Assessing protein stability of the dimeric DNA-binding domain of E2 human papillomavirus 18 with molecular dynamics.

The objective of this study is to understand the structural flexibility and curvature of the E2 protein of human papillomavirus type 18 using molecular dynamics (6 ns). E2 is required for viral DNA replication and its disruption could be an anti-viral strategy. E2 is a dimer, with each monomer folding into a stable open-faced beta-sandwich. We calculated the mobility of the E2 dimer and found that it was asymmetric. These different mobilities of E2 monomers suggest that drugs or vaccines could be targeted to the interface between the two monomers.

Characterization of antigenetic serotypes from the dengue virus in Venezuela by means of Grid Computing.

This work determines the molecular epidemiology of dengue virus in Venezuela by means of phylogenetic calculations performed on the EELA-2 Grid infrastructure with the PhyloGrid application, an open source tool that allows users performing phylogeny reconstruction in their research. In this study, a total of 132 E nucleotide gene sequences of dengue virus from Venezuela recorded in GenBank(R) have been processed in order to reproduce and validate the topology described in the literature.

WISDOM-II: screening against multiple targets implicated in malaria using computational grid infrastructures.

BACKGROUND: Despite continuous efforts of the international community to reduce the impact of malaria on developing countries, no significant progress has been made in the recent years and the discovery of new drugs is more than ever needed. Out of the many proteins involved in the metabolic activities of the Plasmodium parasite, some are promising targets to carry out rational drug discovery. MOTIVATION: Recent years have witnessed the emergence of grids, which are highly distributed computing infrastructures particularly well fitted for embarrassingly parallel computations like docking. In 2005, a first attempt at using grids for large-scale virtual screening focused on plasmepsins and ended up in the identification of previously unknown scaffolds, which were confirmed in vitro to be active plasmepsin inhibitors. Following this success, a second deployment took place in the fall of 2006 focussing on one well known target, dihydrofolate reductase (DHFR), and on a new promising one, glutathione-S-transferase. METHODS: In silico drug design, especially vHTS is a widely and well-accepted technology in lead identification and lead optimization. This approach, therefore builds, upon the progress made in computational chemistry to achieve more accurate in silico docking and in information technology to design and operate large scale grid infrastructures. RESULTS: On the computational side, a sustained infrastructure has been developed: docking at large scale, using different strategies in result analysis, storing of the results on the fly into MySQL databases and application of molecular dynamics refinement are MM-PBSA and MM-GBSA rescoring. The modeling results obtained are very promising. Based on the modeling results, In vitro results are underway for all the targets against which screening is performed. CONCLUSION: The current paper describes the rational drug discovery activity at large scale, especially molecular docking using FlexX software on computational grids in finding hits against three different targets (PfGST, PfDHFR, PvDHFR (wild type and mutant forms) implicated in malaria. Grid-enabled virtual screening approach is proposed to produce focus compound libraries for other biological targets relevant to fight the infectious diseases of the developing world.

Computational models in plant-pathogen interactions: the case of Phytophthora infestans.

BACKGROUND: Phytophthora infestans is a devastating oomycete pathogen of potato production worldwide. This review explores the use of computational models for studying the molecular interactions between P. infestans and one of its hosts, Solanum tuberosum. MODELING AND CONCLUSION: Deterministic logistics models have been widely used to study pathogenicity mechanisms since the early 1950s, and have focused on processes at higher biological resolution levels. In recent years, owing to the availability of high throughput biological data and computational resources, interest in stochastic modeling of plant-pathogen interactions has grown. Stochastic models better reflect the behavior of biological systems. Most modern approaches to plant pathology modeling require molecular kinetics information. Unfortunately, this information is not available for many plant pathogens, including P. infestans. Boolean formalism has compensated for the lack of kinetics; this is especially the case where comparative genomics, protein-protein interactions and differential gene expression are the most common data resources.

The evolution of HPV by means of a phylogenetic study.

In this work we demonstrate the adequacy of revising the classification systems based on molecular phylogenetic calculations by allowing an arbitrary number of taxas that take advantage of high performance computing platforms for the Human papillomavirus (HPV) case. To do so, we have analysed several phylogenetic trees which have been calculated with the PhyloGrid tool, a workflow developed in the framework of the EELA-2 Project.

A biochemical and genetic study of Leishmania donovani pyruvate kinase.

Here we present a biochemical and molecular biology study of the enzyme pyruvate kinase (PYK) from the parasitic protozoa Leishmania donovani. The PYK gene was cloned, mutagenised and over expressed and its kinetic parameters determined. Like in other kinetoplastids, L. donovani PYK is allosterically stimulated by the effector fructose 2,6 biphosphate and not by fructose 1,6 biphosphate. When the putative effector binding site of L. donovani PYK was mutagenised, we obtained two mutants with extreme kinetic behavior: Lys453Leu, which retained a sigmoidal kinetics and was little affected by the effector; and His480Gln, which deployed a hyperbolic kinetics that was not changed by the addition of the effector. Molecular Dynamics (MD) studies revealed that the mutations not only altered the effector binding site of L. donovani PYK but also changed the folding of its domain C.

