adding features such as nonlocal dielectric response, and nonlinearities resulting from dielectric saturation. We begin by describing the central role of electrostatic interactions in biology at the molecular scale, and motivate the development of computationally tractable continuum models using applications in science and engineering. For context, we highlight some of the most important challenges that remain and survey the diverse theoretical formalisms for their treatment, highlighting the rigorous statistical mechanics that support the use and improvement of continuum models. We then address the development and implementation of nonlocal dielectric models, an approach pioneered by Dogonadze, Kornyshev, and their collaborators almost forty years ago. The simplest of these models is just a scalar form of gradient elasticity, and here we use ideas from gradient-based modeling to extend the electrostatic model to include additional length scales. The paper concludes with a discussion of open questions for model development, highlighting the many opportunities for the materials community to leverage its physical, mathematical, and computational expertise to help solve one of the most challenging questions in molecular biology and biophysics. PMID:25505358

  15. Molecular-dynamics simulations of void collapse in shocked model-molecular solids

    NASA Astrophysics Data System (ADS)

    Mintmire, J. W.; Robertson, D. H.; White, C. T.

    1994-06-01

    We have carried out a series of molecular-dynamics simulations on a model three-dimensional molecular solid to study the dynamics of shock-induced collapse of void defects. Molecular-dynamics methods were used for a model system of identical particles arranged as diatomic molecules aligned with the center of mass of each molecule at fcc lattice sites, using a \\{111\\} layering for the two-dimensional boundary conditions. The diatoms were internally coupled via a harmonic potential; all other interactions were modeled with Morse potentials between all particles other than the immediate diatomic partner. Using this model, we have investigated the effect of a cylindrical void at right angles to the direction of layering (and impact). Depending on the strength of the incident shock wave, the void is found to collapse either smoothly and symmetrically (like a balloon gradually losing air), or asymmetrically and turbulently. In the latter case, we note the transient formation (for periods of several hundreds of femtoseconds) of ``hot spots'' at the void location both in terms of the local effective temperature and the vibrational energies of the diatoms.

  16. Molecular mechanism of APC/C activation by mitotic phosphorylation.

    PubMed

    Zhang, Suyang; Chang, Leifu; Alfieri, Claudio; Zhang, Ziguo; Yang, Jing; Maslen, Sarah; Skehel, Mark; Barford, David

    2016-05-12

    In eukaryotes, the anaphase-promoting complex (APC/C, also known as the cyclosome) regulates the ubiquitin-dependent proteolysis of specific cell-cycle proteins to coordinate chromosome segregation in mitosis and entry into the G1 phase. The catalytic activity of the APC/C and its ability to specify the destruction of particular proteins at different phases of the cell cycle are controlled by its interaction with two structurally related coactivator subunits, Cdc20 and Cdh1. Coactivators recognize substrate degrons, and enhance the affinity of the APC/C for its cognate E2 (refs 4-6). During mitosis, cyclin-dependent kinase (Cdk) and polo-like kinase (Plk) control Cdc20- and Cdh1-mediated activation of the APC/C. Hyperphosphorylation of APC/C subunits, notably Apc1 and Apc3, is required for Cdc20 to activate the APC/C, whereas phosphorylation of Cdh1 prevents its association with the APC/C. Since both coactivators associate with the APC/C through their common C-box and Ile-Arg tail motifs, the mechanism underlying this differential regulation is unclear, as is the role of specific APC/C phosphorylation sites. Here, using cryo-electron microscopy and biochemical analysis, we define the molecular basis of how phosphorylation of human APC/C allows for its control by Cdc20. An auto-inhibitory segment of Apc1 acts as a molecular switch that in apo unphosphorylated APC/C interacts with the C-box binding site and obstructs engagement of Cdc20. Phosphorylation of the auto-inhibitory segment displaces it from the C-box-binding site. Efficient phosphorylation of the auto-inhibitory segment, and thus relief of auto-inhibition, requires the recruitment of Cdk-cyclin in complex with a Cdk regulatory subunit (Cks) to a hyperphosphorylated loop of Apc3. We also find that the small-molecule inhibitor, tosyl-l-arginine methyl ester, preferentially suppresses APC/C(Cdc20) rather than APC/C(Cdh1), and interacts with the binding sites of both the C-box and Ile-Arg tail motifs. Our

  17. Molecular Dynamics of "Fuzzy" Transcriptional Activator-Coactivator Interactions.

    PubMed

    Scholes, Natalie S; Weinzierl, Robert O J

    2016-05-01

    Transcriptional activation domains (ADs) are generally thought to be intrinsically unstructured, but capable of adopting limited secondary structure upon interaction with a coactivator surface. The indeterminate nature of this interface made it hitherto difficult to study structure/function relationships of such contacts. Here we used atomistic accelerated molecular dynamics (aMD) simulations to study the conformational changes of the GCN4 AD and variants thereof, either free in solution, or bound to the GAL11 coactivator surface. We show that the AD-coactivator interactions are highly dynamic while obeying distinct rules. The data provide insights into the constant and variable aspects of orientation of ADs relative to the coactivator, changes in secondary structure and energetic contributions stabilizing the various conformers at different time points. We also demonstrate that a prediction of α-helical propensity correlates directly with the experimentally measured transactivation potential of a large set of mutagenized ADs. The link between α-helical propensity and the stimulatory activity of ADs has fundamental practical and theoretical implications concerning the recruitment of ADs to coactivators. PMID:27175900

  18. Molecular Dynamics of "Fuzzy" Transcriptional Activator-Coactivator Interactions

    PubMed Central

    Scholes, Natalie S.; Weinzierl, Robert O. J.

    2016-01-01

    Transcriptional activation domains (ADs) are generally thought to be intrinsically unstructured, but capable of adopting limited secondary structure upon interaction with a coactivator surface. The indeterminate nature of this interface made it hitherto difficult to study structure/function relationships of such contacts. Here we used atomistic accelerated molecular dynamics (aMD) simulations to study the conformational changes of the GCN4 AD and variants thereof, either free in solution, or bound to the GAL11 coactivator surface. We show that the AD-coactivator interactions are highly dynamic while obeying distinct rules. The data provide insights into the constant and variable aspects of orientation of ADs relative to the coactivator, changes in secondary structure and energetic contributions stabilizing the various conformers at different time points. We also demonstrate that a prediction of α-helical propensity correlates directly with the experimentally measured transactivation potential of a large set of mutagenized ADs. The link between α-helical propensity and the stimulatory activity of ADs has fundamental practical and theoretical implications concerning the recruitment of ADs to coactivators. PMID:27175900

  19. Nanoplasmonic molecular ruler for nuclease activity and DNAfootprinting

    SciTech Connect

    Chen, Fanqing Frank; Liu, Gang L.; Yin, Yadong; Gerion, Daniele; Kunchakarra, Siri; Mukherjee, Bipasha; Jett, Stephen D.; Bear, David G.; Alivisatos, Paul; Lee, Luke P.

    2006-08-15

    We have constructed a nanoplasmonic molecular ruler, which can perform label-free and real-time monitoring of DNA length changes and perform DNA footprinting. The ruler was created by tethering double-stranded DNA to single Au nanoparticles. The scattering spectra of Au-DNA nanoconjugates showed red-shifted peak plasmon resonance wavelength dependent on DNA length, which can be measured with sub-nanometer axial resolution, averaging {approx}1.24 nm peak wavelength shift per DNA base pair. The spectra of individual Au-DNA nanoconjugates in the presence of nuclease showed a time-resolved dependence on the reaction dynamics, allowing quantitative, kinetic and real-time measurement of nuclease activity. The ruler was further developed into a new DNA footprinting platform. We showed the specific binding of a protein to DNA and the accurate mapping of its footprint. This work promises a very fast and convenient platform for mapping DNA-protein interactions, for nuclease activity monitoring, and for other DNA size-based methods.

  20. Synthetic Molecular Machines for Active Self-Assembly: Prototype Algorithms, Designs, and Experimental Study

    NASA Astrophysics Data System (ADS)

    Dabby, Nadine L.

    behaviors. This class of behaviors includes any behavior where a passive physical system simply does not have enough physical energy to perform the specified tasks in the requisite amount of time. As we will demonstrate and prove, a sufficiently expressive implementation of an "active" molecular self-assembly approach can achieve these behaviors. Using an external source of fuel solves part of the problem, so the system is not "energetically incomplete." But the programmable system also needs to have sufficient expressive power to achieve the specified behaviors. Perhaps surprisingly, some of these systems do not even require Turing completeness to be sufficiently expressive. Building on a large variety of work by other scientists in the fields of DNA nanotechnology, chemistry and reconfigurable robotics, this thesis introduces several research contributions in the context of active self-assembly. We show that simple primitives such as insertion and deletion are able to generate complex and interesting results such as the growth of a linear polymer in logarithmic time and the ability of a linear polymer to treadmill. To this end we developed a formal model for active-self assembly that is directly implementable with DNA molecules. We show that this model is computationally equivalent to a machine capable of producing strings that are stronger than regular languages and, at most, as strong as context-free grammars. This is a great advance in the theory of active self-assembly as prior models were either entirely theoretical or only implementable in the context of macro-scale robotics. We developed a chain reaction method for the autonomous exponential growth of a linear DNA polymer. Our method is based on the insertion of molecules into the assembly, which generates two new insertion sites for every initial one employed. The building of a line in logarithmic time is a first step toward building a shape in logarithmic time. We demonstrate the first construction of a synthetic

  1. Effect of molecular models on viscosity and thermal conductivity calculations

    NASA Astrophysics Data System (ADS)

    Weaver, Andrew B.; Alexeenko, Alina A.

    2014-12-01

    The effect of molecular models on viscosity and thermal conductivity calculations is investigated. The Direct Simulation Monte Carlo (DSMC) method for rarefied gas flows is used to simulate Couette and Fourier flows as a means of obtaining the transport coefficients. Experimental measurements for argon (Ar) provide a baseline for comparison over a wide temperature range of 100-1,500 K. The variable hard sphere (VHS), variable soft sphere (VSS), and Lennard-Jones (L-J) molecular models have been implemented into a parallel version of Bird's one-dimensional DSMC code, DSMC1, and the model parameters have been recalibrated to the current experimental data set. While the VHS and VSS models only consider the short-range, repulsive forces, the L-J model also includes constributions from the long-range, dispersion forces. Theoretical results for viscosity and thermal conductivity indicate the L-J model is more accurate than the VSS model; with maximum errors of 1.4% and 3.0% in the range 300-1,500 K for L-J and VSS models, respectively. The range of validity of the VSS model is extended to 1,650 K through appropriate choices for the model parameters.

  2. STUDIES OF RELATIONSHIPS BETWEEN MOLECULAR STRUCTURE AND BIOLOGICAL ACTIVITY BY PATTERN RECOGNITION METHODS

    EPA Science Inventory

    The attempt to rationalize the connections between the molecular structures of organic compounds and their biological activities comprises the field of structure-activity relations (SAR) studies. Correlations between structure and activity are important for the understanding and ...

  3. A log-normal distribution model for the molecular weight of aquatic fulvic acids

    USGS Publications Warehouse

    Cabaniss, S.E.; Zhou, Q.; Maurice, P.A.; Chin, Y.-P.; Aiken, G.R.

    2000-01-01

    The molecular weight of humic substances influences their proton and metal binding, organic pollutant partitioning, adsorption onto minerals and activated carbon, and behavior during water treatment. We propose a lognormal model for the molecular weight distribution in aquatic fulvic acids to provide a conceptual framework for studying these size effects. The normal curve mean and standard deviation are readily calculated from measured M(n) and M(w) and vary from 2.7 to 3 for the means and from 0.28 to 0.37 for the standard deviations for typical aquatic fulvic acids. The model is consistent with several types of molecular weight data, including the shapes of high- pressure size-exclusion chromatography (HP-SEC) peaks. Applications of the model to electrostatic interactions, pollutant solubilization, and adsorption are explored in illustrative calculations.The molecular weight of humic substances influences their proton and metal binding, organic pollutant partitioning, adsorption onto minerals and activated carbon, and behavior during water treatment. We propose a log-normal model for the molecular weight distribution in aquatic fulvic acids to provide a conceptual framework for studying these size effects. The normal curve mean and standard deviation are readily calculated from measured Mn and Mw and vary from 2.7 to 3 for the means and from 0.28 to 0.37 for the standard deviations for typical aquatic fulvic acids. The model is consistent with several type's of molecular weight data, including the shapes of high-pressure size-exclusion chromatography (HP-SEC) peaks. Applications of the model to electrostatic interactions, pollutant solubilization, and adsorption are explored in illustrative calculations.

  4. Drug Repositioning by Kernel-Based Integration of Molecular Structure, Molecular Activity, and Phenotype Data

    PubMed Central

    Wang, Yongcui; Chen, Shilong; Deng, Naiyang; Wang, Yong

    2013-01-01

    Computational inference of novel therapeutic values for existing drugs, i.e., drug repositioning, offers the great prospect for faster and low-risk drug development. Previous researches have indicated that chemical structures, target proteins, and side-effects could provide rich information in drug similarity assessment and further disease similarity. However, each single data source is important in its own way and data integration holds the great promise to reposition drug more accurately. Here, we propose a new method for drug repositioning, PreDR (Predict Drug Repositioning), to integrate molecular structure, molecular activity, and phenotype data. Specifically, we characterize drug by profiling in chemical structure, target protein, and side-effects space, and define a kernel function to correlate drugs with diseases. Then we train a support vector machine (SVM) to computationally predict novel drug-disease interactions. PreDR is validated on a well-established drug-disease network with 1,933 interactions among 593 drugs and 313 diseases. By cross-validation, we find that chemical structure, drug target, and side-effects information are all predictive for drug-disease relationships. More experimentally observed drug-disease interactions can be revealed by integrating these three data sources. Comparison with existing methods demonstrates that PreDR is competitive both in accuracy and coverage. Follow-up database search and pathway analysis indicate that our new predictions are worthy of further experimental validation. Particularly several novel predictions are supported by clinical trials databases and this shows the significant prospects of PreDR in future drug treatment. In conclusion, our new method, PreDR, can serve as a useful tool in drug discovery to efficiently identify novel drug-disease interactions. In addition, our heterogeneous data integration framework can be applied to other problems. PMID:24244318

  5. Molecular-orbital model for metal-sapphire interfacial strength

    NASA Technical Reports Server (NTRS)

    Johnson, K. H.; Pepper, S. V.

    1982-01-01

    Self-consistent-field X-Alpha scattered-wave cluster molecular-orbital models have been constructed for transition and noble metals (Fe, Ni, Cu, and Ag) in contact with a sapphire (Al2O3) surface. It is found that a chemical bond is established between the metal d-orbital electrons and the nonbonding 2p-orbital electrons of the oxygen anions on the Al2O3 surface. An increasing number of occupied metal-sapphire antibonding molecular orbitals explains qualitatively the observed decrease of contact shear strength through the series Fe, Ni, Cu, and Ag.

  6. Phase Transitions in Model Active Systems

    NASA Astrophysics Data System (ADS)

    Redner, Gabriel S.

    materials, leading to beautiful and surprising behaviors including the spontaneous generation of topological defect pairs which stream through the system and later annihilate, yielding a complex, seemingly chaotic dynamical steady-state. Here, we describe the emergence of order from this chaos in the form of previously unknown broken-symmetry phases in which the topological defects themselves undergo orientational ordering. We have identified these defect-ordered phases in two realizations of an active nematic: first, a suspension of extensile bundles of microtubules and molecular motor proteins, and second, a computational model of extending hard rods. We will describe the defect-stabilized phases that manifest in these systems, our current understanding of their origins, and discuss whether such phases may be a general feature of extensile active nematics.

  7. Molecular pathway activation features linked with transition from normal skin to primary and metastatic melanomas in human.

    PubMed

    Shepelin, Denis; Korzinkin, Mikhail; Vanyushina, Anna; Aliper, Alexander; Borisov, Nicolas; Vasilov, Raif; Zhukov, Nikolay; Sokov, Dmitry; Prassolov, Vladimir; Gaifullin, Nurshat; Zhavoronkov, Alex; Bhullar, Bhupinder; Buzdin, Anton

    2016-01-01

    Melanoma is the most aggressive and dangerous type of skin cancer, but its molecular mechanisms remain largely unclear. For transcriptomic data of 478 primary and metastatic melanoma, nevi and normal skin samples, we performed high-throughput analysis of intracellular molecular networks including 592 signaling and metabolic pathways. We showed that at the molecular pathway level, the formation of nevi largely resembles transition from normal skin to primary melanoma. Using a combination of bioinformatic machine learning algorithms, we identified 44 characteristic signaling and metabolic pathways connected with the formation of nevi, development of primary melanoma, and its metastases. We created a model describing formation and progression of melanoma at the level of molecular pathway activation. We discovered six novel associations between activation of metabolic molecular pathways and progression of melanoma: for allopregnanolone biosynthesis, L-carnitine biosynthesis, zymosterol biosynthesis (inhibited in melanoma), fructose 2, 6-bisphosphate synthesis and dephosphorylation, resolvin D biosynthesis (activated in melanoma), D-myo-inositol hexakisphosphate biosynthesis (activated in primary, inhibited in metastatic melanoma). Finally, we discovered fourteen tightly coordinated functional clusters of molecular pathways. This study helps to decode molecular mechanisms underlying the development of melanoma. PMID:26624979

  8. Molecular pathway activation features linked with transition from normal skin to primary and metastatic melanomas in human

    PubMed Central

    Shepelin, Denis; Korzinkin, Mikhail; Vanyushina, Anna; Aliper, Alexander; Borisov, Nicolas; Vasilov, Raif; Zhukov, Nikolay; Sokov, Dmitry; Prassolov, Vladimir; Gaifullin, Nurshat; Zhavoronkov, Alex; Bhullar, Bhupinder; Buzdin, Anton

    2016-01-01

    Melanoma is the most aggressive and dangerous type of skin cancer, but its molecular mechanisms remain largely unclear. For transcriptomic data of 478 primary and metastatic melanoma, nevi and normal skin samples, we performed high-throughput analysis of intracellular molecular networks including 592 signaling and metabolic pathways. We showed that at the molecular pathway level, the formation of nevi largely resembles transition from normal skin to primary melanoma. Using a combination of bioinformatic machine learning algorithms, we identified 44 characteristic signaling and metabolic pathways connected with the formation of nevi, development of primary melanoma, and its metastases. We created a model describing formation and progression of melanoma at the level of molecular pathway activation. We discovered six novel associations between activation of metabolic molecular pathways and progression of melanoma: for allopregnanolone biosynthesis, L-carnitine biosynthesis, zymosterol biosynthesis (inhibited in melanoma), fructose 2, 6-bisphosphate synthesis and dephosphorylation, resolvin D biosynthesis (activated in melanoma), D-myo-inositol hexakisphosphate biosynthesis (activated in primary, inhibited in metastatic melanoma). Finally, we discovered fourteen tightly coordinated functional clusters of molecular pathways. This study helps to decode molecular mechanisms underlying the development of melanoma. PMID:26624979

  9. Multi-level molecular modelling for plasma medicine

    NASA Astrophysics Data System (ADS)

    Bogaerts, Annemie; Khosravian, Narjes; Van der Paal, Jonas; Verlackt, Christof C. W.; Yusupov, Maksudbek; Kamaraj, Balu; Neyts, Erik C.

    2016-02-01

    Modelling at the molecular or atomic scale can be very useful for obtaining a better insight in plasma medicine. This paper gives an overview of different atomic/molecular scale modelling approaches that can be used to study the direct interaction of plasma species with biomolecules or the consequences of these interactions for the biomolecules on a somewhat longer time-scale. These approaches include density functional theory (DFT), density functional based tight binding (DFTB), classical reactive and non-reactive molecular dynamics (MD) and united-atom or coarse-grained MD, as well as hybrid quantum mechanics/molecular mechanics (QM/MM) methods. Specific examples will be given for three important types of biomolecules, present in human cells, i.e. proteins, DNA and phospholipids found in the cell membrane. The results show that each of these modelling approaches has its specific strengths and limitations, and is particularly useful for certain applications. A multi-level approach is therefore most suitable for obtaining a global picture of the plasma-biomolecule interactions.

  10. Combined 3D-QSAR, molecular docking and molecular dynamics study on thyroid hormone activity of hydroxylated polybrominated diphenyl ethers to thyroid receptors β

    SciTech Connect

    Li, Xiaolin; Ye, Li; Wang, Xiaoxiang; Wang, Xinzhou; Liu, Hongling; Zhu, Yongliang; Yu, Hongxia

    2012-12-15

    Several recent reports suggested that hydroxylated polybrominated diphenyl ethers (HO-PBDEs) may disturb thyroid hormone homeostasis. To illuminate the structural features for thyroid hormone activity of HO-PBDEs and the binding mode between HO-PBDEs and thyroid hormone receptor (TR), the hormone activity of a series of HO-PBDEs to thyroid receptors β was studied based on the combination of 3D-QSAR, molecular docking, and molecular dynamics (MD) methods. The ligand- and receptor-based 3D-QSAR models were obtained using Comparative Molecular Similarity Index Analysis (CoMSIA) method. The optimum CoMSIA model with region focusing yielded satisfactory statistical results: leave-one-out cross-validation correlation coefficient (q{sup 2}) was 0.571 and non-cross-validation correlation coefficient (r{sup 2}) was 0.951. Furthermore, the results of internal validation such as bootstrapping, leave-many-out cross-validation, and progressive scrambling as well as external validation indicated the rationality and good predictive ability of the best model. In addition, molecular docking elucidated the conformations of compounds and key amino acid residues at the docking pocket, MD simulation further determined the binding process and validated the rationality of docking results. -- Highlights: ► The thyroid hormone activities of HO-PBDEs were studied by 3D-QSAR. ► The binding modes between HO-PBDEs and TRβ were explored. ► 3D-QSAR, molecular docking, and molecular dynamics (MD) methods were performed.

  11. An Algebraic Spline Model of Molecular Surfaces for Energetic Computations

    PubMed Central

    Zhao, Wenqi; Bajaj, Chandrajit; Xu, Guoliang

    2009-01-01

    In this paper, we describe a new method to generate a smooth algebraic spline (AS) approximation of the molecular surface (MS) based on an initial coarse triangulation derived from the atomic coordinate information of the biomolecule, resident in the PDB (Protein data bank). Our method first constructs a triangular prism scaffold covering the PDB structure, and then generates a piecewise polynomial F on the Bernstein-Bezier (BB) basis within the scaffold. An ASMS model of the molecular surface is extracted as the zero contours of F which is nearly C1 and has dual implicit and parametric representations. The dual representations allow us easily do the point sampling on the ASMS model and apply it to the accurate estimation of the integrals involved in the electrostatic solvation energy computations. Meanwhile comparing with the trivial piecewise linear surface model, fewer number of sampling points are needed for the ASMS, which effectively reduces the complexity of the energy estimation. PMID:21519111

  12. Molecular Dynamics Simulations Reveal the Mechanisms of Allosteric Activation of Hsp90 by Designed Ligands

    NASA Astrophysics Data System (ADS)

    Vettoretti, Gerolamo; Moroni, Elisabetta; Sattin, Sara; Tao, Jiahui; Agard, David A.; Bernardi, Anna; Colombo, Giorgio

    2016-04-01

    Controlling biochemical pathways through chemically designed modulators may provide novel opportunities to develop therapeutic drugs and chemical tools. The underlying challenge is to design new molecular entities able to act as allosteric chemical switches that selectively turn on/off functions by modulating the conformational dynamics of their target protein. We examine the origins of the stimulation of ATPase and closure kinetics in the molecular chaperone Hsp90 by allosteric modulators through atomistic molecular dynamics (MD) simulations and analysis of protein-ligand interactions. In particular, we focus on the cross-talk between allosteric ligands and protein conformations and its effect on the dynamic properties of the chaperone’s active state. We examine the impact of different allosteric modulators on the stability, structural and internal dynamics properties of Hsp90 closed state. A critical aspect of this study is the development of a quantitative model that correlates Hsp90 activation to the presence of a certain compound, making use of information on the dynamic adaptation of protein conformations to the presence of the ligand, which allows to capture conformational states relevant in the activation process. We discuss the implications of considering the conformational dialogue between allosteric ligands and protein conformations for the design of new functional modulators.

  13. Molecular Dynamics Simulations Reveal the Mechanisms of Allosteric Activation of Hsp90 by Designed Ligands

    PubMed Central

    Vettoretti, Gerolamo; Moroni, Elisabetta; Sattin, Sara; Tao, Jiahui; Agard, David A.; Bernardi, Anna; Colombo, Giorgio

    2016-01-01

    Controlling biochemical pathways through chemically designed modulators may provide novel opportunities to develop therapeutic drugs and chemical tools. The underlying challenge is to design new molecular entities able to act as allosteric chemical switches that selectively turn on/off functions by modulating the conformational dynamics of their target protein. We examine the origins of the stimulation of ATPase and closure kinetics in the molecular chaperone Hsp90 by allosteric modulators through atomistic molecular dynamics (MD) simulations and analysis of protein-ligand interactions. In particular, we focus on the cross-talk between allosteric ligands and protein conformations and its effect on the dynamic properties of the chaperone’s active state. We examine the impact of different allosteric modulators on the stability, structural and internal dynamics properties of Hsp90 closed state. A critical aspect of this study is the development of a quantitative model that correlates Hsp90 activation to the presence of a certain compound, making use of information on the dynamic adaptation of protein conformations to the presence of the ligand, which allows to capture conformational states relevant in the activation process. We discuss the implications of considering the conformational dialogue between allosteric ligands and protein conformations for the design of new functional modulators. PMID:27032695

  14. Molecular dynamics modeling and characterization of graphene/polymer nanocomposites

    NASA Astrophysics Data System (ADS)

    Rahman, Rezwanur

    The current work focuses on the characterization of graphene based nanocomposites using molecular dynamic simulation and multiscale modeling approaches. Both graphene-epoxy and graphene-cellulose nanocomposites were considered in this study. A hierarchical multiscale modeling approach has been proposed using peridynamics and molecular dynamics simulation. Firstly, the mechanical properties of crosslinked graphene/epoxy (G-Ep) nanocomposites were investigated by molecular mechanics (MM) and molecular dynamics (MD) simulations. The influence of graphene's weight concentration, aspect ratio and dispersion on stress-strain response and elastic properties were studied. The results show significant improvement in Young's modulus and shear modulus for the G-Ep system in comparison to the neat epoxy resin. It appears that the RDF, molecular energy and aspect ratios are influenced by both graphene concentrations and aspect ratios. The graphene concentrations in the range of 1-3% are seen to improve Young's modulus and shorter graphenes are observed to be more effective than larger ones. In addition, the dispersed graphene system is more promising in enhancing in-plane elastic modulus than the agglomerated graphene system. The cohesive and pullout forces versus displacements data were plotted under normal and shear modes in order to characterize interfacial properties. The cohesive force is significantly improved by attaching the graphene with a chemical bond at the graphene-epoxy interface. In the second part of the work, cellulose was considered to study the mechanical properties of graphene-cellulose bionanocomposite. Similar to graphene-epoxy systems, the effect of graphene dispersion and agglomeration were studied in the stress-strain plots of graphene-cellulose system. A pcff forcefield was used to define intermolecular and intramolecular interactions. The effect of graphene's aspect ratio and weight concentration on the structural property of each unitcell was

  15. Synthesis, molecular structure, spectroscopic analysis, thermodynamic parameters and molecular modeling studies of (2-methoxyphenyl)oxalate

    NASA Astrophysics Data System (ADS)

    Şahin, Zarife Sibel; Kantar, Günay Kaya; Şaşmaz, Selami; Büyükgüngör, Orhan

    2015-05-01

    The aim of this study is to find out the molecular characteristic and structural parameters that govern the chemical behavior of a new (2-methoxyphenyl)oxalate compound and to compare predictions made from theory with experimental observations. The title compound, (2-methoxyphenyl)oxalate, (I), (C16H14O6), has been synthesized. The compound has been characterized by elemental analysis, IR, 1H NMR, 13C NMR spectroscopies and single crystal X-ray diffraction techniques. Optimized molecular structure, harmonic vibrational frequencies, 1H and 13C NMR chemical shifts have been investigated by B3LYP/6-31G(d,p) method using density functional theory (DFT). The calculated results show that the predicted geometry can well reproduce structural parameters. In addition, global chemical reactivity descriptors, molecular electrostatic potential map (MEP), frontier molecular orbitals (FMOs), Mulliken population method and natural population analysis (NPA) and thermodynamic properties have also been studied. The energetic behavior of title compound has been examined in solvent media using polarizable continuum model (PCM).

