Estudio de propiedades moleculares del glifosato usando métodos químico-cuánticos computacionales / Study of molecular properties of glyphosate using chemical-quantum computational methods

En este trabajo de investigación se realizó un estudio computacional del glifosato calculando detalladamente las propiedades moleculares del mismo. Se logró a través de este trabajo la caracterización del herbicida glifosato, presentado valores de longitudes de enlace y ángulos así como de propiedades químicas de interés en estudios QSAR, de energías y de bioactividad obtenidos por métodos mecano cuánticos utilizando la mecánica molecular, semiempirico y ab initio. Se analizaron los resultados obtenidos al comparar los datos experimentales del glifosato con los obtenidos computacionalmente demostrando una buena correlación. La estructura del glifosato fue trazada usando la interfaz de Hyperchem; esta fue sometida a cálculos de optimización geométrica inicialmente de Mecánica Molecular para obtener la estructura más estable, posteriormente todas las estructuras fueron analizadas mediante el método semiempirico PM3 para obtener valores más confiables de energía y geometría. Para el método ab initio se usó la base 3-21G. La minimización de la energía de las estructuras se desarrolló por el método Fletcher-Reeves de gradiente conjugado hasta un valor de gradiente RMS (root-mean-square) menor a 0,100 Kcal/(A°mol) o un máximo de 500 ciclos de iteración, el límite de convergencia SCF empleado fue de 0,001 Kcal/mol. Las propiedades moleculares necesarias en QSAR (Relaciones estructura actividad) y la predicción de bioactividad se realizó en el software quimio informático Molinspiration. El ordenamiento de los datos numéricos, las gráficas, regresiones y el ANOVA se realizaron en Excel 2015. Los valores encontrados de longitud de enlace resultan muy satisfactorios, se encontró que el estadístico F (0,1574) es menor al valor crítico (2,479) y la P es mayor a 0,05, aceptándose la hipótesis nula, la desviación media absoluta resultó 0,27Å. La regresión dió coeficientes r2 de 0,89-0,86 y 0,76 para el método semiempirico, mecánica molecular y ab initio respectivamente.Para los ángulos, los valores encontrados también son satisfactorios, el estadístico F (0,226 ) valor crítico (2,43) y la P es mayor a 0,05, desviación media absoluta encontrada fue de 5,02 grados.

In this research work a computational study of glyphosate was carried out, calculating in detail the molecular properties of it. Through this work, the characterization of the glyphosate herbicide was achieved, presenting values of link lengths and angles as well as chemical properties of interest in QSAR studies, of energies and bioactivity obtained by quantum mechano methods using molecular, semi-empirical and ab-mechanical mechanics. Initio the results obtained were analyzed by comparing the experimental data of glyphosate with those obtained computationally demonstrating a good correlation. The structure of glyphosate was plotted using the Hyperchem interface; this was subjected to geometric optimization calculations initially of Molecular Mechanics to obtain the most stable structure, subsequently all structures were analyzed using the PM3 semi-empirical method to obtain more reliable energy and geometry values. For the ab initio method, the 3-21G base was used. The energy minimization of the structures was developed by the Fletcher-Reeves method of conjugate gradient up to a RMS (root-mean-square) gradient value less than 0,100 Kcal / (A°mol) or a maximum of 500 iteration cycles , the SCF convergence limit used was 0,001 Kcal / mol. The molecular properties required in QSAR (Activity structure relationships) and bioactivity prediction were performed in the Molinspiration computer chemo software. The ordering of the numerical data, the graphs, regressions and the ANOVA were performed in Excel 2015. The values found for link length are very satisfactory, it was found that the F statistic (0,1574) is less than the critical value (2,479) and the P is greater than 0.05, accepting the null hypothesis, the absolute mean deviation was 0.27Å. The regression gave r2 coefficients of 0,89-0,86 and 0,76 for the semi-empirical method, molecular mechanics and ab initio respectively. For the angles, the values found are also satisfactory, the statistical F (0,226) critical value (2,43) and P is greater than 0,05, absolute mean deviation found was 5,02 degrees.