Advances in the biomedical applications of the EELA Project.

In the last years an increasing demand for Grid Infrastructures has resulted in several international collaborations. This is the case of the EELA Project, which has brought together collaborating groups of Latin America and Europe. One year ago we presented this e-infrastructure used, among others, by the biomedical groups for the studies of oncological analysis, neglected diseases, sequence alignments and computational phylogenetics. After this period, the achieved advances are summarised in this paper.

Biomedical applications in EELA.

The current demand for Grid Infrastructures to bring collabarating groups between Latina America and Europe has created the EELA proyect. This e-infrastructure is used by Biomedical groups in Latina America and Europe for the studies of ocnological analisis, neglected diseases, sequence alignments and computation plygonetics.

A study of genetic diversity in the gene encoding the circumsporozoite protein (CSP) of Plasmodium falciparum from different transmission areas--XVI. Asembo Bay Cohort Project.

We have investigated the genetic diversity of the gene encoding the CS protein. A total of 75 complete and 96 partial sequences are studied. We find high levels of genetic polymorphisms as evidenced by 50 and 24 alleles at the Th2R and Th3R epitopes, respectively. Overall, we find that African isolates are more polymorphic as compared with parasites from other geographic regions. We conclude that the uneven geographic polymorphism may have an adverse impact on the effectiveness of vaccines based on this antigen alone. We find extensive polymorphism in the repeat allotypes, or RATs. In order to explore how the protein structure may impose restrictions in the number of repeats, we have simulated the stability of the structure of the tandem repeat region. Our analysis suggests that the protein structure may play an important role in the observed polymorphism in the number of CS repeats in Plasmodium falciparum. We explored the linkage and recombination events among the polymorphic sites. We found that putative recombination events overlap with linked sites. We discuss how this pattern is explained by the action of positive natural selection, where the recombination events detected are convergent mutations. We conclude that it is inappropriate to use linkage-recombination patterns on genes under positive selection for assessing the structure of parasite populations.

Phylogenetic analysis of the genus Plasmodium based on the gene encoding adenylosuccinate lyase.

Phylogenetic studies of the genus Plasmodium have been performed using sequences of the nuclear, mitochondrial and plastid genes. Here we have analyzed the adenylosuccinate lyase (ASL) gene, which encodes an enzyme involved in the salvage of host purines needed by malaria parasites for DNA synthesis. The ASL gene is present in several eukaryotic as well as prokaryotic organisms and does not have repeat regions, which facilitates the accuracy of the alignment. Furthermore, it has been shown that ASL is not subject to positive natural selection. We have sequenced the ASL gene of several different Plasmodium species infecting humans, rodents, monkeys and birds and used the obtained sequences along with the previously known P. falciparum ASL sequence, for structural and phylogenetic analysis of the genus Plasmodium. The genetic divergence of ASL is comparable with that observed in other nuclear genes such as cysteine proteinase, although ASL cannot be considered conserved when compared to aldolase or superoxide dismutase, which exhibit a slower rate of evolution. Nevertheless, a protein like ASL has a rate of evolution that provides enough information for elucidating evolutionary relationships. We modeled 3D structures of the ASL protein based on sequences used in the phylogenetic analysis and obtained a consistent structure for four different species despite the divergence observed. Such models would facilitate alignment in further studies with a greater number of plasmodial species or other Apicomplexa.

Can the RNA of the cowpea chlorotic mottle virus be released through a channel by means of free diffusion? A test in silico.

Cowpea chlorotic mottle virus (CCMV), a plant virus which is member of the Bromoviridae family, is used as a model for the diffusion of a random, short, single stranded RNA, [5'-R(PGpGpApCpUpUpCpGpGpUpCpC)-3')], through a channel on the pseudo-three-fold axis using molecular dynamic simulations. This proposition is based the fact that CCMV undergoes a dynamic structural transition as a response to changes of pH, temperature and ionic strength. Results indicate that the RNA looses its secondary structure and moves into the capside channel by free diffusion. These results are congruent with the hypothesis suggesting that the CCMV capside does not have to dissolve in order to release the RNA into the host.

Mapeo computacional de epítopos de células B presentes en el virus del dengue / B-cell epitopes mapping of dengue virus

Dengue es una infección viral de importancia en salud pública. El desarrollo de una vacuna va a depender del conocimiento de aquello epítopos que neutralicen la infección y por ello, se generaron e identificaron computacionalmente aquellos epítopos lineales consenso de células B presentes en el virus del dengue, a partir de los datos depositados en la base de datos Immune Epitope Database (IEDB). Posteriormente, se agruparon en bloques de ocho aminoácidos por cada serotipo mediante el programa Nomad, y cada uno de ellos fue reevaluado con el programa BepiPred para determinar su antigenicidad. Se lograron postular 172 de los 1.239 obtenidos en la IEDB.

