Página 1 dos resultados de 289 itens digitais encontrados em 0.006 segundos

‣ Thermodynamic Stabillity of Hydrogen-Bonded Systems in Polar and Nonpolar Environments

PASALIC, Hasan; AQUINO, Adelia J. A.; TUNEGA, Daniel; HABERHAUER, Georg; GERZABEK, Martin H.; Georg, Herbert de Castro; Moraes, Tatiane Faustino de; Coutinho, Kaline Rabelo; Canuto, Sylvio Roberto Accioly; LISCHKA, Hans
Fonte: JOHN WILEY & SONS INC Publicador: JOHN WILEY & SONS INC
Tipo: Artigo de Revista Científica
Português
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The thermodynamic properties of a selected set of benchmark hydrogen-bonded systems (acetic acid dimer and the complexes of acetic acid with acetamide and methanol) was studied with the goal of obtaining detailed information on solvent effects on the hydrogen-bonded interactions using water, chloroform, and n-heptane as representatives for a wide range in the dielectric constant. Solvent effects were investigated using both explicit and implicit solvation models. For the explicit description of the solvent, molecular dynamics and Monte Carlo simulations in the isothermal isobaric (NpT) ensemble combined with the free energy perturbation technique were performed to determine solvation free energies. Within the implicit solvation approach, the polarizable continuum model and the conductor-like screening model were applied. Combination of gas phase results with the results obtained from the different solvation models through an appropriate thermodynamic cycle allows estimation of complexation free energies, enthalpies, and the respective entropic contributions in solution. Owing to the strong solvation effects of water the cyclic acetic acid dimer is not stable in aqueous solution. In less polar solvents the double hydrogen bond structure of the acetic acid dimer remains stable. This finding is in agreement with previous theoretical and experimental results. A similar trend as for the acetic acid dimer is also observed for the acetamide complex. The methanol complex was found to be thermodynamically unstable in gas phase as well as in any of the three solvents. (C) 2010 Wiley Periodicals...

‣ Characterization of Heparin-induced Glyceraldehyde-3-phosphate Dehydrogenase Early Amyloid-like Oligomers and Their Implication in alpha-Synuclein Aggregation

Torres-Bugeau, Clarisa M.; Avila, Cesar L.; Raisman-Vozari, Rita; Papy-Garcia, Dulce; Itri, Rosangela; Barbosa, Leandro Ramos Souza; Cortez, Leonardo M.; Sim, Valerie L.; Chehin, Rosana N.
Fonte: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC; BETHESDA Publicador: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC; BETHESDA
Tipo: Artigo de Revista Científica
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Lewy bodies and Lewy neurites, neuropathological hallmarks of several neurological diseases, are mainly made of filamentous assemblies of alpha-synuclein. However, other macromolecules including Tau, ubiquitin, glyceraldehyde-3-phosphate dehydrogenase, and glycosaminoglycans are routinely found associated with these amyloid deposits. Glyceraldehyde-3-phosphate dehydrogenase is a glycolytic enzyme that can form fibrillar aggregates in the presence of acidic membranes, but its role in Parkinson disease is still unknown. In this work, the ability of heparin to trigger the amyloid aggregation of this protein at physiological conditions of pH and temperature is demonstrated by infrared and fluorescence spectroscopy, dynamic light scattering, small angle x-ray scattering, circular dichroism, and fluorescence microscopy. Aggregation proceeds through the formation of short rod-like oligomers, which elongates in one dimension. Heparan sulfate was also capable of inducing glyceraldehyde-3-phosphate dehydrogenase aggregation, but chondroitin sulfates A, B, and C together with dextran sulfate had a negligible effect. Aided with molecular docking simulations, a putative binding site on the protein is proposed providing a rational explanation for the structural specificity of heparin and heparan sulfate. Finally...