Thermodynamic study of asparagine and glycyl-asparagine using computational methods

This work aimed to develop an ab initio procedure for accurately calculating pKa values and applied it to study the acidity of asparagine and glycyl-asparagine. DFT methods with B3LYP composed by 6-31+G(d) basis set were applied for calculating the acidic dissociation constant of asparagine and glycyl-asparagine. The formation of intermolecular hydrogen bonds between the available species and water was analyzed using Tomasi,s method. Results showed that in alkaline solutions, the cation, anion and neutral species of asparagine and glycyl-asparagine were solvated with one, two, three and four molecules of water, respectively. There was an excellent similarity between the experimentally attained pKa values and the theoretically ones in this work.

3D Structure Modeling of Human Telomere Repeat Binding Factor 2 and DNA-Protein Docking Studies.

Aims: Human telomere repeat binding factor (hTRF2) is a double stranded telomere binding protein that plays key role in protecting the chromosome ends and a necessary building block of telomere structure maintenance. The aim of the present study was to focus on the modeling of 3D structure of hTRF2 (500 residues long) and its interaction studies with DNA in silico. Study Design: The overall work was designed in different steps starting with the modeling of the concerned protein, its physiochemical properties study, modeling of 3DDNA with specific length and varying bend angle, docking studies of modeled DNA and hTRF2 protein. Place and Duration of Study: Bioinformatics Lab, Department of Biotechnology, Birla Institute of Technology, Mesra, India. November 2012- July 2013. Methodology: 3D structure of hTRF2 was modeled through I-TASSER method. The modeled structure was verified by 5ns of simulation run in solvent (water) condition and also evaluated with different bioinformatics tools. Physiochemical properties were calculated through CLC Protein Workbench. DNA 3D structure was modeled with the conserved nucleotide sequence motif, TTAGGG with varying bend angles of 0° to 60°. The DNA-protein docking studies were carried out through HADDOCK easy interface for each bend angle. Results: The best model was selected depending on minimum RMSD value and C-Score and the Stereochemical quality of that model was verified with different tools, as the Molprobity score (>1) of hTRF2 was predicted 4.2 and Ramachandra favored residue was 80.56%. The selected model protein and DNA structure was docked and among all the docking results the best orientation of DNA and hTRF2 was at 60° DNA bend angle with lowest RMSD and maximum Z-value. The amino acids which are directly involved in the interaction were also selected. Conclusion: In future further study will be planned with further bend angle for getting better information on DNA-protein interactions. In silico studies will also be helpful for the researchers to study the complex structure in vitro.

Estudo e determinação teórica de propriedades físico-químicas de fármacos anti-hipertensivos inibidores da Enzima Conversora de Angiotensina / Theoretical study and determination of physicochemical properties of antihypertensive angiotensin-converting enzyme inhibitors

O pacote de softwares SpartanTM vs 04 foi utilizado para calcular algumas propriedades físico-químicas de uma série de inibidores da Enzima Conversora de Angiotensinogênio ECA. Simultaneamente, o pacote MarvinSketch 5.0.0 foi empregado para calcular o Coeficiente de Partição P dos inibidores. Através da análise dos resultados, conclui-se que: a) o arranjo termodinâmico mais estável desses inibidores mimetiza aquele dos resíduos pré-terminais da angiotensina II, b) há grande similaridade entre as cargas dos átomos que se ligam à macromolécula e c) os cálculos mostram diferenças significativas entre os valores de P para os inibidores. Portanto, as diferenças farmacológicas existentes entre os inibidores estão mais intimamente relacionadas ao coeficiente de partição do que à capacidade destes de inibir o sítio ativo da ECA.

The software package SpartanTM 4.0 was employed to calculate some physicochemical properties of a series of available ACE inhibitors. Simultaneously, the program MarvinSketch 5.0.0 was employed to calculate the partition coefficients (P) of the same compounds. After analyzing the results, we conclude that: a) from a thermodynamic point of view, the most stable conformer of each inhibitor resembles, as expected, the most stable spatial arrangement of the preterminal residues of angiotensin II; b) there is great similarity among the charge profiles of the potential binding sites of all the inhibitors; c) there are large differences in P among these compounds. Summing up, the pharmacological differences reported between the inhibitors are more closely linked to their lipophilic properties than to their capacity to block the ACE active center.