  16. Molecular Evidence for Metabolically Active Bacteria in the Atmosphere

    PubMed Central

    Klein, Ann M.; Bohannan, Brendan J. M.; Jaffe, Daniel A.; Levin, David A.; Green, Jessica L.

    2016-01-01

    Bacterial metabolisms are responsible for critical chemical transformations in nearly all environments, including oceans, freshwater, and soil. Despite the ubiquity of bacteria in the atmosphere, little is known about the metabolic functioning of atmospheric bacterial communities. To gain a better understanding of the metabolism of bacterial communities in the atmosphere, we used a combined empirical and model-based approach to investigate the structure and composition of potentially active bacterial communities in air sampled at a high elevation research station. We found that the composition of the putatively active bacterial community (assayed via rRNA) differed significantly from the total bacterial community (assayed via rDNA). Rare taxa in the total (rDNA) community were disproportionately active relative to abundant taxa, and members of the order Rhodospirillales had the highest potential for activity. We developed theory to explore the effects of random sampling from the rRNA and rDNA communities on observed differences between the communities. We found that random sampling, particularly in cases where active taxa are rare in the rDNA community, will give rise to observed differences in community composition including the occurrence of “phantom taxa”, taxa which are detected in the rRNA community but not the rDNA community. We show that the use of comparative rRNA/rDNA techniques can reveal the structure and composition of the metabolically active portion of bacterial communities. Our observations suggest that metabolically active bacteria exist in the atmosphere and that these communities may be involved in the cycling of organic compounds in the atmosphere. PMID:27252689

  17. Wind from the black-hole accretion disk driving a molecular outflow in an active galaxy

    NASA Astrophysics Data System (ADS)

    Tombesi, F.; Meléndez, M.; Veilleux, S.; Reeves, J. N.; González-Alfonso, E.; Reynolds, C. S.

    2015-03-01

    Powerful winds driven by active galactic nuclei are often thought to affect the evolution of both supermassive black holes and their host galaxies, quenching star formation and explaining the close relationship between black holes and galaxies. Recent observations of large-scale molecular outflows in ultraluminous infrared galaxies support this quasar-feedback idea, because they directly trace the gas from which stars form. Theoretical models suggest that these outflows originate as energy-conserving flows driven by fast accretion-disk winds. Proposed connections between large-scale molecular outflows and accretion-disk activity in ultraluminous galaxies were incomplete because no accretion-disk wind had been detected. Conversely, studies of powerful accretion-disk winds have until now focused only on X-ray observations of local Seyfert galaxies and a few higher-redshift quasars. Here we report observations of a powerful accretion-disk wind with a mildly relativistic velocity (a quarter that of light) in the X-ray spectrum of IRAS F11119+3257, a nearby (redshift 0.189) optically classified type 1 ultraluminous infrared galaxy hosting a powerful molecular outflow. The active galactic nucleus is responsible for about 80 per cent of the emission, with a quasar-like luminosity of 1.5 × 1046 ergs per second. The energetics of these two types of wide-angle outflows is consistent with the energy-conserving mechanism that is the basis of the quasar feedback in active galactic nuclei that lack powerful radio jets (such jets are an alternative way to drive molecular outflows).

  18. Fueling active galactic nuclei. II. Spatially resolved molecular inflows and outflows

    SciTech Connect

    Davies, R. I.; Erwin, P.; Burtscher, L.; Lin, M.; Orban de Xivry, G.; Rosario, D. J.; Schnorr-Müller, A.; Maciejewski, W.; Hicks, E. K. S.; Emsellem, E.; Dumas, G.; Malkan, M. A.; Müller-Sánchez, F.; Tran, A.

    2014-09-10

    We analyze the two-dimensional distribution and kinematics of the stars as well as molecular and ionized gas in the central few hundred parsecs of five active and five matched inactive galaxies. The equivalent widths of the Brγ line indicate that there is no ongoing star formation in their nuclei, although recent (terminated) starbursts are possible in the active galaxies. The stellar velocity fields show no signs of non-circular motions, while the 1-0 S(1) H{sub 2} kinematics exhibit significant deviations from simple circular rotation. In the active galaxies the H{sub 2} kinematics reveal inflow and outflow superimposed on disk rotation. Steady-state circumnuclear inflow is seen in three active galactic nuclei (AGNs), and hydrodynamical models indicate it can be driven by a large-scale bar. In three of the five AGNs, molecular outflows are spatially resolved. The outflows are oriented such that they intersect, or have an edge close to, the disk, which may be the source of molecular gas in the outflow. The relatively low speeds imply the gas will fall back onto the disk, and with moderate outflow rates, they will have only a local impact on the host galaxy. H{sub 2} was detected in two inactive galaxies. These exhibit chaotic circumnuclear dust morphologies and have molecular structures that are counter-rotating with respect to the main gas component, which could lead to gas inflow in the near future. In our sample, all four galaxies with chaotic dust morphology in the circumnuclear region exist in moderately dense groups with 10-15 members where accretion of stripped gas can easily occur.

  19. Wind from the black-hole accretion disk driving a molecular outflow in an active galaxy.

    PubMed

    Tombesi, F; Meléndez, M; Veilleux, S; Reeves, J N; González-Alfonso, E; Reynolds, C S

    2015-03-26

    Powerful winds driven by active galactic nuclei are often thought to affect the evolution of both supermassive black holes and their host galaxies, quenching star formation and explaining the close relationship between black holes and galaxies. Recent observations of large-scale molecular outflows in ultraluminous infrared galaxies support this quasar-feedback idea, because they directly trace the gas from which stars form. Theoretical models suggest that these outflows originate as energy-conserving flows driven by fast accretion-disk winds. Proposed connections between large-scale molecular outflows and accretion-disk activity in ultraluminous galaxies were incomplete because no accretion-disk wind had been detected. Conversely, studies of powerful accretion-disk winds have until now focused only on X-ray observations of local Seyfert galaxies and a few higher-redshift quasars. Here we report observations of a powerful accretion-disk wind with a mildly relativistic velocity (a quarter that of light) in the X-ray spectrum of IRAS F11119+3257, a nearby (redshift 0.189) optically classified type 1 ultraluminous infrared galaxy hosting a powerful molecular outflow. The active galactic nucleus is responsible for about 80 per cent of the emission, with a quasar-like luminosity of 1.5 × 10(46) ergs per second. The energetics of these two types of wide-angle outflows is consistent with the energy-conserving mechanism that is the basis of the quasar feedback in active galactic nuclei that lack powerful radio jets (such jets are an alternative way to drive molecular outflows). PMID:25810204

  20. Modeling of Switching and Hysteresis in Molecular Transport

    NASA Technical Reports Server (NTRS)

    Samanta, Manoj P.; Partridge, Harry (Technical Monitor)

    2002-01-01

    The conventional way of modeling current transport in two and three terminal molecular devices could be inadequate for certain cases involving switching and hysteresis. Here we present an alternate approach. Contrary to the regular way where applied bias directly modulates the conducting energy levels of the molecule, our method introduces a nonlinear potential energy surface varying with the applied bias as a control parameter. A time-dynamics is also introduced properly accounting for switching and hysteresis behavior. Although the model is phenomenological at this stage, we believe any detailed model would contain similar descriptions at its core.

  1. Molecular Models for DSMC Simulations of Metal Vapor Deposition

    SciTech Connect

    Venkattraman, A.; Alexeenko, A. A.

    2011-05-20

    The direct simulation Monte Carlo (DSMC) method is applied here to model the electron-beam (e-beam) physical vapor deposition of copper thin films. A suitable molecular model for copper-copper interactions have been determined based on comparisons with experiments for a 2D slit source. The model for atomic copper vapor is then used in axi-symmetric DSMC simulations for analysis of a typical e-beam metal deposition system with a cup crucible. The dimensional and non-dimensional mass fluxes obtained are compared for two different deposition configurations with non-uniformity as high as 40% predicted from the simulations.

  2. Various Molecular Species of Diacylglycerol Hydroperoxide Activate Human Neutrophils via PKC Activation

    PubMed Central

    Kambayashi, Yasuhiro; Takekoshi, Susumu; Tanino, Yutaka; Watanabe, Keiichi; Nakano, Minoru; Hitomi, Yoshiaki; Takigawa, Tomoko; Ogino, Keiki; Yamamoto, Yorihiro

    2007-01-01

    We have proposed that diacylglycerol hydroperoxide-induced unregulated signal transduction causes oxidative stress-related diseases. In this study, we investigated which molecular species of diacylglycerol hydroperoxide activated human peripheral neutrophils. All diacylglycerol hydroperoxides, diacylglycerol hydroxides, and diacyglycerols tested in the present study induced superoxide production by neutrophils. The ability to activate neutrophils among molecular species containing the same fatty acid composition was as follows; diacylglycerol hydroperoxide>diacylglycerol hydroxide≥diacylglycerol. The diacylglycerol hydroperoxide composed of linoleate was a stronger activator for neutrophils than that composed of arachidonate. 1-Palmitoyl-2-linoleoylglycerol hydroperoxide (PLG-OOH) was the strongest stimulator for neutrophils. We reconfirmed that PLG-OOH activated protein kinase C (PKC) in neutrophils. PLG-OOH induced the phosphorylation of p47phox, a substrate of PKC and a cytosolic component of NADPH oxidase, in neutrophils, as did N-formyl-methionyl-leucyl-phenylalanine or 4β-phorbol-12β-myristate-13α-acetate. Moreover, the time course of p47phox phosphorylation was comparable to that of superoxide production. These results suggest that PLG-OOH activated intracellular protein kinase C. PLG-OOH, produced via an uncontrolled process, can act as a biological second messenger to cause inflammatory disease from oxidative stress. PMID:18392102

  3. Antiaging activity of low molecular weight peptide from Paphia undulate

    NASA Astrophysics Data System (ADS)

    Chen, Xin; Cai, Bingna; Chen, Hua; Pan, Jianyu; Chen, Deke; Sun, Huili

    2013-05-01

    Low molecular weight peptide (LMWP) was prepared from clam Paphia undulate and its antiaging effect on D-galactose-induced acute aging in rats, aged Kunming mice, ultraviolet-exposed rats, and thermally injured rats was investigated. P. undulate flesh was homogenized and digested using papain under optimal conditions, then subjected to Sephadex G-25 chromatography to isolate the LMWP. Administration of LMWP significantly reversed D-galactose-induced oxidative stress by increasing the activities of glutathione peroxidase (GPx) and catalase (CAT), and by decreasing the level of malondialdehyde (MDA). This process was accompanied by increased collagen synthesis. The LMWP prevented photoaging and promoted dermis recovery and remission of elastic fiber hyperplasia. Furthermore, treatment with the LMWP helped to regenerate elastic fibers and the collagen network, increased superoxide dismutase (SOD) in the serum and significantly decreased MDA. Thermal scald-induced inflammation and edema were also relieved by the LWMP, while wound healing in skin was promoted. These results suggest that the LMWP from P. undulate could serve as a new antiaging substance in cosmetics.

  4. Molecularly imprinted hydrogels as functional active packaging materials.

    PubMed

    Benito-Peña, Elena; González-Vallejo, Victoria; Rico-Yuste, Alberto; Barbosa-Pereira, Letricia; Cruz, José Manuel; Bilbao, Ainhoa; Alvarez-Lorenzo, Carmen; Moreno-Bondi, María Cruz

    2016-01-01

    This paper describes the synthesis of novel molecularly imprinted hydrogels (MIHs) for the natural antioxidant ferulic acid (FA), and their application as packaging materials to prevent lipid oxidation of butter. A library of MIHs was synthesized using a synthetic surrogate of FA, 3-(4-hydroxy-3-methoxyphenyl)propionic acid (HFA), as template molecule, ethyleneglycol dimethacrylate (EDMA) as cross-linker, and 1-allylpiperazine (1-ALPP) or 2-(dimethylamino)ethyl methacrylate (DMAEMA), in combination with 2-hydroxyethyl methacrylate (HEMA) as functional monomers, at different molar concentrations. The DMAEMA/HEMA-based MIHs showed the greatest FA loading capacity, while the 1-ALLP/HEMA-based polymers exhibited the highest imprinting effect. During cold storage, FA-loaded MIHs protected butter from oxidation and led to TBARs values that were approximately half those of butter stored without protection and 25% less than those recorded for butter covered with hydrogels without FA, potentially extending the shelf life of butter. Active packaging is a new field of application for MIHs with great potential in the food industry. PMID:26213001

  5. On Modelling Minimal Disease Activity

    PubMed Central

    Jackson, Christopher H.; Su, Li; Gladman, Dafna D.

    2016-01-01

    Objective To explore methods for statistical modelling of minimal disease activity (MDA) based on data from intermittent clinic visits. Methods The analysis was based on a 2‐state model. Comparisons were made between analyses based on “complete case” data from visits at which MDA status was known, and the use of hidden model methodology that incorporated information from visits at which only some MDA defining criteria could be established. Analyses were based on an observational psoriatic arthritis cohort. Results With data from 856 patients and 7,024 clinic visits, analysis was based on virtually all visits, although only 62.6% provided enough information to determine MDA status. Estimated mean times for an episode of MDA varied from 4.18 years to 3.10 years, with smaller estimates derived from the hidden 2‐state model analysis. Over a 10‐year period, the estimated expected times spent in MDA episodes of longer than 1 year was 3.90 to 4.22, and the probability of having such an MDA episode was estimated to be 0.85 to 0.91, with longer times and greater probabilities seen with the hidden 2‐state model analysis. Conclusion A 2‐state model provides a useful framework for the analysis of MDA. Use of data from visits at which MDA status can not be determined provide more precision, and notable differences are seen in estimated quantities related to MDA episodes based on complete case and hidden 2‐state model analyses. The possibility of bias, as well as loss of precision, should be recognized when complete case analyses are used. PMID:26315478

  6. Molecular activities, biosynthesis and evolution of triterpenoid saponins.

    PubMed

    Augustin, Jörg M; Kuzina, Vera; Andersen, Sven B; Bak, Søren

    2011-04-01

    Saponins are bioactive compounds generally considered to be produced by plants to counteract pathogens and herbivores. Besides their role in plant defense, saponins are of growing interest for drug research as they are active constituents of several folk medicines and provide valuable pharmacological properties. Accordingly, much effort has been put into unraveling the modes of action of saponins, as well as in exploration of their potential for industrial processes and pharmacology. However, the exploitation of saponins for bioengineering crop plants with improved resistances against pests as well as circumvention of laborious and uneconomical extraction procedures for industrial production from plants is hampered by the lack of knowledge and availability of genes in saponin biosynthesis. Although the ability to produce saponins is rather widespread among plants, a complete synthetic pathway has not been elucidated in any single species. Current conceptions consider saponins to be derived from intermediates of the phytosterol pathway, and predominantly enzymes belonging to the multigene families of oxidosqualene cyclases (OSCs), cytochromes P450 (P450s) and family 1 UDP-glycosyltransferases (UGTs) are thought to be involved in their biosynthesis. Formation of unique structural features involves additional biosynthetical enzymes of diverse phylogenetic background. As an example of this, a serine carboxypeptidase-like acyltransferase (SCPL) was recently found to be involved in synthesis of triterpenoid saponins in oats. However, the total number of identified genes in saponin biosynthesis remains low as the complexity and diversity of these multigene families impede gene discovery based on sequence analysis and phylogeny. This review summarizes current knowledge of triterpenoid saponin biosynthesis in plants, molecular activities, evolutionary aspects and perspectives for further gene discovery. PMID:21333312

  7. Molecular modeling studies of [6,6,5] Tricyclic Fused Oxazolidinones as FXa inhibitors using 3D-QSAR, Topomer CoMFA, molecular docking and molecular dynamics simulations.

    PubMed

    Xu, Cheng; Ren, Yujie

    2015-10-15

    Coagulation factor Xa (Factor Xa, FXa) is a particularly promising target for novel anticoagulant therapy. The first oral factor Xa inhibitor has been approved in the EU and Canada in 2008. In this work, 38 [6,6,5] Tricyclic Fused Oxazolidinones were studied using a combination of molecular modeling techniques including three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, molecular dynamics and Topomer CoMFA (comparative molecular field analysis) were used to build 3D-QSAR models. The results show that the best CoMFA model has q(2)=0.511 and r(2)=0.984, the best CoMSIA (comparative molecular similarity indices analysis) model has q(2)=0.700 and r(2)=0.993 and the Topomer CoMFA analysis has q(2)=0.377 and r(2)=0.886. The results indicated the steric, hydrophobic, H-acceptor and electrostatic fields play key roles in models. Molecular docking and molecular dynamics explored the binding relationship of the ligand and the receptor protein. PMID:26343829

  8. On the coalescence-dispersion modeling of turbulent molecular mixing

    NASA Technical Reports Server (NTRS)

    Givi, Peyman; Kosaly, George

    1987-01-01

    The general coalescence-dispersion (C/D) closure provides phenomenological modeling of turbulent molecular mixing. The models of Curl and Dopazo and O'Brien appear as two limiting C/D models that bracket the range of results one can obtain by various models. This finding is used to investigate the sensitivtiy of the results to the choice of the model. Inert scalar mixing is found to be less model-sensitive than mixing accompanied by chemical reaction. Infinitely fast chemistry approximation is used to relate the C/D approach to Toor's earlier results. Pure mixing and infinite rate chemistry calculations are compared to study further a recent result of Hsieh and O'Brien who found that higher concentration moments are not sensitive to chemistry.

  9. Kinetics of model high molecular weight organic compounds biodegradation in soil aquifer treatment.

    PubMed

    Fox, Peter; Makam, Roshan

    2011-10-01

    Soil Aquifer Treatment (SAT) is a process where treated wastewater is purified during transport through unsaturated and saturated zones. Easily biodegradable compounds are rapidly removed in the unsaturated zone and the residual organic carbon is comprised of primarily high molecular weight compounds. This research focuses on flow in the saturated zone where flow conditions are predictable and high molecular weight compounds are degraded. Flow through the saturated zone was investigated with 4 reactors packed with 2 different particle sizes and operated at 4 different flow rates. The objective was to evaluate the kinetics of transformation for high molecular weight organics during SAT. Dextran was used as a model compound to eliminate the complexity associated with studying a mixture of high molecular weight organics. The hydrolysis products of dextran are easily degradable sugars. Batch experiments with media taken from the reactors were used to determine the distribution of microbial activity in the reactors. Zero-order kinetics were observed for the removal of dextran in batch experiments which is consistent with hydrolysis of high molecular weight organics where extracellular enzymes limit the substrate utilization rate. Biomass and microbial activity measurements demonstrated that the biomass was independent of position in the reactors. A Monod based substrate/biomass growth kinetic model predicted the performance of dextran removal in the reactors. The rate limiting step appears to be hydrolysis and the overall rate was not affected by surface area even though greater biomass accumulation occurred as the surface area decreased. PMID:21723581

  10. Anti-AIDS agents 79. Design, synthesis, molecular modeling and structure-activity relationships of novel dicamphanoyl-2′,2′-dimethyldihydropyranochromone (DCP) analogs as potent anti-HIV agents

    PubMed Central

    Zhou, Ting; Shi, Qian; Chen, Chin-Ho; Zhu, Hao; Huang, Li; Ho, Phong; Lee, Kuo-Hsiung

    2010-01-01

    In a continued study, 23 3′R,4′R-di-O-(−)-camphanoyl-2′,2′-dimethyldihydropyrano[2,3-f]chromone (DCP) derivatives (5–27) were synthesized, and screened for anti-HIV activity against both a non-drug-resistant NL4-3 strain and multiple reverse transcriptase (RT) inhibitor-resistant (RTMDR-1) strain, using 2-EDCP (4) and 2-MDCP (35) as controls. New DCP analogs 5, 9, 14, and 22 exhibited potent anti-HIV activity against HIVNL4-3 with EC50 and therapeutic index (TI) values ranging from 0.036 μM to 0.14 μM and from 110 to 420, respectively. Compounds 5 and 9 also exhibited good activity against RTMDR-1 (EC50 0.049 and 0.054 μM; TI 310 and 200, respectively), and were two-fold more potent than the leads 4 and 35 (EC50 0.11 and 0.19 μM; TI 60 and 58, respectively). Evaluation of water solubility showed that 5 and 22 were 5–10 times more water soluble than 4. Quantitative structure-activity relationship (QSAR) modeling results were first performed on this compound type, and the models should aid in design of future anti-HIV DCP analogs and potential clinical drug candidates. PMID:20728367

  11. Anti-AIDS agents 79. Design, synthesis, molecular modeling and structure-activity relationships of novel dicamphanoyl-2',2'-dimethyldihydropyranochromone (DCP) analogs as potent anti-HIV agents.

    PubMed

    Zhou, Ting; Shi, Qian; Chen, Chin-Ho; Zhu, Hao; Huang, Li; Ho, Phong; Lee, Kuo-Hsiung

    2010-09-15

    In a continued study, 23 3'R,4'R-di-O-(-)-camphanoyl-2',2'-dimethyldihydropyrano[2,3-f]chromone (DCP) derivatives (5-27) were synthesized, and screened for anti-HIV activity against both a non-drug-resistant NL4-3 strain and multiple reverse transcriptase (RT) inhibitor-resistant (RTMDR-1) strain, using 2-EDCP (4) and 2-MDCP (35) as controls. New DCP analogs 5, 9, 14, and 22 exhibited potent anti-HIV activity against HIVNL4-3 with EC50 and therapeutic index (TI) values ranging from 0.036 microM to 0.14 microM and from 110 to 420, respectively. Compounds 5 and 9 also exhibited good activity against RTMDR-1 (EC50 0.049 and 0.054 microM; TI 310 and 200, respectively), and were twofold more potent than the leads 4 and 35 (EC50 0.11 and 0.19 microM; TI 60 and 58, respectively). Evaluation of water solubility showed that 5 and 22 were 5-10 times more water soluble than 4. Quantitative structure-activity relationship (QSAR) modeling results were first performed on this compound type, and the models should aid in design of future anti-HIV DCP analogs and potential clinical drug candidates. PMID:20728367

  12. Pharmacophore modeling, in silico screening, molecular docking and molecular dynamics approaches for potential alpha-delta bungarotoxin-4 inhibitors discovery

    PubMed Central

    Kumar, R. Barani; Suresh, M. Xavier; Priya, B. Shanmuga

    2015-01-01

    Background: The alpha-delta bungartoxin-4 (α-δ-Bgt-4) is a potent neurotoxin produced by highly venomous snake species, Bungarus caeruleus, mainly targeting neuronal acetylcholine receptors (nAchRs) and producing adverse biological malfunctions leading to respiratory paralysis and mortality. Objective: In this study, we predicted the three-dimensional structure of α-δ-Bgt-4 using homology modeling and investigated the conformational changes and the key residues responsible for nAchRs inhibiting activity. Materials and Methods: From the selected plants, which are traditionally used for snake bites, the active compounds are taken and performed molecular interaction studies and also used for modern techniques like pharmacophore modeling and mapping and absorption, distribution, metabolism, elimination and toxicity analysis which may increase the possibility of success. Results: Moreover, 100's of drug-like compounds were retrieved and analyzed through computational virtual screening and allowed for pharmacokinetic profiling, molecular docking and dynamics simulation. Conclusion: Finally the top five drug-like compounds having competing level of inhibition toward α-δ-Bgt-4 toxin were suggested based on their interaction with α-δ-Bgt-4 toxin. PMID:26109766

  13. Molecular modeling study of dihydrofolate reductase inhibitors. Molecular dynamics simulations, quantum mechanical calculations, and experimental corroboration.