‣ CXC and CC Chemokines Form Mixed Heterodimers: ASSOCIATION FREE ENERGIES FROM MOLECULAR DYNAMICS SIMULATIONS AND EXPERIMENTAL CORRELATIONS*S⃞

Nesmelova, Irina V.; Sham, Yuk; Gao, Jiali; Mayo, Kevin H.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Publicado em 29/08/2008 Português
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CXC and CC chemokines are involved in numerous biological processes, and their function in situ may be significantly influenced by heterodimer formation, as was recently reported, for example, for CXC chemokines CXCL4/PF4 and CXCL8/IL8 that interact to form heterodimers that modulate chemotactic and cell proliferation activities. Here we used molecular dynamics simulations to determine relative association free energies (overall average and per residue) for homo- and heterodimer pairs of CXC (CXCL4/PF4, CXCL8/IL8, CXCL1/Gro-α, and CXCL7/NAP-2) and CC (CCL5/RANTES, CCL2/MCP-1, and CCL8/MCP-2) chemokines. Even though structural homology among monomer folds of all CXC and CC chemokines permits heterodimer assembly, our calculated association free energies depend upon the particular pair of chemokines in terms of the net electrostatic and nonelectrostatic forces involved, as well as (for CC/CXC mixed chemokines) the selection of dimer type (CC or CXC). These relative free energies indicate that association of some pairs of chemokines is more favorable than others. Our approach is validated by correlation of calculated and experimentally determined free energies. Results are discussed in terms of CXC and CC chemokine function and have significant biological implications.

‣ Curvature Dynamics of α-Synuclein Familial Parkinson Disease Mutants: MOLECULAR SIMULATIONS OF THE MICELLE- AND BILAYER-BOUND FORMS*S⃞

Perlmutter, Jason D.; Braun, Anthony R.; Sachs, Jonathan N.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Publicado em 13/03/2009 Português
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α-Synuclein remains a protein of interest due to its propensity to form fibrillar aggregates in neurodegenerative disease and its putative function in synaptic vesicle regulation. Herein, we present a series of atomistic molecular dynamics simulations of wild-type α-synuclein and three Parkinson disease familial mutants (A30P, A53T, and E46K) in two distinct environments. First, in order to match recent NMR experiments, we have simulated each protein bound to an SDS detergent micelle. Second, in order to connect more closely to the true biological environment, we have simulated the proteins bound to a 1,2-dioleoyl-sn-glycero-3-phosphoserine lipid bilayer. In the micelle-bound case, we find that the wild type and all of the variants of α-synuclein flatten the underlying micelle, decreasing its surface area. A30P is known to lessen α-synuclein/membrane affinity and, consistent with experiment, destabilizes the simulated secondary structure. In the case of A53T, our simulations reveal a range of stabilizing hydrogen bonds that form with the threonine. In both environments, the E46K mutation, which is known to increase bilayer affinity, leads to an additional hydrogen bond between the protein and either the detergent or lipid. Simulations indicate that αS and its variants are less dynamic in the bilayer than in the micelle. Furthermore...

‣ Molecular Dynamics Simulations of the Apo-, Holo-, and Acyl-forms of Escherichia coli Acyl Carrier Protein*S⃞

Chan, David I.; Stockner, Thomas; Tieleman, D. Peter; Vogel, Hans J.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Publicado em 28/11/2008 Português
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Acyl carrier protein (ACP) is an essential co-factor protein in fatty acid biosynthesis that shuttles covalently bound fatty acyl intermediates in its hydrophobic pocket to various enzyme partners. To characterize acyl chain-ACP interactions and their influence on enzyme interactions, we performed 19 molecular dynamics (MD) simulations of Escherichia coli apo-, holo-, and acyl-ACPs. The simulations were started with the acyl chain in either a solvent-exposed or a buried conformation. All four short-chain (≤C10) and one long-chain (C16) unbiased acyl-ACP MD simulation show the transition of the solvent-exposed acyl chain into the hydrophobic pocket of ACP, revealing its pathway of acyl chain binding. Although the acyl chain resides inside the pocket, Thr-39 and Glu-60 at the entrance stabilize the phosphopantetheine linker through hydrogen bonding. Comparisons of the different ACP forms indicate that the loop region between helices II and III and the prosthetic linker may aid in substrate recognition by enzymes of fatty acid synthase systems. The MD simulations consistently show that the hydrophobic binding pocket of ACP is best suited to accommodate an octanoyl group and is capable of adjusting in size to accommodate chain lengths as long as decanoic acid. The simulations also reveal a second...

