Seminars – Hard Problems in Systems Biology

EVENT : JOINT seminar

C3BI &

Department of Structural Biology AND Chemistry

Hard Problems in Systems Biology

Main speaker : Chris Sander, from Dana-Farber Cancer Institute and Harvard Medical School, Boston Date : 29/09/2016 at 02:00 pm Location : Amphitheater Duclaux – DUCLAUX (01), Institut Pasteur, Paris

Hard Problems in Systems Biology: 1. Prediction of Large Protein and RNA 3D Structures 2. Design of Cancer Combination Therapy

Part 1: Collaborative efforts combining computational biology, structural biology and statistical physics expertise provide a solution to the computational protein folding problem. Genomic sequences contain rich evolutionary information about functional constraints on macromolecules such as proteins. This information can be efficiently mined to detect evolutionary couplings between residues in proteins and address the long-standing challenge to compute protein and RNA three-dimensional structures from sequences alone. Substantial progress on the evolutionary couplings approach, since the initial attempts in 1994, has become possible because of the explosive growth in available sequences and the application of global statistical methods, such as maximum entropy distillation of correlated mutation patterns. In addition to proteins and RNA 3D structure, this powerful analysis of covariation helps identify functional residues involved in ligand binding, complex formation and conformational changes. We expect computation of evolutionary covariation patterns to help elucidate the full spectrum of protein and RNA structures, their functional interactions and evolutionary dynamics. Collaboration between the Sander and Marks (Harvard Medical School) groups, as well as initially with Martin Weigt, Andrea Pagnani and Riccardo Zecchina at Politecnico di Torino. Use the server to compute EVcouplings and to predict 3D structure for large sequence families. Ref: – Protein 3D Structure from high-throughput sequencing. Ref: – 3D RNA and Functional Interactions from Evolutionary Couplings. Part 2: Cells and organisms have evolved as robust to external perturbations and adaptable to changing conditions. This capacity poses severe problems for cancer patients. Some targeted anti-cancer drugs work remarkably well, yet resistance is almost certain to emerge. Three particular scientific challenges arise: (1) discover the escape routes in response to drugs and how to block the exits by combinatorial intervention; (2) in The Cancer Genome Atlas empirically describe the landscape of oncogenic alterations for improved therapeutic navigation and (3) use experimental perturbation biology (systematic perturbation coupled with rich observation of response, such as changes in protein levels and protein modifications) to derive executable network models for cancer cells that guide the development of combination therapy. Work done in collaboration with  Anil Korkut, Evan Molinelli, Martin Miller, Wei Qing Wang, Xiaohong Jing, Alex Root, Deb Bemis, David Solit, Christine Pratilas, Emek Demir, Arman Aksoy, Onur Sumer, Özgün Babur, Andrea Pagnani, Martin Weigt, Riccardo Zecchina, Giovanni Ciriello, Nikolaus Schultz, Sven Nelander, Debora Marks et alii. Ref: -Perturbation biology nominates upstream–downstream drug combinations in RAF inhibitor resistant melanoma cells. The end.  

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