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LECTURE 1 - THE MOLECULAR SOCIOLOGY OF THE CELL

LECTURE 1 - THE MOLECULAR SOCIOLOGY OF THE CELL. C. V. Robinson et al. The molecular sociology of the cel l, Nature 450 , 973, 2007. B. Andrew et al., Integrative structural biology , Science, 339, 913, 2013. This of molecular sociology is an example of INTEGRATIVE approach,

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LECTURE 1 - THE MOLECULAR SOCIOLOGY OF THE CELL

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  1. LECTURE 1 - THE MOLECULAR SOCIOLOGY OF THE CELL C. V. Robinson et al. The molecular sociology of the cell, Nature 450, 973, 2007. B. Andrew et al., Integrative structural biology, Science, 339, 913, 2013. This of molecular sociology is an example of INTEGRATIVE approach, complementing those of more classical molecular biophysics (i.e. physical biochemistry, based on single molecules, dilute environments, controlled rarefied interactions)

  2. From Andrej Sali Lab.

  3. INTEGRATIVE STRUCTURAL BIOLOGY

  4. A LIST OF TECHNIQUES FOR INTEGRATIVE STRUCTURAL BIOLOGY OF THE CELL • X-ray crystallography • NMR Spectroscopy • SAXS (SANS) • Cryo-electron microscopy • FRET spectroscopy • Sequence comparison (Evolutive pressure on structures. Paradigm: sequence > structure > function) • Co-purification • Hydrogen-deuterium exchange mass spectrometry (XDXMS) • Single molecule fluorescence • Atomic force spectroscopy • Light scattering • Electron paramagnetic resonance • Double electron-electron resonance • Chemical cross-linking • Mutagenesis Let us build individual lexicons (any idea about free software?)

  5. Examples of integrative structure determinations(from Robinson2007) Alpha-clathrin D6 barrel 26S proteasome To understand what 26S means see for example par 12.4.5 of PBC (physical Biology of the cell. In a nutshell: S (Svedberg). In a centrifuge: VD= m gc/ γ ; S = m/γ x 10 13 is the sedimentation coefficient)

  6. Nuclear pore complex NPC A. From Robinson2007

  7. Nuclear pore complex NPC B. From Robinson2007

  8. Summary: integrative structural approach (scalable, applicable from single proteins to complexes) Data generation Data translation into spatial restraints Optimization (computational fitting, score functions) Ensemble analysis (Bayesian inference ? Important examples Rosetta (www.rosettacommons.org (David Backer)) Integrative modeling (www.integrativemodeling.org)

  9. Inferential Structure Determination W. Rieping et al. see www.isd.bio.cam.ac.uk

  10. Numerical sampling of the posterior distribution: Gibbs sampler Drawback: getting trapped into metastable states

  11. Avoiding metastabilities: Replica exchange + Tsallis ensemble

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