‣ Coupled Flow-Structure-Biochemistry Simulations of Dynamic Systems of Blood Cells Using an Adaptive Surface Tracking Method

Hoskins, M.H.; Kunz, R.F.; Bistline, J.E.; Dong, C.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/07/2009 Português
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A method for the computation of low Reynolds number dynamic blood cell systems is presented. The specific system of interest here is interaction between cancer cells and white blood cells in an experimental flow system. Fluid dynamics, structural mechanics, six-degree-of freedom motion control and surface biochemistry analysis components are coupled in the context of adaptive octree-based grid generation. Analytical and numerical verification of the quasi-steady assumption for the fluid mechanics is presented. The capabilities of the technique are demonstrated by presenting several three-dimensional cell system simulations, including the collision/interaction between a cancer cell and an endothelium adherent polymorphonuclear leukocyte (PMN) cell in a shear flow.

‣ Molecular Dynamics Simulations Show That Conformational Selection Governs the Binding Preferences of Imatinib for Several Tyrosine Kinases*

Aleksandrov, Alexey; Simonson, Thomas
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Português
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Tyrosine kinases transmit cellular signals through a complex mechanism, involving their phosphorylation and switching between inactive and active conformations. The cancer drug imatinib binds tightly to several homologous kinases, including Abl, but weakly to others, including Src. Imatinib specifically targets the inactive, so-called “DFG-out” conformation of Abl, which differs from the preferred, “DFG-in” conformation of Src in the orientation of a conserved Asp-Phe-Gly (DFG) activation loop. However, recent x-ray structures showed that Src can also adopt the DFG-out conformation and uses it to bind imatinib. The Src/Abl-binding free energy difference can thus be decomposed into two contributions. Contribution i measures the different protein-imatinib interactions when either kinase is in its DFG-out conformation. Contribution ii depends on the ability of imatinib to select or induce this conformation, i.e. on the relative stabilities of the DFG-out and DFG-in conformations of each kinase. Neither contribution has been measured experimentally. We use molecular dynamics simulations to show that contribution i is very small, 0.2 ± 0.6 kcal/mol; imatinib interactions are very similar in the two kinases, including long range electrostatic interactions with the imatinib positive charge. Contribution ii...

‣ Three-dimensional, multiwavelength Monte Carlo simulations of dermally implantable luminescent sensors

Long, Ruiqi; McShane, Mike
Fonte: Society of Photo-Optical Instrumentation Engineers Publicador: Society of Photo-Optical Instrumentation Engineers
Tipo: Artigo de Revista Científica
Português
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Dermally implanted luminescent sensors have been proposed for monitoring of tissue biochemistry, which has the potential to improve treatments for conditions such as diabetes and kidney failure. Effective in vivo monitoring via noninvasive transdermal measurement of emission from injected microparticles requires a matched optoelectronic system for excitation and collection of luminescence. We applied Monte Carlo modeling to predict the characteristics of output luminescence from microparticles in skin to facilitate hardware design. Three-dimensional, multiwavelength Monte Carlo simulations were used to determine the spatial and spectral distribution of the escaping luminescence for different implantation depths, excitation light source properties, particle characteristics, and particle packing density. Results indicate that the ratio of output emission to input excitation power ranged 10−3 to 10−6 for sensors at the upper and lower dermal boundaries, respectively, and 95% of the escaping emission photons induced by a 10-mm-diam excitation beam were confined within an 18-mm circle. Tightly packed sensor configurations yielded higher output intensity with fewer particles, even after luminophore concentration effects were removed. Most importantly...