Comparative protein modelling of metallothionein 1B protein acting as a potential chemoprotector against hepatic neoplasia.

Background and objectives: Primary liver cancer also called hepatocellular carcinoma or hepatoma is the fifth most common cancer in the world with a poor prognosis. An Indian medicinal plant Acanthus ilicifolius shows encouraging results in preventing liver cancer cells from progressing. The aqueous leaf extract (ALE) of the plant was substantially effective in preventing hepatic DNA alterations and sister-chromatid exchanges (a type of chromosomal damage) in tumor-bearing mice. The ALE treatment was able to limit liver metallothionein 1B expression, a potential marker for cell proliferation, and lengthen the mean survival of animals to a significant extent. The findings suggest that Acanthus ilicifolius may be used as a potential chemoprotector against hepatic neoplasia. Methods: The protein ID from Swissprot data base was selected for obtaining the description and function of the protein, its domains structure, post-translational modifications etc. BLAST analysis was performed to identify template protein sequence for metallothionein protein. The comparative modelling of the Metallothionein 1Bby different algorithms like Hidden Markov Model of homology modelling and multiple threading alignments and iterative alignments methods for Ab initio was performed by using the programs like Swiss Model, CPH Model, Wurst and I.TASSES respectively. Results: The obtained models were verified with structure validation programs like, PROCHEK & SAVS. Interpretation and Conclusions: Schrodinger was used for energy refinement of the model. Active site determination through CASTp and surface visualization by Molegro Virtual Docker suggests that this protein can act as a potential drug target.

Electron angula distributions in dissociative photoionization of the hydrogen moleclle / Distribuiones anngulares electrónicas en la fotoionización disociativa de la molécula de hidrógeno / Distriuições anggulare de elétrons na fotoionizaçao dissociativa da mmolécula de hidrogênio

A method to calculate angular distributions for electrons ejected from fixed-in-space molecular hydrogen molecules subject to ultrashort intense laser pulses is proposed, based on the ab initio solution of the time-dependent Schrodinger equation. This method of solution allows for a temporal picture of interferences arising in the dissociative ionization channel (in the proton kinetic energy spectrum) due to the presence of the autoionizing double excited states in the Hydrogen molecule. In particular, we show how this autoionization during the dissociative photoionization process may also induce a counterintuitive asymmetry in the angular distribution of the ionized electron with respect to nuclei inversion, in spite of dealing with an homonuclear system.

Se propone un método para calcular distribuciones angulares de electrones ionizados en la molécula de hidrógeno fija en el espacio sometida a pulsos láser intensos y ultracortos, basado en la solución desde primeros principios de la ecuación de Schrodinger dependiente del tiempo. Esta solución nos permite tener una visión temporal de la interferencias generadas en el canal de ionización disociativa (en el espectro de energía cinética de los protones) debido a la presencia de la autoionización de estados doblemente excitados de la molécula de hidrógeno. Se muestra específicamente cómo la autoionización durante el proceso de fotoionización disociativa también puede inducir una asimetría en la distribución angular del electrón ionizado con respecto a la inversión nuclear, un efecto no intuitivo a pesar de estar tratando con un sistema homonuclear.

Propõe-se um método para calcular as distribuições angulares de elétrons ionizados de uma molécula de hidrogênio fixa no espaço, sujeita a pulsos de laser intensos e ultra-curtos, baseado na soluçao desde primeiros princípios da equaçao de Schrõdinger dependente do tempo. Esta soluçao nos permite ter uma visão temporal das interferências geradas no canal de ionizaçao dissociativa (no espectro de energia cinética dos prótons) devido á presença da auto-ionização de estados duplamente excitados da molécula de hidrogênio. Mostra-se especificamente como a auto-ionização durante o processo de foto-ionização dissociativa pode também induzir uma assimetria na distribuição angular do elétron ionizado com respeito á inversão nuclear, um efeito não intuitivo apesar de estar se tratando de um sistema homonuclear.