    PubMed

    Tosso, Rodrigo D; Andujar, Sebastian A; Gutierrez, Lucas; Angelina, Emilio; Rodríguez, Ricaurte; Nogueras, Manuel; Baldoni, Héctor; Suvire, Fernando D; Cobo, Justo; Enriz, Ricardo D

    2013-08-26

    A molecular modeling study on dihydrofolate reductase (DHFR) inhibitors was carried out. By combining molecular dynamics simulations with semiempirical (PM6), ab initio, and density functional theory (DFT) calculations, a simple and generally applicable procedure to evaluate the binding energies of DHFR inhibitors interacting with the human enzyme is reported here, providing a clear picture of the binding interactions of these ligands from both structural and energetic viewpoints. A reduced model for the binding pocket was used. This approach allows us to perform more accurate quantum mechanical calculations as well as to obtain a detailed electronic analysis using the quantum theory of atoms in molecules (QTAIM) technique. Thus, molecular aspects of the binding interactions between inhibitors and the DHFR are discussed in detail. A significant correlation between binding energies obtained from DFT calculations and experimental IC₅₀ values was obtained, predicting with an acceptable qualitative accuracy the potential inhibitor effect of nonsynthesized compounds. Such correlation was experimentally corroborated synthesizing and testing two new inhibitors reported in this paper. PMID:23834278

  14. Using Active Modeling in Counterterrorism

    NASA Astrophysics Data System (ADS)

    Su, Yi-Jen; Jiau, Hewijin C.; Tsai, Shang-Rong

    Terrorist organizations attain their goals by attacking various targets to jeopardize human lives and intimidate governments. As new terrorist attacks almost always aim to break the mold of old plots, tracing the dynamic behaviors of terrorists becomes crucial to national defense. This paper proposes using active modeling in analyzing unconventional attacks in the design of counterterrorism system. The intelligent terrorism detection system not only detects potential threats by monitoring terrorist networks with identified threat patterns, but also continually integrates new threat features in terrorist behaviors and the varying relationships among terrorists.

  15. Model-free simulation approach to molecular diffusion tensors.

    PubMed

    Chevrot, Guillaume; Hinsen, Konrad; Kneller, Gerald R

    2013-10-21

    In the present work, we propose a simple model-free approach for the computation of molecular diffusion tensors from molecular dynamics trajectories. The method uses a rigid body trajectory of the molecule under consideration, which is constructed a posteriori by an accumulation of quaternion-based superposition fits of consecutive conformations. From the rigid body trajectory, we compute the translational and angular velocities of the molecule and by integration of the latter also the corresponding angular trajectory. All quantities can be referred to the laboratory frame and a molecule-fixed frame. The 6 × 6 diffusion tensor is computed from the asymptotic slope of the tensorial mean square displacement and, for comparison, also from the Kubo integral of the velocity correlation tensor. The method is illustrated for two simple model systems - a water molecule and a lysozyme molecule in bulk water. We give estimations of the statistical accuracy of the calculations. PMID:24160503

  16. Model-free simulation approach to molecular diffusion tensors

    NASA Astrophysics Data System (ADS)

    Chevrot, Guillaume; Hinsen, Konrad; Kneller, Gerald R.

    2013-10-01

    In the present work, we propose a simple model-free approach for the computation of molecular diffusion tensors from molecular dynamics trajectories. The method uses a rigid body trajectory of the molecule under consideration, which is constructed a posteriori by an accumulation of quaternion-based superposition fits of consecutive conformations. From the rigid body trajectory, we compute the translational and angular velocities of the molecule and by integration of the latter also the corresponding angular trajectory. All quantities can be referred to the laboratory frame and a molecule-fixed frame. The 6 × 6 diffusion tensor is computed from the asymptotic slope of the tensorial mean square displacement and, for comparison, also from the Kubo integral of the velocity correlation tensor. The method is illustrated for two simple model systems - a water molecule and a lysozyme molecule in bulk water. We give estimations of the statistical accuracy of the calculations.

  17. Molecular modeling of the affinity chromatography of monoclonal antibodies.

    PubMed

    Paloni, Matteo; Cavallotti, Carlo

    2015-01-01

    Molecular modeling is a methodology that offers the possibility of studying complex systems such as protein-ligand complexes from an atomistic point of view, making available information that can be difficultly obtained from experimental studies. Here, a protocol for the construction of molecular models of the interaction between antibodies and ligands that can be used for an affinity chromatography process is presented. The outlined methodology focuses mostly on the description of a procedure that may be adopted to determine the structure and free energy of interaction between the antibody and the affinity ligand. A procedure to extend the proposed methodology to include the effect of the environment (buffer solution, spacer, support matrix) is also briefly outlined. PMID:25749965

  18. Supporting Students' Knowledge Transfer in Modeling Activities

    ERIC Educational Resources Information Center

    Piksööt, Jaanika; Sarapuu, Tago

    2014-01-01

    This study investigates ways to enhance secondary school students' knowledge transfer in complex science domains by implementing question prompts. Two samples of students applied two web-based models to study molecular genetics--the model of genetic code (n = 258) and translation (n = 245). For each model, the samples were randomly divided into…

  19. Assessing High School Chemistry Students' Modeling Sub-Skills in a Computerized Molecular Modeling Learning Environment

    ERIC Educational Resources Information Center

    Dori, Yehudit Judy; Kaberman, Zvia

    2012-01-01

    Much knowledge in chemistry exists at a molecular level, inaccessible to direct perception. Chemistry instruction should therefore include multiple visual representations, such as molecular models and symbols. This study describes the implementation and assessment of a learning unit designed for 12th grade chemistry honors students. The organic…

  20. 24 CFR 1006.225 - Model activities.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 24 Housing and Urban Development 4 2012-04-01 2012-04-01 false Model activities. 1006.225 Section... NATIVE HAWAIIAN HOUSING BLOCK GRANT PROGRAM Eligible Activities § 1006.225 Model activities. NHHBG funds may be used for housing activities under model programs that are: (a) Designed to carry out...

  1. 24 CFR 1006.225 - Model activities.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 24 Housing and Urban Development 4 2013-04-01 2013-04-01 false Model activities. 1006.225 Section... NATIVE HAWAIIAN HOUSING BLOCK GRANT PROGRAM Eligible Activities § 1006.225 Model activities. NHHBG funds may be used for housing activities under model programs that are: (a) Designed to carry out...

  2. 24 CFR 1006.225 - Model activities.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 24 Housing and Urban Development 4 2010-04-01 2010-04-01 false Model activities. 1006.225 Section... NATIVE HAWAIIAN HOUSING BLOCK GRANT PROGRAM Eligible Activities § 1006.225 Model activities. NHHBG funds may be used for housing activities under model programs that are: (a) Designed to carry out...

  3. 24 CFR 1006.225 - Model activities.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 24 Housing and Urban Development 4 2011-04-01 2011-04-01 false Model activities. 1006.225 Section... NATIVE HAWAIIAN HOUSING BLOCK GRANT PROGRAM Eligible Activities § 1006.225 Model activities. NHHBG funds may be used for housing activities under model programs that are: (a) Designed to carry out...

  4. 24 CFR 1006.225 - Model activities.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 24 Housing and Urban Development 4 2014-04-01 2014-04-01 false Model activities. 1006.225 Section... NATIVE HAWAIIAN HOUSING BLOCK GRANT PROGRAM Eligible Activities § 1006.225 Model activities. NHHBG funds may be used for housing activities under model programs that are: (a) Designed to carry out...

  5. Modeling of growth factor-receptor systems: from molecular-level protein interaction networks to whole-body compartment models

    PubMed Central

    Wu, Florence T.H.; Stefanini, Marianne O.; Mac Gabhann, Feilim; Popel, Aleksander S.

    2010-01-01

    Most physiological processes are subjected to molecular regulation by growth factors, which are secreted proteins that activate chemical signal transduction pathways through binding of specific cell-surface receptors. One particular growth factor system involved in the in vivo regulation of blood vessel growth is called the vascular endothelial growth factor (VEGF) system. Computational and numerical techniques are well-suited to handle the molecular complexity (the number of binding partners involved, including ligands, receptors, and inert binding sites) and multi-scale nature (intra-tissue vs. inter-tissue transport and local vs. systemic effects within an organism) involved in modeling growth factor system interactions and effects. This paper introduces a variety of in silico models that seek to recapitulate different aspects of VEGF system biology at various spatial and temporal scales: molecular-level kinetic models focus on VEGF ligand-receptor interactions at and near the endothelial cell surface; meso-scale single-tissue 3D models can simulate the effects of multi-cellular tissue architecture on the spatial variation in VEGF ligand production and receptor activation; compartmental modeling allows efficient prediction of average interstitial VEGF concentrations and cell-surface VEGF signaling intensities across multiple large tissue volumes, permitting the investigation of whole-body inter-tissue transport (e.g., vascular permeability and lymphatic drainage). The given examples will demonstrate the utility of computational models in aiding both basic science and clinical research on VEGF systems biology. PMID:19897104

  6. Effect of bead and illustrations models on high school students' achievement in molecular genetics

    NASA Astrophysics Data System (ADS)

    Rotbain, Yosi; Marbach-Ad, Gili; Stavy, Ruth

    2006-05-01

    Our main goal in this study was to explore whether the use of models in molecular genetics instruction in high school can contribute to students' understanding of concepts and processes in genetics. Three comparable groups of 11th and 12th graders participated: The control group (116 students) was taught in the traditional lecture format, while the others received instructions which integrated a bead model (71 students), or an illustration model (71 students). Similar instructions and the same guiding questions accompanied the two models. We used three instruments: a multiple-choice and an open-ended written questionnaire, as well as personal interviews. Five of the multiple-choice questions were also given to students before receiving their genetics instruction (pretest). We found that students who used one of the two types of models improved their knowledge in molecular genetics compared to the control group. However, the open-ended questions revealed that bead model activity was significantly more effective than illustration activity. On the basis of these findings we conclude that, though it is advisable to use a three-dimensional model, such as the bead model, engaging students in activities with illustrations can still improve their achievement in comparison to traditional instruction.

  7. Pharmacological activities in thermal proteins: relationships in molecular evolution

    NASA Technical Reports Server (NTRS)

    Fox, S. W.; Hefti, F.; Hartikka, J.; Junard, E.; Przybylski, A. T.; Vaughan, G.

    1987-01-01

    The model of protobiological events that has been presented in these pages has increasing relevance to pharmacological research. The thermal proteins that function as key substances in the proteinoid theory have recently been found to prolong the survival of rat forebrain neurons in culture and to stimulate the growth of neurites. A search for such activity in thermal proteins added to cultures of modern neurons was suggested by the fact that some of the microspheres assembled from proteinoids rich in hydrophobic amino acids themselves generate fibrous outgrowths.

  8. Activity Prediction and Molecular Mechanism of Bovine Blood Derived Angiotensin I-Converting Enzyme Inhibitory Peptides

    PubMed Central

    Zhang, Ting; Nie, Shaoping; Liu, Boqun; Yu, Yiding; Zhang, Yan; Liu, Jingbo

    2015-01-01

    Development of angiotensin I-converting enzyme (ACE, EC 3.4.15.1) inhibitory peptides from food protein is under extensive research as alternative for the prevention of hypertension. However, it is difficult to identify peptides released from food sources. To accelerate the progress of peptide identification, a three layer back propagation neural network model was established to predict the ACE-inhibitory activity of pentapeptides derived from bovine hemoglobin by simulated enzyme digestion. The pentapeptide WTQRF has the best predicted value with experimental IC50 23.93 μM. The potential molecular mechanism of the WTQRF / ACE interaction was investigated by flexible docking. PMID:25768442

  9. Molecular dynamics simulation study on the molecular structures of the amylin fibril models.

    PubMed

    Xu, Weixin; Su, Haibin; Zhang, John Z H; Mu, Yuguang

    2012-12-01

    The structural characterization of amyloid fibers is one of the most investigated areas in structural biology. Recently, protofibril models for amylin, i.e., the 37-residue human islet amyloid polypeptide or hIAPP were suggested by two groups based on NMR (Biochemistry 2007, 46, 13505-13522) and X-ray (Protein Sci. 2008, 17, 1467-1474) techniques. However, there are significant differences in the two models which maybe originate from the polymorphic nature of amylin fibrils. To obtain further insights into the packing and stability features of the different models, we performed a series of molecular dynamics simulations on them. Our analysis showed that even pairs of β-sheets composed of a limited number of β-strands are stable in the 100-ns simulations, which suggests that steric zipper interactions at a β-sheet-β-sheet interface strongly contribute to the stability of these amyloid aggregates. For both models, outer strands are more flexible, which might coincide with the dynamical requirement that outer strands act as growing sites facilitating conformational changes of new incoming chains. Moreover, simulation results showed that the X-ray models are structurally more compact than the NMR models and have more intimate patterns, which lead to more rigid amyloid models. As a result, the X-ray models are energetically more stable than the NMR models. Further modeling analyses verify the most likely amylin fibril model among both NMR and X-ray models. Upon further study of the force-induced dissociation of a single chain from the protofibrils, the binding energy and the mechanical stability of the fibril models are revealed. On these bases, it is possible to reconcile the crystallographic and the NMR data on the basic amylin fiber unit. PMID:23145779

  10. Characterization, molecular modeling and antimicrobial activity of metal complexes of tridentate Schiff base derived from 5-acetyl-4-hydroxy-2H-1,3-thiazine-2,6(3H)-dione and 2-aminophenol

    NASA Astrophysics Data System (ADS)

    Adly, Omima M. I.

    Metal complexes of Ni(II), Co(II), Cd(II), VO(IV) and UO2(VI) as well as several Cu(II) salts, including Cl,NO3-,AcO,ClO4- and SO4-2 with a tridentate O2N donor Schiff base ligand (H2L), synthesized by condensation of 5-acetyl-4-hydroxy-2H-1,3-thiazine-2,6(3H)-dione with 2-aminophenol, were prepared and characterized on the basis of elemental analyses, spectral, magnetic, molar conductance and thermal gravimetric analysis. Square planar, tetrahedral and octahedral geometries have been assigned to the prepared complexes. Molecular parameters of the ligand and its metal complexes have been calculated and correlated with the experimental data, and the changes of bond lengths are linearly correlated with IR data. The antimicrobial activities of the synthesized compounds were tested in vitro against the sensitive organisms Staphylococcus aureus as Gram positive bacteria, Proteus vulgaris as Gram negative bacteria and Candida albicans as fungus strain, and the results are discussed.

  11. Two Models of Magnetic Support for Photoevaporated Molecular Clouds

    SciTech Connect

    Ryutov, D; Kane, J; Mizuta, A; Pound, M; Remington, B

    2004-05-05

    The thermal pressure inside molecular clouds is insufficient for maintaining the pressure balance at an ablation front at the cloud surface illuminated by nearby UV stars. Most probably, the required stiffness is provided by the magnetic pressure. After surveying existing models of this type, we concentrate on two of them: the model of a quasi-homogeneous magnetic field and the recently proposed model of a ''magnetostatic turbulence''. We discuss observational consequences of the two models, in particular, the structure and the strength of the magnetic field inside the cloud and in the ionized outflow. We comment on the possible role of reconnection events and their observational signatures. We mention laboratory experiments where the most significant features of the models can be tested.

  12. Mechanistic modeling confronts the complexity of molecular cell biology.

    PubMed

    Phair, Robert D

    2014-11-01

    Mechanistic modeling has the potential to transform how cell biologists contend with the inescapable complexity of modern biology. I am a physiologist-electrical engineer-systems biologist who has been working at the level of cell biology for the past 24 years. This perspective aims 1) to convey why we build models, 2) to enumerate the major approaches to modeling and their philosophical differences, 3) to address some recurrent concerns raised by experimentalists, and then 4) to imagine a future in which teams of experimentalists and modelers build-and subject to exhaustive experimental tests-models covering the entire spectrum from molecular cell biology to human pathophysiology. There is, in my view, no technical obstacle to this future, but it will require some plasticity in the biological research mind-set. PMID:25368428

  13. Importance of molecular computer modeling in anticancer drug development.

    PubMed

    Geromichalos, George D

    2007-09-01

    Increasing insight into the genetics and molecular biology of cancer has resulted in the identification of an increasing number of potential molecular targets for anticancer drug discovery and development. These targets can be approached through exploitation of emerging structural biology, "rational" drug design, screening of chemical libraries, or a combination of these methods. The result is the rapid discovery of new anticancer drugs. The processes used by academic and industrial scientists to discover new drugs has recently experienced a true renaissance with many new and exciting techniques being developed in the past 5-10 years. In this review, we will attempt to outline these latest protocols that chemists and biomedical scientists are currently employing to rapidly bring new drugs to the clinic. Structure-based drug design is perhaps the most elegant approach for discovering compounds exhibiting high specificity and efficacy. Nowadays, a number of recent successful drugs have in part or in whole emerged from a structure-based research approach. Many advances including crystallography and informatics are behind these successes. Of great importance is also the impact these advances in structure-based drug design are likely to have on the economics of drug discovery. As the structures of more and more proteins and nucleic acids become available, molecular docking is increasingly considered for lead discovery. Recent studies consider the hit-rate enhancement of docking screens and the accuracy of docking structure predictions. As more structures are determined experimentally, docking against homology-modeled targets also becomes possible for more proteins. With more docking studies being undertaken, the "drug-likeness" and specificity of docking hits is also being examined. In this article we discuss the application of molecular modeling, molecular docking and virtual molecular high-throughput, targeted drug screening to anticancer drug discovery. Currently

  14. Molecular Docking Screens Using Comparative Models of Proteins

    PubMed Central

    Fan, Hao; Irwin, John J.; Webb, Benjamin M.; Klebe, Gerhard; Shoichet, Brian K.; Sali, Andrej

    2009-01-01

    Two orders of magnitude more protein sequences can be modeled by comparative modeling than have been determined by X-ray crystallography and NMR spectroscopy. Investigators have nevertheless been cautious about using comparative models for ligand discovery because of concerns about model errors. We suggest how to exploit comparative models for molecular screens, based on docking against a wide range of crystallographic structures and comparative models with known ligands. To account for the variation in the ligand-binding pocket as it binds different ligands, we calculate “consensus” enrichment by ranking each library compound by its best docking score against all available comparative models and/or modeling templates. For the majority of the targets, the consensus enrichment for multiple models was better or comparable to that of the holo and apo X-ray structures. Even for single models, the models are significantly more enriching than the template structure if the template is paralogous and shares more than 25% sequence identity with the target. PMID:19845314

  15. Three dimensional quantitative structure-activity relationships of sulfonamides binding monoclonal antibody by comparative molecular field analysis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The three-dimensional quantitative structure-activity relationship (3D-QSAR) model of sulfonamide analogs, binding a monoclonal antibody (MabSMR) produced against sulfamerazine was carried out by comparative molecular field analysis (CoMFA). The affinities of MabSMR, expressed as Log10IC50, for 17 ...

  16. Molecular Dynamics Simulations of Fracture of Model Epoxies

    SciTech Connect

    STEVENS,MARK J.

    2000-01-18

    The failure of thermosetting polymer adhesives is an important problem which particularly lacks understanding from the molecular viewpoint. While linear elastic fracture mechanics works well for such polymers far from the crack tip, the method breaks down near the crack tip where large plastic deformation occurs and the molecular details become important [1]. Results of molecular dynamics simulations of highly crosslinked polymer networks bonded to a solid surface are presented here. Epoxies are used as the guide for modeling. The focus of the simulations is the network connectivity and the interfacial strength. In a random network, the bond stress is expected to vary, and the most stressed bonds will break first [2]. Crack initiation should occur where a cluster of highly constrained bonds exists. There is no reason to expect crack initiation to occur at the interface. The results to be presented show that the solid surface limits the interfacial bonding resulting in stressed interfacial bonds and interfacial fracture. The bonds in highly-crosslinked random networks do not become stressed as expected. The sequence of molecular structural deformations that lead to failure has been determined and found to be strongly dependent upon the network connectivity. The structure of these networks and its influence on the stress-strain behavior will be discussed in general. A set of ideal, ordered networks have been constructed to manipulate the deformation sequence to achieve different fracture modes (i.e. cohesive vs. adhesive).

  17. MOLECULAR MODEL OF CYTOTOXIN-1 FROM NAJA MOSSAMBICA MOSSAMBICA VENOM IN COMPLEX WITH CHYMOTRYPSIN.

    PubMed

    Munawar, Aisha; Akrem, Ahmed; Hussain, Ashiq; Spencer, Patrick; Betzel, Christian

    2015-01-01

    Snake venom is a myriad of biologically active proteins and peptides. Three finger toxins are highly conserved in their molecular structure, but interestingly possess diverse biological functions. During the course of evolution the introduction of subtle mutations in loop regions and slight variations in the three dimensional structure, has resulted in their functional versatility. Cytotoxin-1 (UniProt ID: P01467), isolated from Naja mossambica mossambica, showed the potential to inhibit chymotrypsin and the chymotryptic activity of the 20S proteasome. In the present work we describe a molecular model of cytotoxin-1 in complex with chymotrypsin, prepared by the online server ClusPro. Analysis of the molecular model shows that Cytotoxin-1 (P01467) binds to chymotrypsin through its loop I located near the N-terminus. The concave side of loop I of the toxin fits well in the substrate binding pocket of the protease. We propose Phe10 as the dedicated P1 site of the ligand. Being a potent inhibitor of the 20S proteasome, cytotoxin-1 (P01467) can serve as a potential antitumor agent. Already snake venom cytotoxins have been investigated for their ability as an anticancer agent. The molecular model of cytotoxin-1 in complex with chymotrypsin provides important information towards understanding the complex formation. PMID:27167912

  18. Towards synthetic molecular motors: a model elastic-network study

    NASA Astrophysics Data System (ADS)

    Sarkar, Amartya; Flechsig, Holger; Mikhailov, Alexander S.

    2016-04-01

    Protein molecular motors play a fundamental role in biological cells and development of their synthetic counterparts is a major challenge. Here, we show how a model motor system with the operation mechanism resembling that of muscle myosin can be designed at the concept level, without addressing the implementation aspects. The model is constructed as an elastic network, similar to the coarse-grained descriptions used for real proteins. We show by numerical simulations that the designed synthetic motor can operate as a deterministic or Brownian ratchet and that there is a continuous transition between such two regimes. The motor operation under external load, approaching the stall condition, is also analysed.

  19. Micro- and Nanostructured Materials for Active Devices and Molecular Electronics

    SciTech Connect

    Martin, Peter M.; Graff, Gordon L.; Gross, Mark E.; Burrows, Paul E.; Bennett, Wendy D.; Mast, Eric S.; Hall, Michael G.; Bonham, Charles C.; Zumhoff, Mac R.; Williford, Rick E.

    2003-10-01

    Traditional single layer barrier coatings are not adequate in preventing degradation of the performance of organic molecular electronic and other active devices. Most advanced devices used in display technology now consist of micro and nanostructured small molecule, polymer and inorganic coatings with thin high reactive group 1A metals. This includes organic electronics such as organic light emitting devices (OLED). The lifetimes of these devices rapidly degrades when they are exposed to atmospheric oxygen and water vapor. Thin film photovoltaics and batteries are also susceptible to degradation by moisture and oxygen. Using in-line coating techniques we apply a composite nanostructured inorganic/polymer thin film barrier that restricts moisture and oxygen permeation to undetectable levels using conventional permeation test equipment. We describe permeation mechanisms for this encapsulation coating and flat panel display and other device applications. Permeation through the multilayer barrier coating is defect and pore limited and can be described by Knudsen diffusion involving a long and tortuous path. Device lifetime is also enhanced by the long lag times required to reach the steady state flux regime. Permeation rates in the range of 10-6 cc,g/m2/d have been achieved and OLED device lifetimes. The structure is robust, yet flexible. The resulting device performance and lifetimes will also be described. The barrier film can be capped with a thin film of transparent conductive oxide yielding an engineered nanostructured device for next generation, rugged, lightweight or flexible displays. This enables, for the first time, thin film encapsulation of emissive organic displays.

  20. Photodynamic activation as a molecular switch to promote osteoblast cell differentiation via AP-1 activation.

    PubMed

    Kushibiki, Toshihiro; Tu, Yupeng; Abu-Yousif, Adnan O; Hasan, Tayyaba

    2015-01-01

    In photodynamic therapy (PDT), cells are impregnated with a photosensitizing agent that is activated by light irradiation, thereby photochemically generating reactive oxygen species (ROS). The amounts of ROS produced depends on the PDT dose and the nature of the photosensitizer. Although high levels of ROS are cytotoxic, at physiological levels they play a key role as second messengers in cellular signaling pathways, pluripotency, and differentiation of stem cells. To investigate further the use of photochemically triggered manipulation of such pathways, we exposed mouse osteoblast precursor cells and rat primary mesenchymal stromal cells to low-dose PDT. Our results demonstrate that low-dose PDT can promote osteoblast differentiation via the activation of activator protein-1 (AP-1). Although PDT has been used primarily as an anti-cancer therapy, the use of light as a photochemical "molecular switch" to promote differentiation should expand the utility of this method in basic research and clinical applications. PMID:26279470

  1. Photodynamic activation as a molecular switch to promote osteoblast cell differentiation via AP-1 activation

    PubMed Central

    Kushibiki, Toshihiro; Tu, Yupeng; Abu-Yousif, Adnan O.; Hasan, Tayyaba

    2015-01-01

    In photodynamic therapy (PDT), cells are impregnated with a photosensitizing agent that is activated by light irradiation, thereby photochemically generating reactive oxygen species (ROS). The amounts of ROS produced depends on the PDT dose and the nature of the photosensitizer. Although high levels of ROS are cytotoxic, at physiological levels they play a key role as second messengers in cellular signaling pathways, pluripotency, and differentiation of stem cells. To investigate further the use of photochemically triggered manipulation of such pathways, we exposed mouse osteoblast precursor cells and rat primary mesenchymal stromal cells to low-dose PDT. Our results demonstrate that low-dose PDT can promote osteoblast differentiation via the activation of activator protein-1 (AP-1). Although PDT has been used primarily as an anti-cancer therapy, the use of light as a photochemical “molecular switch” to promote differentiation should expand the utility of this method in basic research and clinical applications. PMID:26279470

  2. Neutral dioxovanadium(V) complexes of biomimetic hydrazones ONO donor ligands of bioinorganic and medicinal relevance: Synthesis via air oxidation of bis(acetylaceto-nato)oxovanadium(IV), characterization, biological activity and 3D molecular modeling

    NASA Astrophysics Data System (ADS)

    Maurya, R. C.; Rajput, S.

    2007-05-01

    The interaction of bis(acetylacetonato)oxovanadium(IV), [VO(acac) 2] with biomimetic hydrazone ONO donor ligands HL in 1:1 mole ratio [where, HL = N-(4'-benzoylidene-3'-methyl-1'-phenyl-2'-pyrazolin-5'-one)-isonicotinic acid hydrazide (bmphp-inH, I), N-(4'-butyrylidene-3'-methyl-1'-phenyl-2'-pyrazolin-5'-one)-isonicotinic acid hydrazide (bumphp-inH, II), N-(4'-acetylidene-3'-methyl-1'-phenyl-2'-pyrazolin-5'-one)-isonicotinic acid hydrazide (amphp-inH, III), N-(3'-methyl-1'-phenyl-4'-propionylidene-2'-pyrazolin-5'-one)-isonicotinic acid hydrazide (mphpp-inH, IV) and N-(4'- iso-butyrylidene-3'-methyl-1'-phenyl-2'-pyrazolin-5'-one)-isonicotinic acid hydrazide ( iso-bumphp-inH, V)] in a mixed solvent (ethanol-methanol, 1:10) via aerial oxidation for 2-3 days yield dioxovanadium(V) complexes of composition [VO 2(L)(H 2O)] · H 2O. The compounds so obtained were characterized on the basis of elemental analyses, thermogravimetry, vanadium determination, IR, Electronic, 51V NMR, 1H NMR and mass spectral studies. The 3D molecular modeling and analysis for bond lengths and bond angles have also been carried out for one of the representative compounds, [VO 2(ampph-in)(H 2O)] ( 3).