‣ Analysis of the Conformational Stability and Activity of Candida antarctica Lipase B in Organic Solvents: INSIGHT FROM MOLECULAR DYNAMICS AND QUANTUM MECHANICS/SIMULATIONS*

Li, Cong; Tan, Tianwei; Zhang, Haiyang; Feng, Wei
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Português
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The conformational stability and activity of Candida antarctica lipase B (CALB) in the polar and nonpolar organic solvents were investigated by molecular dynamics and quantum mechanics/molecular mechanics simulations. The conformation change of CALB in the polar and nonpolar solvents was examined in two aspects: the overall conformation change of CALB and the conformation change of the active site. The simulation results show that the overall conformation of CALB is stable in the organic solvents. In the nonpolar solvents, the conformation of the active site keeps stable, whereas in the polar solvents, the solvent molecules reach into the active site and interact intensively with the active site. This interaction destroys the hydrogen bonding between Ser105 and His224. In the solvents, the activation energy of CALB and that of the active site region were further simulated by quantum mechanics/molecular mechanics simulation. The results indicate that the conformation change in the region of active sites is the main factor that influences the activity of CALB.

‣ Full Reconstruction of a Vectorial Protein Folding Pathway by Atomic Force Microscopy and Molecular Dynamics Simulations*

Lee, Whasil; Zeng, Xiancheng; Zhou, Huan-Xiang; Bennett, Vann; Yang, Weitao; Marszalek, Piotr E.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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During co-translational folding, the nascent polypeptide chain is extruded sequentially from the ribosome exit tunnel and, under severe conformational constraints, is dictated by its one-dimensional geometry. How do such vectorial constraints impact the folding pathway? Here, we combine single-molecule atomic force spectroscopy and steered molecular dynamics simulations to examine protein folding in the presence of one-dimensional constraints that are similar to those imposed on the nascent polypeptide chain. The simulations exquisitely reproduced the experimental unfolding and refolding force extension relationships and led to the full reconstruction of the vectorial folding pathway of a large polypeptide, the 253-residue consensus ankyrin repeat protein, NI6C. We show that fully stretched and then relaxed NI6C starts folding by the formation of local secondary structures, followed by the nucleation of three N-terminal repeats. This rate-limiting step is then followed by the vectorial and sequential folding of the remaining repeats. However, after partial unfolding, when allowed to refold, the C-terminal repeats successively regain structures without any nucleation step by using the intact N-terminal repeats as a template. These results suggest a pathway for the co-translational folding of repeat proteins and have implications for mechanotransduction.

‣ Validation of previous computer models and MD simulations of discoidal HDL by a recent crystal structure of apoA-I

Segrest, Jere P.; Jones, Martin K.; Catte, Andrea; Thirumuruganandham, Saravana P.
Fonte: The American Society for Biochemistry and Molecular Biology Publicador: The American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Publicado em /09/2012 Português
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HDL is a population of apoA-I-containing particles inversely correlated with heart disease. Because HDL is a soft form of matter deformable by thermal fluctuations, structure determination has been difficult. Here, we compare the recently published crystal structure of lipid-free (Δ185-243)apoA-I with apoA-I structure from models and molecular dynamics (MD) simulations of discoidal HDL. These analyses validate four of our previous structural findings for apoA-I: i) a baseline double belt diameter of 105 Å ii) central α helixes with an 11/3 pitch; iii) a “presentation tunnel” gap between pairwise helix 5 repeats hypothesized to move acyl chains and unesterified cholesterol from the lipid bilayer to the active sites of LCAT; and iv) interchain salt bridges hypothesized to stabilize the LL5/5 chain registry. These analyses are also consistent with our finding that multiple salt bridge-forming residues in the N-terminus of apoA-I render that conserved domain “sticky.” Additionally, our crystal MD comparisons led to two new hypotheses: i) the interchain leucine-zippers previously reported between the pair-wise helix 5 repeats drive lipid-free apoA-I registration; ii) lipidation induces rotations of helix 5 to allow formation of interchain salt bridges...

