Are there dynamical effects in enzyme catalysis? Some thoughts concerning the enzymatic chemical step

AbstractWe offer some thoughts on the much debated issue of dynamical effects in enzyme catalysis, and more specifically on their potential role in the acceleration of the chemical step. Since the term ‘dynamics’ has been used with different meanings, we find it useful to first return to the Transition State Theory rate constant, its assumptions and the choices it involves, and detail the various sources of deviations from it due to dynamics (or not). We suggest that much can be learned about the key current questions for enzyme catalysis from prior extensive studies of dynamical and other effects in the case of reactions in solution. We analyze dynamical effects both in the neighborhood of the transition state and far from it, together with the situation when quantum nuclear motion is central to the reaction, and we illustrate our discussion with various examples of enzymatic reactions

Predictive and diagnostic biomarkers for gestational diabetes and its associated metabolic and cardiovascular diseases

Gestational diabetes mellitus (GDM) is defined as the presence of high blood glucose levels with the onset, or detected for the first time during pregnancy, as a result of increased insulin resistance. GDM may be induced by dysregulation of pancreatic β-cell function and/or by alteration of secreted gestational hormones and peptides related with glucose homeostasis. It may affect one out of five pregnancies, leading to perinatal morbidity and adverse neonatal outcomes, and high risk of chronic metabolic and cardiovascular injuries in both mother and offspring. Currently, GDM diagnosis is based on evaluation of glucose homeostasis at late stages of pregnancy, but increased age and body-weight, and familiar or previous occurrence of GDM, may conditionate this criteria. In addition, an earlier and more specific detection of GDM with associated metabolic and cardiovascular risk could improve GDM development and outcomes. In this sense, 1st–2nd trimester-released biomarkers found in maternal plasma including adipose tissue-derived factors such as adiponectin, visfatin, omentin-1, fatty acid-binding protein-4 and retinol binding-protein-4 have shown correlations with GDM development. Moreover, placenta-related factors such as sex hormone-binding globulin, afamin, fetuin-A, fibroblast growth factors-21/23, ficolin-3 and follistatin, or specific micro- RNAs may participate in GDM progression and be useful for its recognition. Finally, urine-excreted metabolites such as those related with serotonin system, non-polar amino-acids and ketone bodies, may complete a predictive or earlydiagnostic panel of biomarkers for GDMThis work was supported by the grant PI17/01495, from the Fondo de Investigación Sanitaria (ISC-III) and Fondo Europeo de Desarrollo Regional (FEDER) (for EJ), and grant SAF2017-84776-R, from Ministerio de Educación y Ciencia (for PC)

Molecular dynamics simulations of elementary chemical processes in liquid water using combined density functional and molecular mechanics potentials. I. Proton transfer in strongly H-bonded complexes

The first molecular dynamics (MD) simulation of a chemical process in solution with an ab initio description of the reactant species and a classical representation of the solvent is presented. We study the dynamics of proton (deuterium) transfer in strongly hydrogen-bonded systems characterized by an energy surface presenting a double well separated by a low activation barrier. We have chosen the hydroxyl-water complex in liquid water to analyze the coupling between the reactive system and the environment. The proton is transferred from one well to the other with a frequency close to 1 ps−1 which is comparable to the low-frequency band associated to hindered translations, diffusional translation and reorientation of water molecules in water. The proton transfer takes place in 20–30 fs whereas the solvent response is delayed by about 50 fs. Therefore, the reaction occurs in an essentially frozen-solvent configuration. In principle, this would produce a barrier increase with respect to the equilibrium reaction path. However, solvent fluctuations play a substantial role by catalyzing the proton transfer. The solvent relaxation time after proton transfer has been evaluated. Since it falls in the same time scale than the reactive events (0.6 ps) it substantially influences the proton dynamics. The present study is intended to model charge transfer processes in polar media having a low activation barrier for which many reactive events may be predicted in a MD simulation. The case of reactions with large activation barriers would require the use of special techniques to simulate rare events. But still in that case, hybrid QM/MM simulations represent a suitable tool to analyze reaction dynamics and non-equilibrium solvent effects in solution [email protected]

Molecular dynamics simulations of elementary chemical processes in liquid water using combined density functional and molecular mechanics potentials. II. Charge separation processes

