Correntes críticas e comportamento dinâmico dos vórtices em fitas supercondutoras do tipo II com arranjos conformes de centros de aprisionamento

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Um novo protocolo in silico para a predição de complexos flexíveis entre proteínas: estudo de caso para inibidores plasmáticos de fosfolipase A2 de serpentes

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Employing perichromism for probing the properties of carboxymethyl cellulose films: an expedient, accurate method for the determination of the degree of substitution of the biopolymer derivative

The properties of films of carboxymethyl cellulose, CMC, of different degree of substitution, DS, have been examined by the use of perichromic indicators (probes). The film properties that have been determined are: empirical polarity, E-T(33); "acidity", alpha; "basicity", beta; and dipolarity/polarizability, pi*. This has been achieved by employing the following perichromic probes: 4-nitroaniline, 4-nitroanisole, 4-nitro-N,N-dimethylaniline, and 2,6-dichloro-4-(2,4,6-triphenyl-pyridinium-1-yl)phenolate, WB. The correlations between both E-T(33)- or pi* and DS were found to be linear; that between beta and DS is a second order polynomial; no obvious correlation was found between alpha and DS. The polarities of CMC films are in the range of those of butyl alcohols. As models for CMC, we have employed cellulose plus CMC of high DS; oxidized cellulose with degree of oxidation = 0.5; sodium glucuronate. The former model behaved akin to CMC, but the plots of the perichromic properties versus DS showed different slopes/intercepts. FTIR data and molecular dynamics simulations on the solvation of WB have shown that this difference can be traced to more efficient hydrogen bonding between the film of the model and the probe. This affects the intra-molecular charge-transfer energy of the latter, leading to different responses to the variation of DS. Based on the excellent linear correlation between E-T(33) and DS, for CMC from different origins, we suggest that perichromism is a simple, accurate, and expedient alternative for the determination of DS of the biopolymer derivative.

Directed and elliptic flow of charged particles in Cu plus Cu collisions at root s(NN)=22.4 GeV

This paper reports results for directed flow v(1) and elliptic flow v(2) of charged particles in Cu + Cu collisions at root s(NN) = 22.4 GeV at the Relativistic Heavy Ion Collider. The measurements are for the 0-60% most central collisions, using charged particles observed in the STAR detector. Our measurements extend to 22.4-GeV Cu + Cu collisions the prior observation that v1 is independent of the system size at 62.4 and 200 GeV and also extend the scaling of v(1) with eta/y(beam) to this system. The measured v(2)(p(T)) in Cu + Cu collisions is similar for root s(NN) throughout the range 22.4 to 200 GeV. We also report a comparison with results from transport model (ultrarelativistic quantum molecular dynamics and multiphase transport model) calculations. The model results do not agree quantitatively with the measured v(1)(eta), v(2)(p(T)), and v(2)(eta).

Gold-platinum alloys and Vegard's law on the nanoscale

The structure of gold-platinum nanoparticles is heavily debated as theoretical calculations predict core-shell particles, whereas x-ray diffraction experiments frequently detect randomly mixed alloys. By calculating the structure of gold-platinum nanoparticles with diameters of up to approximate to 3.5 nm and simulating their x-ray diffraction patterns, we show that these seemingly opposing findings need not be in contradiction: Shells of gold are hardly visible in usual x-ray scattering, and the interpretation of Vegard's law is ambiguous on the nanoscale. DOI: 10.1103/PhysRevB.86.241403

Hb S-Sao Paulo: A new sickling hemoglobin with stable polymers and decreased oxygen affinity

Hb S-Sao Paulo (SP) [HBB:c.20A > T p.Glu6Val: c.196A > G p.Lys65Glu] is a new double-mutant hemoglobin that was found in heterozygosis in an 18-month-old Brazilian male with moderate anemia. It behaves like Hb S in acid electrophoresis, isoelectric focusing and solubility testing but shows different behavior in alkaline electrophoresis, cation-exchange HPLC and RP-HPLC. The variant is slightly unstable, showed reduced oxygen affinity and also appeared to form polymers more stable than the Hb S. Molecular dynamics simulation suggests that the polymerization is favored by interfacial electrostatic interactions. This provides a plausible explanation for some of the reported experimental observations. (C) 2012 Elsevier Inc. All rights reserved.

Extensive structural change of the envelope protein of dengue virus induced by a tuned ionic strength: conformational and energetic analyses