‣ MD simulations suggest important surface differences between reconstituted and circulating spherical HDL1[S]

Segrest, Jere P.; Jones, Martin K.; Catte, Andrea
Fonte: The American Society for Biochemistry and Molecular Biology Publicador: The American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Publicado em /10/2013 Português
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Since spheroidal HDL particles (sHDL) are highly dynamic, molecular dynamics (MD) simulations are useful for obtaining structural models. Here we use MD to simulate sHDL with stoichiometries of reconstituted and circulating particles. The hydrophobic effect during simulations rapidly remodels discoidal HDL containing mixed lipids to sHDL containing a cholesteryl ester/triglyceride (CE/TG) core. We compare the results of simulations of previously characterized reconstituted sHDL particles containing two or three apoA-I created in the absence of phospholipid transfer protein (PLTP) with simulations of circulating human HDL containing two or three apoA-I without apoA-II. We find that circulating sHDL compared with reconstituted sHDL with the same number of apoA-I per particle contain approximately equal volumes of core lipid but significantly less surface lipid monolayers. We conclude that in vitro reconstituted sHDL particles contain kinetically trapped excess phospholipid and are less than ideal models for circulating sHDL particles. In the circulation, phospholipid transfer via PLTP decreases the ratio of phospholipid to apolipoprotein for all sHDL particles. Further, sHDL containing two or three apoA-I adapt to changes in surface area by condensation of common conformational motifs. These results represent an important step toward resolving the complicated issue of the protein and lipid stoichiometry of circulating HDL.

‣ Analyzing machupo virus-receptor binding by molecular dynamics simulations

Meyer, Austin G.; Sawyer, Sara L.; Ellington, Andrew D.; Wilke, Claus O.
Fonte: PeerJ Inc. Publicador: PeerJ Inc.
Tipo: Artigo de Revista Científica
Publicado em 27/02/2014 Português
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In many biological applications, we would like to be able to computationally predict mutational effects on affinity in protein–protein interactions. However, many commonly used methods to predict these effects perform poorly in important test cases. In particular, the effects of multiple mutations, non alanine substitutions, and flexible loops are difficult to predict with available tools and protocols. We present here an existing method applied in a novel way to a new test case; we interrogate affinity differences resulting from mutations in a host–virus protein–protein interface. We use steered molecular dynamics (SMD) to computationally pull the machupo virus (MACV) spike glycoprotein (GP1) away from the human transferrin receptor (hTfR1). We then approximate affinity using the maximum applied force of separation and the area under the force-versus-distance curve. We find, even without the rigor and planning required for free energy calculations, that these quantities can provide novel biophysical insight into the GP1/hTfR1 interaction. First, with no prior knowledge of the system we can differentiate among wild type and mutant complexes. Moreover, we show that this simple SMD scheme correlates well with relative free energy differences computed via free energy perturbation. Second...

‣ Study of the Affinity between the Protein Kinase PKA and Peptide Substrates Derived from Kemptide Using Molecular Dynamics Simulations and MM/GBSA

Mena-Ulecia, Karel; Vergara-Jaque, Ariela; Poblete, Horacio; Tiznado, William; Caballero, Julio
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 02/10/2014 Português
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We have carried out a protocol in computational biochemistry including molecular dynamics (MD) simulations and MM/GBSA free energy calculations on the complex between the protein kinase A (PKA) and the specific peptide substrate Kemptide (LRRASLG). We made the same calculations on other PKA complexes that contain Kemptide derivatives (with mutations of the arginines, and with deletions of N and C-terminal amino acids). We predicted shifts in the free energy changes from the free PKA to PKA-substrate complex (ΔΔGE→ES) when Kemptide structure is modified (we consider that the calculated shifts correlate with the experimental shifts of the free energy changes from the free PKA to the transition states (ΔΔGE→TS) determined by the catalytic efficiency (kcat/KM) changes). Our results demonstrate that it is possible to predict the kinetic properties of protein kinases using simple computational biochemistry methods. As an additional benefit, these methods give detailed molecular information that permit the analysis of the atomic forces that contribute to the affinity between protein kinases and their substrates.