  3. An optimized molecular inclusion complex of diferuloylmethane: enhanced physical properties and biological activity

    PubMed Central

    Tan, Qunyou; Li, Yi; Wu, Jianyong; Mei, Hu; Zhao, Chunjing; Zhang, Jingqing

    2012-01-01

    Objective The purpose of this study was to explore and evaluate the enhanced physical properties and biological activity of a molecular inclusion complex (MICDH) comprising diferuloylmethane (DFM) and hydroxypropyl-β-cyclodextrin. Methods The preparation conditions of MICDH were optimized using an orthogonal experimental design. The solubility, in vitro release and model fitting, microscopic morphology, molecular structure simulation, anti-lung cancer activity, and action mechanism of MICDH were evaluated. Results The solubility of DFM was improved 4400-fold upon complexation with hydroxypropyl-β-cyclodextrin. The release rate of DFM was significantly higher from MICDH than from free DFM. MICDH exhibited higher antitumor activity against human lung adenocarcinoma A549 cells than free DFM. More cells were arrested in the S/G2 phase of the cell cycle or were induced to undergo apoptosis when treated with MICDH than when treated with free DFM. Furthermore, increased reactive oxygen species and intracellular calcium ion levels and decreased mitochondrial membrane potential were observed in cells treated with MICDH. Conclusion MICDH markedly improved the physical properties and antitumor activity of DFM. MICDH may prove to be a preferred alternative to free DFM as a formulation for DFM delivery in lung cancer treatment. PMID:23091376

  4. Libraries of Extremely Localized Molecular Orbitals. 1. Model Molecules Approximation and Molecular Orbitals Transferability.

    PubMed

    Meyer, Benjamin; Guillot, Benoît; Ruiz-Lopez, Manuel F; Genoni, Alessandro

    2016-03-01

    Despite more and more remarkable computational ab initio results are nowadays continuously obtained for large macromolecular systems, the development of new linear-scaling techniques is still an open and stimulating field of research in theoretical chemistry. In this family of methods, an important role is occupied by those strategies based on the observation that molecules are generally constituted by recurrent functional units with well-defined intrinsic features. In this context, we propose to exploit the notion of extremely localized molecular orbitals (ELMOs) that, due to their strict localization on small molecular fragments (e.g., atoms, bonds, or functional groups), are in principle transferable from one molecule to another. Accordingly, the construction of orbital libraries to almost instantaneously build up approximate wave functions and electron densities of very large systems becomes conceivable. In this work, the ELMOs transferability is further investigated in detail and, furthermore, suitable rules to construct model molecules for the computation of ELMOs to be stored in future databanks are also defined. The obtained results confirm the reliable transferability of the ELMOs and show that electron densities obtained from the transfer of extremely localized molecular orbitals are very close to the corresponding Hartree-Fock ones. These observations prompt us to construct new ELMOs databases that could represent an alternative/complement to the already popular pseudoatoms databanks both for determining electron densities and for refining crystallographic structures of very large molecules. PMID:26799516

  5. Coumarins as Potential Antioxidant Agents Complemented with Suggested Mechanisms and Approved by Molecular Modeling Studies.

    PubMed

    Al-Majedy, Yasameen K; Al-Duhaidahawi, Dunya L; Al-Azawi, Khalida F; Al-Amiery, Ahmed A; Kadhum, Abdul Amir H; Mohamad, Abu Bakar

    2016-01-01

    Syntheses of coumarins, which are a structurally interesting antioxidant activity, was done in this article. The modification of 7-hydroxycoumarin by different reaction steps was done to yield target compounds. Molecular structures were characterized by different spectroscopical techniques (Fourier transformation infrared and nuclear magnetic resonance). Antioxidant activities were performed by using various in vitro spectrophometric assays against 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and hydrogen peroxide (H2O2). All compounds exhibited high efficiency as antioxidants compared to ascorbic acid. The highest efficiency scavenging activity was found for compound 3 (91.0 ± 5.0), followed by compounds 2 and 4 (88.0 ± 2.00; and 87.0 ± 3.00). Ascorbic acid C was used as a standard drug with a percentage inhibition of 91.00 ± 1.5. The mechanism of the synthesized compounds as antioxidants was also studied. Hartree-Fock-based quantum chemical studies have been carried out with the basis set to 3-21G, in order to obtain information about the three-dimensional (3D) geometries, electronic structure, molecular modeling, and electronic levels, namely HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital), to understand the antioxidant activity for the synthesized compounds. PMID:26805811

  6. COMPUTER-ASSISTED STUDIES OF MOLECULAR STRUCTURE-BIOLOGICAL ACTIVITY RELATIONSHIPS

    EPA Science Inventory

    Computer-assisted methods can be used to investigate the relationships between the molecular structures of compounds and their biological activity. A number of approaches have been reported in the literature, including correlations of activity with substituent constants, conforma...

  7. Staphylococcal SplB serine protease utilizes a novel molecular mechanism of activation.

    PubMed

    Pustelny, Katarzyna; Zdzalik, Michal; Stach, Natalia; Stec-Niemczyk, Justyna; Cichon, Przemyslaw; Czarna, Anna; Popowicz, Grzegorz; Mak, Pawel; Drag, Marcin; Salvesen, Guy S; Wladyka, Benedykt; Potempa, Jan; Dubin, Adam; Dubin, Grzegorz

    2014-05-30

    Staphylococcal SplB protease belongs to the chymotrypsin family. Chymotrypsin zymogen is activated by proteolytic processing at the N terminus, resulting in significant structural rearrangement at the active site. Here, we demonstrate that the molecular mechanism of SplB protease activation differs significantly and we characterize the novel mechanism in detail. Using peptide and protein substrates we show that the native signal peptide, or any N-terminal extension, has an inhibitory effect on SplB. Only precise N-terminal processing releases the full proteolytic activity of the wild type analogously to chymotrypsin. However, comparison of the crystal structures of mature SplB and a zymogen mimic show no rearrangement at the active site whatsoever. Instead, only the formation of a unique hydrogen bond network, distant form the active site, by the new N-terminal glutamic acid of mature SplB is observed. The importance of this network and influence of particular hydrogen bond interactions at the N terminus on the catalytic process is demonstrated by evaluating the kinetics of a series of mutants. The results allow us to propose a consistent model where changes in the overall protein dynamics rather than structural rearrangement of the active site are involved in the activation process. PMID:24713703

  8. Modelling of Cosmic Molecular Masers: Introduction to a Computation Cookbook

    NASA Astrophysics Data System (ADS)

    Sobolev, Andrej M.; Gray, Malcolm D.

    2012-07-01

    Numerical modeling of molecular masers is necessary in order to understand their nature and diagnostic capabilities. Model construction requires elaboration of a basic description which allows computation, that is a definition of the parameter space and basic physical relations. Usually, this requires additional thorough studies that can consist of the following stages/parts: relevant molecular spectroscopy and collisional rate coefficients; conditions in and around the masing region (that part of space where population inversion is realized); geometry and size of the masing region (including the question of whether maser spots are discrete clumps or line-of-sight correlations in a much bigger region) and propagation of maser radiation. Output of the maser computer modeling can have the following forms: exploration of parameter space (where do inversions appear in particular maser transitions and their combinations, which parameter values describe a `typical' source, and so on); modeling of individual sources (line flux ratios, spectra, images and their variability); analysis of the pumping mechanism; predictions (new maser transitions, correlations in variability of different maser transitions, and the like). Described schemes (constituents and hierarchy) of the model input and output are based mainly on the experience of the authors and make no claim to be dogmatic.

  9. Molecular models need to be tested: the case of a solar flares discoidal HDL model.

    PubMed

    Shih, Amy Y; Sligar, Stephen G; Schulten, Klaus

    2008-06-01

    In the absence of atomic structures of high-density lipoproteins in their lipid-bound states, many molecular models have been produced based on experimental data. Using molecular dynamics, we show that a recently proposed "solar-flares" model of discoidal high-density lipoprotein is implausible. Our simulations show a collapse of the protruding solar-flare loops and a notable protein rearrangement due to an energetically unfavorable orientation of the hydrophobic protein surface toward the aqueous solvent. PMID:18375520

  10. Laboratory Activities to Support Student Understanding of the Molecular Mechanisms of Mutation & Natural Selection

    ERIC Educational Resources Information Center

    Hubler, Tina; Adams, Patti; Scammell, Jonathan

    2015-01-01

    The molecular basis of evolution is an important and challenging concept for students to understand. In a previous article, we provided some of the scientific background necessary to teach this topic. This article features a series of laboratory activities demonstrating that molecular events can alter the genomes of organisms. These activities are…

  11. cAMP-specific phosphodiesterase HSPDE4D3 mutants which mimic activation and changes in rolipram inhibition triggered by protein kinase A phosphorylation of Ser-54: generation of a molecular model.

    PubMed Central

    Hoffmann, R; Wilkinson, I R; McCallum, J F; Engels, P; Houslay, M D

    1998-01-01

    Ser-13 and Ser-54 were shown to provide the sole sites for the protein kinase A (PKA)-mediated phosphorylation of the human cAMP-specific phosphodiesterase isoform HSPDE4D3. The ability of PKA to phosphorylate and activate HSPDE4D3 was mimicked by replacing Ser-54 with either of the negatively charged amino acids, aspartate or glutamate, within the consensus motif of RRES54. The PDE4 selective inhibitor rolipram ¿4-[3-(cyclopentoxy)-4-methoxyphenyl]-2-pyrrolidone¿ inhibited both PKA-phosphorylated HSPDE4D3 and the Ser-54-->Asp mutant, with an IC50 value that was approximately 8-fold lower than that seen for the non-PKA-phosphorylated enzyme. Lower IC50 values for inhibition by rolipram were seen for a wide range of non-activated residue 54 mutants, except for those which had side-chains able to serve as hydrogen-bond donors, namely the Ser-54-->Thr, Ser-54-->Tyr and Ser-54-->Cys mutants. The Glu-53-->Ala mutant exhibited an activity comparable with that of the PKA phosphorylated native enzyme and the Ser-54-->Asp mutant but, in contrast to the native enzyme, was insensitive to activation by PKA, despite being more rapidly phosphorylated by this protein kinase. The activated Glu-53-->Ala mutant exhibited a sensitivity to inhibition by rolipram which was unchanged from that of the native enzyme. The double mutant, Arg-51-->Ala/Arg-52-->Ala, showed no change in either enzyme activity or rolipram inhibition from the native enzyme and was incapable of providing a substrate for PKA phosphorylation at Ser-54. No difference in inhibition by dipyridamole was seen for the native enzyme and the Ser-54-->Asp and Ser-54-->Ala mutants. A model is proposed which envisages that phosphorylation by PKA triggers at least two distinct conformational changes in HSPDE4D3; one of these gives rise to enzyme activation and another enhances sensitivity to inhibition by rolipram. Activation of HSPDE4D3 by PKA-mediated phosphorylation is suggested to involve disruption of an ion

  12. Molecular Imaging of Vulnerable Atherosclerotic Plaques in Animal Models.

    PubMed

    Gargiulo, Sara; Gramanzini, Matteo; Mancini, Marcello

    2016-01-01

    Atherosclerosis is characterized by intimal plaques of the arterial vessels that develop slowly and, in some cases, may undergo spontaneous rupture with subsequent heart attack or stroke. Currently, noninvasive diagnostic tools are inadequate to screen atherosclerotic lesions at high risk of acute complications. Therefore, the attention of the scientific community has been focused on the use of molecular imaging for identifying vulnerable plaques. Genetically engineered murine models such as ApoE(-/-) and ApoE(-/-)Fbn1C1039G(+/-) mice have been shown to be useful for testing new probes targeting biomarkers of relevant molecular processes for the characterization of vulnerable plaques, such as vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, intercellular adhesion molecule (ICAM)-1, P-selectin, and integrins, and for the potential development of translational tools to identify high-risk patients who could benefit from early therapeutic interventions. This review summarizes the main animal models of vulnerable plaques, with an emphasis on genetically altered mice, and the state-of-the-art preclinical molecular imaging strategies. PMID:27618031

  13. Biological evaluation and molecular modelling study of thiosemicarbazide derivatives as bacterial type IIA topoisomerases inhibitors.

    PubMed

    Paneth, Agata; Stączek, Paweł; Plech, Tomasz; Strzelczyk, Aleksandra; Dzitko, Katarzyna; Wujec, Monika; Kuśmierz, Edyta; Kosikowska, Urszula; Grzegorczyk, Agnieszka; Paneth, Piotr

    2016-01-01

    In the present article, we describe the inhibitory potency of nine thiosemicarbazide derivatives against bacterial type IIA topoisomerases, their antibacterial profile and molecular modelling evaluation. We found that one of the tested compounds, compound 7, significantly inhibits activity of Staphylococcus aureus DNA gyrase with an IC(50) below 15 μM. Besides, this compound displays antibacterial activity on reference Staphylococuss spp. and Enterococcus faecalis strains as well as clinical S. aureus isolates at non-cytotoxic concentrations in mammalian cells with MIC values ranging from 16 to 32 μg/mL thereby indicating, in some cases, equipotent or even more effective action than standard drugs such as vancomycin, ampicillin and nitrofurantoin. The computational studies showed that both molecular geometry and the electron density distribution have a great impact on antibacterial activity of thiosemicarbazide derivatives. PMID:25792505

  14. Structural and molecular modeling studies of quinazolinone anticonvulsants.

    PubMed

    Duke, N E; Codding, P W

    1993-08-01

    Studies of derivatives of the anticonvulsant methaqualone led to the discovery that unsaturation in the 2-substituent produced active but less toxic compounds; accordingly, 2-arylethanone derivatives have been developed. The crystal structures of five 2-arylethanone derivatives of methaqualone were determined to probe structure-activity relationships. Although these compounds display different activities, the solid-state and calculated structures are similar: each compound is observed as the neamine tautomer containing an intramolecular hydrogen bond between the ethanone and the amine N atom and the molecular conformations are the same. These studies conclude that recognition of the anticonvulsants arises from specific binding of an ortho substituent on the N(3) phenyl substituent, rather than from binding of a particular conformation or tautomeric form adopted by the compound containing an ortho substituent, and that such recognition is characteristic of a broad range of anticonvulsant drugs. Crystal data: [see text]. PMID:8397980

  15. Wanted: Active Role Models for Today's Kids

    MedlinePlus

    ... this page please turn Javascript on. Feature: Reducing Childhood Obesity Wanted: Active Role Models for Today's Kids Past ... the active role models they can get. "With childhood obesity at an all-time high, we need to ...

  16. A Model of How Different Biology Experts Explain Molecular and Cellular Mechanisms

    PubMed Central

    Trujillo, Caleb M.; Anderson, Trevor R.; Pelaez, Nancy J.

    2015-01-01

    Constructing explanations is an essential skill for all science learners. The goal of this project was to model the key components of expert explanation of molecular and cellular mechanisms. As such, we asked: What is an appropriate model of the components of explanation used by biology experts to explain molecular and cellular mechanisms? Do explanations made by experts from different biology subdisciplines at a university support the validity of this model? Guided by the modeling framework of R. S. Justi and J. K. Gilbert, the validity of an initial model was tested by asking seven biologists to explain a molecular mechanism of their choice. Data were collected from interviews, artifacts, and drawings, and then subjected to thematic analysis. We found that biologists explained the specific activities and organization of entities of the mechanism. In addition, they contextualized explanations according to their biological and social significance; integrated explanations with methods, instruments, and measurements; and used analogies and narrated stories. The derived methods, analogies, context, and how themes informed the development of our final MACH model of mechanistic explanations. Future research will test the potential of the MACH model as a guiding framework for instruction to enhance the quality of student explanations. PMID:25999313

  17. Molecular modeling of organophosphorous agents and their aqueous solutions.

    PubMed

    Vishnyakov, Aleksey; Gor, Gennady Yu; Lee, Ming-Tsung; Neimark, Alexander V

    2011-05-26

    Using molecular dynamics simulations, we modeled solvation and diffusion in aqueous solutions of organophosphorous compounds, including nerve G-agents sarin and soman (methylphosphonofluoridates) and their common simulants DMMP (dimethyl methylphosphonate) and DIFP (diisopropyl fluorophosphate). The aqueous solutions of the organophosphorous compounds were found to display complex molecular scale structures and dynamic properties due to competing interactions between strongly hydrophobic and hydrophilic groups. The mixing of agents with water was proved to be exothermic with negative excess mixing volume, indicating a strongly hydrophilic solvation. This effect was confirmed in a specially performed experiment. We discuss to what extent DMMP and DIFP are suitable simulants for G-agents in experimental studies, as far as their interactions with water are concerned. We also focus on the relevance of the structural features and mobilities of agents in water to their interactions with permselective polyelectrolyte membranes that may be employed as protective barriers against chemical warfare agents. PMID:21542641

  18. Molecular Mechanisms of Large-Conductance Ca2+-Activated Potassium Channel Activation by Ginseng Gintonin

    PubMed Central

    Choi, S. H.; Lee, B. H.; Hwang, S. H.; Kim, H. J.; Lee, S. M.; Kim, H. C.; Rhim, H. W.; Nah, S. Y.

    2013-01-01

    Gintonin is a unique lysophosphatidic acid (LPA) receptor ligand found in Panax ginseng. Gintonin induces transient [Ca2+]i through G protein-coupled LPA receptors. Large-conductance Ca2+-activated K+ (BKCa) channels are expressed in blood vessels and neurons and play important roles in blood vessel relaxation and attenuation of neuronal excitability. BKCa channels are activated by transient [Ca2+]i and are regulated by various Ca2+-dependent kinases. We investigated the molecular mechanisms of BKCa channel activation by gintonin. BKCa channels are heterologously expressed in Xenopus oocytes. Gintonin treatment induced BKCa channel activation in oocytes expressing the BKCa channel α subunit in a concentration-dependent manner (EC50 = 0.71 ± 0.08 µg/mL). Gintonin-mediated BKCa channel activation was blocked by a PKC inhibitor, calphostin, and by the calmodulin inhibitor, calmidazolium. Site-directed mutations in BKCa channels targeting CaM kinase II or PKC phosphorylation sites but not PKA phosphorylation sites attenuated gintonin action. Mutations in the Ca2+ bowl and the regulator of K+ conductance (RCK) site also blocked gintonin action. These results indicate that gintonin-mediated BKCa channel activations are achieved through LPA1 receptor-phospholipase C-IP3-Ca2+-PKC-calmodulin-CaM kinase II pathways and calcium binding to the Ca2+ bowl and RCK domain. Gintonin could be a novel contributor against blood vessel constriction and over-excitation of neurons. PMID:23662129

  19. Analysis of conjugation of chloramphenicol and hemoglobin by fluorescence, circular dichroism and molecular modeling

    NASA Astrophysics Data System (ADS)

    Ding, Fei; Liu, Wei; Sun, Ye; Yang, Xin-Ling; Sun, Ying; Zhang, Li

    2012-01-01

    Chloramphenicol is a low cost, broad spectrum, highly active antibiotic, and widely used in the treatment of serious infections, including typhoid fever and other life-threatening infections of the central nervous system and respiratory tract. The purpose of the present study was to examine the conjugation of chloramphenicol with hemoglobin (Hb) and compared with albumin at molecular level, utilizing fluorescence, UV/vis absorption, circular dichroism (CD) as well as molecular modeling. Fluorescence data indicate that drug bind Hb generate quenching via static mechanism, this corroborates UV/vis absorption measurements that the ground state complex formation with an affinity of 10 4 M -1, and the driving forces in the Hb-drug complex are hydrophilic interactions and hydrogen bonds, as derived from computational model. The accurate binding site of drug has been identified from the analysis of fluorescence and molecular modeling, α1β2 interface of Hb was assigned to possess high-affinity for drug, which located at the β-37 Trp nearby. The structural investigation of the complexed Hb by synchronous fluorescence, UV/vis absorption, and CD observations revealed some degree of Hb structure unfolding upon complexation. Based on molecular modeling, we can draw the conclusion that the binding affinity of drug with albumin is superior, compared with Hb. These phenomena can provide salient information on the absorption, distribution, pharmacology, and toxicity of chloramphenicol and other drugs which have analogous configuration with chloramphenicol.

  20. Physics Beyond the Standard Model from Molecular Hydrogen Spectroscopy

    NASA Astrophysics Data System (ADS)

    Ubachs, Wim; Salumbides, Edcel John; Bagdonaite, Julija

    2015-06-01

    The spectrum of molecular hydrogen can be measured in the laboratory to very high precision using advanced laser and molecular beam techniques, as well as frequency-comb based calibration [1,2]. The quantum level structure of this smallest neutral molecule can now be calculated to very high precision, based on a very accurate (10-15 precision) Born-Oppenheimer potential [3] and including subtle non-adiabatic, relativistic and quantum electrodynamic effects [4]. Comparison between theory and experiment yields a test of QED, and in fact of the Standard Model of Physics, since the weak, strong and gravitational forces have a negligible effect. Even fifth forces beyond the Standard Model can be searched for [5]. Astronomical observation of molecular hydrogen spectra, using the largest telescopes on Earth and in space, may reveal possible variations of fundamental constants on a cosmological time scale [6]. A study has been performed at a 'look-back' time of 12.5 billion years [7]. In addition the possible dependence of a fundamental constant on a gravitational field has been investigated from observation of molecular hydrogen in the photospheres of white dwarfs [8]. The latter involves a test of the Einsteins equivalence principle. [1] E.J. Salumbides et al., Phys. Rev. Lett. 107, 143005 (2011). [2] G. Dickenson et al., Phys. Rev. Lett. 110, 193601 (2013). [3] K. Pachucki, Phys. Rev. A82, 032509 (2010). [4] J. Komasa et al., J. Chem. Theory Comp. 7, 3105 (2011). [5] E.J. Salumbides et al., Phys. Rev. D87, 112008 (2013). [6] F. van Weerdenburg et al., Phys. Rev. Lett. 106, 180802 (2011). [7] J. Badonaite et al., Phys. Rev. Lett. 114, 071301 (2015). [8] J. Bagdonaite et al., Phys. Rev. Lett. 113, 123002 (2014).

  1. A computational kinetic model of diffusion for molecular systems

    PubMed Central

    Teo, Ivan; Schulten, Klaus

    2013-01-01

    Regulation of biomolecular transport in cells involves intra-protein steps like gating and passage through channels, but these steps are preceded by extra-protein steps, namely, diffusive approach and admittance of solutes. The extra-protein steps develop over a 10–100 nm length scale typically in a highly particular environment, characterized through the protein's geometry, surrounding electrostatic field, and location. In order to account for solute energetics and mobility of solutes in this environment at a relevant resolution, we propose a particle-based kinetic model of diffusion based on a Markov State Model framework. Prerequisite input data consist of diffusion coefficient and potential of mean force maps generated from extensive molecular dynamics simulations of proteins and their environment that sample multi-nanosecond durations. The suggested diffusion model can describe transport processes beyond microsecond duration, relevant for biological function and beyond the realm of molecular dynamics simulation. For this purpose the systems are represented by a discrete set of states specified by the positions, volumes, and surface elements of Voronoi grid cells distributed according to a density function resolving the often intricate relevant diffusion space. Validation tests carried out for generic diffusion spaces show that the model and the associated Brownian motion algorithm are viable over a large range of parameter values such as time step, diffusion coefficient, and grid density. A concrete application of the method is demonstrated for ion diffusion around and through the Eschericia coli mechanosensitive channel of small conductance ecMscS. PMID:24089741

  2. A computational kinetic model of diffusion for molecular systems

    NASA Astrophysics Data System (ADS)

    Teo, Ivan; Schulten, Klaus

    2013-09-01

    Regulation of biomolecular transport in cells involves intra-protein steps like gating and passage through channels, but these steps are preceded by extra-protein steps, namely, diffusive approach and admittance of solutes. The extra-protein steps develop over a 10-100 nm length scale typically in a highly particular environment, characterized through the protein's geometry, surrounding electrostatic field, and location. In order to account for solute energetics and mobility of solutes in this environment at a relevant resolution, we propose a particle-based kinetic model of diffusion based on a Markov State Model framework. Prerequisite input data consist of diffusion coefficient and potential of mean force maps generated from extensive molecular dynamics simulations of proteins and their environment that sample multi-nanosecond durations. The suggested diffusion model can describe transport processes beyond microsecond duration, relevant for biological function and beyond the realm of molecular dynamics simulation. For this purpose the systems are represented by a discrete set of states specified by the positions, volumes, and surface elements of Voronoi grid cells distributed according to a density function resolving the often intricate relevant diffusion space. Validation tests carried out for generic diffusion spaces show that the model and the associated Brownian motion algorithm are viable over a large range of parameter values such as time step, diffusion coefficient, and grid density. A concrete application of the method is demonstrated for ion diffusion around and through the Eschericia coli mechanosensitive channel of small conductance ecMscS.

  3. A new parametrizable model of molecular electronic structure

    NASA Astrophysics Data System (ADS)

    Laikov, Dimitri N.

    2011-10-01

    A new electronic structure model is developed in which the ground state energy of a molecular system is given by a Hartree-Fock-like expression with parametrized one- and two-electron integrals over an extended (minimal + polarization) set of orthogonalized atom-centered basis functions, the variational equations being solved formally within the minimal basis but the effect of polarization functions being included in the spirit of second-order perturbation theory. It is designed to yield good dipole polarizabilities and improved intermolecular potentials with dispersion terms. The molecular integrals include up to three-center one-electron and two-center two-electron terms, all in simple analytical forms. A method to extract the effective one-electron Hamiltonian of nonlocal-exchange Kohn-Sham theory from the coupled-cluster one-electron density matrix is designed and used to get its matrix representation in a molecule-intrinsic minimal basis as an input to the parametrization procedure - making a direct link to the correlated wavefunction theory. The model has been trained for 15 elements (H, Li-F, Na-Cl, 720 parameters) on a set of 5581 molecules (including ions, transition states, and weakly bound complexes) whose first- and second-order properties were computed by the coupled-cluster theory as a reference, and a good agreement is seen. The model looks promising for the study of large molecular systems, it is believed to be an important step forward from the traditional semiempirical models towards higher accuracy at nearly as low a computational cost.

