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Seminars, events & talks

Friday, 20th January, 2012, 11:00-12:00,

Computational Biophysics

Template Based Protein-Protein Interaction Prediction and Towards Structural Interactomes

Protein–protein interaction networks provide valuable information in understanding of cellular functions and biological processes. Recent advances in high-throughput techniques have resulted in large amount of data on protein-protein interactions and lead to construction of large protein-protein interaction networks. However, these networks lack structural (3D) details of most interactions, and these structural details are the key components usually for understanding the function of proteins. Therefore, integrating structural information into protein networks on the proteome scale is important because it allows prediction of protein function, helps drug discovery and takes steps toward genome-wide structural systems   biology. In this talk, a fast method for structural modeling of protein-protein interactions that combines template-interface-based docking with flexible refinement will be presented. Its application towards building structural protein-interaction networks will be discussed with the examples on p53 interactions and E2-E3  interactions. In addition, how the structural networks can help drug discovery along the line of emerging polypharmacology paradigm will be discussed.

Speaker: Prof. ATTILA GURSOY, College of Engineering, Koc University, Istanbul, Turkey

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

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)

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)

Friday, 3rd June, 2011, 11:00-12:00

Computational Biophysics

Unravelling the complexity of molecular kinetics: states, pathways and experimental evidence

Simulations of the conformational equilibrium of macromolecules typically reveal a complex network of conformational states and transition rates between the states. In contrast, experimental results, such as dynamical fingerprints of macromolecules, often seem to indicate two- or three state kinetics. Markov state models, which are an efficient method to capture and summarize the information obtained from molecular simulation, can be used to predict these dynamical fingerprints and to reconcile experiment with simulation. In the first part of the lecture, I will given an overview of how to extract metastable states and dominant pathways from a given Markov model. Then, I will use a four-state model of a protein folding equilibrium to illustrate how dynamical fingerprints can be predicted from a given Markov model. From the equations of this method it becomes evident that (i) there might be no process which corresponds to the common notion of folding; (ii) often the experiment will be insensitive to some of the processes present in the system. These effects cause the difference in complexity between experimental and simulation results. Lastly, it is not only possible to predict dynamical fingerprints, but one can also use Markov models to design experiments to selectively measure specific processes. This will be demonstrated for a fluorescence quenching experiment of the MR121-G9-W peptide.

Speaker: Dr. Bettina Keller (Computational Molecular Biology, Freie Universität Berlin, Germany)

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

Friday, 29th April, 2011, 11:00-12:00

Computational Biophysics

A combined experimental and theoretical approach to study protein aggregation

Protein misfolding and aggregation into amyloid structures are associated with dozens of human diseases. Recent studies have provided compelling evidence for the formation of aggregates conformationally related to those underlying such disorders in yeast and bacterial cytosols. Thus, myloid-like aggregation seems to be an omnipresent process in both eukaryotic and prokaryotic organisms. The ease with which yeast and bacteria can be genetically and biochemically manipulated suggest that they might become useful systems for studying how and why proteins aggregate inside the cell and could provide a tractable environment to rationally model such phenomenon. This “in the cell” studies, combined with the computational analysis of the common as well as the differential structural and sequential properties of the proteins involved in human amyloid diseases might be of much help in deciphering the molecular mechanisms behind protein aggregation.

Speaker: Prof. Salvador Ventura - Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona

Room Room Xipre 173.06 (PRBB – 1st Floor)

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

Computational Biophysics

Linking function to dynamics in globular, multidomain and unstructured proteins using NMR

A detailed understanding of the biological function of macromolecules requires knowledge of both, their three dimensional structure and their time-dependent fluctuations. Methods to determine the structure of proteins are now well established and the static representations that they provide have contributed much to our understanding of the stability and biological function of proteins (structure-function relationship). In contrast, the characterization of structural fluctuations at atomic resolution is still in its infancy, particularly for motions taking place at biologically relevant time scales (dynamics-function relationship). Such information can be derived from residual dipolar couplings (RDCs) measured by nuclear magnetic resonance (NMR). In this communication we present the determination of native ensembles for globular, multi-domain and disordered proteins that explicitly represent their structural heterogeneity in the sub-millisecond time scale. The detailed descriptions of macromolecular dynamics achieved have allowed us to characterize: i) the transfer of structural information across a surface patch in ubiquitin involved in molecular recognition by the proteins that regulate protein degradation [1], ii) the role of inter-domain motions of T4 Lysozyme in enzymatic catalysis [2], and iii) the native (residual) contacts in chemically denatured ubiquitin that initiate the folding of this protein [3].

Speaker: XAVIER SALVATELLA - Laboratory of Molecular Biophysics, Institute for Research in Biomedicine.

Room Room 473.10 (PRBB - 4th Floor)

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