|
|
|
AbstractsOctober 8, 2014
Protein-Protein Interactions and Systems Biology 14:10-15:10 - Emmanuel LEVY – Weizmann Institute of Science, Rehovot, Israel Promiscuous protein-protein interactions: a burden for the cell and a tool for the biologist [1] Levy ED et al. Cellular crowding imposes global constraints on the chemistry and evolution of proteomes. PNAS 2012. [2] Levy ED et al. Protein abundance is key to distinguish promiscuous from functional phosphorylation based on evolutionary information. Philos Trans R Soc Lond B Biol Sci. 2012. [3] Levy ED et al. High-resolution mapping of protein concentration reveals principles of proteome architecture and adaptation, Cell Reports 2014.
15:10-16:10 - Shoshana WODAK - University of Toronto, Canada Protein-protein interaction data: All that glitters is not gold Major progress has been achieved in the experimental techniques used for the detection of protein interactions and in processing and analyzing the vast amount of data that they generate. However, we still do not understand why the set of identified interactions remains so highly dependent on the particular detection methode. We will present an overview of major PPI datasets produced by high-throughput experimental methods over the last 10 years. We will highlight the biases associated with different methods and their associated computational procedures and discuss the challenges of assessing the quality of these datasets. More specifically, evidence will be presented that the poor overlap between the PPI datasets derived by different methods stems mainly from the fact that these datasets contain a sizable fraction of non-specific associations, which current computational filters are unable to eliminate. Such associations form as a result of mass action; they likely have no specific functional roles, but they are tolerated by the cell and are stable enough to be detected. Going forward therefore, highest priority should be given to experimental and computational approaches capable of identifying the functional portions of the interactome as well as characterizing its non-functional complement. Joint work: Shoshana J. Wodak(1,2,3,4), James Vlasblom(1), Shuye Pu(1), Andrei Turinsky(1) -- (1) Molecular Structure and Function program, Hospital for Sick Children, Toronto, Canada; (2) Department of Molecular Genetics, University of Toronto, Canada; (3) Department of Biochemistry, University of Toronto, Canada, (4) VIB Department of Structural Biology, VUB, Brussels Belgium. Wodak SJ, Vlasblom J, Turinsky AL, Pu S. Protein-protein interaction networks: the puzzling riches. Curr Opin Struct Biol. 2013 Dec;23(6):941-53.
16:40-17h40 - Patrick ALOY - Institute for Research in Biomedecine, Barcelona, Spain Structural Systems Pharmacology: the role of 3D structures in next generation drug development Structural systems pharmacology offers a novel way of approaching drug discovery by considering the global physiological environment of protein targets, and the effects derived of tinkering with them, without losing the key molecular details. In this talk, I will review some recent advances in the structural annotation of cell networks and discuss their potential impact on some of the hottest areas of drug development. In particular, I will present recent structure-based strategies to target networks, protein interaction interfaces and allosteric sites, and how they will help in the development of more potent and specific treatments. Finally, I will show how mapping genetic variations onto pharmacological targets can rationalize interindividual variability in drug response, giving valuable hints to advance towards personalized medicine.
October 9, 2014
Protein design principles 9:00-10:00 - Gideon SCHREIBER – Weizmann Institute of Science, Rehovot, Israel Connecting the dots: relevance of binding kinetics and affinities in dictating biological processes in the complex in-vivo environment Specific, rapid interactions between proteins are essential for most biological processes. For many years, we and others have investigated the kinetics and thermodynamics of protein-interactions in the test tube. In parallel, the biological context and importance of many protein interactions in driving biological processes were reviled. However, due to experimental difficulties, little was done to connect between the biophysical and structural parameters of protein-interactions in-vitro and their relevance within the crowded and complex in vivo environment. In this talk I will focus of our efforts in recent years to bridge this gap, and will show that the efforts invested in in-vitro measurements was not in wain.
10:30-11:30 - Rama RANGANATHAN – University of Texas, Southwestern Medical Center, Dallas, USA The Evolutionary “Design” of Proteins Natural proteins can fold spontaneously into well-defined three-dimensional structures, and can display complex biochemical properties such as signal transmission, efficient catalysis of chemical reactions, specificity in molecular recognition, and allosteric conformational change. All of this is achieved while also preserving the capacity for rapid adaptive variation in response to fluctuating selection pressures, a central feature of evolving systems. What are the basic principles in the “design” of natural proteins that underlie all of these properties? To address this, we developed an approach (the statistical coupling analysis or SCA) for globally estimating the pattern of functional interactions between sites on proteins through statistical analysis of the evolutionary divergence of a protein family1,2,14. This analysis indicates a novel decomposition of proteins into sparse groups of co-evolving amino acids that we term “protein sectors”9. The sectors comprise physically connected networks in the tertiary structure and can be modular – with different sectors representing different functional properties. Experiments in several protein systems demonstrate the functional and adaptive importance of the sectors 1,3,4,7,8,10,11,12 and recently, the SCA information was shown to the necessary and sufficient to design functional artificial members of two protein families in the absence of any structural or chemical information5,6. These results support the hypothesis that sectors represent the basic architecture underlying folding, function, and adaptive variation in proteins. We are now working on two key problems: (1) understanding the physical mechanisms underlying sectors, and (2) defining how the dynamics of the evolutionary process controls the emergence and structural architecture of sectors in proteins. [1] Lockless, R. Ranganathan, Science, 286, 295-9 (1999). [2] Suel et al., Nature Struct. Biol., 10., 59-69 (2003). [3] Hatley, et al., PNAS, 100: 14445-14450 (2003). [4] Shulman et al., Cell, 116: 417-429 (2004). [5] Socolich et al., Nature, 437: 512-518 (2005). [6] Russ et al., Nature, 437: 579-583 (2005). [7] Mishra et al., Cell, 131: 80-92 (2007). [8] Lee et al., Science 322: 438-442 (2008). [9] Halabi et al., Cell 138: 774-785 (2009). [10] Smock et al., Mol. Sys. Biol.: 6: 414 (2010). [11] Reynolds et al., Cell, 147: 1564-1575 (2011). [12] McLaughlin et al., Nature 491: 138-142 (2012). [13] Stiffler et al., in review. [14] Rivoire et al., in preparation.