  4. A new parametrizable model of molecular electronic structure.

    PubMed

    Laikov, Dimitri N

    2011-10-01

    A new electronic structure model is developed in which the ground state energy of a molecular system is given by a Hartree-Fock-like expression with parametrized one- and two-electron integrals over an extended (minimal + polarization) set of orthogonalized atom-centered basis functions, the variational equations being solved formally within the minimal basis but the effect of polarization functions being included in the spirit of second-order perturbation theory. It is designed to yield good dipole polarizabilities and improved intermolecular potentials with dispersion terms. The molecular integrals include up to three-center one-electron and two-center two-electron terms, all in simple analytical forms. A method to extract the effective one-electron Hamiltonian of nonlocal-exchange Kohn-Sham theory from the coupled-cluster one-electron density matrix is designed and used to get its matrix representation in a molecule-intrinsic minimal basis as an input to the parametrization procedure--making a direct link to the correlated wavefunction theory. The model has been trained for 15 elements (H, Li-F, Na-Cl, 720 parameters) on a set of 5581 molecules (including ions, transition states, and weakly bound complexes) whose first- and second-order properties were computed by the coupled-cluster theory as a reference, and a good agreement is seen. The model looks promising for the study of large molecular systems, it is believed to be an important step forward from the traditional semiempirical models towards higher accuracy at nearly as low a computational cost. PMID:21992295

  5. The continuous molecular fields approach to building 3D-QSAR models.

    PubMed

    Baskin, Igor I; Zhokhova, Nelly I

    2013-05-01

    The continuous molecular fields (CMF) approach is based on the application of continuous functions for the description of molecular fields instead of finite sets of molecular descriptors (such as interaction energies computed at grid nodes) commonly used for this purpose. These functions can be encapsulated into kernels and combined with kernel-based machine learning algorithms to provide a variety of novel methods for building classification and regression structure-activity models, visualizing chemical datasets and conducting virtual screening. In this article, the CMF approach is applied to building 3D-QSAR models for 8 datasets through the use of five types of molecular fields (the electrostatic, steric, hydrophobic, hydrogen-bond acceptor and donor ones), the linear convolution molecular kernel with the contribution of each atom approximated with a single isotropic Gaussian function, and the kernel ridge regression data analysis technique. It is shown that the CMF approach even in this simplest form provides either comparable or enhanced predictive performance in comparison with state-of-the-art 3D-QSAR methods. PMID:23719959

  6. Application of Molecular Modeling to Development of New Factor Xa Inhibitors

    PubMed Central

    Sulimov, Vladimir B.; Gribkova, Irina V.; Kochugaeva, Maria P.; Katkova, Ekaterina V.; Sulimov, Alexey V.; Kutov, Danil C.; Shikhaliev, Khidmet S.; Medvedeva, Svetlana M.; Krysin, Michael Yu.; Sinauridze, Elena I.; Ataullakhanov, Fazoil I.

    2015-01-01

    In consequence of the key role of factor Xa in the clotting cascade and absence of its activity in the processes that do not affect coagulation, this protein is an attractive target for development of new blood coagulation inhibitors. Factor Xa is more effective and convenient target for creation of anticoagulants than thrombin, inhibition of which may cause some side effects. This study is aimed at finding new inhibitors of factor Xa by molecular computer modeling including docking SOL and postdocking optimization DISCORE programs. After validation of molecular modeling methods on well-known factor Xa inhibitors the virtual screening of NCI Diversity and Voronezh State University databases of ready-made low molecular weight species has been carried out. Seventeen compounds selected on the basis of modeling results have been tested experimentally in vitro. It has been found that 12 of them showed activity against factor Xa (IC50 = 1.8–40 μM). Based on analysis of the results, the new original compound was synthesized and experimentally verified. It shows activity against factor Xa with IC50 value of 0.7 μM. PMID:26484350

  7. Role of Nonspecific Interactions in Molecular Chaperones through Model-Based Bioinformatics

    PubMed Central

    White, Andrew D.; Huang, Wenjun; Jiang, Shaoyi

    2012-01-01

    Molecular chaperones are large proteins or protein complexes from which many proteins require assistance in order to fold. One unique property of molecular chaperones is the cavity they provide in which proteins fold. The interior surface residues which make up the cavities of molecular chaperone complexes from different organisms has recently been identified, including the well-studied GroEL-GroES chaperonin complex found in Escherichia coli. It was found that the interior of these protein complexes is significantly different than other protein surfaces and that the residues found on the protein surface are able to resist protein adsorption when immobilized on a surface. Yet it remains unknown if these residues passively resist protein binding inside GroEL-GroEs (as demonstrated by experiments that created synthetic mimics of the interior cavity) or if the interior also actively stabilizes protein folding. To answer this question, we have extended entropic models of substrate protein folding inside GroEL-GroES to include interaction energies between substrate proteins and the GroEL-GroES chaperone complex. This model was tested on a set of 528 proteins and the results qualitatively match experimental observations. The interior residues were found to strongly discourage the exposure of any hydrophobic residues, providing an enhanced hydrophobic effect inside the cavity that actively influences protein folding. This work provides both a mechanism for active protein stabilization in GroEL-GroES and a model that matches contemporary understanding of the chaperone protein. PMID:23260050

  8. Molecular cloning of a Poria cocos protein that activates Th1 immune response and allays Th2 cytokine and IgE production in a murine atopic dermatitis model.

    PubMed

    Lu, Ya-Ting; Kuan, Yen-Chou; Chang, Hui-Hsin; Sheu, Fuu

    2014-04-01

    Edible fungus Poria cocos (Schw.) Wolf is a cooking material that has myriad health benefits. However, its active constituents have not been well-defined. We previously purified an immunomodulatory protein, PCP, from P. cocos and described its biochemical features and its ability to activate primary macrophage via TLR4. In this study, we cloned the gene of PCP and demonstrated its ability to activate Th1 response in cell cultures and in mice. The complete cDNA sequence of PCP consisted of 807 bp, which included a 579 bp coding sequence that encoded 194 amino acids. With the addition of co-stimulatory CD3/CD28 signals, PCP significantly increased the surface expression of CD44 and CD69 on effector T cells. PCP could also up-regulate T-bet and STAT4 expressions and IFN-γ and IL-2 secretions. Oral administration of PCP suppressed the production of both total and OVA-specific IgG1 in serum and enhanced the amounts of serum and OVA-specific IgG2a and Th1-related cytokine production in BALB/c splenocytes. In addition, oral administration of PCP significantly reduced IL-4 and IgE expressions in a murine model of atopic dermatitis. In conclusion, these results provide evidence that PCP could regulate mammalian immune cells and reveal their pharmaceutical potential in developing therapeutic strategies against Th2-mediated immune disorders. PMID:24625278

  9. Validating clustering of molecular dynamics simulations using polymer models

    PubMed Central

    2011-01-01

    Background Molecular dynamics (MD) simulation is a powerful technique for sampling the meta-stable and transitional conformations of proteins and other biomolecules. Computational data clustering has emerged as a useful, automated technique for extracting conformational states from MD simulation data. Despite extensive application, relatively little work has been done to determine if the clustering algorithms are actually extracting useful information. A primary goal of this paper therefore is to provide such an understanding through a detailed analysis of data clustering applied to a series of increasingly complex biopolymer models. Results We develop a novel series of models using basic polymer theory that have intuitive, clearly-defined dynamics and exhibit the essential properties that we are seeking to identify in MD simulations of real biomolecules. We then apply spectral clustering, an algorithm particularly well-suited for clustering polymer structures, to our models and MD simulations of several intrinsically disordered proteins. Clustering results for the polymer models provide clear evidence that the meta-stable and transitional conformations are detected by the algorithm. The results for the polymer models also help guide the analysis of the disordered protein simulations by comparing and contrasting the statistical properties of the extracted clusters. Conclusions We have developed a framework for validating the performance and utility of clustering algorithms for studying molecular biopolymer simulations that utilizes several analytic and dynamic polymer models which exhibit well-behaved dynamics including: meta-stable states, transition states, helical structures, and stochastic dynamics. We show that spectral clustering is robust to anomalies introduced by structural alignment and that different structural classes of intrinsically disordered proteins can be reliably discriminated from the clustering results. To our knowledge, our framework is the

  10. Improved molecular collision models for nonequilibrium rarefied gases

    NASA Astrophysics Data System (ADS)

    Parsons, Neal

    The Direct Simulation Monte Carlo (DSMC) method typically used to model thermochemical nonequilibrium rarefied gases requires accurate total collision cross sections, reaction probabilities, and molecular internal energy exchange models. However, the baseline total cross sections are often determined from extrapolations of relatively low-temperature viscosity data, reaction probabilities are defined such that experimentally determined equilibrium reaction rates are replicated, and internal energy relaxation models are phenomenological in nature. Therefore, these models have questionable validity in modeling strongly nonequilibrium gases with temperatures greater than those possible in experimental test facilities. To rectify this deficiency, the Molecular Dynamics/Quasi-Classical Trajectories (MD/QCT) method can be used to accurately compute total collision cross sections, reaction probabilities, and internal energy exchange models based on first principles for hypervelocity collision conditions. In this thesis, MD/QCT-based models were used to improve simulations of two unique nonequilibrium rarefied gas systems: the Ionian atmosphere and hypersonic shocks in Earth's atmosphere. The Jovian plasma torus flows over Io at ≈ 57 km/s, inducing high-speed collisions between atmospheric SO2 and the hypervelocity plasma's O atoms and ions. The DSMC method is well-suited to model the rarefied atmosphere, so MD/QCT studies are therefore conducted to improve DSMC collision models of the critical SO2-O collision pair. The MD/QCT trajectory simulations employed a new potential energy surface that was developed using a ReaxFF fit to a set of ab initio calculations. Compared to the MD/QCT results, the baseline DSMC models are found to significantly under-predict total cross sections, use reaction probabilities that are unrealistically high, and give unphysical internal energies above the dissociation energy for non-reacting inelastic collisions and under-predicts post

  11. Molecular docking and 3D-QSAR studies on the glucocorticoid receptor antagonistic activity of hydroxylated polychlorinated biphenyls.

    PubMed

    Liu, S; Luo, Y; Fu, J; Zhou, J; Kyzas, G Z

    2016-02-01

    The glucocorticoid receptor (GR) antagonistic activities of hydroxylated polychlorinated biphenyls (HO-PCBs) were recently characterised. To further explore the interactions between HO-PCBs and the GR, and to elucidate structural characteristics that influence the GR antagonistic activity of HO-PCBs, molecular docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed. Comparative molecular similarity indices analysis (CoMSIA) was performed using both ligand- and receptor-based alignment schemes. Results generated from the receptor-based model were found to be more satisfactory, with q(2) of 0.632 and r(2) of 0.931 compared with those from the ligand-based model. Some internal validation strategies (e.g. cross-validation analysis, bootstrapping analysis and Y-randomisation) and an external validation method were used respectively to further assess the stability and predictive ability of the derived model. Graphical interpretation of the model provided some insights into the structural features that affected the GR antagonistic activity of HO-PCBs. Molecular docking studies revealed that some key residues were critical for ligand-receptor interactions by forming hydrogen bonds (Glu540) and hydrophobic interactions with ligands (Ile539, Val543 and Trp577). Although CoMSIA sometimes depends on the alignment of the molecules, the information provided is beneficial for predicting the GR antagonistic activities of HO-PCB homologues and is helpful for understanding the binding mechanisms of HO-PCBs to GR. PMID:26848875

  12. Synthetic Molecular Machines for Active Self-Assembly: Prototype Algorithms, Designs, and Experimental Study

    NASA Astrophysics Data System (ADS)

    Dabby, Nadine L.

    behaviors. This class of behaviors includes any behavior where a passive physical system simply does not have enough physical energy to perform the specified tasks in the requisite amount of time. As we will demonstrate and prove, a sufficiently expressive implementation of an "active" molecular self-assembly approach can achieve these behaviors. Using an external source of fuel solves part of the problem, so the system is not "energetically incomplete." But the programmable system also needs to have sufficient expressive power to achieve the specified behaviors. Perhaps surprisingly, some of these systems do not even require Turing completeness to be sufficiently expressive. Building on a large variety of work by other scientists in the fields of DNA nanotechnology, chemistry and reconfigurable robotics, this thesis introduces several research contributions in the context of active self-assembly. We show that simple primitives such as insertion and deletion are able to generate complex and interesting results such as the growth of a linear polymer in logarithmic time and the ability of a linear polymer to treadmill. To this end we developed a formal model for active-self assembly that is directly implementable with DNA molecules. We show that this model is computationally equivalent to a machine capable of producing strings that are stronger than regular languages and, at most, as strong as context-free grammars. This is a great advance in the theory of active self-assembly as prior models were either entirely theoretical or only implementable in the context of macro-scale robotics. We developed a chain reaction method for the autonomous exponential growth of a linear DNA polymer. Our method is based on the insertion of molecules into the assembly, which generates two new insertion sites for every initial one employed. The building of a line in logarithmic time is a first step toward building a shape in logarithmic time. We demonstrate the first construction of a synthetic

  13. Design, synthesis, crystal structure, insecticidal activity, molecular docking, and QSAR studies of novel N3-substituted imidacloprid derivatives.

    PubMed

    Wang, Mei-Juan; Zhao, Xiao-Bo; Wu, Dan; Liu, Ying-Qian; Zhang, Yan; Nan, Xiang; Liu, Huanxiang; Yu, Hai-Tao; Hu, Guan-Fang; Yan, Li-Ting

    2014-06-18

    Three novel series of N3-substituted imidacloprid derivatives were designed and synthesized, and their structures were identified on the basis of satisfactory analytical and spectral ((1)H NMR, (13)C NMR, MS, elemental analysis, and X-ray) data. Preliminary bioassays indicated that all of the derivatives exhibited significant insecticidal activities against Aphis craccivora, with LC50 values ranging from 0.00895 to 0.49947 mmol/L, and the insecticidal activities of some of them were comparable to those of the control imidacloprid. Some key structural features related to their insecticidal activities were identified, and the binding modes between target compounds and nAChR model were also further explored by molecular docking. By comparing the interaction features of imidacloprid and compound 26 with highest insecticidal activity, the origin of the high insecticidal activity of compound 26 was identified. On the basis of the conformations generated by molecular docking, a satisfactory 2D-QSAR model with six selected descriptors was built using genetic algorithm-multiple linear regression (GA-MLR) method. The analysis of the built model showed the molecular size, shape, and the ability to form hydrogen bond were important for insecticidal potency. The information obtained in the study will be very helpful for the design of new derivatives with high insecticidal activities. PMID:24834971

  14. Molecular dioxygen enters the active site of 12/15-lipoxygenase via dynamic oxygen access channels.

    PubMed

    Saam, Jan; Ivanov, Igor; Walther, Matthias; Holzhütter, Hermann-Georg; Kuhn, Hartmut

    2007-08-14

    Cells contain numerous enzymes that use molecular oxygen for their reactions. Often, their active sites are buried deeply inside the protein, which raises the question whether there are specific access channels guiding oxygen to the site of catalysis. Choosing 12/15-lipoxygenase as a typical example for such oxygen-dependent enzymes, we determined the oxygen distribution within the protein and defined potential routes for oxygen access. For this purpose, we have applied an integrated strategy of structural modeling, molecular dynamics simulations, site-directed mutagenesis, and kinetic measurements. First, we computed the 3D free-energy distribution for oxygen, which led to identification of four oxygen channels in the protein. All channels connect the protein surface with a region of high oxygen affinity at the active site. This region is localized opposite to the nonheme iron providing a structural explanation for the reaction specificity of this lipoxygenase isoform. The catalytically most relevant path can be obstructed by L367F exchange, which leads to a strongly increased Michaelis constant for oxygen. The blocking mechanism is explained in detail by reordering the hydrogen-bonding network of water molecules. Our results provide strong evidence that the main route for oxygen access to the active site of the enzyme follows a channel formed by transiently interconnected cavities whereby the opening and closure are governed by side chain dynamics. PMID:17675410

  15. Molecular Modeling and Experimental Study of Nonlinear Optical Compounds: Mono-Substituted Derivatives of Dicyanovinylbenzene

    NASA Technical Reports Server (NTRS)

    Timofeeva, Tatyana V.; Nesterov, Vladimir N.; Antipin, Mikhael Y.; Clark, R. D.; Sanghadasa, M.; Cardelino, B. H.; Moore, C. E.; Frazier, Donald O.

    2000-01-01

    A search for potential nonlinear optical (NLO) compounds has been performed using the Cambridge Structural Database and molecular modeling. We have studied a series of mono-substituted derivatives of dicyanovinylbenzene as the NLO properties of one of its derivatives (o-methoxy-dicyanovinylbenzene, DIVA) were described earlier. The molecular geometry in the series of the compounds studied was investigated with an X- ray analysis and discussed along with results of molecular mechanics and ab initio quantum chemical calculations. The influence of crystal packing on the molecular planarity has been revealed. Two new compounds from the series studied were found to be active for second harmonic generation (SHG) in the powder. The measurements of SHG efficiency have shown that the o-F- and p-Cl-derivatives of dicyanovinylbenzene are about 10 and 20- times more active than urea, respectively. The peculiarities of crystal structure formation in the framework of balance between the van der Waals and electrostatic interactions have been discussed. The crystal morphology of DIVA and two new SHG-active compounds have been calculated on the basis of their known crystal structures.

  16. Structural and Molecular Modeling Features of P2X Receptors

    PubMed Central

    Alves, Luiz Anastacio; da Silva, João Herminio Martins; Ferreira, Dinarte Neto Moreira; Fidalgo-Neto, Antonio Augusto; Teixeira, Pedro Celso Nogueira; de Souza, Cristina Alves Magalhães; Caffarena, Ernesto Raúl; de Freitas, Mônica Santos

    2014-01-01

    Currently, adenosine 5′-triphosphate (ATP) is recognized as the extracellular messenger that acts through P2 receptors. P2 receptors are divided into two subtypes: P2Y metabotropic receptors and P2X ionotropic receptors, both of which are found in virtually all mammalian cell types studied. Due to the difficulty in studying membrane protein structures by X-ray crystallography or NMR techniques, there is little information about these structures available in the literature. Two structures of the P2X4 receptor in truncated form have been solved by crystallography. Molecular modeling has proven to be an excellent tool for studying ionotropic receptors. Recently, modeling studies carried out on P2X receptors have advanced our knowledge of the P2X receptor structure-function relationships. This review presents a brief history of ion channel structural studies and shows how modeling approaches can be used to address relevant questions about P2X receptors. PMID:24637936

  17. Methods for improved selectivity in photo-activation and detection of molecular diagnostic agents

    DOEpatents

    Wachter, Eric A.; Fisher, Walter G.; Dees, H. Craig

    2008-03-18

    A method for the imaging of a particular volume of plant or animal tissue, wherein the plant or animal tissue contains at least one photo-active molecular agent. The method comprises the steps of treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of the photo-active molecular agent contained in the particular volume of the plant or animal tissue, photo-activating at least one of the at least one photo-active molecular agent in the particular volume of the plant or animal tissue, thereby producing at least one photo-activated molecular agent, wherein the at least one photo-activated molecular agent emits energy, detecting the energy emitted by the at least one photo-activated molecular agent, and producing a detected energy signal which is characteristic of the particular volume of plant or animal tissue. The present invention also provides a method for the imaging of a particular volume of material, wherein the material contains at least one photo-active molecular agent.

  18. Method for improved selectivity in photo-activation and detection of molecular diagnostic agents

    DOEpatents

    Wachter, E.A.; Fisher, W.G.; Dees, H.C.

    1998-11-10

    A method for the imaging of a particular volume of plant or animal tissue, wherein the plant or animal tissue contains at least one photo-active molecular agent. The method includes the steps of treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of the photo-active molecular agent contained in the particular volume of the plant or animal tissue, photo-activating at least one of the at least one photo-active molecular agent in the particular volume of the plant or animal tissue, thereby producing at least one photo-activated molecular agent, wherein the at least one photo-activated molecular agent emits energy, detecting the energy emitted by the at least one photo-activated molecular agent, and producing a detected energy signal which is characteristic of the particular volume of plant or animal tissue. The present invention is also a method for the imaging of a particular volume of material, wherein the material contains at least one photo-active molecular agent. 13 figs.

  19. Method for improved selectivity in photo-activation and detection of molecular diagnostic agents

    DOEpatents

    Wachter, Eric A.; Fisher, Walter G.; Dees, H. Craig

    1998-01-01

    A method for the imaging of a particular volume of plant or animal tissue, wherein the plant or animal tissue contains at least one photo-active molecular agent. The method includes the steps of treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of the photo-active molecular agent contained in the particular volume of the plant or animal tissue, photo-activating at least one of the at least one photo-active molecular agent in the particular volume of the plant or animal tissue, thereby producing at least one photo-activated molecular agent, wherein the at least one photo-activated molecular agent emits energy, detecting the energy emitted by the at least one photo-activated molecular agent, and producing a detected energy signal which is characteristic of the particular volume of plant or animal tissue. The present invention is also a method for the imaging of a particular volume of material, wherein the material contains at least one photo-active molecular agent.

  20. Construction, molecular modeling, and simulation of Mycobacterium tuberculosis cell walls.

    PubMed

    Hong, Xuan; Hopfinger, A J

    2004-01-01

    The mycobacterial cell wall is extraordinarily thick and tight consisting mainly of (1). long chain fatty acids, the mycolic acids, and (2). a unique polysaccharide, arabinogalactan (AG). These two chemical constituents are covalently linked through ester bonds. Minnikin (The Biology of the Mycobacteria; Academic: London, 1982) proposed that the mycobacterial cell wall is composed of an asymmetric lipid bilayer. The inner leaflet of the cell wall contains mycolic acids covalently linked to AG. This inner leaflet is believed to have the lowest permeability to organic compounds of the overall cell wall. Conformational search and molecular dynamics simulation were used to explore the conformational profile of AG and the conformations and structural organization of the mycolic acid-AG complex, and overall, an inner leaflet molecular model of the cell wall was constructed. The terminal arabinose residues of AG that serve as linkers between AG and mycolic acids were found to exist in four major chemical configurations. The mycolate hydrocarbon chains were determined to be tightly packed and perpendicular to the "plane" formed by the oxygen atoms of the 5-hydroxyl groups of the terminal arabinose residues. For Mycobacterium tuberculosis, the average packing distance between mycolic acids is estimated to be approximately 7.3 A. Thus, Minnikin's model is supported by this computational study. Overall, this modeling and simulation approach provides a way to probe the mechanism of low permeability of the cell wall and the intrinsic drug resistance of M. tuberculosis. In addition, monolayer models were built for both dipalmitoylphosphatidylethanolamine and dimyristoylphosphatidylcholine, two common phospholipids in bacterial and animal membranes, respectively. Structural comparisons of these cell wall phospholipid membrane models were made to the M. tuberculosis cell wall model. PMID:15132700

  1. A source model for the L134N molecular cloud

    NASA Technical Reports Server (NTRS)

    Swade, Daryl A.; Schloerb, F. P.

    1992-01-01

    The dark molecular cloud L134N is observed at millimeter wavelengths in the CS (J = 3-2), OCS (J = 7-6), and HDO (1 sub 11-1 sub 10) transitions. The CS (J = 3-2) transition was observed at four positions within the cloud, while the other two transitions were observed at one position each. Fractional abundances in the LTE approximation are calculated for each emission line detected. L134N appears to have a high-density core characterized by NH3, C3H2, and H(C-13)O(+) emission maps. A lower density envelope characterized by C(0-18), CS (J = 2-1), and SO emission surrounds the core. There appears to be a gas-phase oxygen abundance gradient in L134N with atomic oxygen depleted in the high-density core. Observed molecular distributions within L134N can be explained by a model in which chemical and physical processes in icy-dust-grain mantles influence the gas-phase molecular abundances.

  2. Towards Accurate Molecular Modeling of Plastic Bonded Explosives

    NASA Astrophysics Data System (ADS)

    Chantawansri, T. L.; Andzelm, J.; Taylor, D.; Byrd, E.; Rice, B.

    2010-03-01

    There is substantial interest in identifying the controlling factors that influence the susceptibility of polymer bonded explosives (PBXs) to accidental initiation. Numerous Molecular Dynamics (MD) simulations of PBXs using the COMPASS force field have been reported in recent years, where the validity of the force field in modeling the solid EM fill has been judged solely on its ability to reproduce lattice parameters, which is an insufficient metric. Performance of the COMPASS force field in modeling EMs and the polymeric binder has been assessed by calculating structural, thermal, and mechanical properties, where only fair agreement with experimental data is obtained. We performed MD simulations using the COMPASS force field for the polymer binder hydroxyl-terminated polybutadiene and five EMs: cyclotrimethylenetrinitramine, 1,3,5,7-tetranitro-1,3,5,7-tetra-azacyclo-octane, 2,4,6,8,10,12-hexantirohexaazazisowurzitane, 2,4,6-trinitro-1,3,5-benzenetriamine, and pentaerythritol tetranitate. Predicted EM crystallographic and molecular structural parameters, as well as calculated properties for the binder will be compared with experimental results for different simulation conditions. We also present novel simulation protocols, which improve agreement between experimental and computation results thus leading to the accurate modeling of PBXs.

  3. Molecular Dynamics Trajectory Compression with a Coarse-Grained Model

    PubMed Central

    Cheng, Yi-Ming; Gopal, Srinivasa Murthy; Law, Sean M.; Feig, Michael

    2012-01-01

    Molecular dynamics trajectories are very data-intensive thereby limiting sharing and archival of such data. One possible solution is compression of trajectory data. Here, trajectory compression based on conversion to the coarse-grained model PRIMO is proposed. The compressed data is about one third of the original data and fast decompression is possible with an analytical reconstruction procedure from PRIMO to all-atom representations. This protocol largely preserves structural features and to a more limited extent also energetic features of the original trajectory. PMID:22025759

  4. Large scale molecular dynamics modeling of materials fabrication processes

    SciTech Connect

    Belak, J.; Glosli, J.N.; Boercker, D.B.; Stowers, I.F.

