Dissecting the mechanistic bases of allosteric transduction in proteins: a coarse-grained approach

Date	Do, 03.11.2011 - Do, 03.11.2011
Time	10.15
Speaker	Prof. Francesco Piazza, Université d'Orléans, Département de Physique, Centre de Biophysique Moléculaire, Orléans, France
Location	Universität Bern, Institut für Angewandte Physik, Gebäude exakte Wissenschaften, Hörsaal B77, Sidlerstrasse 5, 3012 Bern
Program	Control at the molecular level is essential for the functioning of biological processes, both within molecules and between molecules. Intramolecular control often implies the effect of one ligand on the binding or catalysis of another with no direct interaction between the two effectors. To describe such interaction at a distance, often referred to also as intramolecular signaling, the adjective allosteric (from the greek "allos", other and, "stereos", hard, stiff) was coined in 1961 by Jacques Monod and Francois Jacob [1]. Although their importance is now widely recognized, the mechanistic bases of allosteric mechanisms remain rather elusive. Recent findings seem to confirm that in all proteins allosteric signals propagate through multiple, pre-existing fold- rooted pathways. Which pathways dominate depend on protein topologies, specific nature of the binding events, covalent modifications, and cellular (environmental) conditions, such as crowding effects [2]. Such picture is also confirmed by sequence-based statistical methods, suggesting that evolutionarily conserved sparse networks of amino acid interactions representstructural motifs for allosteric transduction [3,4]. In this talk I will illustrate how nonlinear effects in a coarse-grained network model of protein dynamics prove highly effectively in dissecting the relevant "hot-spot" sites and energy transduction pathways [5-9]. After reviewing the methods and the main techniques, I will survey different recent applications as well as the future challenges. Finally, I will show how our techniques allow to shed light on the result of recent NMR measurements reporting previously unknown collective motions spanning four beta-strands separated by up to 15 Angstroem in ubiquitin [10]. REFERENCES [1] J. Monod and F. Jacob. Teleonomic mechanisms in cellular metabolism, growth, and differentiation. Cold Spring Harb. Symp. Quant. Biol., 26, 389–401 (1961). [2] A. del Sol, C. J. Tsai, B. Y. Ma, and R. Nussinov. The origin of allosteric functional modulation: Multiple pre- existing pathways. Structure, 17(8), 1042–1050 (2009). [3] S. W. Lockless and R. Ranganathan. Evolutionarily conserved pathways of energetic connectivity in protein families. Science, 286(5438), 295–299, 10 (1999). [4] Gurol M. Suel, Steve W. Lockless, Mark A. Wall, and Rama Ranganathan. Evolutionarily conserved networks of residues mediate allosteric communication in proteins. Nat Struct Mol Biol, 10(1), 59–69, 01 (2003). [5] B. Juanico, Y.-H. Sanejouand, F. Piazza, and P. De Los Rios. Discrete breathers in nonlinear network models of proteins. Phys. Rev. Lett., 99, 238104 (2007). [6] F. Piazza and Y.-H. Sanejouand. Discrete breathers in protein structures. Phys. Biol, 5,026001 (2008). [7] F. Piazza and Y.-H. Sanejouand. Long-range energy transfer in proteins. Physical Biology, 6, 046014 (2009). [8] F. Piazza and Y.-H. Sanejouand. Energy transfer in nonlinear network models of proteins. Europhysics Letters, 88, 68001 (2009). [9] F. Piazza and Y.-H. Sanejouand. Breather-mediated energy transfer in proteins, Discrete and Continuous Dynamical Systems, Series S 4, 1247–1266 (2010). [10] R. B. Fenwick, S. Esteban-Martin, B. Richter, D. Lee, K. F. A. Walter, D. Milovanovic, S. Becker, N. A. Lakomek, C. Griesinger and X. Salvatella, Journal of the American Chemical Society 133, 10336–10339 (2011)
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