11 :30-12 :30 - Juan FERNANDEZ-RECIO – Barcelona Supercomputing Center, Barcelona, Spain Functional characterization and modeling of protein-protein interfaces: lessons from docking Protein-protein interactions are involved in virtually all cell processes, and their structural and functional annotation is essential to understand biological and pathological phenomena. The construction of predictive models based on properties arising from structure provides an intermediate layer between structure and function in protein-protein association. We have recently brought together many different methods for characterising protein-protein interfaces, some of which are successful in discriminating near-native solutions from docking decoys. Multi-parametric models based on these potentials, as well as on experimental affinities and docking calculations, are used to identify residues that largely affect the interaction, which is essential for protein-protein interface design. This can also help to characterize pathological mutations in a personalized medicine context and to foster drug discovery targeting protein interactions.
Protein affinities and specificities 14:15-15:15 - Alexandre BONVIN – Utrecht University, The Netherlands Modelling structure, affinity and specificity of biomolecular complexes Biomolecular interactions underlie most cellular processes, including signal transduction and apoptosis. Understanding how the cell works requires describing these at molecular level, which is bound to have a dramatic impact on current and future structure-based drug design. Computational methods may assist in this task, particularly when some experimental data can be obtained. I will describe our information-driven docking approach HADDOCK (http://haddock.science.uu.nl), illustrating it with various examples including results from the CAPRI blind docking experiment. I will then discuss the problem of binding affinity prediction, showing that current scoring functions in macromolecular docking fail at predicting the affinity of protein-protein complexes. For binding affinity calculation, the surface buried upon complexation is not the absolute determinant and inclusion of additional structural parameters, previously neglected is deemed mandatory for near-accurate predictions. Related to affinity, understanding the structural determinant of specificity is another challenging problem which I will illustrate showing how a conserved Asp to Glu mutation can switch the specificity profile of ubiquitination enzymes. In conclusion, current biophysical models are far more adequate in predicting accurate conformations of protein-protein complexes rather than assessing the affinity and specificity of their interactions. [1] Karaca, E.; Bonvin, A.M.J.J. Methods 59, 372-381, 2013. [2] Kastritis, P.L.; Bonvin, A.M.J.J. Curr. Opin. Struct. Biol. 23, 868-877, 2013. [3] de Vries, S.J.L.; Melquiond, A.S.J.; de Vries, S.J.; Timmers, H.Th.M; Bonvin, A.M.J.J. PLoS Comp. Biol., 8(11), e1002754, 2012.
15:15-16:15 - Alan COOPER - University of Glasgow, UK Experimental Thermodynamics of Proteins and their Interactions Biological macromolecules and their complexes are cooperative structures that are held together by a multiplicity of weak, non-covalent interactions. This has inevitable consequences for the functionally-significant dynamics and thermodynamics of such systems. I will review the experimental background and describe simple statistical thermodynamic models that rationalize this sometimes unexpected behaviour.
Proteins in the cell 16:45-17:45 - Eugene SHAKHNOVICH – Harvard University, Cambridge, USA Protein-protein interactions in living cells: fitness costs and benefits of finding the right partners and avoiding the wrong ones In my talk I will present theoretical and experimental results of the study of collective effects of protein-protein interactions (PPI) in crowded cellular environment. Statistical-mechanical theory outlines ‘’phase diagram’’ of a living cell highlighting the limitations on the abundances and diversity of cell proteomes due to loss of protein material to promiscuous PPI. Experimental study based on novel ‘’bottom up’’ genome editing approach provides further insight into fitness cost and occasional benefits of non-native PPI and suggests possible evolutionary implications.
October 10, 2014 Molecular docking 9:15-10:15 - Martin ZACHARIAS – Technische Universität München, Germany Exploring protein-protein interactions by coarse-grained and atomistic models Most biological processes are mediated by protein-protein or protein-nucleic acid interactions. Computational docking of proteins is of importance allowing to generate structural models of dimeric and multimeric protein complexes. Often biomolecular recognition and association events are coupled to conformational changes of the binding partners. We employ a coarse-grained model for predicting protein-protein interactions as well as protein-nucleic acid interactions that accounts efficiently for local and global conformational changes during systematic searches. In order to optimize the refinement of predicted complexes we have developed new atomistic approaches that will be discussed. In a second part the detailed free energy change associated with biomolecular complex formation simulated at atomic resolution and including explicit solvent will be presented.
10:45-11:45 - Zhiping WENG - University of Massachusetts Medical School, USA Protein-protein docking and design I will present our recent work on protein-protein docking and design. We have designed a benchmark and a suite of algorithms for predicting the complex structures of protein-protein complexes. Recent developments include two solutions to increase the speed of the docking algorithms by 50-fold while maintaining the same accuracy. We have also designed an algorithm for detecting protein interaction interfaces. Finally I will describe our effort of designing T cell receptors.
11:45-12:45 - Matteo DAL PERARO – École Polytechnique Fédérale de Lausanne, Switzerland Unveiling the structure of macromolecular assemblies using integrative dynamic modeling
|
| Online user: 1 | e
|