    1994-02-01

    An atomistic molecular dynamics model of materials fabrication processes is presented. Several material removal processes are shown to be within the domain of this simulation method. Results are presented for orthogonal cutting of copper and silicon and for crack propagation in silica glass. Both copper and silicon show ductile behavior, but the atomistic mechanisms that allow this behavior are significantly different in the two cases. The copper chip remains crystalline while the silicon chip transforms into an amorphous state. The critical stress for crack propagation in silica glass was found to be in reasonable agreement with experiment and a novel stick-slip phenomenon was observed.

  5. Multiensemble Markov models of molecular thermodynamics and kinetics.

    PubMed

    Wu, Hao; Paul, Fabian; Wehmeyer, Christoph; Noé, Frank

    2016-06-01

    We introduce the general transition-based reweighting analysis method (TRAM), a statistically optimal approach to integrate both unbiased and biased molecular dynamics simulations, such as umbrella sampling or replica exchange. TRAM estimates a multiensemble Markov model (MEMM) with full thermodynamic and kinetic information at all ensembles. The approach combines the benefits of Markov state models-clustering of high-dimensional spaces and modeling of complex many-state systems-with those of the multistate Bennett acceptance ratio of exploiting biased or high-temperature ensembles to accelerate rare-event sampling. TRAM does not depend on any rate model in addition to the widely used Markov state model approximation, but uses only fundamental relations such as detailed balance and binless reweighting of configurations between ensembles. Previous methods, including the multistate Bennett acceptance ratio, discrete TRAM, and Markov state models are special cases and can be derived from the TRAM equations. TRAM is demonstrated by efficiently computing MEMMs in cases where other estimators break down, including the full thermodynamics and rare-event kinetics from high-dimensional simulation data of an all-atom protein-ligand binding model. PMID:27226302

  6. Molecular Communication Modeling of Antibody-Mediated Drug Delivery Systems.

    PubMed

    Chahibi, Youssef; Akyildiz, Ian F; Balasubramaniam, Sasitharan; Koucheryavy, Yevgeni

    2015-07-01

    Antibody-mediated Drug Delivery Systems (ADDS) are emerging as one of the most encouraging therapeutic solutions for treating several diseases such as human cancers. ADDS use small molecules (antibodies) that propagate in the body and bind selectively to their corresponding receptors (antigens) expressed at the surface of the diseased cells. In this paper, the Molecular Communication (MC) paradigm, where information is conveyed through the concentration of molecules, is advocated for the engineering of ADDS and modeling their complex behavior, to provide a realistic model without the over-complication of system biology models, and the limitations of experimental approaches. The peculiarities of antibodies, including their anisotropic transport and complex electrochemical structure, are taken into account to develop an analytical model of the ADDS transport and antigen-binding kinetics. The end-to-end response of ADDS, from the drug injection to the drug absorption, is mathematically derived based on the geometry of the antibody molecule, the electrochemical structure of the antibody-antigen complex, and the physiology of the patient. The accuracy of the MC model is validated by finite-element (COMSOL) simulations. The implications of the complex interplay between the transport and kinetics parameters on the performance of ADDS are effectively captured by the proposed MC model. The MC model of ADDS will enable the discovery and optimization of drugs in a versatile, cost-efficient, and reliable manner. PMID:25675450

  7. Molecular radiotherapy: The NUKFIT software for calculating the time-integrated activity coefficient

    SciTech Connect

    Kletting, P.; Schimmel, S.; Luster, M.; Kestler, H. A.; Hänscheid, H.; Fernández, M.; Lassmann, M.; Bröer, J. H.; Nosske, D.; Glatting, G.

    2013-10-15

    Purpose: Calculation of the time-integrated activity coefficient (residence time) is a crucial step in dosimetry for molecular radiotherapy. However, available software is deficient in that it is either not tailored for the use in molecular radiotherapy and/or does not include all required estimation methods. The aim of this work was therefore the development and programming of an algorithm which allows for an objective and reproducible determination of the time-integrated activity coefficient and its standard error.Methods: The algorithm includes the selection of a set of fitting functions from predefined sums of exponentials and the choice of an error model for the used data. To estimate the values of the adjustable parameters an objective function, depending on the data, the parameters of the error model, the fitting function and (if required and available) Bayesian information, is minimized. To increase reproducibility and user-friendliness the starting values are automatically determined using a combination of curve stripping and random search. Visual inspection, the coefficient of determination, the standard error of the fitted parameters, and the correlation matrix are provided to evaluate the quality of the fit. The functions which are most supported by the data are determined using the corrected Akaike information criterion. The time-integrated activity coefficient is estimated by analytically integrating the fitted functions. Its standard error is determined assuming Gaussian error propagation. The software was implemented using MATLAB.Results: To validate the proper implementation of the objective function and the fit functions, the results of NUKFIT and SAAM numerical, a commercially available software tool, were compared. The automatic search for starting values was successfully tested for reproducibility. The quality criteria applied in conjunction with the Akaike information criterion allowed the selection of suitable functions. Function fit

  8. Model morphing and sequence assignment after molecular replacement

    SciTech Connect

    Terwilliger, Thomas C.; Read, Randy J.; Adams, Paul D.; Brunger, Axel T.; Afonine, Pavel V.; Hung, Li-Wei

    2013-11-01

    A procedure for model building is described that combines morphing a model to match a density map, trimming the morphed model and aligning the model to a sequence. A procedure termed ‘morphing’ for improving a model after it has been placed in the crystallographic cell by molecular replacement has recently been developed. Morphing consists of applying a smooth deformation to a model to make it match an electron-density map more closely. Morphing does not change the identities of the residues in the chain, only their coordinates. Consequently, if the true structure differs from the working model by containing different residues, these differences cannot be corrected by morphing. Here, a procedure that helps to address this limitation is described. The goal of the procedure is to obtain a relatively complete model that has accurate main-chain atomic positions and residues that are correctly assigned to the sequence. Residues in a morphed model that do not match the electron-density map are removed. Each segment of the resulting trimmed morphed model is then assigned to the sequence of the molecule using information about the connectivity of the chains from the working model and from connections that can be identified from the electron-density map. The procedure was tested by application to a recently determined structure at a resolution of 3.2 Å and was found to increase the number of correctly identified residues in this structure from the 88 obtained using phenix.resolve sequence assignment alone (Terwilliger, 2003 ▶) to 247 of a possible 359. Additionally, the procedure was tested by application to a series of templates with sequence identities to a target structure ranging between 7 and 36%. The mean fraction of correctly identified residues in these cases was increased from 33% using phenix.resolve sequence assignment to 47% using the current procedure. The procedure is simple to apply and is available in the Phenix software package.

  9. Anti-inflammatory activity and molecular mechanism of delphinidin 3-sambubioside, a Hibiscus anthocyanin.

    PubMed

    Sogo, Takayuki; Terahara, Norihiko; Hisanaga, Ayami; Kumamoto, Takuma; Yamashiro, Takaaki; Wu, Shusong; Sakao, Kozue; Hou, De-Xing

    2015-01-01

    Delphinidin 3-sambubioside (Dp3-Sam), a Hibiscus anthocyanin, was isolated from the dried calices of Hibiscus sabdariffa L, which has been used for folk beverages and herbal medicine although the molecular mechanisms are poorly defined. Based on the properties of Dp3-Sam and the information of inflammatory processes, we investigated the anti-inflammatory activity and molecular mechanisms in both cell and animal models in the present study. In the cell model, Dp3-Sam and Delphinidin (Dp) reduced the levels of inflammatory mediators including iNOS, NO, IL-6, MCP-1, and TNF-α induced by LPS. Cellular signaling analysis revealed that Dp3-Sam and Dp downregulated NF-κB pathway and MEK1/2-ERK1/2 signaling. In animal model, Dp3-Sam and Dp reduced the production of IL-6, MCP-1 and TNF-α and attenuated mouse paw edema induced by LPS. Our in vitro and in vivo data demonstrated that Hibiscus Dp3-Sam possessed potential anti-inflammatory properties. PMID:25728636

  10. An improved molecular design of obtaining NLO active molecular glasses using triphenyl moieties as amorphous phase formation enhancers

    NASA Astrophysics Data System (ADS)

    Traskovskis, Kaspars; Mihailovs, Igors; Tokmakovs, Andrejs; Kokars, Valdis; Rutkis, Martins

    2012-06-01

    New molecular design of obtaining molecular glasses has been developed by linking triphenylmethyl moieties to chromophore core by flexible C-C bridge. Compounds capable of forming stable amorphous phase with good optical quality have been acquired with increased chemical and thermal sustainability compared to the previously reported design. NLO activity of compounds has been measured after corona discharge polling. Compared to previously synthesized trityloxy fragment containing compounds increase of d33 coefficient by up to 17 times was achieved for the same chromophore core containing compounds.

  11. Evolution & Phylogenetic Analysis: Classroom Activities for Investigating Molecular & Morphological Concepts

    ERIC Educational Resources Information Center

    Franklin, Wilfred A.

    2010-01-01

    In a flexible multisession laboratory, students investigate concepts of phylogenetic analysis at both the molecular and the morphological level. Students finish by conducting their own analysis on a collection of skeletons representing the major phyla of vertebrates, a collection of primate skulls, or a collection of hominid skulls.

  12. Molecular photoacoustic imaging of breast cancer using an actively targeted conjugated polymer

    PubMed Central

    Balasundaram, Ghayathri; Ho, Chris Jun Hui; Li, Kai; Driessen, Wouter; Dinish, US; Wong, Chi Lok; Ntziachristos, Vasilis; Liu, Bin; Olivo, Malini

    2015-01-01

    Conjugated polymers (CPs) are upcoming optical contrast agents in view of their unique optical properties and versatile synthetic chemistry. Biofunctionalization of these polymer-based nanoparticles enables molecular imaging of biological processes. In this work, we propose the concept of using a biofunctionalized CP for noninvasive photoacoustic (PA) molecular imaging of breast cancer. In particular, after verifying the PA activity of a CP nanoparticle (CP dots) in phantoms and the targeting efficacy of a folate-functionalized version of the same (folate-CP dots) in vitro, we systemically administered the probe into a folate receptor-positive (FR+ve) MCF-7 breast cancer xenograft model to demonstrate the possible application of folate-CP dots for imaging FR+ve breast cancers in comparison to CP dots with no folate moieties. We observed a strong PA signal at the tumor site of folate-CP dots-administered mice as early as 1 hour after administration as a result of the active targeting of the folate-CP dots to the FR+ve tumor cells but a weak PA signal at the tumor site of CP-dots-administered mice as a result of the passive accumulation of the probe by enhanced permeability and retention effect. We also observed that folate-CP dots produced ~4-fold enhancement in the PA signal in the tumor, when compared to CP dots. These observations demonstrate the great potential of this active-targeting CP to be used as a contrast agent for molecular PA diagnostic imaging in various biomedical applications. PMID:25609951

  13. Probing the origins of aromatase inhibitory activity of disubstituted coumarins via QSAR and molecular docking

    PubMed Central

    Worachartcheewan, Apilak; Suvannang, Naravut; Prachayasittikul, Supaluk; Prachayasittikul, Virapong; Nantasenamat, Chanin

    2014-01-01

    This study investigated the quantitative structure-activity relationship (QSAR) of imidazole derivatives of 4,7-disubstituted coumarins as inhibitors of aromatase, a potential therapeutic protein target for the treatment of breast cancer. Herein, a series of 3,7- and 4,7-disubstituted coumarin derivatives (1-34) with R1 and R2 substituents bearing aromatase inhibitory activity were modeled as a function of molecular and quantum chemical descriptors derived from low-energy conformer geometrically optimized at B3LYP/6-31G(d) level of theory. Insights on origins of aromatase inhibitory activity was afforded by the computed set of 7 descriptors comprising of F10[N-O], Inflammat-50, Psychotic-80, H-047, BELe1, B10[C-O] and MAXDP. Such significant descriptors were used for QSAR model construction and results indicated that model 4 afforded the best statistical performance. Good predictive performance were achieved as verified from the internal (comprising the training and the leave-one-out cross-validation (LOO-CV) sets) and external sets affording the following statistical parameters: R2Tr = 0.9576 and RMSETr = 0.0958 for the training set; Q2CV = 0.9239 and RMSECV = 0.1304 for the LOO-CV set as well as Q2Ext = 0.7268 and RMSEExt = 0.2927 for the external set. Significant descriptors showed correlation with functional substituents, particularly, R1 in governing high potency as aromatase inhibitor. Molecular docking calculations suggest that key residues interacting with the coumarins were predominantly lipophilic or non-polar while a few were polar and positively-charged. Findings illuminated herein serve as the impetus that can be used to rationally guide the design of new aromatase inhibitors. PMID:26417339

  14. Multiensemble Markov models of molecular thermodynamics and kinetics

    PubMed Central

    Wu, Hao; Paul, Fabian; Noé, Frank

    2016-01-01

    We introduce the general transition-based reweighting analysis method (TRAM), a statistically optimal approach to integrate both unbiased and biased molecular dynamics simulations, such as umbrella sampling or replica exchange. TRAM estimates a multiensemble Markov model (MEMM) with full thermodynamic and kinetic information at all ensembles. The approach combines the benefits of Markov state models—clustering of high-dimensional spaces and modeling of complex many-state systems—with those of the multistate Bennett acceptance ratio of exploiting biased or high-temperature ensembles to accelerate rare-event sampling. TRAM does not depend on any rate model in addition to the widely used Markov state model approximation, but uses only fundamental relations such as detailed balance and binless reweighting of configurations between ensembles. Previous methods, including the multistate Bennett acceptance ratio, discrete TRAM, and Markov state models are special cases and can be derived from the TRAM equations. TRAM is demonstrated by efficiently computing MEMMs in cases where other estimators break down, including the full thermodynamics and rare-event kinetics from high-dimensional simulation data of an all-atom protein–ligand binding model. PMID:27226302

  15. Molecular Dynamics Modeling of Heat Transport in Metals and Semiconductors

    SciTech Connect

    Narumanchi, S.; Kim, K.

    2010-01-01

    Interfacial thermal transport is of great importance in a number of practical applications where interfacial resistance between layers is frequently a major bottleneck to effective heat dissipation. For example, efficient heat transfer at silicon/aluminum and silicon/copper interfaces is very critical in power electronics packages used in hybrid electric vehicle applications. It is therefore important to understand the factors that govern and impact thermal transport at semiconductor/metal interfaces. Hence, in this study, we use classical molecular dynamics modeling to understand and study thermal transport in silicon and aluminum, and some preliminary modeling to study thermal transport at the interface between silicon and aluminum. A good match is shown between our modeling results for thermal conductivity in silicon and aluminum and the experimental data. The modeling results from this study also match well with relevant numerical studies in the literature for thermal conductivity. In addition, preliminary modeling results indicate that the interfacial thermal conductance for a perfect silicon/aluminum interface is of the same order as experimental data in the literature as well as diffuse mismatch model results accounting for realistic phonon dispersion curves.

  16. The molecular mechanisms and physiological consequences of oxidative stress: lessons from a model bacterium

    PubMed Central

    Imlay, James A.

    2014-01-01

    Oxic environments are hazardous. Molecular oxygen adventitiously abstracts electrons from many redox enzymes, continuously forming intracellular superoxide and hydrogen peroxide. These species can destroy the activities of metalloenzymes and the integrity of DNA, which forces organisms to protect themselves with scavenging enzymes and repair systems. Nevertheless, elevated levels of oxidants quickly poison bacteria, and both microbial competitors and hostile eukaryotic hosts exploit this vulnerability by assaulting them with peroxides or superoxide-forming antibiotics. In response, bacteria activate elegant adaptive strategies. In this Review, I summarize our current knowledge of oxidative stress in Escherichia coli, the model organism for which our understanding of damage and defence is most well-developed. PMID:23712352

  17. Molecular Complexity via C–H Activation: A Dehydrogenative Diels-Alder Reaction

    PubMed Central

    Stang, Erik M.; White, M. Christina

    2011-01-01

    Traditionally, C–H oxidation reactions install oxidized functionality onto a preformed molecular skeleton, resulting in a local molecular change. The use of C–H activation chemistry to construct complex molecular scaffolds is a new area with tremendous potential in synthesis. We report a Pd(II)/bis-sulfoxide catalyzed dehydrogenative Diels-Alder reaction that converts simple terminal olefins into complex cycloadducts in a single operation. PMID:21842902

  18. Modeling and Computer Simulation: Molecular Dynamics and Kinetic Monte Carlo

    SciTech Connect

    Wirth, B.D.; Caturla, M.J.; Diaz de la Rubia, T.

    2000-10-10

    Recent years have witnessed tremendous advances in the realistic multiscale simulation of complex physical phenomena, such as irradiation and aging effects of materials, made possible by the enormous progress achieved in computational physics for calculating reliable, yet tractable interatomic potentials and the vast improvements in computational power and parallel computing. As a result, computational materials science is emerging as an important complement to theory and experiment to provide fundamental materials science insight. This article describes the atomistic modeling techniques of molecular dynamics (MD) and kinetic Monte Carlo (KMC), and an example of their application to radiation damage production and accumulation in metals. It is important to note at the outset that the primary objective of atomistic computer simulation should be obtaining physical insight into atomic-level processes. Classical molecular dynamics is a powerful method for obtaining insight about the dynamics of physical processes that occur on relatively short time scales. Current computational capability allows treatment of atomic systems containing as many as 10{sup 9} atoms for times on the order of 100 ns (10{sup -7}s). The main limitation of classical MD simulation is the relatively short times accessible. Kinetic Monte Carlo provides the ability to reach macroscopic times by modeling diffusional processes and time-scales rather than individual atomic vibrations. Coupling MD and KMC has developed into a powerful, multiscale tool for the simulation of radiation damage in metals.

  19. Assessment of a Molecular Diffusion Model in MELCOR

    SciTech Connect

    Chang OH; Richard Moore

    2005-06-01

    The MELCOR (version 1.8.5) [1] computer code with INEEL revisions is being improved for the analysis of very high temperature gas-cooled reactors [2]. Following a loss-of-coolant accident, flow through the reactor vessel may initially stagnate due to a non-uniform concentration of helium and air. However, molecular diffusion will eventually result in a uniform concentration of air and helium. The differences in fluid temperatures within the reactor vessel will then result in the establishment of a natural circulation flow that can supply significant amounts of air to the reactor core. The heat released by the resulting oxidation of graphite in the reactor core has the potential to increase the peak fuel temperature. In order to analyze the effects of oxidation on the response of the reactor during accidents, a molecular diffusion model was added to MELCOR. The model is based on Fick's Second Law for spatially uniform pressure and temperature. This paper describes equimolal counter diffusion experiments in a two bulb diffusion cell and the results of the assessment calculations.

  20. A molecular mechanical model for N-heterocyclic carbenes.

    PubMed

    Gehrke, Sascha; Hollóczki, Oldamur

    2016-08-10

    In this work we present a set of force fields for nine synthetically relevant and/or structurally interesting N-heterocyclic carbenes, including imidazol-, thiazol-, triazol-, imidazolidin-, and pyridine-ylidenes. The bonding parameters were calculated by using a series of geometry optimizations by ab initio methods. For fitting the non-bonding interactions, a water molecule was employed as a probe. The interaction energy between the carbene and the probe molecule was sampled along two coordinates for each carbene, representing the interaction through the lone pair, or the π system of the molecule. The corresponding reference interaction energies were obtained by CCSD(T)/CBS calculations. To describe the direction dependence of the intermolecular potential energy, an extra, massless Coulombic interaction site was included for all carbenes, which represents the lone pair of the divalent carbon atom. The resulting fitted carbene force field (CaFF) showed a robust behavior regarding probe molecule, as changing the molecular mechanical water model, or employing, instead, an OPLS methanol molecule did not introduce significant deviations in the potential energies. The obtained CaFF models are easy to merge with standard OPLS or AMBER force fields, therefore the molecular simulations of a large number of N-heterocyclic carbenes becomes available. PMID:27426687

  1. Excited states of ribosome translocation revealed through integrative molecular modeling

    PubMed Central

    Whitford, Paul C.; Ahmed, Aqeel; Yu, Yanan; Hennelly, Scott P.; Tama, Florence; Spahn, Christian M. T.; Onuchic, José N.; Sanbonmatsu, Karissa Y.

    2011-01-01

    The dynamic nature of biomolecules leads to significant challenges when characterizing the structural properties associated with function. While X-ray crystallography and imaging techniques (such as cryo-electron microscopy) can reveal the structural details of stable molecular complexes, strategies must be developed to characterize configurations that exhibit only marginal stability (such as intermediates) or configurations that do not correspond to minima on the energy landscape (such as transition-state ensembles). Here, we present a methodology (MDfit) that utilizes molecular dynamics simulations to generate configurations of excited states that are consistent with available biophysical and biochemical measurements. To demonstrate the approach, we present a sequence of configurations that are suggested to be associated with transfer RNA (tRNA) movement through the ribosome (translocation). The models were constructed by combining information from X-ray crystallography, cryo-electron microscopy, and biochemical data. These models provide a structural framework for translocation that may be further investigated experimentally and theoretically to determine the precise energetic character of each configuration and the transition dynamics between them. PMID:22080606

  2. Excited states of ribosome translocation revealed through integrative molecular modeling.

    PubMed

    Whitford, Paul C; Ahmed, Aqeel; Yu, Yanan; Hennelly, Scott P; Tama, Florence; Spahn, Christian M T; Onuchic, José N; Sanbonmatsu, Karissa Y

    2011-11-22

    The dynamic nature of biomolecules leads to significant challenges when characterizing the structural properties associated with function. While X-ray crystallography and imaging techniques (such as cryo-electron microscopy) can reveal the structural details of stable molecular complexes, strategies must be developed to characterize configurations that exhibit only marginal stability (such as intermediates) or configurations that do not correspond to minima on the energy landscape (such as transition-state ensembles). Here, we present a methodology (MDfit) that utilizes molecular dynamics simulations to generate configurations of excited states that are consistent with available biophysical and biochemical measurements. To demonstrate the approach, we present a sequence of configurations that are suggested to be associated with transfer RNA (tRNA) movement through the ribosome (translocation). The models were constructed by combining information from X-ray crystallography, cryo-electron microscopy, and biochemical data. These models provide a structural framework for translocation that may be further investigated experimentally and theoretically to determine the precise energetic character of each configuration and the transition dynamics between them. PMID:22080606

  3. Aggregation of model asphaltenes: a molecular dynamics study.

    PubMed

    Costa, J L L F S; Simionesie, D; Zhang, Z J; Mulheran, P A

    2016-10-01

    Natural asphaltenes are defined as polyaromatic compounds whose chemical composition and structure are dependent on their geological origin and production history, hence are regarded as complex molecules with aromatic cores and aliphatic tails that occur in the heaviest fraction of crude oil. The aggregation of asphaltenes presents a range of technical challenges to the production and processing of oil. In this work we study the behaviour of the model asphaltene-like molecule hexa-tert-butylhexa-peri-hexabenzocoronene (HTBHBC) using molecular dynamics simulation. It was found that the regular arrangement of the tert-butyl side chains prevents the formation of strongly-bound dimers by severely restricting the configurational space of the aggregation pathway. In contrast, a modified molecule with only 3 side chains is readily able to form dimers. This work therefore confirms the influence of the molecular structure of polyaromatic compounds on their aggregation mechanism, and reveals the unexpected design rules required for model systems that can mimic the behavior of asphaltenes. PMID:27465036

  4. Molecular docking study and development of an empirical binding free energy model for phosphodiesterase 4 inhibitors.

    PubMed

    Oliveira, Fernanda G; Sant'Anna, Carlos M R; Caffarena, Ernesto R; Dardenne, Laurent E; Barreiro, Eliezer J

    2006-09-01

    In the present work, several computational methodologies were combined to develop a model for the prediction of PDE4B inhibitors' activity. The adequacy of applying the ligand docking approach, keeping the enzyme rigid, to the study of a series of PDE4 inhibitors was confirmed by a previous molecular dynamics analysis of the complete enzyme. An exhaustive docking procedure was performed to identify the most probable binding modes of the ligands to the enzyme, including the active site metal ions and the surrounding structural water molecules. The enzyme-inhibitor interaction enthalpies, refined by using the semiempirical molecular orbital approach, were combined with calculated solvation free energies and entropy considerations in an empirical free energy model that enabled the calculation of binding free energies that correlated very well with experimentally derived binding free energies. Our results indicate that both the inclusion of the structural water molecules close to the ions in the binding site and the use of a free energy model with a quadratic dependency on the ligand free energy of solvation are important aspects to be considered for molecular docking investigations involving the PDE4 enzyme family. PMID:16843671

  5. Consistent flamelet modeling of differential molecular diffusion for turbulent non-premixed flames

    NASA Astrophysics Data System (ADS)

    Wang, Haifeng

    2016-03-01

    Treating differential molecular diffusion correctly and accurately remains as a great challenge to the modeling of turbulent non-premixed combustion. The aim of this paper is to develop consistent modeling strategies for differential molecular diffusion in flamelet models. Two types of differential molecular diffusion models are introduced, linear differential diffusion models and nonlinear differential diffusion models. A multi-component turbulent mixing layer problem is analyzed in detail to gain insights into differential molecular diffusion and its characteristics, particularly the dependence of differential molecular diffusion on the Reynolds number and the Lewis number. These characteristics are then used to validate the differential molecular diffusion models. Finally, the new models are applied to the modeling of a series of laboratory-scale turbulent non-premixed jet flames with different Reynolds number (Sandia Flames B, C, and D) to further assess the models' performance.

  6. Method for improved selectivity in photo-activation of molecular agents

    DOEpatents

    Fisher, Walter G.; Wachter, Eric A.; Dees, H. Craig

    2000-01-01

    An apparatus for the treatment of a particular volume of plant or animal tissue by treating the plant or animal tissue with at least one photo-active molecular agent, wherein the particular volume of the plant or animal tissue retains at least a portion of the at least one photo-active molecular agent, and then treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of at least one of the at least one photo-active molecular agent retained in the particular volume of the plant or animal tissue, wherein the at least one photo-active molecular agent becomes active in the particular volume of the plant or animal tissue.

  7. Molecular modeling of high-pressure ramp waves in tantalum

    NASA Astrophysics Data System (ADS)

    Lane, J. Matthew D.; Lim, Hojun; Brown, Justin L.

    2015-03-01

    Ramp wave compression experiments of bcc metals under extreme conditions have produced differing measurements of material strength response. These variations are often attributed to differing experimental techniques, and varying material factors such as microstructure, and strain-rate. We present non-equilibrium molecular dynamics simulations of tantalum for single crystal and two polycrystalline nanostructures out to 250 GPa, over strain states ranging from 108 to 1011 1/s. Results will be compared to recent Z-machine strength experiments, meso-scale crystal plasticity models and continuum-scale polycrystalline model. Sandia National Laboratories is a multi program laboratory managed and operated by Sandia Corporation, a wholly owned subsidiary of Lockheed Martin Corporation, for the U.S. Department of Energy's National Nuclear Security Administration under contract DE-AC04-94AL85000.

