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Seminars, events & talks

Thursday, 19th January, 2012, 11:00

Evolutionary Genomics

Evolutionary dynamics of short indels in mammalian genomes

Insertions and deletions (indels), together with nucleotide substitutions, are major drivers of sequence evolution. An excess of deletions over insertions in genomic sequences-the so-called deletional bias-has been reported in a wide range of species, including mammals. However, this bias has not been found in the coding sequences of some mammalian species, such as human and mouse. To determine the strength of the deletional bias in mammals, and the influence of mutation and selection, we have quantified indels in both neutrally evolving noncoding sequences and protein-coding sequences, in six mammalian branches: human, macaque, ancestral primate, mouse, rat, and ancestral rodent. The results  indicate that contrary to previous results, the only mammalian branch with a strong deletional bias is the rodent ancestral branch. We estimate that such a bias has resulted in an 2.5% sequence loss of mammalian syntenic region in the ancestor of the mouse and rat. Further, a comparison of coding and noncoding sequences shows that negative selection is acting more strongly against mutations generating amino acid insertions than against mutations resulting in amino acid deletions. The strength of selection against indels is found to be higher in the rodent branches than in the primate branches, consistent with the larger effective population sizes of the rodents.

Speaker: Steve Laurie, Biomedical Informatics, IMIM-UPF

Room Marie Curie

Wednesday, 18th January, 2012, 12:00h

Computational RNA Biology

Understanding RNA through massively parallel sequencing (RNA in the ENCODE project)

The unfolding of the instructions encoded in the genome is triggered by the transcription of DNA into RNA, and the subsequent processing of the resulting primary RNA transcripts into functional mature RNAs. RNA is thus the first phenotype of the genome, mediating all other phenotypic changes at the organism level caused by changes in the DNA sequence. While current technology is too primitive to provide accurate measurements of the RNA content of the cell, the recent development of Massively Parallel Sequencing Instruments has dramatically increased the resolution with which we can monitor cellular RNA. Using these instruments, the ENCODE project has surveyed the RNA content of multiple cell lines and subcellular compartments. The results of these surveys underscore pervasive transcription, as well as great RNA heterogeneity between and within cells. Comparison of RNA surveys with other genome wide epigenetic surveys—such as those of binding sites for Transcription Factors, or of Histone modifications—reveals a very tightly coupling between the different pathways involved in RNA processing, transcription and splicing in particular.

Speaker: Roderic Guigó, CRG

Room Auditorium PRBB

Wednesday, 11th January, 2012, 12:00

GPCR drug discovery

Cracking the cancer code, a bioinformatics journey

Nuria Lopez-Bigas obtained her PhD for work on the molecular causes of hereditary deafness at the group of Xavier Estivill. After a postdoc on computational genomics at the European Bioinformatics Institute (with Christos Ouzounis) and at the CRG (with Roderic Guigó), she established her laboratory at the University Pompeu Fabra in 2006. In 2011 she was appointed ICREA research professor.

Thanks to the advance of genomic technologies it is currently possible to obtain a comprehensive catalog of genomic alterations in cancer cells. However the identification of alterations directly involved in the development of the tumor is challenging. Nuria Lopez-Bigas current research focuses on the development of computational approaches to analyse cancer genomic data with the objective to identify genes and pathways driving tumorigenesis.

Speaker: Nuria López-Bigas, GRIB (IMIM - UPF)

Room Auditorium PRBB

Friday, 18th November, 2011, 11:00-12:00

Computational Biophysics

Protein flexibility in docking with discrete molecular dynamics simulations

The aim of protein-protein docking is to predict how two proteins associate to form a complex. This means determining where will be the interface. This is a complex problem with many degrees of freedom. To reduce the sampling space, in general both proteins are considered to be rigid bodies (rigid docking). This reduces the problem to 6 degrees of freedom (3 for translation and 3 for rotation). The rigid body docking is a rude approach, since the proteins have flexibility and may undergo relevant conformational changes upon binding to the other protein when forming the complex. We have used discrete molecular dynamics (DMD) simulations to include the protein flexibility in docking configurations, and we have improved the predictive power of the method. DMD is a simplified molecular dynamics method much faster than standard MD, specially for systems with less that 10^3 particles.

