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Seminars, events & talks

Monday, 17th February, 2014, 11:00

Computational Biophysics

Rethinking Binding and Binding Kinetics

Speaker: Jose Duca, Head of Computer-Aided Drug Discovery at Novartis

Room Marie Curie Room

Friday, 5th July, 2013, 11:00-12:00

Computational Biophysics

Gold, protein and a ribosome: Simulating macromolecular encounters.

How do proteins recognise their diverse binding partners? How do they do this in the macromolecularly crowded and confined cellular environment? How do non-specific interactions affect protein motion and binding? We are developing molecular models and Brownian and molecular dynamics simulation procedures to address such questions [1-3]. I will discuss recent applications, including docking of an N-terminal processing enzyme to the ribosome [4], the binding of proteins to gold nanoparticles [5], and the simulation of protein diffusion and oligomerization in highly concentrated protein solutions [6,7].

[1] Gabdoulline, RR; Wade, RC. J. Am. Chem. Soc. (2009) 131, 9230-9238.

[2] Mereghetti, P. and Wade, R.C. J Phys Chem B. (2012) 116, 8523-33.

[3] Kokh, D.B., Corni, S., Winn, P.J., Hoefling, M., Gottschalk, K.,E., Wade, R.C. J.Chem. Theor. Comp. (2010) 6, 1753-68.

[4] Sankdikci, A., Gloge, F., Martinez, M., Mayer, M.P., Wade, R.C., Bukau, B., Kramer, G., Nat. Struct. Mol. Biol. (2013), in press.

[5] Brancolini, G., Kokh, D.B., Calzolai, L., Wade, R.C., Corni, S. ACS Nano. (2012), 6, 9863-78

[6] Mereghetti, P. and Wade, R.C. AIP Conf. Proc., (2013) 1518, 511.

[7] Balbo, J., Mereghetti, P., Herten, D-P, Wade, R.C.  Biophys. J., (2013) 104, 1576-84.

Speaker: Rebecca C. Wade, Heidelberg Institute for Theoretical Studies (HITS), and Zentrum für Molekulare Biologie (ZMBH), Heidelberg University, Germany

Room Xipre (seminar 173.06-183.01), PRBB.

Friday, 28th June, 2013, 11:00-12:00

Computational Biophysics

Visual phototransduction: from rhodopsin mutations to retinal disease

Rhodopsin is the visual pigment of the vertebrate retina responsible for light capture in the first molecular events of the complex process of vision. This photoreceptor protein has served as a prototypical model for G-protein coupled receptors (GPCRs) superfamily. Upon photoactivation, rhodopsin binds and activates the specific G- protein transducin. The details of this light-dependent activation, including the molecular interaction with transducin, have not been fully elucidated. Mutations in rhodopsin have been associated with the retinal degenerative disease retinitis pigmentosa (RP). The folding, degradation and aggregation of some of these mutant rhodopsins can be manipulated by drugs or molecular chaperones. Our goal is to deepen our knowledge of the molecular consequences of such mutations while gaining, at the same time, new insights into the structural requirements of the photoactivation process. We are also interested in the effect of lipids and metal ions on the structure, stability and function of rhodopsin, and the ligand protein interactions comparison between rhodopsin and cone opsin pigments. We will describe recent results on rhodopsin mutations associated to RP or potentially relevant for visual pigment evolution, the effect of docosohexaenoic acid lipid on the stability of purified rhodopsin and the kinetic differences between rhodopsin and red cone opsin ligand binding after photoactivation. Overall, our studies may enhance our understanding of the molecular mechanisms of phototransduction, the biology of GPCRs in general, and importantly, they may help develop potential approaches to treat RP caused by rhodopsin mutations.

(Supported by grants SAF2011-30216-C02-01 from MICINN, CIVP16A1861 from Fundación Ramón Areces, and Grups de Recerca Consolidats de la Generalitat de Catalunya (2009 SGR 1402).

Speaker: Pere Garriga, Department of Chemical Engineering, Universitat Politècnica de Catalunya (UPC)

Room Xipre (seminar 173.06-183.01), PRBB.

Wednesday, 19th June, 2013

Computational Biophysics

Structure-Based Drug Design conference

BIO-IT, 19-21 June 2013, Cambridge, Massachusetts, USA.

Speaker: Gianni de Fabritiis

Monday, 3rd June, 2013

Computational Biophysics

Conference of the Russian Biophysical society

3-7 June 2013, Moscow, Russia.

Speaker: Gianni de Fabritiis

Monday, 8th April, 2013

Computational Biophysics

Conference of the american chemical society

8-11 April 2013 New Orleans,USA.

Speaker: Gianni de Fabritiis

Monday, 25th March, 2013

Computational Biophysics

Biomolecular Simulation 2013

25-27 March 2013, Nottingham, UK.

Speaker: Gianni de Fabritiis

Friday, 15th March, 2013, 12.00-13.00

Computational Biophysics

Using docking and molecular dynamics to design drugs

We have discovered by high-throughput fragment-based docking several novel chemotypes of potent (single-digit nanomolar) and selective tyrosine kinase inhibitors [1-4].  Explicit solvent molecular dynamics has played an important role for the in silico validation of binding modes and  the selection of compounds for testing in vitro.  Definitive validation of the binding mode has been obtained by X-ray crystallography in our group [1,2].  The most advanced of our tyrosine kinase inhibitors are active on a subset of the NCI 60 cancer cell lines.  Furthermore, some of our  inhibitors have shown good pharmacokinetic properties in mice (including oral bioavailability) and are being currently selected for testing in tumor xenograft models.

[1] K. Lafleur et al. Structure-based Optimization of Inhibitors of the Tyrosine Kinase EphB4. Part 2: Cellular Potency Improvement and Binding Mode Validation by X-ray Crystallography. J. Med. Chem. 56, 84, 2013.

[2] H. Zhao, J. Dong, K. Lafleur, C. Nevado, and A. Caflisch.
Discovery of a novel chemotype of tyrosine kinase inhibitors by fragment-based docking and molecular dynamics. ACS Med. Chem. Lett. 3, 834, 2012.

[3] H. Zhao, D. Huang, and A. Caflisch. Discovery of tyrosine kinase inhibitors by docking into an inactive kinase conformation generated by molecular dynamics. ChemMedChem 7, 1983, 2012.

[4] K. Lafleur et al. Structure-based optimization of potent and selective inhibitors of the tyrosine kinase erythropoietin producing human hepatocellular carcinoma receptor B4 (EphB4).
J. Med. Chem. 52, 6433, 2009.

Speaker: Amedeo Caflisch, Computational Structural Biology, University of Zurich, Switzerland.

Room Seminar room 473.10

Monday, 4th February, 2013

Computational Biophysics

Fragment based drug discovery by simulation

CDDD - Computationally Driven Drug Discovery, Istituto Italiano di Tecnologia (IIT), Geneve (Italy) 4-6 February 2013

Speaker: Gianni de Fabritiis

Friday, 25th January, 2013, 12.00

Computational Biophysics

Structural Bioinformatics applied to Bio-Nanotechnology

Speaker: Fernando Danilo González Nilo, Center for Bioinformatics and Integrative Biology (CBIB), Santiago de Chile, Chile.

Room Marie Curie

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