  8. Model for the intense molecular line emission from OMC-1

    SciTech Connect

    Draine, B.T.; Roberge, W.G.

    1982-08-15

    We present a model which attributes the observed H/sub 2/ and CO line emission OMC-1 to a magnetohydrodynamic shock propagating into magnetized molecular gas. By requiring the shock to reporoduce the observed line intensities, we determine the shock speed to be v/sub s/roughly-equal38 km s/sup -1/ and the preshock density and (transverse) magnetic field to be n/sub H/roughly-equal7 x 10/sup 5/ cm/sup -3/, B/sub O/roughly-equal1.5 milligauss. The model is compared to observations of H/sub 2/, CO, OH, O I, and C I in emission and of CO in absorption. The shock gas may be detectible in H I 21 cm emission.

  9. Interactive display of molecular models using a microcomputer system

    NASA Technical Reports Server (NTRS)

    Egan, J. T.; Macelroy, R. D.

    1980-01-01

    A simple, microcomputer-based, interactive graphics display system has been developed for the presentation of perspective views of wire frame molecular models. The display system is based on a TERAK 8510a graphics computer system with a display unit consisting of microprocessor, television display and keyboard subsystems. The operating system includes a screen editor, file manager, PASCAL and BASIC compilers and command options for linking and executing programs. The graphics program, written in USCD PASCAL, involves the centering of the coordinate system, the transformation of centered model coordinates into homogeneous coordinates, the construction of a viewing transformation matrix to operate on the coordinates, clipping invisible points, perspective transformation and scaling to screen coordinates; commands available include ZOOM, ROTATE, RESET, and CHANGEVIEW. Data file structure was chosen to minimize the amount of disk storage space. Despite the inherent slowness of the system, its low cost and flexibility suggests general applicability.

  10. A review of molecular modelling of electric double layer capacitors.

    PubMed

    Burt, Ryan; Birkett, Greg; Zhao, X S

    2014-04-14

    Electric double-layer capacitors are a family of electrochemical energy storage devices that offer a number of advantages, such as high power density and long cyclability. In recent years, research and development of electric double-layer capacitor technology has been growing rapidly, in response to the increasing demand for energy storage devices from emerging industries, such as hybrid and electric vehicles, renewable energy, and smart grid management. The past few years have witnessed a number of significant research breakthroughs in terms of novel electrodes, new electrolytes, and fabrication of devices, thanks to the discovery of innovative materials (e.g. graphene, carbide-derived carbon, and templated carbon) and the availability of advanced experimental and computational tools. However, some experimental observations could not be clearly understood and interpreted due to limitations of traditional theories, some of which were developed more than one hundred years ago. This has led to significant research efforts in computational simulation and modelling, aimed at developing new theories, or improving the existing ones to help interpret experimental results. This review article provides a summary of research progress in molecular modelling of the physical phenomena taking place in electric double-layer capacitors. An introduction to electric double-layer capacitors and their applications, alongside a brief description of electric double layer theories, is presented first. Second, molecular modelling of ion behaviours of various electrolytes interacting with electrodes under different conditions is reviewed. Finally, key conclusions and outlooks are given. Simulations on comparing electric double-layer structure at planar and porous electrode surfaces under equilibrium conditions have revealed significant structural differences between the two electrode types, and porous electrodes have been shown to store charge more efficiently. Accurate electrolyte and

  11. Modeling the physical and excitation conditions of the molecular envelope of NGC 7027

    NASA Astrophysics Data System (ADS)

    Santander-García, M.; Bujarrabal, V.; Alcolea, J.

    2012-09-01

    Context. The link between the shaping of bipolar planetary nebulae and the mass ejection activity of their central stars is still poorly understood. Appropriately characterizing the evolution of shells ejected during the late stages of stellar evolution and the interaction between these shells is fundamental to gain insight into the mechanism of nebular shaping. It must include the study of the molecular emission, which tracks the mass-loss history during the late asymptotic giant branch (AGB) and post-AGB stages, when the nebula is being actively shaped. Aims: The Heterodyne Instrument for the Far Infrared (HIFI) aboard Herschel is an invaluable tool because it opens a new window (most of the sub-mm and far-infrared range is only accessible from space) from which to probe warm molecular gas (~50-1000 K). This paper presents a radiative transfer, spatio-kinematic modeling of the molecular envelope of the young planetary nebula NGC 7027 in several high- and low-J12CO and 13CO transitions observed by Herschel/HIFI and the IRAM 30-m radio telescope, and discusses the structure and dynamics of the molecular envelope. Methods: We developed a code that, used along with the SHAPE software, implements spatio-kinematic modeling with accurate non-LTE calculations of line excitation and radiative transfer in molecular species. We used this code to build a relatively simple "Russian doll" model to account for the physical and excitation conditions of the molecular envelope of NGC 7027. Results: The model nebula consists of four nested, mildly bipolar shells plus a pair of high-velocity blobs. The innermost shell is the thinnest and shows a significant increase in physical conditions (temperature, density, abundance and velocity) compared to the adjacent shell. This is a clear indication of a shock front in the system, which may have played a role in shaping the nebula. Each of the high-velocity blobs is divided into two sections with considerably different physical conditions

  12. Quantitative structure-activity relationship correlation between molecular structure and the Rayleigh enantiomeric enrichment factor.

    PubMed

    Jammer, S; Rizkov, D; Gelman, F; Lev, O

    2015-08-01

    It was recently demonstrated that under environmentally relevant conditions the Rayleigh equation is valid to describe the enantiomeric enrichment - conversion relationship, yielding a proportional constant called the enantiomeric enrichment factor, εER. In the present study we demonstrate a quantitative structure-activity relationship model (QSAR) that describes well the dependence of εER on molecular structure. The enantiomeric enrichment factor can be predicted by the linear Hansch model, which correlates biological activity with physicochemical properties. Enantioselective hydrolysis of sixteen derivatives of 2-(phenoxy)propionate (PPMs) have been analyzed during enzymatic degradation by lipases from Pseudomonas fluorescens (PFL), Pseudomonas cepacia (PCL), and Candida rugosa (CRL). In all cases the QSAR relationships were significant with R(2) values of 0.90-0.93, and showed high predictive abilities with internal and external validations providing QLOO(2) values of 0.85-0.87 and QExt(2) values of 0.8-0.91. Moreover, it is demonstrated that this model enables differentiation between enzymes with different binding site shapes. The enantioselectivity of PFL and PCL was dictated by electronic properties, whereas the enantioselectivity of CRL was determined by lipophilicity and steric factors. The predictive ability of the QSAR model demonstrated in the present study may serve as a helpful tool in environmental studies, assisting in source tracking of unstudied chiral compounds belonging to a well-studied homologous series. PMID:26153539

  13. Design, synthesis, cytotoxic activity and molecular docking studies of new 20(S)-sulfonylamidine camptothecin derivatives.

    PubMed

    Song, Zi-Long; Wang, Mei-Juan; Li, Lanlan; Wu, Dan; Wang, Yu-Han; Yan, Li-Ting; Morris-Natschke, Susan L; Liu, Ying-Qian; Zhao, Yong-Long; Wang, Chih-Ya; Liu, Huanxiang; Goto, Masuo; Liu, Heng; Zhu, Gao-Xiang; Lee, Kuo-Hsiung

    2016-06-10

    In an ongoing investigation of 20-sulfonylamidine derivatives (9, YQL-9a) of camptothecin (1) as potential anticancer agents directly and selectively inhibiting topoisomerase (Topo) I, the sulfonylamidine pharmacophore was held constant, and a camptothecin derivatives with various substitution patterns were synthesized. The new compounds were evaluated for antiproliferative activity against three human tumor cell lines, A-549, KB, and multidrug resistant (MDR) KB subline (KBvin). Several analogs showed comparable or superior antiproliferative activity compared to the clinically prescribed 1 and irinotecan (3). Significantly, the 20-sulfonylamidine derivatives exhibited comparable cytotoxicity against KBvin, while 1 and 3 were less active against this cell line. Among them, compound 15c displayed much better cytotoxic activity than the controls 1, 3, and 9. Novel key structural features related to the antiproliferative activities were identified by structure-activity relationship (SAR) analysis. In a molecular docking model, compounds 9 and 15c interacted with Topo I-DNA through a different binding mode from 1 and 3. The sulfonylamidine side chains of 9 and 15c could likely form direct hydrogen bonds with Topo I, while hydrophobic interaction with Topo I and π-π stacking with double strand DNA were also confirmed as binding driving forces. The results from docking models were consistent with the SAR conclusions. The introduction of bulky substituents at the 20-position contributed to the altered binding mode of the compound by allowing them to form new interactions with Topo I residues. The information obtained in this study will be helpful for the design of new derivatives of 1 with most promising anticancer activity. PMID:26994847

  14. Deciphering the GPER/GPR30-agonist and antagonists interactions using molecular modeling studies, molecular dynamics, and docking simulations.

    PubMed

    Méndez-Luna, D; Martínez-Archundia, M; Maroun, Rachid C; Ceballos-Reyes, G; Fragoso-Vázquez, M J; González-Juárez, D E; Correa-Basurto, J

    2015-01-01

    The G-protein coupled estrogen receptor 1 GPER/GPR30 is a transmembrane seven-helix (7TM) receptor involved in the growth and proliferation of breast cancer. Due to the absence of a crystal structure of GPER/GPR30, in this work, molecular modeling studies have been carried out to build a three-dimensional structure, which was subsequently refined by molecular dynamics (MD) simulations (up to 120 ns). Furthermore, we explored GPER/GPR30's molecular recognition properties by using reported agonist ligands (G1, estradiol (E2), tamoxifen, and fulvestrant) and the antagonist ligands (G15 and G36) in subsequent docking studies. Our results identified the E2 binding site on GPER/GPR30, as well as other receptor cavities for accepting large volume ligands, through GPER/GPR30 π-π, hydrophobic, and hydrogen bond interactions. Snapshots of the MD trajectory at 14 and 70 ns showed almost identical binding motifs for G1 and G15. It was also observed that C107 interacts with the acetyl oxygen of G1 (at 14 ns) and that at 70 ns the residue E275 interacts with the acetyl group and with the oxygen from the other agonist whereas the isopropyl group of G36 is oriented toward Met141, suggesting that both C107 and E275 could be involved in the protein activation. This contribution suggest that GPER1 has great structural changes which explain its great capacity to accept diverse ligands, and also, the same ligand could be recognized in different binding pose according to GPER structural conformations. PMID:25587872

  15. Understanding Molecular Genetics through a Drawing-Based Activity

    ERIC Educational Resources Information Center

    Rotbain, Yosi; Marbach-Ad, Gili; Stavy, Ruth

    2005-01-01

    The activity uses drawings typically found in textbooks, engaging students in physical and mental activities such as drawing, painting and figure completion--as well as finding missing words and answering guiding questions. The activity deals with three topics: the structure of DNA, DNA replication and protein synthesis. In this study we…

  16. Transcriptional activity around bacterial cell death reveals molecular biomarkers for cell viability

    PubMed Central

    Kort, Remco; Keijser, Bart J; Caspers, Martien PM; Schuren, Frank H; Montijn, Roy

    2008-01-01

    Background In bacteriology, the ability to grow in selective media and to form colonies on nutrient agar plates is routinely used as a retrospective criterion for the detection of living bacteria. However, the utilization of indicators for bacterial viability-such as the presence of specific transcripts or membrane integrity-would overcome bias introduced by cultivation and reduces the time span of analysis from initiation to read out. Therefore, we investigated the correlation between transcriptional activity, membrane integrity and cultivation-based viability in the Gram-positive model bacterium Bacillus subtilis. Results We present microbiological, cytological and molecular analyses of the physiological response to lethal heat stress under accurately defined conditions through systematic sampling of bacteria from a single culture exposed to gradually increasing temperatures. We identified a coherent transcriptional program including known heat shock responses as well as the rapid expression of a small number of sporulation and competence genes, the latter only known to be active in the stationary growth phase. Conclusion The observed coordinated gene expression continued even after cell death, in other words after all bacteria permanently lost their ability to reproduce. Transcription of a very limited number of genes correlated with cell viability under the applied killing regime. The transcripts of the expressed genes in living bacteria – but silent in dead bacteria-include those of essential genes encoding chaperones of the protein folding machinery and can serve as molecular biomarkers for bacterial cell viability. PMID:19061518

  17. Circadian Rhythmicity of Active GSK3 Isoforms Modulates Molecular Clock Gene Rhythms in the Suprachiasmatic Nucleus

    PubMed Central

    Besing, R.C.; Paul, J.R.; Hablitz, L.M.; Rogers, C.O.; Johnson, R.L.; Young, M.E.; Gamble, K.L.

    2015-01-01

    The suprachiasmatic nucleus (SCN) drives and synchronizes daily rhythms at the cellular level via transcriptional-translational feedback loops comprised of clock genes such as Bmal1 and Period (Per). Glycogen synthase kinase 3 (GSK3), a serine/threonine kinase, phosphorylates at least five core clock proteins and shows diurnal variation in phosphorylation state (inactivation) of the GSK3β isoform. Whether phosphorylation of the other primary isoform (GSK3α) varies across the subjective day-night cycle is unknown. The purpose of this study was to determine if the endogenous rhythm of GSK3 (α and β) phosphorylation is critical for rhythmic BMAL1 expression and normal amplitude and periodicity of the molecular clock in the SCN. Significant circadian rhythmicity of phosphorylated GSK3 (α and β) was observed in the SCN from wild-type mice housed in constant darkness for two weeks. Importantly, chronic activation of both GSK3 isoforms impaired rhythmicity of the GSK3 target BMAL1. Furthermore, chronic pharmacological inhibition of GSK3 with 20 μM CHIR-99021 enhanced the amplitude and shortened the period of PER2::luciferase rhythms in organotypic SCN slice cultures. These results support the model that GSK3 activity status is regulated by the circadian clock and that GSK3 feeds back to regulate the molecular clock amplitude in the SCN. PMID:25724980

  18. 78 FR 7394 - Foreign-Trade Zone 121-Albany, NY; Authorization of Production Activity; Albany Molecular...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-01

    ... notice in the Federal Register inviting public comment (77 FR 63290, 10/16/2012). The FTZ Board has... Molecular Research, Inc.; Subzone 121A (Pharmaceutical Chemicals Production); Rensselaer, NY On September 26, 2012, Albany Molecular Research, Inc., submitted a notification of proposed production activity to...

  19. Use of Computational Modeling to Evaluate Hypotheses About the Molecular and Cellular Mechanisms of Bystander Effects

    SciTech Connect

    Zhao, Yuchao; Conolly, Rory B; Andersen, Melvin E.

    2006-11-21

    This report describes the development of a computational systems biology approach to evaluate the hypotheses of molecular and cellular mechanisms of adaptive response to low dose ionizing radiation. Our concept is that computational models of signaling pathways can be developed and linked to biologically based dose response models to evaluate the underlying molecular mechanisms which lead to adaptive response. For development of quantitatively accurate, predictive models, it will be necessary to describe tissues consisting of multiple cell types where the different types each contribute in their own way to the overall function of the tissue. Such a model will probably need to incorporate not only cell type-specific data but also spatial information on the architecture of the tissue and on intercellular signaling. The scope of the current model was more limited. Data obtained in a number of different biological systems were synthesized to describe a chimeric, “average” population cell. Biochemical signaling pathways involved in sensing of DNA damage and in the activation of cell cycle checkpoint controls and the apoptotic path were also included. As with any computational modeling effort, it was necessary to develop these simplified initial descriptions (models) that can be iteratively refined. This preliminary model is a starting point which, with time, can evolve to a level of refinement where large amounts of detailed biological information are synthesized and a capability for robust predictions of dose- and time-response behaviors is obtained.

  20. Lanthanide and transition metal complexes of bioactive coumarins: molecular modeling and spectroscopic studies.

    PubMed

    Georgieva, I; Mihaylov, Tz; Trendafilova, N

    2014-06-01

    The present paper summarizes theoretical and spectroscopic investigations on a series of active coumarins and their lanthanide and transition metal complexes with application in medicine and pharmacy. Molecular modeling as well as IR, Raman, NMR and electronic spectral simulations at different levels of theory were performed to obtain important molecular descriptors: total energy, formation energy, binding energy, stability, conformations, structural parameters, electron density distribution, molecular electrostatic potential, Fukui functions, atomic charges, and reactive indexes. The computations are performed both in gas phase and in solution with consideration of the solvent effect on the molecular structural and energetic parameters. The investigations have shown that the advanced computational methods are reliable for prediction of the metal-coumarin binding mode, electron density distribution, thermodynamic properties as well as the strength and nature of the metal-coumarin interaction (not experimentally accessible) and correctly interpret the experimental spectroscopic data. Known results from biological tests for cytotoxic, antimicrobial, anti-fungal, spasmolytic and anti-HIV activities on the studied metal complexes are reported and discussed. PMID:24680836

  1. Molecular mechanisms of human IRE1 activation through dimerization and ligand binding

    PubMed Central

    Joshi, Amar; Newbatt, Yvette; McAndrew, P. Craig; Stubbs, Mark; Burke, Rosemary; Richards, Mark W.; Bhatia, Chitra; Caldwell, John J.; McHardy, Tatiana; Collins, Ian; Bayliss, Richard

    2015-01-01

    IRE1 transduces the unfolded protein response by splicing XBP1 through its C-terminal cytoplasmic kinase-RNase region. IRE1 autophosphorylation is coupled to RNase activity through formation of a back-to-back dimer, although the conservation of the underlying molecular mechanism is not clear from existing structures. We have crystallized human IRE1 in a back-to-back conformation only previously seen for the yeast homologue. In our structure the kinase domain appears primed for catalysis but the RNase domains are disengaged. Structure-function analysis reveals that IRE1 is autoinhibited through a Tyr-down mechanism related to that found in the unrelated Ser/Thr protein kinase Nek7. We have developed a compound that potently inhibits human IRE1 kinase activity while stimulating XBP1 splicing. A crystal structure of the inhibitor bound to IRE1 shows an increased ordering of the kinase activation loop. The structures of hIRE in apo and ligand-bound forms are consistent with a previously proposed model of IRE1 regulation in which formation of a back-to-back dimer coupled to adoption of a kinase-active conformation drive RNase activation. The structures provide opportunities for structure-guided design of IRE1 inhibitors. PMID:25968568

  2. Molecular Modeling Approaches to Study the Binding Mode on Tubulin of Microtubule Destabilizing and Stabilizing Agents

    NASA Astrophysics Data System (ADS)

    Botta, Maurizio; Forli, Stefano; Magnani, Matteo; Manetti, Fabrizio

    Tubulin targeting agents constitute an important class of anticancer drugs. By acting either as microtubule stabilizers or destabilizers, they disrupt microtubule dynamics, thus inducing mitotic arrest and, ultimately, cell death by apoptosis. Three different binding sites, whose exact location on tubulin has been experimentally detected, have been identified so far for antimitotic compound targeting microtubules, namely the taxoid, the colchicine and the vinka alkaloid binding site. A number of ligand- and structure-based molecular modeling studies in this field has been reported over the years, aimed at elucidating the binding modes of both stabilizing and destabilizing agent, as well as the molecular features responsible for their efficacious interaction with tubulin. Such studies are described in this review, focusing on information provided by different modeling approaches on the structural determinants of antitubulin agents and the interactions with the binding pockets on tubulin emerged as fundamental for antitumor activity.To describe molecular modeling approaches applied to date to molecules known to bind microtubules, this paper has been divided into two main parts: microtubule destabilizing (Part 1) and stabilizing (Part 2) agents. The first part includes structure-based and ligand-based approaches to study molecules targeting colchicine (1.1) and vinca alkaloid (1.2) binding sites, respectively. In the second part, the studies performed on microtubule-stabilizing antimitotic agents (MSAA) are described. Starting from the first representative compound of this class, paclitaxel, molecular modeling studies (quantitative structure-activity relationships - QSAR - and structure-based approaches), performed on natural compounds acting with the same mechanism of action and temptative common pharmacophoric hypotheses for all of these compounds, are reported.

  3. Investigation on the protein-binding properties of icotinib by spectroscopic and molecular modeling method

    NASA Astrophysics Data System (ADS)

    Zhang, Hua-xin; Xiong, Hang-xing; Li, Li-wei

    2016-05-01

    Icotinib is a highly-selective epidermal growth factor receptor tyrosine kinase inhibitor with preclinical and clinical activity in non-small cell lung cancer, which has been developed as a new targeted anti-tumor drug in China. In this work, the interaction of icotinib and human serum albumin (HSA) were studied by three-dimensional fluorescence spectra, ultraviolet spectra, circular dichroism (CD) spectra, molecular probe and molecular modeling methods. The results showed that icotinib binds to Sudlow's site I in subdomain IIA of HSA molecule, resulting in icotinib-HSA complexes formed at ground state. The number of binding sites, equilibrium constants, and thermodynamic parameters of the reaction were calculated at different temperatures. The negative enthalpy change (ΔHθ) and entropy change (ΔSθ) indicated that the structure of new complexes was stabilized by hydrogen bonds and van der Waals power. The distance between donor and acceptor was calculated according to Förster's non-radiation resonance energy transfer theory. The structural changes of HSA caused by icotinib binding were detected by synchronous spectra and circular dichroism (CD) spectra. Molecular modeling method was employed to unfold full details of the interaction at molecular level, most of which could be supported by experimental results. The study analyzed the probability that serum albumins act as carriers for this new anticarcinogen and provided fundamental information on the process of delivering icotinib to its target tissues, which might be helpful in understanding the mechanism of icotinib in cancer therapy.

  4. Molecular Characterization of Growth Hormone-producing Tumors in the GC Rat Model of Acromegaly

    PubMed Central

    Martín-Rodríguez, Juan F.; Muñoz-Bravo, Jose L.; Ibañez-Costa, Alejandro; Fernandez-Maza, Laura; Balcerzyk, Marcin; Leal-Campanario, Rocío; Luque, Raúl M.; Castaño, Justo P.; Venegas-Moreno, Eva; Soto-Moreno, Alfonso; Leal-Cerro, Alfonso; Cano, David A.

    2015-01-01

    Acromegaly is a disorder resulting from excessive production of growth hormone (GH) and consequent increase of insulin-like growth factor 1 (IGF-I), most frequently caused by pituitary adenomas. Elevated GH and IGF-I levels results in wide range of somatic, cardiovascular, endocrine, metabolic, and gastrointestinal morbidities. Subcutaneous implantation of the GH-secreting GC cell line in rats leads to the formation of tumors. GC tumor-bearing rats develop characteristics that resemble human acromegaly including gigantism and visceromegaly. However, GC tumors remain poorly characterized at a molecular level. In the present work, we report a detailed histological and molecular characterization of GC tumors using immunohistochemistry, molecular biology and imaging techniques. GC tumors display histopathological and molecular features of human GH-producing tumors, including hormone production, cell architecture, senescence activation and alterations in cell cycle gene expression. Furthermore, GC tumors cells displayed sensitivity to somatostatin analogues, drugs that are currently used in the treatment of human GH-producing adenomas, thus supporting the GC tumor model as a translational tool to evaluate therapeutic agents. The information obtained would help to maximize the usefulness of the GC rat model for research and preclinical studies in GH-secreting tumors. PMID:26549306

  5. Investigation on the protein-binding properties of icotinib by spectroscopic and molecular modeling method.

    PubMed

    Zhang, Hua-Xin; Xiong, Hang-Xing; Li, Li-Wei

    2016-05-15

    Icotinib is a highly-selective epidermal growth factor receptor tyrosine kinase inhibitor with preclinical and clinical activity in non-small cell lung cancer, which has been developed as a new targeted anti-tumor drug in China. In this work, the interaction of icotinib and human serum albumin (HSA) were studied by three-dimensional fluorescence spectra, ultraviolet spectra, circular dichroism (CD) spectra, molecular probe and molecular modeling methods. The results showed that icotinib binds to Sudlow's site I in subdomain IIA of HSA molecule, resulting in icotinib-HSA complexes formed at ground state. The number of binding sites, equilibrium constants, and thermodynamic parameters of the reaction were calculated at different temperatures. The negative enthalpy change (ΔH(θ)) and entropy change (ΔS(θ)) indicated that the structure of new complexes was stabilized by hydrogen bonds and van der Waals power. The distance between donor and acceptor was calculated according to Förster's non-radiation resonance energy transfer theory. The structural changes of HSA caused by icotinib binding were detected by synchronous spectra and circular dichroism (CD) spectra. Molecular modeling method was employed to unfold full details of the interaction at molecular level, most of which could be supported by experimental results. The study analyzed the probability that serum albumins act as carriers for this new anticarcinogen and provided fundamental information on the process of delivering icotinib to its target tissues, which might be helpful in understanding the mechanism of icotinib in cancer therapy. PMID:26963729

  6. Fracture of Carbon Nanotube - Amorphous Carbon Composites: Molecular Modeling

    NASA Technical Reports Server (NTRS)

    Jensen, Benjamin D.; Wise, Kristopher E.; Odegard, Gregory M.