Dengue virus has emerged as a major public health problem. An epitope-based approach to the development of vaccines, and for this reason, based on Immune Epitope Database database (IEDB), linear consensus B-cell epitopes were computationally generated and identified from dengue virus. Then, amino acids were grouped into blocks of eight amino acids per serotype through Nomad program. Each block was evaluated using BepiPred for determining antigenic prediction. 172 out of 1239 were obtained from IEDB.

La dinámica de transmisión del Covid-19 desde una perspectiva matemática / The Transmission Dynamics of Covid-19 from a MathematicalPerspective

El presente trabajo plantea un modelo matemático capaz de reproducir la dinámica de transmisión del nuevo coronavirus (Covid-19) en grupos humanos a partir de un sistema de ecuaciones diferenciales. Para ello se dividió a la población en tres clases diferentes dependiendo de los estadios de la enfermedad: aquellos que son susceptibles de contraer el virus, los infectados y los recuperados. Los parámetros fueron determinados por mínimos cuadrados a partir de los registros diarios del Covid-19 realizados por la Universidad Johns Hopkins, y se validó en cuatro países seleccionados al azar: China, Estados Unidos, Brasil y Venezuela. Simultáneamente, se exploró la calidad de los datos para detectar cualquier manipulación o alteración de las cifras de contagios en estos cuatro países, a partir de dos metodologías computacionales empleadas en análisis forense de información digital. Así, será posible predecir grosso modo el número de contagios en el tiempo: a modo de ejemplo, se estimó que pudieran darse 597 casos de contagios en la República Bolivariana de Venezuela hasta el 22 de junio del presente año en función de la información analizada hasta el 20 de abril, fuertemente influenciada por los brotes detectados(AU)

The present work proposes a Mathematical model capable of reproducing the transmission dynamics of the new coronavirus (Covid-19) in human groups, from a system of differential equations. The total population was divided into three different types: susceptible, infected, and recovered. Parameters were developed using the least squared method, based on Johns Hopkins' Covid-19 data, and were validated in four countries: China, the United States, Brazil and Venezuela. Simultaneously, the quality of the data was explored to detect any manipulation or alteration of the numbers of infections in these four countries, based on two computational methodologies used in forensic analysis of digital information. Finally, it will be possible to estimate that 597 cases of infection could occur in the Bolivarian Republic of Venezuela, until June 22 of this year, based on the information analyzed up to April 20, heavily influenced by the detected break out(AU)

Identificación de nuevos medicamentos a través de métodos computacionales / Identification of new drugs through computational methods

El desarrollo de nuevos medicamentos es un problema complejo que carece de una solución única y automática desde un punto de vista computacional, debido a la carencia de programas que permitan manejar grandes volúmenes de información que están distribuidos a lo largo de todo el mundo entre múltiples bases de datos. Por ello se describe una metodología que permita realizar experimentos in silico para la identificación actual de nuevos medicamentos.

The development of new drugs is a problem that nowadays has no solution in terms of computational power due to the lack of software for handling the big volume of available information; besides, these data are stored in multiple formats and are distributed all around the world. To resolve that, a development of an in silico drug design methodology.

Assessing protein stability of the dimeric DNA-binding domain of E2 human papillomavirus 18 with molecular dynamics

The objective of this study is to understand the structural flexibility and curvature of the E2 protein of human papillomavirus type 18 using molecular dynamics (6 ns). E2 is required for viral DNA replication and its disruption could be an anti-viral strategy. E2 is a dimer, with each monomer folding into a stable open-faced â-sandwich. We calculated the mobility of the E2 dimer and found that it was asymmetric. These different mobilities of E2 monomers suggest that drugs or vaccines could be targeted to the interface between the two monomers.

Simulando la dinámica de transmisión de pacientes coinfectados con la Covid-19 y dengue / Simulating the transmission dynamics of patients coinfected with Covid-19 and Dengue

Recientemente se han detectado pacientes infectados por la Covid-19 y con dengue en Tailandia y Singapur al mismo tiempo (coinfectados), y por tanto, se deben comenzar a diseñar medidas preventivas para el monitoreo de estos casos especiales en Latinoamérica. A raíz de ello, se presenta un modelo matemático que permite analizar este tipo de coinfección en la población humana. Finalmente, se resuelve analítica y numéricamente el modelo(AU)

Patients infected with Covid-19 and with Dengue have been detected in Thailand and Singapore at the same time (coinfected), it is necessary to monitor these cases in Latin America. For that reason we present a mathematical model that allows analyzing this type of coinfection in the human population. Finally, the model is analytically and numerically resolved according to a possible scenario in a given country(AU)