Speaker: Dr. Agustí Emperador-Institut for Research in Biomedicine (IRB, Barcelona)

Room Seminar Room “Xipre” 173.06 (PRBB – 1st floor)

Thursday, 17th November, 2011, 11:00-12:00

GPCR drug discovery

Co-Alterations in Human Cancer

Big efforts are being made to reveal the alterations that have occurred in the genomes of cancerous cells. Especially the Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) will contribute by collecting data in a standardized way and make it publicly available.

With the already available data, an abundance of alterations of different types have been found – some so-called driver alterations that drive the cell towards its cancerous state and some passenger alterations that are a by-product of the cancer development.

It is an ongoing challenge to discriminate driver from the passenger mutations even though a variety of methods have been proposed up to this day. These include methods based on recurrence of alterations (RBM) across a cohort of samples and sequence based methods (SBM) that assess the impact of mutations on the functionality of the protein product.

We are working on how to detect the coaltered pairs that are candidates for having a synergistic effect. We hypothesize that some driver alterations may only have their driver effect when occurring with a certain other driver alteration – synergistic drivers. This could be reflected by either the strict co-occurrence of the driver alterations along the samples and/or similar expression patterns of reporter genes of the candidate drivers.

Speaker: Michael P. Schroeder

Room 473.10_Aula

Friday, 28th October, 2011, 11:00 - 12:00

Computational Biophysics

Understanding allosteric effects in receptor and non-receptor kinases

Protein kinases (PK) are one of the largest and most functionally diverse protein families and are involved in most cellular pathways. PK malfunction is related to an important number of human diseases, such as cancer, diabetes and cardiovascular diseases. Thus, PK represent major targets for drug development. Historically, drug discovery programs have been dominated by efforts to develop antagonists that compete for binding with endogenous ligands at orthosteric sites. However, allosteric drugs might offer several therapeutic advantages over traditional orthosteric ligands, including greater safety and/or selectivity. Here, by combining of state-of-the-art computer simulations as well as spectroscopy, chemical and molecular biology approaches we  study in great details complex allosteric effects in the pharmaceutically relevant Abl and FGFr kinases. In Abl a shift of the SH2 domain from the C- to the N-terminus of the catalytic domain has been found to be involved in activation [1]. The allosteric mechanism, by which the SH2 domain induces conformational changes at the active site, is still debated. We have used elastic network models, normal mode analysis, molecular dynamics simulation and mutagenesis to gain insight into the interplay between the SH2 domain and the relevant motifs at the catalytic site. We propose a mechanism, by which the SH2 domain influences the dynamics of the crucial residues directly involved in the catalytic process. In FgFr we use free energy calculations, crystallography and NMR approaches to shed light on the mode of action of a novel allosteric inhibitor. [2]
[1] Nagar B, Hantschel O, Seeliger M, Davies JM, Weis WI, Superti-Furga G, Kuriyan J Molecular Cell 2006, 21, 787-798.
[2] F. Bono et al., submitted.

Speaker: Dr. Francesco Gervasio - Computational Biophysics Groups. CNIO, Madrid

Room Seminar Room “Xipre” 173.06 (PRBB – 1st floor)

Friday, 14th October, 2011, 11:00-12:00

Computational Biophysics

Markov models of molecular conformation dynamics: Computing rare events in biomolecules

The simulation of conformational dynamics, inclucing protein folding, aggregation and conformational switching, is one of the main challenges of the molecular sciences. Unfortunately, these processes are rare events such that single long molecular dynamics simulations often fail to sample them. One way out is to distribute many short simulation trajectories onto independent processors, which are then combined into a single Markov model of the conformation dynamics. It can be shown that Markov models can successfully predict slow kinetics even when they are constructed from short trajectories, thus bridging the gap from short simulations to long timescales. Here, I will show how Markov models and related ideas are useful to understand the kinetics of protein folding and the conformational dynamics of the polymeric protein Dynamin. 