    2015-01-01

    Carbon nanotubes (CNTs) are promising candidates for use as reinforcements in next generation structural composite materials because of their extremely high specific stiffness and strength. They cannot, however, be viewed as simple replacements for carbon fibers because there are key differences between these materials in areas such as handling, processing, and matrix design. It is impossible to know for certain that CNT composites will represent a significant advance over carbon fiber composites before these various factors have been optimized, which is an extremely costly and time intensive process. This work attempts to place an upper bound on CNT composite mechanical properties by performing molecular dynamics simulations on idealized model systems with a reactive forcefield that permits modeling of both elastic deformations and fracture. Amorphous carbon (AC) was chosen for the matrix material in this work because of its structural simplicity and physical compatibility with the CNT fillers. It is also much stiffer and stronger than typical engineering polymer matrices. Three different arrangements of CNTs in the simulation cell have been investigated: a single-wall nanotube (SWNT) array, a multi-wall nanotube (MWNT) array, and a SWNT bundle system. The SWNT and MWNT array systems are clearly idealizations, but the SWNT bundle system is a step closer to real systems in which individual tubes aggregate into large assemblies. The effect of chemical crosslinking on composite properties is modeled by adding bonds between the CNTs and AC. The balance between weakening the CNTs and improving fiber-matrix load transfer is explored by systematically varying the extent of crosslinking. It is, of course, impossible to capture the full range of deformation and fracture processes that occur in real materials with even the largest atomistic molecular dynamics simulations. With this limitation in mind, the simulation results reported here provide a plausible upper limit on

  7. Protein flexibility and ligand recognition: challenges for molecular modeling.

    PubMed

    Spyrakis, Francesca; BidonChanal, Axel; Barril, Xavier; Luque, F Javier

    2011-01-01

    The intrinsic dynamics of macromolecules is an essential property to relate the structure of biomolecular systems with their function in the cell. In the field of ligand-receptor recognition, numerous evidences have revealed the limitations of the lock-and-key theory, and the need to elaborate models that take into account the inherent plasticity of biomolecules, such as the induced-fit model or the existence of an ensemble of pre-equilibrated conformations. Depending on the nature of the target system, ligand binding can be associated with small local adjustments in side chains or even the backbone to large-scale motions of structural fragments, domains or even subunits. Reproducing the inherent flexibility of biomolecules has thus become one of the most challenging issues in molecular modeling and simulation studies, as it has direct implications in our understanding of the structure-function relationships, but even in areas such as virtual screening and structure-based drug discovery. Given the intrinsic limitation of conventional simulation tools, only events occurring in short time scales can be reproduced at a high accuracy level through all-atom techniques such as Molecular Dynamics simulations. However, larger structural rearrangements demand the use of enhanced sampling methods relying on modified descriptions of the biomolecular system or the potential surface. This review illustrates the crucial role that structural plasticity plays in mediating ligand recognition through representative examples. In addition, it discusses some of the most powerful computational tools developed to characterize the conformational flexibility in ligand-receptor complexes. PMID:20939788

  8. Molecular vibration-activity relationship in the agonism of adenosine receptors.

    PubMed

    Chee, Hyun Keun; Oh, S June

    2013-12-01

    The molecular vibration-activity relationship in the receptor-ligand interaction of adenosine receptors was investigated by structure similarity, molecular vibration, and hierarchical clustering in a dataset of 46 ligands of adenosine receptors. The resulting dendrogram was compared with those of another kind of fingerprint or descriptor. The dendrogram result produced by corralled intensity of molecular vibrational frequency outperformed four other analyses in the current study of adenosine receptor agonism and antagonism. The tree that was produced by clustering analysis of molecular vibration patterns showed its potential for the functional classification of adenosine receptor ligands. PMID:24465242

  9. Molecular Vibration-Activity Relationship in the Agonism of Adenosine Receptors

    PubMed Central

    Chee, Hyun Keun

    2013-01-01

    The molecular vibration-activity relationship in the receptor-ligand interaction of adenosine receptors was investigated by structure similarity, molecular vibration, and hierarchical clustering in a dataset of 46 ligands of adenosine receptors. The resulting dendrogram was compared with those of another kind of fingerprint or descriptor. The dendrogram result produced by corralled intensity of molecular vibrational frequency outperformed four other analyses in the current study of adenosine receptor agonism and antagonism. The tree that was produced by clustering analysis of molecular vibration patterns showed its potential for the functional classification of adenosine receptor ligands. PMID:24465242

  10. MOLECULAR INTERACTION POTENTIALS FOR THE DEVELOPMENT OF STRUCTURE-ACTIVITY RELATIONSHIPS

    EPA Science Inventory

    Abstract
    One reasonable approach to the analysis of the relationships between molecular structure and toxic activity is through the investigation of the forces and intermolecular interactions responsible for chemical toxicity. The interaction between the xenobiotic and the bio...

  11. Multi-scale modelling of supercapacitors: From molecular simulations to a transmission line model

    NASA Astrophysics Data System (ADS)

    Pean, C.; Rotenberg, B.; Simon, P.; Salanne, M.

    2016-09-01

    We perform molecular dynamics simulations of a typical nanoporous-carbon based supercapacitor. The organic electrolyte consists in 1-ethyl-3-methylimidazolium and hexafluorophosphate ions dissolved in acetonitrile. We simulate systems at equilibrium, for various applied voltages. This allows us to determine the relevant thermodynamic (capacitance) and transport (in-pore resistivities) properties. These quantities are then injected in a transmission line model for testing its ability to predict the charging properties of the device. The results from this macroscopic model are in good agreement with non-equilibrium molecular dynamics simulations, which validates its use for interpreting electrochemical impedance experiments.

  12. Mechanical Properties of Nanostructured Materials Determined Through Molecular Modeling Techniques

    NASA Technical Reports Server (NTRS)

    Clancy, Thomas C.; Gates, Thomas S.

    2005-01-01

    The potential for gains in material properties over conventional materials has motivated an effort to develop novel nanostructured materials for aerospace applications. These novel materials typically consist of a polymer matrix reinforced with particles on the nanometer length scale. In this study, molecular modeling is used to construct fully atomistic models of a carbon nanotube embedded in an epoxy polymer matrix. Functionalization of the nanotube which consists of the introduction of direct chemical bonding between the polymer matrix and the nanotube, hence providing a load transfer mechanism, is systematically varied. The relative effectiveness of functionalization in a nanostructured material may depend on a variety of factors related to the details of the chemical bonding and the polymer structure at the nanotube-polymer interface. The objective of this modeling is to determine what influence the details of functionalization of the carbon nanotube with the polymer matrix has on the resulting mechanical properties. By considering a range of degree of functionalization, the structure-property relationships of these materials is examined and mechanical properties of these models are calculated using standard techniques.

  13. Making Connections by Using Molecular Models in Geometry.

    ERIC Educational Resources Information Center

    Pacyga, Robert

    1995-01-01

    Describes two activities to analyze unit-cell structures from a geometric viewpoint and invites students to apply their mathematical understanding to scientific phenomena. Students form models of the simple cube, a building block of crystalline structures, and a methane molecule. (MKR)

  14. Modelling Molecular Mechanisms: A Framework of Scientific Reasoning to Construct Molecular-Level Explanations for Cellular Behaviour

    NASA Astrophysics Data System (ADS)

    van Mil, Marc H. W.; Boerwinkel, Dirk Jan; Waarlo, Arend Jan

    2013-01-01

    Although molecular-level details are part of the upper-secondary biology curriculum in most countries, many studies report that students fail to connect molecular knowledge to phenomena at the level of cells, organs and organisms. Recent studies suggest that students lack a framework to reason about complex systems to make this connection. In this paper, we present a framework that could help students to reason back and forth between cells and molecules. It represents both the general type of explanation in molecular biology and the research strategies scientists use to find these explanations. We base this framework on recent work in the philosophy of science that characterizes explanations in molecular biology as mechanistic explanations. Mechanistic explanations describe a phenomenon in terms of the entities involved, the activities displayed and the way these entities and activities are organized. We conclude that to describe cellular phenomena scientists use entities and activities at multiple levels between cells and molecules. In molecular biological research, scientists use heuristics based on these intermediate levels to construct mechanistic explanations. They subdivide a cellular activity into hypothetical lower-level activities (top-down approaches) and they predict and test the organization of macromolecules into functional modules that play a role in higher-level activities (bottom-up approaches). We suggest including molecular mechanistic reasoning in biology education and we identify criteria for designing such education. Education using molecular mechanistic reasoning can build on common intuitive reasoning about mechanisms. The heuristics that scientists use can help students to apply this intuitive notion to the levels in between molecules and cells.

  15. Using Active Learning in a Studio Classroom to Teach Molecular Biology

    ERIC Educational Resources Information Center

    Nogaj, Luiza A.

    2013-01-01

    This article describes the conversion of a lecture-based molecular biology course into an active learning environment in a studio classroom. Specific assignments and activities are provided as examples. The goal of these activities is to involve students in collaborative learning, teach them how to participate in the learning process, and give…

  16. Modeling and Bio molecular Self-assembly via Molecular Dynamics and Dissipative Particle Dynamics

    NASA Astrophysics Data System (ADS)

    Rakesh, L.

    2009-09-01

    Surfactants like materials can be used to increase the solubility of poorly soluble drugs in water and to increase drug bioavailability. A typical case study will be demonstrated using DPD simulation to model the distribution of anti-inflammatory drug molecules. Computer simulation is a convenient approach to understand drug distribution and solubility concepts without much wastage and costly experiments in the laboratory. Often in molecular dynamics (MD) the atoms are represented explicitly and the equation of motion as described by Newtonian dynamics is integrated explicitly. MD has been used to study spontaneous formation of micelles by hydrophobic molecules with amphiphilic head groups in bulk water, as well as stability of pre-configured micelles and membranes. DPD is a state-of the- art mesoscale simulation, it is a more recent molecular dynamics technique, originally developed for simulating complex fluids but lately also applied to membrane dynamics, hemodynamic in biomedical applications. Such fluids pervade industrial research from paints to pharmaceuticals and from cosmetics to the controlled release of drugs. Dissipative particle dynamics (DPD) can provide structural and dynamic properties of fluids in equilibrium, under shear or confined to narrow cavities, at length- and time-scales beyond the scope of traditional atomistic molecular dynamics simulation methods. Mesoscopic particles are used to represent clusters of molecules. The interaction conserves mass and momentum and as a consequence the dynamics is consistent with Navier-Stokes equations. In addition to the conservative forces, stochastic drive and dissipation is introduced to represent internal degrees of freedom in the mesoscopic particles. In this research, an initial study is being conducted using the aqueous solubilization of the nonsteroidal, anti-inflammatory drug is studied theoretically in micellar solution of nonionic (dodecyl hexa(ethylene oxide), C12E6) surfactants possessing the

  17. Stereoselective synthesis and molecular modeling of chiral cyclopentanes.

    PubMed

    Abdel-Jalil, Raid J; Steinbrecher, Thomas; Al-Harthy, Thuraya; Mahal, Ahmed; Abou-Zied, Osama K; Voelter, Wolfgang

    2015-10-13

    The reaction of 3-methyseleno-2-methylselenomethyl-propene with benzyl 2,3-anhydro-4-O-triflyl-β-L-ribopyranoside provides a major convenient enantiomeric product of 1-methylene-(benzyl3,4-dideoxy-α-D-arabinopyranoso)-[3,4-c]-cyclopentane, with benzyl-2,3-anhydro-4-deoxy-4-C-(2-methyl- propen-3-yl)-α-D-lyxopyranoside as a minor product. While the reaction of 3-methyseleno-2-[methylselenomethyl]-propene with benzyl 2,3-anhydro-4-O-triflyl-α-D-ribopyranoside produces a good yield of benzyl-2,3-anhydro-4-deoxy-4-C-(2-methylpropen-3-yl)-α-D-lyxo-pyranoside. Molecular modeling and molecular dynamics simulations indicate that the intermediate in the reaction of the β-L sugar frequently occupies an optimal conformation that leads to the formation of cyclopentane, while the intermediate in the reaction of the α-D sugar has a very small probability. The results point to the dominant role of the β-L sugar intermediate in controlling the cyclopentane formation. PMID:26267888

  18. The molecular face of lipid rafts in model membranes

    PubMed Central

    Risselada, H. Jelger; Marrink, Siewert J.

    2008-01-01

    Cell membranes contain a large number of different lipid species. Such a multicomponent mixture exhibits a complex phase behavior with regions of structural and compositional heterogeneity. Especially domains formed in ternary mixtures, composed of saturated and unsaturated lipids together with cholesterol, have received a lot of attention as they may resemble raft formation in real cells. Here we apply a simulation model to assess the molecular nature of these domains at the nanoscale, information that has thus far eluded experimental determination. We are able to show the spontaneous separation of a saturated phosphatidylcholine (PC)/unsaturated PC/cholesterol mixture into a liquid-ordered and a liquid-disordered phase with structural and dynamic properties closely matching experimental data. The near-atomic resolution of the simulations reveals remarkable features of both domains and the boundary domain interface. Furthermore, we predict the existence of a small surface tension between the monolayer leaflets that drives registration of the domains. At the level of molecular detail, raft-like lipid mixtures show a surprising face with possible implications for many cell membrane processes. PMID:18987307

  19. Femtosecond molecular dynamics of tautomerization in model base pairs

    NASA Astrophysics Data System (ADS)

    Douhal, A.; Kim, S. K.; Zewail, A. H.

    1995-11-01

    HYDROGEN bonds commonly lend robustness and directionality to molecular recognition processes and supramolecular structures1,2. In particular, the two or three hydrogen bonds in Watson-Crick base pairs bind the double-stranded DNA helix and determine the complementarity of the pairing. Watson and Crick pointed out3, however, that the possible tautomers of base pairs, in which hydrogen atoms become attached to the donor atom of the hydrogen bond, might disturb the genetic code, as the tautomer is capable of pairing with different partners. But the dynamics of hydrogen bonds in general, and of this tautomerization process in particular, are not well understood. Here we report observations of the femtosecond dynamics of tautomerization in model base pairs (7-azaindole dimers) containing two hydrogen bonds. Because of the femtosecond resolution of proton motions, we are able to examine the cooperativity of formation of the tautomer (in which the protons on each base are shifted sequentially to the other base), and to determine the characteristic timescales of the motions in a solvent-free environment. We find that the first step occurs on a timescale of a few hundred femtoseconds, whereas the second step, to form the full tautomer, is much slower, taking place within several picoseconds; the timescales are changed significantly by replacing hydrogen with deuterium. These results establish the molecular basis of the dynamics and the role of quantum tunnelling.

  20. Molecular model for force production and transmission during vertebrate gastrulation.

    PubMed

    Pfister, Katherine; Shook, David R; Chang, Chenbei; Keller, Ray; Skoglund, Paul

    2016-02-15

    Vertebrate embryos undergo dramatic shape changes at gastrulation that require locally produced and anisotropically applied forces, yet how these forces are produced and transmitted across tissues remains unclear. We show that depletion of myosin regulatory light chain (RLC) levels in the embryo blocks force generation at gastrulation through two distinct mechanisms: destabilizing the myosin II (MII) hexameric complex and inhibiting MII contractility. Molecular dissection of these two mechanisms demonstrates that normal convergence force generation requires MII contractility and we identify a set of molecular phenotypes correlated with both this failure of convergence force generation in explants and of blastopore closure in whole embryos. These include reduced rates of actin movement, alterations in C-cadherin dynamics and a reduction in the number of polarized lamellipodia on intercalating cells. By examining the spatial relationship between C-cadherin and actomyosin we also find evidence for formation of transcellular linear arrays incorporating these proteins that could transmit mediolaterally oriented tensional forces. These data combine to suggest a multistep model to explain how cell intercalation can occur against a force gradient to generate axial extension forces. First, polarized lamellipodia extend mediolaterally and make new C-cadherin-based contacts with neighboring mesodermal cell bodies. Second, lamellipodial flow of actin coalesces into a tension-bearing, MII-contractility-dependent node-and-cable actin network in the cell body cortex. And third, this actomyosin network contracts to generate mediolateral convergence forces in the context of these transcellular arrays. PMID:26884399

  1. Comparison of antimicrobial activities of newly obtained low molecular weight scorpion chitosan and medium molecular weight commercial chitosan.

    PubMed

    Kaya, Murat; Asan-Ozusaglam, Meltem; Erdogan, Sevil

    2016-06-01

    In this study the antimicrobial activity of low molecular weight (3.22 kDa) chitosan, obtained for the first time from a species belonging to the Scorpiones, was screened against nine pathogenic microorganisms (seven bacteria and two yeasts) and compared with that of medium molecular weight commercial chitosan (MMWCC). It was observed that the antimicrobial activity of the low molecular weight scorpion chitosan (LMWSC) was specific to bacterial species in general rather than gram-negative or gram-positive bacterial groups. It was also determined that LMWSC had a stronger inhibitory effect than the MMWCC, particularly on the bacterium Listeria monocytogenes and the yeast Candida albicans, which are important pathogens for public health. In addition, it was recorded that the MMWCC had a greater inhibitory effect on Bacillus subtilis than LMWSC. According to the results obtained by the disc diffusion method, the antibacterial activity of both LMWSC and MMWCC against B. subtilis and Salmonella enteritidis was higher than the widely used antibiotic Gentamicin (CN, 10 μg/disc). PMID:26702952

  2. High and low molecular weight hyaluronic acid differentially influence macrophage activation

    PubMed Central

    Rayahin, Jamie E.; Buhrman, Jason S.; Zhang, Yu; Koh, Timothy J.; Gemeinhart, Richard A.

    2015-01-01

    Macrophages exhibit phenotypic diversity permitting wide-ranging roles in maintaining physiologic homeostasis. Hyaluronic acid, a major glycosaminoglycan of the extracellular matrix, has been shown to have differential signaling based on its molecular weight. With this in mind, the main objective of this study was to elucidate the role of hyaluronic acid molecular weight on macrophage activation and reprogramming. Changes in macrophage activation were assessed by activation state selective marker measurement, specifically quantitative real time polymerase chain reaction, and cytokine enzyme-linked immunoassays, after macrophage treatment with differing molecular weights of hyaluronic acid under four conditions: the resting state, concurrent with classical activation, and following inflammation involving either classically or alternatively activated macrophages. Regardless of initial polarization state, low molecular weight hyaluronic acid induced a classically activated-like state, confirmed by up-regulation of pro-inflammatory genes, including nos2, tnf, il12b, and cd80, and enhanced secretion of nitric oxide and TNF-α. High molecular weight hyaluronic acid promoted an alternatively activated-like state, confirmed by up regulation of pro-resolving gene transcription, including arg1, il10, and mrc1, and enhanced arginase activity. Overall, our observations suggest that macrophages undergo phenotypic changes dependent on molecular weight of hyaluronan that correspond to either (1) pro-inflammatory response for low molecular weight HA or (2) pro-resolving response for high molecular weight HA. These observations bring significant further understanding of the influence of extracellular matrix polymers, hyaluronic acid in particular, on regulating the inflammatory response of macrophages. This knowledge can be used to guide the design of HA-containing biomaterials to better utilize the natural response to HAs. PMID:26280020

  3. Leukocyte arrest: Biomechanics and molecular mechanisms of β2 integrin activation

    PubMed Central

    Fan, Zhichao; Ley, Klaus

    2016-01-01

    Integrins are a group of heterodimeric transmembrane receptors that play essential roles in cell–cell and cell–matrix interaction. Integrins are important in many physiological processes and diseases. Integrins acquire affinity to their ligand by undergoing molecular conformational changes called activation. Here we review the molecular biomechanics during conformational changes of integrins, integrin functions in leukocyte biorheology (adhesive functions during rolling and arrest) and molecules involved in integrin activation. PMID:26684674

  4. Molecular Simulations of RNA 2’-O-Transesterification Reaction Models in Solution

    PubMed Central

    Radak, Brian K.; Harris, Michael E.

    2013-01-01

    We employ quantum mechanical/molecular mechanical umbrella sampling simulations to probe the free energy surfaces of a series of increasingly complex reaction models of RNA 2’-O-transesterification in aqueous solution under alkaline conditions. Such models are valuable for understanding the uncatalyzed processes underlying catalytic cleavage of the phosphodiester backbone of RNA, a reaction of fundamental importance in biology. The chemically reactive atoms are modeled by the AM1/d-PhoT quantum model for phosphoryl transfer, whereas the aqueous solvation environment is modeled with a molecular mechanics force field. Several simulation protocols were compared that used different ionic conditions and force field models. The results provide insight into how variation of the structural environment of the nucleophile and leaving group affects the free energy profile for the transesterification reaction. Results for a simple RNA backbone model are compared with recent experiments by Harris et al. on the specific base catalyzed cleavage of a UpG dinucleotide. The calculated and measured free energies of activation match extremely well (ΔF‡ = 19.9–20.8 versus 19.9 kcal/mol). Solvation is seen to play a crucial role and is characterized by a network of hydrogen bonds that envelopes the pentacoordinate dianionic phosphorane transition state and provides preferential stabilization relative to the reactant state. PMID:23214417

  5. A Self-Organized Model for Cell-Differentiation Based on Variations of Molecular Decay Rates

    PubMed Central

    Hanel, Rudolf; Pöchacker, Manfred; Schölling, Manuel; Thurner, Stefan

    2012-01-01

    Systemic properties of living cells are the result of molecular dynamics governed by so-called genetic regulatory networks (GRN). These networks capture all possible features of cells and are responsible for the immense levels of adaptation characteristic to living systems. At any point in time only small subsets of these networks are active. Any active subset of the GRN leads to the expression of particular sets of molecules (expression modes). The subsets of active networks change over time, leading to the observed complex dynamics of expression patterns. Understanding of these dynamics becomes increasingly important in systems biology and medicine. While the importance of transcription rates and catalytic interactions has been widely recognized in modeling genetic regulatory systems, the understanding of the role of degradation of biochemical agents (mRNA, protein) in regulatory dynamics remains limited. Recent experimental data suggests that there exists a functional relation between mRNA and protein decay rates and expression modes. In this paper we propose a model for the dynamics of successions of sequences of active subnetworks of the GRN. The model is able to reproduce key characteristics of molecular dynamics, including homeostasis, multi-stability, periodic dynamics, alternating activity, differentiability, and self-organized critical dynamics. Moreover the model allows to naturally understand the mechanism behind the relation between decay rates and expression modes. The model explains recent experimental observations that decay-rates (or turnovers) vary between differentiated tissue-classes at a general systemic level and highlights the role of intracellular decay rate control mechanisms in cell differentiation. PMID:22693554

  6. A self-organized model for cell-differentiation based on variations of molecular decay rates.

    PubMed

    Hanel, Rudolf; Pöchacker, Manfred; Schölling, Manuel; Thurner, Stefan

    2012-01-01

    Systemic properties of living cells are the result of molecular dynamics governed by so-called genetic regulatory networks (GRN). These networks capture all possible features of cells and are responsible for the immense levels of adaptation characteristic to living systems. At any point in time only small subsets of these networks are active. Any active subset of the GRN leads to the expression of particular sets of molecules (expression modes). The subsets of active networks change over time, leading to the observed complex dynamics of expression patterns. Understanding of these dynamics becomes increasingly important in systems biology and medicine. While the importance of transcription rates and catalytic interactions has been widely recognized in modeling genetic regulatory systems, the understanding of the role of degradation of biochemical agents (mRNA, protein) in regulatory dynamics remains limited. Recent experimental data suggests that there exists a functional relation between mRNA and protein decay rates and expression modes. In this paper we propose a model for the dynamics of successions of sequences of active subnetworks of the GRN. The model is able to reproduce key characteristics of molecular dynamics, including homeostasis, multi-stability, periodic dynamics, alternating activity, differentiability, and self-organized critical dynamics. Moreover the model allows to naturally understand the mechanism behind the relation between decay rates and expression modes. The model explains recent experimental observations that decay-rates (or turnovers) vary between differentiated tissue-classes at a general systemic level and highlights the role of intracellular decay rate control mechanisms in cell differentiation. PMID:22693554

  7. Molecular switch for CLC-K Cl- channel block/activation: optimal pharmacophoric requirements towards high-affinity ligands.

    PubMed

    Liantonio, Antonella; Picollo, Alessandra; Carbonara, Giuseppe; Fracchiolla, Giuseppe; Tortorella, Paolo; Loiodice, Fulvio; Laghezza, Antonio; Babini, Elena; Zifarelli, Giovanni; Pusch, Michael; Camerino, Diana Conte

    2008-01-29

    ClC-Ka and ClC-Kb Cl(-) channels are pivotal for renal salt reabsorption and water balance. There is growing interest in identifying ligands that allow pharmacological interventions aimed to modulate their activity. Starting from available ligands, we followed a rational chemical strategy, accompanied by computational modeling and electrophysiological techniques, to identify the molecular requisites for binding to a blocking or to an activating binding site on ClC-Ka. The major molecular determinant that distinguishes activators from blockers is the level of planarity of the aromatic portions of the molecules: only molecules with perfectly coplanar aromatic groups display potentiating activity. Combining several molecular features of various CLC-K ligands, we discovered that phenyl-benzofuran carboxylic acid derivatives yield the most potent ClC-Ka inhibitors so far described (affinity <10 microM). The increase in affinity compared with 3-phenyl-2-p-chlorophenoxy-propionic acid (3-phenyl-CPP) stems primarily from the conformational constraint provided by the phenyl-benzofuran ring. Several other key structural elements for high blocking potency were identified through a detailed structure-activity relationship study. Surprisingly, some benzofuran-based drugs inhibit ClC-Kb with a similar affinity of <10 microM, thus representing the first inhibitors for this CLC-K isoform identified so far. Based on our data, we established a pharmacophore model that will be useful for the development of drugs targeting CLC-K channels. PMID:18216243

  8. Molecular Recognition of Agonist and Antagonist for Peroxisome Proliferator-Activated Receptor-α Studied by Molecular Dynamics Simulations

    PubMed Central

    Liu, Mengyuan; Wang, Lushan; Zhao, Xian; Sun, Xun

    2014-01-01

    Peroxisome proliferator activated receptor-α (PPAR-α) is a ligand-activated transcription factor which plays important roles in lipid and glucose metabolism. The aim of this work is to find residues which selectively recognize PPAR-α agonists and antagonists. To achieve this aim, PPAR-α/13M and PPAR-α/471 complexes were subjected to perform molecular dynamics simulations. This research suggests that several key residues only participate in agonist recognition, while some other key residues only contribute to antagonist recognition. It is hoped that such work is useful for medicinal chemists to design novel PPAR-α agonists and antagonists. PMID:24837836

  9. Synthesis, molecular modeling and structural characterization of vanillin derivatives as antimicrobial agents

    NASA Astrophysics Data System (ADS)

    Sun, Juan; Yin, Yong; Sheng, Gui-Hua; Yang, Zhi-Bo; Zhu, Hai-Liang

    2013-05-01

    Two vanillin derivatives have been designed and synthesized and their biological activities were also evaluated for antimicrobial activity. Their chemical structures are characterized by single crystal X-ray diffraction studies, 1H NMR, MS, and elemental analysis. Structural stabilization of them followed by intramolecular as well as intermolecular H-bonds makes these molecules as perfect examples in molecular recognition with self-complementary donor and acceptor units within a single molecule. Docking simulations have been performed to position compounds into the FtsZ active site to determine their probable binding model. Compound 3a shows the most potent biological activity, which may be a promising antimicrobial leading compound for the further research.

  10. Synthesis, Biological Evaluation and Molecular Modelling of 2'-Hydroxychalcones as Acetylcholinesterase Inhibitors.

    PubMed

    Sukumaran, Sri Devi; Chee, Chin Fei; Viswanathan, Geetha; Buckle, Mi