Influence of temperature on the topological features of inner cavities in cytoglobin

Cytoglobin (Cygb) is a novel member of the globin family in man, but there is no clear evidence about its biological function. Cygb exhibits a highly complex ligand rebinding kinetics, which agrees with the structural plasticity of the inner cavities and tunnels found in the protein matrix. In this work we have examined the effect of temperature on the topological features of Cygb. To this end, the structural and dynamical properties of human Cygb are compared with those determined for the Antarctic fish Chaenocephalus aceratus. The results support a distinct temperature-dependence of the topological features in the two proteins, suggesting different adaptations to cold and warm environments

Towards a molecular dynamics consensus view of B-DNA flexibility

We present a systematic study of B-DNA flexibility in aqueous solution using long-scale molecular dynamics simulations with the two more recent versions of nucleic acids force fields (CHARMM27 and parmbsc0) using four long duplexes designed to contain several copies of each individual base pair step. Our study highlights some differences between pambsc0 and CHARMM27 families of simulations, but also extensive agreement in the representation of DNA flexibility. We also performed additional simulations with the older AMBER force fields parm94 and parm99, corrected for non-canonical backbone flips. Taken together, the results allow us to draw for the first time a consensus molecular dynamics picture of B-DNA flexibilit

Conformational landscape of small ligands: a multilevel strategy to determine the conformational penalty of bioactive ligands

Determining the conformational penalty required for adopting the bioactive conformation is still a challenging question in drug design, because a small uncertainty in this free energy component can lead to significant errors in the predicted activities. Herein, we use the Multilevel strategy, a methodology recently developed by our group, to explore the conformational preferences of ligands in solution, and to estimate the conformational cost of selecting the bioactive conformation

The relative flexibility of B-DNA and A-RNA duplexes: database analysis

An extensive analysis of structural databases is carried out to investigate the relative flexibility of B-DNA and A-RNA duplexes in crystal form. Our results show that the general anisotropic concept of flexibility is not very useful to compare the deformability of B-DNA and A-RNA duplexes, since the flexibility patterns of B-DNA and A-RNA are quite different. In other words, ‘flexibility' is a dangerous word for describing macromolecules, unless it is clearly defined. A few soft essential movements explain most of the natural flexibility of A-RNA, whereas many are necessary for B-DNA. Essential movements occurring in naked B-DNAs are identical to those necessary to deform DNA in DNA-protein complexes, which suggest that evolution has designed DNA-protein complexes so that B-DNA is deformed according to its natural tendency. DNA is generally more flexible, but for some distortions A-RNA is easier to deform. Local stiffness constants obtained for naked B-DNAs and DNA complexes are very close, demonstrating that global distortions in DNA necessary for binding to proteins are the result of the addition of small concerted deformations at the base-pair level. Finally, it is worth noting that in general the picture of the relative deformability of A-RNA and DNA derived from database analysis agrees very well with that derived from state of the art molecular dynamics (MD) simulation

Estratègies i recursos per a no nadius per a la impartició d'assignatures en anglès de química en els graus d'enginyeria

Una eina per aconseguir el domini d’una llengua estrangera, és l’aprenentatge integrat de continguts i llengües estrangeres. Aquesta comunicació es focalitza en l’experiència acadèmica adquirida a partir de la impartició del Grau d’Enginyeria Química a l’Escola Politècnica Superior d’Enginyeria de Manresa (UPC). L’estratègia seguida s’ha basat en la disponibilitat del professorat per impartir assignatures en anglès. Inicialment s’imparteix en anglès l’assignatura de Química ubicada en el primer quadrimestre. Això permet que a l’inici de la carrera, professorat i estudiantat comparteixin un glossari bàsic. Més endavant es familiaritzen amb el llenguatge de laboratori a l’assignatura d’Anàlisi Química Instrumental. El fet que les classes siguin en anglès aconsegueix, en la majoria d’hores de classe, que el nivell d’atenció sigui més alt i això s’ha reflectit en uns millors resultats acadèmics dels estudiants. Com a recursos han estat claus, en primer lloc, el curs “Intensive Interactive Teacher Speaking Skills & Strategies” (ICE, UPC) per estimular la impartició de classes en anglès. Segonament, s’ha disposat d’un recurs molt útil per donar classes de qualsevol assignatura en anglès, el “Class Talk” http://www.upc.edu/slt/classtalk/, elaborat per professors de l’EPSEM i el SLT de la UPC. També cal destacar el recurs anomenat “Multilingual Formulae” (http://mformulae.epsem.upc.edu), que defineix en anglès conceptes químics, fórmules, equacions i altres expressions simbòliques. Finalment s’han elaborat material de les assignatures en anglès (presentacions, apunts, llistat de problemes i guions de pràctiques) com a material suplementari per ajudar a la comprensió de las classes.Peer Reviewe

Carbon isotopes of graphite: Implications on fluid history

Stable carbon isotope geochemistry provides important information for the recognition of fundamental isotope exchange processes related to the movement of carbon in the lithosphere and permits the elaboration of models for the global carbon cycle. Carbon isotope ratios in fluid-Deposited graphite are powerful tools for unravelling the ultimate origin of carbon (organic matter, mantle, or carbonates) and help to constrain the fluid history and the mechanisms involved in graphite deposition.Graphite precipitation in fluid-deposited occurrences results from CO2- and/or CH4-bearing aqueous fluids. Fluid flow can be considered as both a closed (without replenishment of the fluid) or an open system (with renewal of the fluid by successive fluid batches). In closed systems, carbon isotope systematics in graphite is mainly governed by Rayleigh precipitation and/or by changes in temperature affecting the fractionation factor between fluid and graphite. Such processes result in zoned graphite crystals or in successive graphite generations showing, in both cases, isotopic variation towards progressive 13C or 12C enrichment (depending upon the dominant carbon phase in the fluid, CO2 or CH4, respectively). In open systems, in which carbon is episodically introduced along the fracture systems, the carbon systematics is more complex and individual graphite crystals may display oscillatory zoning because of Rayleigh precipitation or heterogeneous variations of d13C values when mixing of fluids or changes in the composition of the fluids are the mechanisms responsible for graphite precipitation

