The Community for Technology Leaders
RSS Icon
Issue No.02 - March/April (2011 vol.8)
pp: 487-498
Sébastien Loriot , INRIA Sophia-Antipolis, France
Sushant Sachdeva , Princeton University, USA
Karine Bastard , Université de Nantes, CNRS, France
Chantal Prévost , CNRS, France
Frédéric Cazals , INRIA Sophia-Antipolis, France
To address challenging flexible docking problems, a number of docking algorithms pregenerate large collections of candidate conformers. To remove the redundancy from such ensembles, a central problem in this context is to report a selection of conformers maximizing some geometric diversity criterion. We make three contributions to this problem. First, we resort to geometric optimization so as to report selections maximizing the molecular volume or molecular surface area (MSA) of the selection. Greedy strategies are developed, together with approximation bounds. Second, to assess the efficacy of our algorithms, we investigate two conformer ensembles corresponding to a flexible loop of four protein complexes. By focusing on the MSA of the selection, we show that our strategy matches the MSA of standard selection methods, but resorting to a number of conformers between one and two orders of magnitude smaller. This observation is qualitatively explained using the Betti numbers of the union of balls of the selection. Finally, we replace the conformer selection problem in the context of multiple-copy flexible docking. On the aforementioned systems, we show that using the loops selected by our strategy can improve the result of the docking process.
Flexibility, conformer selection, flexible docking, geometric optimization, Van der Waals models, molecular surface area (MSA).
Sébastien Loriot, Sushant Sachdeva, Karine Bastard, Chantal Prévost, Frédéric Cazals, "On the Characterization and Selection of Diverse Conformational Ensembles with Applications to Flexible Docking", IEEE/ACM Transactions on Computational Biology and Bioinformatics, vol.8, no. 2, pp. 487-498, March/April 2011, doi:10.1109/TCBB.2009.59
[1] J. Janin and S. Wodak, "The Third CAPRI Assessment Meeting Toronto, Canada, April 20-21, 2007," Structure, vol. 15, no. 7, pp. 755-759, 2007.
[2] J. Monod, J. Wyman, and J. Changeux, "On the Nature of Allosteric Transitions: A Plausible Model," J. Molecular Biology, vol. 12, pp. 88-118, 1965.
[3] R. Grunberg, J. Leckner, and M. Nilges, "Complementarity of Structure Ensembles in Protein-Protein Binding," Structure, vol. 12, pp. 2125-2136, 2004.
[4] A. Canutescu, A.A. Shelenkov, and R. Dunbrack, "A Graph Theory Algorithm for Protein Side-Chain Prediction," Protein Science, vol. 12, pp. 2001-2014, 2003.
[5] K. Bastard, C. Prévost, and M. Zacharias, "Accounting for Loop Flexibility during Protein-Protein Docking," Proteins, vol. 62, no. 4, pp. 956-969, 2006.
[6] J. Cortés, T. Siméon, V. Ruiz de Angulo, D. Guieysse, M. Remaud-Siméon, and V. Tran, "A Path Planning Approach for Computing Large-Amplitude Motions of Flexible Molecules," Bioinformatics, vol. 21, pp. 116-125, 2005.
[7] A. Dhanik, P. Yao, N. Marz, R. Propper, C. Kou, G. Liu, H. van den Bedem, and J. Latombe, "Efficient Algorithms to Explore Conformation Spaces of Flexible Protein Loops," Proc. Seventh Workshop Algorithms in Bioinformatics (WABI), pp. 265-276, 2007.
[8] A. Malevanets, F. Sirota-Leite, and S. Wodak, "Mechanism and Energy Landscape of Domain Swapping in the (B1) Domain of Protein (G)," J. Molecular Biology, vol. 382, no. 1, pp. 223-235, 2008.
[9] M.R. Garey and D.S. Johnson, Computers and Intractability: A Guide to the Theory of NP-Completeness. W.H. Freeman, 1979.
[10] U. Feige, "A Threshold of ln n for Approximating Set Cover," J. ACM, vol. 45, no. 4, pp. 634-652, , 1998.
[11] P. Fishburn and W. Gehrlein, "Pick-and Choose Heuristics for Partial Set Covering," Discrete Applied Math., vol. 22, no. 2, pp. 119-132, 1989.