Speaker: Dr. Frank Noé -Computational Molecular Biology (CMB) - Freie Universität Berlin, Germany

Room Seminar Room “Xipre” 173.06 (PRBB – 1st Floor)

Friday, 7th October, 2011, 11:00-12:00

Computational Biophysics

New approaches for G protein-coupled receptor modulation

G protein-coupled receptors (GPCRs) are one of the most prevailing protein families in the human genome. GPCRs are receptors for sensory
signals of external origin such as odors, pheromones, or tastes; and for endogenous signals such as neurotransmitters, (neuro)peptides, hormones, and others. These proteins are key in cell physiology, and their malfunction is commonly translated into pathological outcomes. Thus, GPCRs constitute one of the most attractive drug targets.

In the ligand-free basal state, GPCRs exist in equilibrium of conformations, each stabilized by a network of intramolecular interactions. Ligand binding at the native (or orthosteric) site modulates receptor function by stabilizing new interaction networks and establishing new conformational equilibria. Activating ligands, or agonists, stabilize conformational changes in cytoplasmic domains that increase receptor signaling. Conversely, inverse agonists decrease the basal, agonist-independent level of signaling by stabilizing different conformational changes. In addition, ligand binding to an allosteric site (that is topographically distinct from the orthosteric site) might modulate the signalling of the orthosteric ligand. Positive allosteric modulators enhance the response of orthosteric agonists, while negative allosteric modulators decrease the effect.

We will show, combining the latest information about GPCR structure with chemical synthesis, site-directed mutagenesis, biophysical experiments and computational modeling, how the binding of the ligand to the allosteric or orthosteric site influences this equilibrium of conformations.

Speaker: Dr. Leonardo Pardo. Laboratori de Medicina Computacional, Unitat de Bioestadística, Facultat de Medicina, UAB

Room Seminar Room “Xipre” 173.06 (PRBB – 1st Floor)

Wednesday, 7th September, 2011, 11:00-12:00

Computational Biophysics

Assessment of peptide conformational features by computational methods and the design of peptidomimetics

Peptides are important mediators in the regulation of physiological processes of living organisms, exercising actions as agonists, antagonist or enzyme substrates and inhibitors. Moreover, they have also been successfully used as disruptors of protein-protein interactions. Unfortunately peptides exhibit a low pharmacological profile and small molecule peptidomimetics are helpful alternatives. The process of designing a peptidomimetic using computational methods goes through a deep understanding of the conformational profile of a peptide. These are flexible molecules with a large number of low energy conformations. In this talk I shall address the problem of conformational profile characterization and how this information can be used for peptidomimetic design.

Speaker: Juan Jesús Pérez EQ/UPC

Room Seminar room 173.06 - PRBB

Friday, 15th July, 2011, 11:00-12:00

Computational Biophysics

NMR and metabolomic applications to the development of novel molecularly targeted antineoplastic agents

An increased understanding of the molecular etiology of cancer has enabled the development of novel therapies that are collectively referred to as molecularly targeted agents. Unlike the drugs used in conventional therapy, these agents are designed to specifically interfere with key molecular events that are responsible for the malignant phenotype. The challenges associated with the development of these novel targeted therapies are distinct from those faced in conventional chemotherapy. They include, among other factors, the need to obtain a detailed knowledge of the 3D architecture of the molecular targets, as very often these strategies rely on structure-based approaches. Furthermore, the successful application of these approaches requires the identification of biomarkers that enable a better understanding of the mechanism of action and the clinical effects of these agents, as well as facilitate the selection of patient populations that are most likely to benefit from the treatment.

This presentation will review our current strategy to identify novel inhibitors, based on fragment-based screening and 3D structure determination, against protein targets involved in cell invasion and metastasis. This approach relies on the combination of NMR with other biochemical, biophysical and computational approaches. Metabolomics by NMR, a relatively new strategy for measuring the metabolic profile of biological samples, will also be reviewed. This methodology is extremely useful to perform comparative analysis of healthy and diseased individuals, information that can be used to identify disease biomarkers and stratify patients based on molecular subgroups.

Speaker: Dr. Antonio Pineda-Lucena-Centro de Investigación Príncipe Felipe, Valencia (Spain)

Room Seminar Room “Xipre” 173.06 (PRBB – 1st Floor)



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