Mechanistic Insight into the Enzymatic Reduction of Truncated Hemoglobin N of Mycobacterium tuberculosis: role of the CD loop and pre-A Motif in electron cycling

Background: The HbN of Mycobacterium tuberculosis carries a potent nitric-oxide dioxygenase activity despite lacking a reductase domain. Results: The NADH-ferredoxin reductase system acts as an efficient partner for the reduction of HbN. Conclusion: The interactions of HbN with the reductase are modulated by its CD loop and the Pre-A region. Significance: The present study provides new insights into the mechanism of electron transfer during nitric oxide detoxification by HbN.Fil: Singh, Sandeep. Institute of Microbial Technology; IndiaFil: Thakur, Naveen. Institute of Microbial Technology; IndiaFil: Oliveira, Ana. Universidad de Barcelona; EspañaFil: Petruk, Ariel Alcides. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaFil: Hade, Mangesh Dattu. Institute of Microbial Technology; IndiaFil: Sethi, Deepti. Institute of Microbial Technology; IndiaFil: Bidon Chanal, Axel. Universidad de Barcelona; EspañaFil: Marti, Marcelo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaFil: Datta, H.. Institute of Microbial Technology; IndiaFil: Parkesh, R.. Institute of Microbial Technology; IndiaFil: Estrin, Dario Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaFil: Luque, F. Javier. Universidad de Barcelona; EspañaFil: Dikshit, Kanak L.. Institute of Microbial Technology; Indi

Downregulation of functional Reelin receptors in projection neurons implies that primary Reelin action occurs at early/premigratory stages

Reelin signaling is essential for correct development of the mammalian brain. Reelin binds to apolipoprotein E receptor 2 and very low-density lipoprotein receptor and induces phosphorylation of Dab1. However, when and where these reactions occur is essentially unknown, and the primary function(s) of Reelin remain unclear. Here, we used alkaline phosphatase fusion of the receptor-binding region of Reelin to quantitatively investigate the localization of functional Reelin receptors (i.e., those on the plasma membrane as mature forms) in the developing brain. In the wild-type cerebral cortex, they are mainly present in the intermediate and subventricular zones, as well as in radial fibers, but much less in the cell bodies of the cortical plate. Functional Reelin receptors are much more abundant in the Reelin-deficient cortical plate, indicating that Reelin induces their downregulation and that it begins before the neurons migrate out of the intermediate zone. In the wild-type cerebellum, functional Reelin receptors are mainly present in the cerebellar ventricular zone but scarcely expressed by Purkinje cells that have migrated out of it. It is thus strongly suggested that Reelin exerts critical actions on migrating projection neurons at their early/premigratory stages en route to their final destinations, in the developing cerebral cortex and cerebellum. Copyright © 2009 Society for Neuroscience.This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture (M.H., A.B.), Ono Medical Research Foundation, and Kanae Foundation for the Promotion of Medical Science (M.H.). T.H. is a Research Fellow of Japan Society for the Promotion of Science. J.M.L. is a Ramón y Cajal Research Fellow funded by Grant SAF2004-07685 and Fundación Mutua Madrileña.Peer Reviewe

Contrasting Mineralizing Processes in Volcanic-Hosted Graphite Deposits

The only two known graphite vein-deposits hosted by volcanic rocks (Borrowdale, United Kingdom, and Huelma, Southern Spain) show remarkable similarities and differences. The lithology, age of the magmatism and geodynamic contexts are distinct, but the mineralized bodies are controlled by fractures. Evidence of assimilation of metasedimentary rocks by the magmas and hydrothermal alteration are also common features to both occurrences. Graphite morphologies at the Borrowdale deposit vary from flakes (predominant) to spherulites and cryptocrystalline aggregates, whereas at Huelma, flaky graphite is the only morphology observed. The structural characterization of graphite indicates a high degree of ordering along both the c axis and the basal plane. Stable carbon isotope ratios of graphite point to a biogenic origin of carbon, most probably related to the assimilation of metasedimentary rocks. Bulk į13C values are quite homogeneous in both occurrences, probably related to precipitation in short time periods. Fluid inclusion data reveal that graphite precipitated from C-O-H fluids at moderate temperature (500 ºC) in Borrowdale and crystallized at high temperature from magma in Huelma, In addition, graphite mineralization occurred under contrasting fO2 conditions. All these features can be used as potential exploration tools for volcanic-hosted graphite deposits

Dynamic undocking and the quasi-bound state as tools for drug discovery

There is a pressing need for new technologies that improve the efficacy and efficiency of drug discovery. Structure-based methods have contributed towards this goal but they focus on predicting the binding affinity of protein–ligand complexes, which is notoriously difficult. We adopt an alternative approach that evaluates structural, rather than thermodynamic, stability. As bioactive molecules present a static binding mode, we devised dynamic undocking (DUck), a fast computational method to calculate the work necessary to reach a quasi-bound state at which the ligand has just broken the most important native contact with the receptor. This non-equilibrium property is surprisingly effective in virtual screening because true ligands form more-resilient interactions than decoys. Notably, DUck is orthogonal to docking and other ‘thermodynamic’ methods. We demonstrate the potential of the docking–undocking combination in a fragment screening against the molecular chaperone and oncology target Hsp90, for which we obtain novel chemotypes and a hit rate that approaches 40