‣ Inferring Carbon Sources from Gene Expression Profiles Using Metabolic Flux Models

Brandes, Aaron; Lun, Desmond S.; Ip, Kuhn; Colijn, Caroline; Weiner, Brian; Zucker, Jeremy Daniel Hofeld; Galagan, James E.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
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Background: Bacteria have evolved the ability to efficiently and resourcefully adapt to changing environments. A key means by which they optimize their use of available nutrients is through adjustments in gene expression with consequent changes in enzyme activity. We report a new method for drawing environmental inferences from gene expression data. Our method prioritizes a list of candidate carbon sources for their compatibility with a gene expression profile using the framework of flux balance analysis to model the organism’s metabolic network. Principal Findings: For each of six gene expression profiles for Escherichia coli grown under differing nutrient conditions, we applied our method to prioritize a set of eighteen different candidate carbon sources. Our method ranked the correct carbon source as one of the top three candidates for five of the six expression sets when used with a genome-scale model. The correct candidate ranked fifth in the remaining case. Additional analyses show that these rankings are robust with respect to biological and measurement variation, and depend on specific gene expression, rather than general expression level. The gene expression profiles are highly adaptive: simulated production of biomass averaged 94.84% of maximum when the in silico carbon source matched the in vitro source of the expression profile...

‣ Exploring the Contextual Sensitivity of Factors that Determine Cell-to-Cell Variability in Receptor-Mediated Apoptosis

Spencer, Sabrina L.; Gaudet, Suzanne; Chen, William Wei-Lun; Sorger, Peter Karl
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
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Stochastic fluctuations in gene expression give rise to cell-to-cell variability in protein levels which can potentially cause variability in cellular phenotype. For TRAIL (TNF-related apoptosis-inducing ligand) variability manifests itself as dramatic differences in the time between ligand exposure and the sudden activation of the effector caspases that kill cells. However, the contribution of individual proteins to phenotypic variability has not been explored in detail. In this paper we use feature-based sensitivity analysis as a means to estimate the impact of variation in key apoptosis regulators on variability in the dynamics of cell death. We use Monte Carlo sampling from measured protein concentration distributions in combination with a previously validated ordinary differential equation model of apoptosis to simulate the dynamics of receptor-mediated apoptosis. We find that variation in the concentrations of some proteins matters much more than variation in others and that precisely which proteins matter depends both on the concentrations of other proteins and on whether correlations in protein levels are taken into account. A prediction from simulation that we confirm experimentally is that variability in fate is sensitive to even small increases in the levels of Bcl-2. We also show that sensitivity to Bcl-2 levels is itself sensitive to the levels of interacting proteins. The contextual dependency is implicit in the mathematical formulation of sensitivity...

‣ Reconstruction and Validation of a Genome-Scale Metabolic Model for the Filamentous Fungus Neurospora crassa Using FARM

Dreyfuss, Jonathan M.; Zucker, Jeremy D.; Hood, Heather M.; Ocasio, Linda R.; Sachs, Matthew S.; Galagan, James E.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
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The filamentous fungus Neurospora crassa played a central role in the development of twentieth-century genetics, biochemistry and molecular biology, and continues to serve as a model organism for eukaryotic biology. Here, we have reconstructed a genome-scale model of its metabolism. This model consists of 836 metabolic genes, 257 pathways, 6 cellular compartments, and is supported by extensive manual curation of 491 literature citations. To aid our reconstruction, we developed three optimization-based algorithms, which together comprise Fast Automated Reconstruction of Metabolism (FARM). These algorithms are: LInear MEtabolite Dilution Flux Balance Analysis (limed-FBA), which predicts flux while linearly accounting for metabolite dilution; One-step functional Pruning (OnePrune), which removes blocked reactions with a single compact linear program; and Consistent Reproduction Of growth/no-growth Phenotype (CROP), which reconciles differences between in silico and experimental gene essentiality faster than previous approaches. Against an independent test set of more than 300 essential/non-essential genes that were not used to train the model, the model displays 93% sensitivity and specificity. We also used the model to simulate the biochemical genetics experiments originally performed on Neurospora by comprehensively predicting nutrient rescue of essential genes and synthetic lethal interactions...