The Dengue has become a global public health threat, with over 100 million infections annually; to date there is no specific vaccine or any antiviral drug. The structures of the envelope (E) proteins of the four known serotype of the dengue virus (DENV) are already known, but there are insufficient molecular details of their structural behavior in solution in the distinct environmental conditions in which the DENVs are submitted, from the digestive tract of the mosquito up to its replication inside the host cell. Such detailed knowledge becomes important because of the multifunctional character of the E protein: it mediates the early events in cell entry, via receptor endocytosis and, as a class II protein, participates determinately in the process of membrane fusion. The proposed infection mechanism asserts that once in the endosome, at low pH, the E homodimers dissociate and insert into the endosomal lipid membrane, after an extensive conformational change, mainly on the relative arrangement of its three domains. In this work we employ all-atom explicit solvent Molecular Dynamics simulations to specify the thermodynamic conditions in that the E proteins are induced to experience extensive structural changes, such as during the process of reducing pH. We study the structural behavior of the E protein monomer at acid pH solution of distinct ionic strength. Extensive simulations are carried out with all the histidine residues in its full protonated form at four distinct ionic strengths. The results are analyzed in detail from structural and energetic perspectives, and the virtual protein movements are described by means of the principal component analyses. As the main result, we found that at acid pH and physiological ionic strength, the E protein suffers a major structural change; for lower or higher ionic strengths, the crystal structure is essentially maintained along of all extensive simulations. On the other hand, at basic pH, when all histidine residues are in the unprotonated form, the protein structure is very stable for ionic strengths ranging from 0 to 225 mM. Therefore, our findings support the hypothesis that the histidines constitute the hot points that induce configurational changes of E protein in acid pH, and give extra motivation to the development of new ideas for antivirus compound design.

Interactions between 1-butyl-3-methylimidazolium tetrafluoroborate ionic liquid and gamma-Al2O3 (100) surface calculated by density functional theory

The main aim of this work is to investigate the 1-butyl-3-methylimidazolium tetrafluoroborate ([C4C1Im]+[BF4]-) ionic liquid (IL) adsorption on the gamma-Al2O3 (100) by density functional theory calculations to try to rationalize the adsorption as an electrostatic phenomenon. Optimized geometries and interaction energies of IL one-monolayer on the gamma-Al2O3 were obtained on high surface coverage (one cationanion pair per 94.96 nm2). A study of dispersion force was made to estimate its contribution to the adsorption. Overall, the process is ruled by electrostatic interaction between ions and surface. Adsorption of the anion [BF4]- and cation [C4C1Im]+ was also studied by Bader charge analysis and charge density difference for supported and unsupported situations. It is suggested that the IL ions have their charges maintained with significant anion cloud polarization inward to the acid aluminum sites. (c) 2012 Wiley Periodicals, Inc.

Site localization of Cd impurities in sapphire

By combining first-principles electronic structure calculations and existing time-differential gamma-gamma perturbed-angular-correlation experiments we studied the site localization, the local environment, and the electronic structure of Cd impurities in sapphire (alpha-Al2O3) single crystals in different charged states. The ab initio calculations were performed with the full-potential augmented plane wave plus local orbitals method and the projector augmented wave method. Comparing the calculated electric-field-gradient tensor at the Cd nuclei in the alpha-Al2O3 host lattice and the corresponding available experimental values, we have seen that it is equally possible for Cd to replace an Al atom (in a negative charge state) or to be placed in an interstitial site (in a neutral charge state). To finally address the issue of the Cd impurity localization, we performed formation energy calculations. These results have shown that Cd placed in the substitutional Al site, in the negatively charged state, is the most probable configuration.

The Carmaphycins: New Proteasome Inhibitors Exhibiting an alpha,beta-Epoxyketone Warhead from a Marine Cyanobacterium

Two new peptidic proteasome inhibitors were isolated as trace components from a Curacao collection of the marine cyanobacterium Symploca sp. Carmaphycin A (1) and carmaphycin B (2) feature a leucine-derived a,beta-epoxyketone warhead directly connected to either methionine sulfoxide or methionine sulfone. Their structures were elucidated on the basis of extensive NMR and MS analyses and confirmed by total synthesis, which in turn provided more material for further biological evaluations. Pure carmaphycins A and B were found to inhibit the beta 5 subunit (chymotrypsin-like activity) of the S. cerevisiae 20S proteasome in the low nanomolar range. Additionally, they exhibited strong cytotoxicity to lung and colon cancer cell lines, as well as exquisite antiproliferative effects in the NCI60 cell-line panel. These assay results as well as initial structural biology studies suggest a distinctive binding mode for these new inhibitors.

Medium Chain Fatty Acids Are Selective Peroxisome Proliferator Activated Receptor (PPAR) gamma Activators and Pan-PPAR Partial Agonists

Thiazolidinediones (TZDs) act through peroxisome proliferator activated receptor (PPAR) gamma to increase insulin sensitivity in type 2 diabetes (T2DM), but deleterious effects of these ligands mean that selective modulators with improved clinical profiles are needed. We obtained a crystal structure of PPAR gamma ligand binding domain (LBD) and found that the ligand binding pocket (LBP) is occupied by bacterial medium chain fatty acids (MCFAs). We verified that MCFAs (C8-C10) bind the PPAR gamma LBD in vitro and showed that they are low-potency partial agonists that display assay-specific actions relative to TZDs; they act as very weak partial agonists in transfections with PPAR gamma LBD, stronger partial agonists with full length PPAR gamma and exhibit full blockade of PPAR gamma phosphorylation by cyclin-dependent kinase 5 (cdk5), linked to reversal of adipose tissue insulin resistance. MCFAs that bind PPAR gamma also antagonize TZD-dependent adipogenesis in vitro. X-ray structure B-factor analysis and molecular dynamics (MD) simulations suggest that MCFAs weakly stabilize C-terminal activation helix (H) 12 relative to TZDs and this effect is highly dependent on chain length. By contrast, MCFAs preferentially stabilize the H2-H3/beta-sheet region and the helix (H) 11-H12 loop relative to TZDs and we propose that MCFA assay-specific actions are linked to their unique binding mode and suggest that it may be possible to identify selective PPAR gamma modulators with useful clinical profiles among natural products.