A new approach to carry out molecular dynamics simulations of chemical reactions in solution using combined density functional theory/molecular mechanics potentials is presented. We focus our attention on the analysis of reactive trajectories, dynamic solvent effects and transmission coefficient rather than on the evaluation of free energy which is another important topic that will be examined elsewhere. In a previous paper we have described the generalities of this hybrid molecular dynamics method and it has been employed to investigate low energy barrier proton transfer process in water. The study of processes with activation energies larger than a few kT requires the use of specific techniques adapted to “rare events” simulations. We describe here a method that consists in the simulation of short trajectories starting from an equilibrated transition state in solution, the structure of which has been approximately established. This calculation is particularly efficient when carried out with parallel computers since the study of a reactive process is decomposed in a set of short time trajectories that are completely independent. The procedure is close to that used by other authors in the context of classical molecular dynamics but present the advantage of describing the chemical system with rigorous quantum mechanical calculations. It is illustrated through the study of the first reaction step in electrophilic bromination of ethylene in water. This elementary process is representative of many charge separation reactions for which static and dynamic solvent effects play a fundamental [email protected]

The influence of semantic and phonological factors on syntactic decisions: An event-related brain potential study

During language production and comprehension, information about a word's syntactic properties is sometimes needed. While the decision about the grammatical gender of a word requires access to syntactic knowledge, it has also been hypothesized that semantic (i.e., biological gender) or phonological information (i.e., sound regularities) may influence this decision. Event-related potentials (ERPs) were measured while native speakers of German processed written words that were or were not semantically and/or phonologically marked for gender. Behavioral and ERP results showed that participants were faster in making a gender decision when words were semantically and/or phonologically gender marked than when this was not the case, although the phonological effects were less clear. In conclusion, our data provide evidence that even though participants performed a grammatical gender decision, this task can be influenced by semantic and phonological factors

Sports, morality and body. The voices of sportswomen under Franco's dictatorship

The aim of this research is to study sportswomen's perceptions and experiences of women's sport in Francoist Spain (1939-1975). The main objective is to analyse the social, moral and aesthetic elements that are present in the experience of these athletes. This study was carried out with an intentional sample of 24 women from Andalusia, Aragon, Asturias, Basque Country, Catalonia and Valencia. They were interviewed by a network of researchers from six universities. Outstanding results show the existence of social limitations to start sports practice (particularly in the post-war period); the importance of sport as a character-building aspect; sport's remarkable influence on their body self-concept; and the incidence on sports of the mainstream moral discourse, which created a female model that even affected sports clothing. The main conclusion is that sportswomen in that period were pioneers and had to fight against most of society in order to develop their facet as athletes, as they would not follow the established model

Influence of IFN-gamma and its receptors in human breast cancer

<p>Abstract</p> <p>Background</p> <p>Interferons are a group of proteins that trigger multiple responses including prevention of viral replication, inhibition of cell growth, and modulation of cell differentiation. In different mammary carcinoma cell lines IFNγ induces growth arrest at mid-G1. At the present there are no <it>in vivo </it>studies in human breast. The aim of this study was to investigate the expression patterns of IFNγ and its two receptors (IFNγ-Rα and IFNγ-Rβ) by Western blot and immunohistochemistry, in order to elucidate its role in the different types of human breast cancer (<it>in situ </it>and infiltrative).</p> <p>Methods</p> <p>Immunohistochemical and semiquantitative study of IFNγ, its receptors types (IFNγ-Rα and IFNγ-Rβ), cell proliferation (proliferating cell nuclear antigen, also named PCNA), and apoptosis (TUNEL method) was carried between the three breast groups (fibrocystic lesions, <it>in situ</it> tumors and infiltrating tumors).</p> <p>Results</p> <p>In the three groups of patients, IFNγ and IFNγ-Rα immunoreactions appeared in the cytoplasm while IFNγ-Rβ also was found in the nucleus. The optical density to IFNγ was higher in <it>in situ </it>carcinoma than in benign and infiltrating tumors. When we observed IFNγ-Rα, the optical density was lower in infiltrating carcinoma than in benign and <it>in situ </it>tumors (the higher density). To IFNγ-Rβ, the optical density was similar in the three group samples. In tumor samples PCNA and TUNEL index was significantly higher; than in benign diseases. PCNA index increased with the malignance. No significant differences were found between cancer types to TUNEL. IFNγ could be a potential therapeutic tool in breast cancer. However, tumor cells are able to escape from the control of this cytokine in the early tumor stages; this is probably due to a decreased expression of IFNγ, or also to an alteration of either its receptors or some transduction elements.</p> <p>Conclusion</p> <p>We conclude that the decrease in the % positive samples that expressed IFNγ and IFNγ-Rα together with the nuclear localization of IFNγ-Rβ, could be a tumoral cell response, although perhaps insufficient to inhibit the uncontrolled cell proliferation. Perhaps, IFNγ might be unable to activate p21 to stop the cell cycle, suggesting a possible participation in breast cancer development.</p