Interactive reading of sequences

• Alexander Grossmann

This will be a presentation of a straightforward semi-graphical tool for exploring a family of sequences.

Non-specific DNA-protein interaction: how proteins can diffuse along DNA

• Maria Barbi

The structure of DNA binding proteins (DNA-BPs) enables a strong interaction with their specific target site on DNA through direct interactions with DNA base pairs. However, recent single molecule experiment reported that proteins can diffuse on DNA. Interactions between proteins and non-specific DNA should therefore play a crucial role during the target search. Nucleotides being negatively charged, the positive surface of DNA-BPs is expected to collapse onto DNA. This is indeed what is observed by means of Monte Carlo simulations for an oversimplified model of the system where the DNA is represented by a cylinder and the protein by a sphere. However, the most characteristic aspect of DNA-BPs is their shape complementarity with DNA [1]. We showed that, if the concave shape of DNA-BPs is taken into account, a counter-intuitive repulsion between the two oppositely charged macromolecules exists at a nanometer range [2,3], which pushes the protein in a free energy minimum at a distance from DNA. As a consequence, a favorable path exists along which proteins can slide without interacting with the DNA bases. When a protein encounters its target, the osmotic barrier is completely counter-balanced by the local H-bond interaction, thus enabling the sequence recognition. The implications of such a behavior on the protein 1D diffusion along DNA recently observed both in vitro and in vivo [4,5] will be the goal of future investigations. [1] S. Jones, P. van Heyningen, H.M. Berman, and J.M. Thornton Protein-DNA interactions: a structural analysis J. Mol. Biol., 287:877–896, 1999. [2] V. Dahirel, F. Paillusson, M. Jardat, M. Barbi, J-M. Victor Non-specific DNA-protein interaction: Why proteins can diffuse along DNA, Phys. Rev. Lett., in press (2009) -- arXiv:0902.2708. [3] F. Paillusson, M. Barbi, J-M. Victor Poisson-Boltzmann for oppositely charged bodies: an explicit derivation, Molecular Physics, in press (2009) -- arXiv:0902.1457. [4] J. Gorman, and E.C. Greene, Visualizing One-dimensional Diffusion of Proteins along DNA Nature Structural and Molecular Biology15:5752-5757 (2008). [5] J. Elf, G.W. Li, and X.S. Xie. Probing Transcription Factor Dynamics at the Single-Molecule Level in a Living Cell Science, 316:1191 – 1194, 2007.

Protein-protein interactions: modeling structure and affinity

• Joel Janin

The Protein Data Bank (PDB) illustrates many types of protein-protein interactions, specific in oligomeric proteins and in transient complexes, non-specific at crystal packing contacts. The information in it is geometric and chemical in nature, but it can also be interpreted in terms of the physics (thermodynamic stability and binding mechanisms) and the biology of the interaction (function, specificity, and evolution) [1-2]. Protein-protein docking methods yield structural models that a community-wide experiment (CAPRI, Critical Assessment of PRedicted Interactions, http://capri.ebi.ac.uk) tests in blind predictions. In ten years of CAPRI, the prediction has succeeded on 70% of the targets, and most of the failures were due to major conformation changes accompanying the interaction. As conformation changes also govern affinity [4], the challenge is now to model protein flexibility and predict both the structure of the assembly and its thermodynamic stability. 1. Janin J, Bahadur RP, Chakrabarti P (2008). Protein-protein interaction and quaternary structure. Quart. Rev. Biophysics 41:133-180. 2. Dey S, Pal A, Chakrabarti P, Janin J. (2010). The subunit interfaces of weakly associated homodimeric proteins. J. Mol. Biol. 398:146-160. 3. Janin J (2010) Protein-protein docking tested in blind predictions: the CAPRI experiment. Mol. Biosystems 6, 2351–2362. 4. A structure-based benchmark for protein-protein binding affinity. Kastritis PL, Moal IH, Hwang H, Bonvin AMJJ, Bates PA, Weng Z, Janin J (2011) Protein Sci. 20:482—491.

Assessing the stability of protein complexes within large assemblies

• Frédéric Cazals

Structural genomics projects exploiting Tandem Affinity Purification (TAP) or similar data have revealed remarkable features of proteomes [G06]. While these insights are essentially of combinatorial nature---selected proteins are known to interact within a complex, leveraging this information requires building three dimensional models of these complexes. Such an endeavour has recently been completed for the Nuclear Pore Complex (NPC), for which plausible reconstructions have been computed from different experimental data, including TAP data [A07a-b]. Yet, a full synergy between TAP data and the reconstruction is not at play for two reasons. First, the models built are qualitative. Second, the reconstruction does not elucidate the precise connexion between the model and TAP data. In particular, deciding whether proteins seen in a TAP experiment correspond to a single complex or a mixture of complexes within the NPC is not addressed. This talk will present a method addressing these limitations. First, we shall introduce toleranced models to inherently model uncertain shapes. A toleranced model is a one-parameter family of shapes (a continuum of geometries) representing an uncertain shape, which can be used to investigate stable complexes amidst the continuum. Second, for models reconstructed from TAP data, we shall explain how toleranced models and their built-in geometric statistics can be used to infer stable contacts, and also to investigate protein complexes associated to specific protein types. Illustrations will be provided on NPC models derived from the density maps presented in [A07a-b]. Bibliography [G06] A-C. Gavin et al; Nature, 440, 2006. [A07a-b] F. Alber and Al; Nature, 450, 2007. [CD10] F. Cazals and T. Dreyfus; Symposium on Geometry Processing, 2010; http://hal.inria.fr/inria-00497688/en [CD11] F. Cazals and T. Dreyfus; INRIA Techreport 7513, 2011; http://hal.inria.fr/inria-00559117/en

Protein Interfaces: a networking story

• Giovanni Feverati (LAPTH)

The assembly of subunits in protein oligomers is an important topic to study as a vast number of proteins exists as stable or transient oligomers. Only a few of the amino acids that constitute a protein oligomer seem to regulate the capacity of the protein to assemble (to form interfaces), and some of these amino acids are localized at the interfaces that link the different chains. We have developed a series of programs, under the common name of Gemini, that can select the subset of the residues that is involved in the interfaces of a protein oligomer, and generate a 2D interaction network (or graph) of the subset. We have used these programs to investigate interfaces made of two adjacent beta strands (one on each side of the interface). The graphs show a peculiar presence of two subnetworks, one of the backbone-backbone interactions and one with side chain interactions. A differential use of the amino acids emerges.

A minimum principle in codon-anticodon interaction

• Paul Sorba

Imposing a minimum principle in the framework of the so called crystal basis model of the genetic code, we determine the structure of the minimum set of 22 anticodons which allows the translation-transcription for animal mitochondrial code. The results are in very good agreement with the observed anticodons.

Quantitative biology

• Michele Caselle (Università di Torino)

The talk will be devoted to a general survey of the applications of the tools of theoretical physics to modern molecular biology. After a general introduction to modern genomics, to the sequencing projects and to the so called "Systems Biology" approach, I will discuss in more detail three examples: the role of evolution in shaping the genome, the network properties of gene regulation and the use of statistical mechanics tools to describe chemotaxis.