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

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, whereby "ideal" PPAR gamma-based therapeutics stabilize the beta-sheet/Ser-273 region and inhibit Cdk5-mediated phosphorylation while minimally invoking adipogenesis and classical agonism, is indeed a valid framework to develop improved PPAR gamma modulators that retain antidiabetic actions while minimizing untoward effects.

Electronic Properties of Water in Liquid Environment. A Sequential QM/MM Study Using the Free Energy Gradient Method

There is a continuous search for theoretical methods that are able to describe the effects of the liquid environment on molecular systems. Different methods emphasize different aspects, and the treatment of both the local and bulk properties is still a great challenge. In this work, the electronic properties of a water molecule in liquid environment is studied by performing a relaxation of the geometry and electronic distribution using the free energy gradient method. This is made using a series of steps in each of which we run a purely molecular mechanical (MM) Monte Carlo Metropolis simulation of liquid water and subsequently perform a quantum mechanical/molecular mechanical (QM/MM) calculation of the ensemble averages of the charge distribution, atomic forces, and second derivatives. The MP2/aug-cc-pV5Z level is used to describe the electronic properties of the QM water. B3LYP with specially designed basis functions are used for the magnetic properties. Very good agreement is found for the local properties of water, such as geometry, vibrational frequencies, dipole moment, dipole polarizability, chemical shift, and spin-spin coupling constants. The very good performance of the free energy method combined with a QM/MM approach along with the possible limitations are briefly discussed.

Mode of Peroxisome Proliferator-Activated Receptor gamma Activation by Luteolin

The peroxisome proliferator-activated receptor gamma (PPAR gamma) is a target for treatment of type II diabetes and other conditions. PPAR gamma full agonists, such as thiazolidinediones (TZDs), are effective insulin sensitizers and anti-inflammatory agents, but their use is limited by adverse side effects. Luteolin is a flavonoid with anti-inflammatory actions that binds PPAR gamma but, unlike TZDs, does not promote adipocyte differentiation. However, previous reports suggested variously that luteolin is a PPAR gamma agonist or an antagonist. We show that luteolin exhibits weak partial agonist/antagonist activity in transfections, inhibits several PPAR gamma target genes in 3T3-L1 cells (LPL, ORL1, and CEBP alpha) and PPAR gamma-dependent adipogenesis, but activates GLUT4 to a similar degree as rosiglitazone, implying gene-specific partial agonism. The crystal structure of the PPAR gamma ligand-binding domain (LBD) reveals that luteolin occupies a buried ligand-binding pocket (LBP) but binds an inactive PPAR gamma LBD conformer and occupies a space near the beta-sheet region far from the activation helix (H12), consistent with partial agonist/antagonist actions. A single myristic acid molecule simultaneously binds the LBP, suggesting that luteolin may cooperate with other ligands to bind PPAR gamma, and molecular dynamics simulations show that luteolin and myristic acid cooperate to stabilize the Omega-loop among H2', H3, and the beta-sheet region. It is noteworthy that luteolin strongly suppresses hypertonicity-induced release of the pro-inflammatory interleukin-8 from human corneal epithelial cells and reverses reductions in transepithelial electrical resistance. This effect is PPAR gamma-dependent. We propose that activities of luteolin are related to its singular binding mode, that anti-inflammatory activity does not require H12 stabilization, and that our structure can be useful in developing safe selective PPAR gamma modulators.

Conformation analysis of a surface loop that controls active site access in the GH11 xylanase A from Bacillus subtilis

Xylanases (EC 3.2.1.8 endo-1,4-glycosyl hydrolase) catalyze the hydrolysis of xylan, an abundant hemicellulose of plant cell walls. Access to the catalytic site of GH11 xylanases is regulated by movement of a short beta-hairpin, the so-called thumb region, which can adopt open or closed conformations. A crystallographic study has shown that the D11F/R122D mutant of the GH11 xylanase A from Bacillus subtilis (BsXA) displays a stable "open" conformation, and here we report a molecular dynamics simulation study comparing this mutant with the native enzyme over a range of temperatures. The mutant open conformation was stable at 300 and 328 K, however it showed a transition to the closed state at 338 K. Analysis of dihedral angles identified thumb region residues Y113 and T123 as key hinge points which determine the open-closed transition at 338 K. Although the D11F/R122D mutations result in a reduction in local inter-intramolecular hydrogen bonding, the global energies of the open and closed conformations in the native enzyme are equivalent, suggesting that the two conformations are equally accessible. These results indicate that the thumb region shows a broader degree of energetically permissible conformations which regulate the access to the active site region. The R122D mutation contributes to the stability of the open conformation, but is not essential for thumb dynamics, i.e., the wild type enzyme can also adapt to the open conformation.