‣ GQ-16, a Novel Peroxisome Proliferator-activated Receptor gamma (PPAR gamma) Ligand, Promotes Insulin Sensitization without Weight Gain

Amato, Angelica A.; Rajagopalan, Senapathy; Lin, Jean Z.; Carvalho, Bruno M.; Figueira, Ana C. M.; Lu, Jenny; Ayers, Stephen D.; Mottin, Melina; Silveira, Rodrigo L.; Souza, Paulo C. T.; Mourao, Rosa H. V.; Saad, Mario J. A.; Togashi, Marie; Simeoni, Luiz
Fonte: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC; BETHESDA Publicador: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC; BETHESDA
Tipo: Artigo de Revista Científica
Português
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The recent discovery that peroxisome proliferator-activated receptor gamma (PPAR gamma) targeted anti-diabetic drugs function by inhibiting Cdk5-mediated phosphorylation of the receptor has provided a new viewpoint to evaluate and perhaps develop improved insulin-sensitizing agents. Herein we report the development of a novel thiazolidinedione that retains similar anti-diabetic efficacy as rosiglitazone in mice yet does not elicit weight gain or edema, common side effects associated with full PPAR gamma activation. Further characterization of this compound shows GQ-16 to be an effective inhibitor of Cdk5-mediated phosphorylation of PPAR gamma. The structure of GQ-16 bound to PPAR gamma demonstrates that the compound utilizes a binding mode distinct from other reported PPAR gamma ligands, although it does share some structural features with other partial agonists, such as MRL-24 and PA-082, that have similarly been reported to dissociate insulin sensitization from weight gain. Hydrogen/deuterium exchange studies reveal that GQ-16 strongly stabilizes the beta-sheet region of the receptor, presumably explaining the compound's efficacy in inhibiting Cdk5-mediated phosphorylation of Ser-273. Molecular dynamics simulations suggest that the partial agonist activity of GQ-16 results from the compound's weak ability to stabilize helix 12 in its active conformation. Our results suggest that the emerging model...

‣ Multiscale Simulations of Biomolecules in Condensed Phase: from Solutions to Proteins

Zeng, Xiancheng
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação
Publicado em //2010 Português
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The thesis contains two directions in the simulations of biomolecular systems. The first part (Chapter 2 - Chapter 4) mainly focuses on the simulations of electron transfer processes in condensed phase; the second part (Chapter 5 - Chapter 6) investigates the conformational sampling of polysaccharides and proteins. Electron transfer (ET) reaction is one of the most fundamental processes in chemistry and biology. Because of the quantum nature of the processes and the complicated roles of the solvent, calculating the accurate kinetic and dynamic properties of ET reactions is challenging but extremely useful. Based on the Marcus theory for thermal ET in weak coupling limit, we combined the rigorous ab initio quantum mechanical (QM) method and well-established molecular mechanical (MM) force field and developed an approach to directly calculate a key factor that affects the ET kinetics: the redox free energy. A novel reaction order parameter fractional number of electrons (FNE) was used to characterize the ET progress and to drive the QM/MMMD sampling of the nonadiabatic free energy surface. This method was used for two aqueous metal cations, iron and ruthenium in solution, and generated satisfactory results compared to experiments. In order to further reduce the computational cost...

‣ Molecular Dynamics Simulations of Human Prion Protein: Importance of Correct Treatment of Electrostatic Interactions

Zuegg, J.; Gready, Jill
Fonte: American Chemical Society Publicador: American Chemical Society
Tipo: Artigo de Revista Científica
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Molecular dynamics simulations have been used to investigate the dynamical and structural behavior of a homology model of human prion protein HuPrP(90-230) generated from the NMR structure of the Syrian hamster prion protein ShPrP(90-231) and of ShPrP(90-231) itself. These PrPs have a large number of charged residues on the protein surface. At the simulation pH 7, HuPrP(90-230) has a net charge of - 1 eu from 15 positively and 14 negatively charged residues. Simulations for both PrPs, using the AMBER94 force field in a periodic box model with explicit water molecules, showed high sensitivity to the correct treatment of the electrostatic interactions. Highly unstable behavior of the structured region of the PrPs (127-230) was found using the truncation method, and stable trajectories could be achieved only by including all the long-range electrostatic interactions using the particle mesh Ewald (PME) method. The instability using the truncation method could not be reduced by adding sodium and chloride ions nor by replacing some of the sodium ions with calcium ions. The PME simulations showed, in accordance with NMR experiments with ShPrP and mouse PrP, a flexibly disordered N- terminal part, PrP(90-126), and a structured C-terminal part...