[12] G. Cornuejols, M. Fisher, and G. Nemhauser, "Location of Bank Accounts to Optimize Float: An Analytic Study of Exact and Approximate Algorithms," Management Science, vol. 23, no. 8, pp. 789-810, 1977.
[13] G. Nemhauser, L. Wolsey, and M. Fisher, "An Analysis of Approximations for Maximizing Submodular Set Functions," Math. Programming, vol. 14, no. 1, pp. 265-294, 1978.
[14] S. Loriot, S. Sachdeva, K. Bastard, C. Prevost, and F. Cazals, "On the Characterization and Selection of Diverse Conformational Ensembles," Research Report 6503, INRIA, https://hal.inria.frinria-00252046, 2009.
[15] F. Cazals and S. Loriot, "Computing the Exact Arrangement of Circles on a Sphere, with Applications in Structural Biology," Proc. 23rd Ann. Symp. Computational Geometry-Video/Multimedia Track, 2007.
[16] F. Cazals and S. Loriot, "Computing the Arrangement of Circles on a Sphere, with Applications in Structural Biology," Computational Geometry: Theory and Applications, vol. 42, nos. 6/7, pp. 551-565, 2009.
[17] P.M. de Castro, F. Cazals, S. Loriot, and M. Teillaud, "Design of the CGAL 3D Spherical Kernel and Application to Arrangements of Circles on a Sphere," Computational Geometry: Theory and Applications, vol. 42, nos. 6/7, pp. 536-550, 2009.
[18] M. Zacharias, "Protein-Protein Docking with a Reduced Protein Model Accounting for Side-Chain Flexibility," Protein Science, vol. 12, no. 6, pp. 1271-1282, 2003.
[19] M. Lensink, R. Mendez, and S. Wodak, "Docking and Scoring Protein Complexes: CAPRI Third Edition," Proteins, vol. 69, no. 4, pp. 704-718, 2007.
[20] R. Chen, J. Mintseris, J. Janin, and Z. Weng, "A Protein-Protein Docking Benchmark," Proteins, vol. 52, no. 1, pp. 88-91, 2003.
[21] M. Zacharias, "Attract: Protein-Protein Docking in Capri Using a Reduced Protein Model," Proteins, vol. 60, pp. 252-256, 2005.
[22] R. Mendez, R. Leplae, M. Lensink, and S. Wodak, "Assessment of Capri Predictions in Rounds 3-5 Shows Progress in Docking Procedures," Proteins, vol. 60, pp. 150-169, 2005.
[23] Z. Xiang, C. Soto, and B. Honig, "Evaluating Conformational Free Energies: The Colony Energy and Its Application to the Problem of Loop Prediction," Proc. Nat'l Academy of Sciences USA, vol. 99, no. 11, pp. 7432-7437, 2002.
[24] K. Noonan, D. O'Brien, and J. Snoeyink, "Probik: Protein Backbone Motion by Inverse Kinematics," The Int'l J. Robotics Research, vol. 24, no. 11, pp. 971-982, 2005.
[25] A. Shehu, C. Clementi, and L. Kavraki, "Modeling Protein Conformational Ensembles: From Missing Loops to Equilibrium Fluctuations," Proteins: Structure, Function, and Bioinformatics, vol. 65, no. 1, pp. 164-179, 2006.
[26] G. Schröder, A. Brunger, and M. Levitt, "Combining Efficient Conformational Sampling with a Deformable Elastic Network Model Facilitates Structure Refinement at Low Resolution," Structure, vol. 15, pp. 1630-1641, 2007.
[27] A. Fiser, R. Do, and A. Šali, "Modeling of Loops in Protein Structures," Protein Science, vol. 9, no. 9, pp. 1753-1773, 2000.
[28] E. Lindahl, B. Hess, and D. van der Spoel, "GROMACS 3.0: A Package for Molecular Simulation and Trajectory Analysis," J. Molecular Modeling, vol. 7, no. 8, pp. 306-317, 2001.
[29] G. Saporta and J. Bouroche, L'Analyse des Données. Presses Univ. de France, 1985.
[30] J. Chambers, W. Cleveland, B. Kleiner, and P. Tukey, Graphical Methods for Data Analysis. Belmont, 1983.
[31] "CGAL, Computational Geometry Algorithms Library," http:/, 2010.
[32] A. Gordon, Classification. Chapman & Hall/CRC, 1999.
[33] M. Henle, A Combinatorial Introduction to Topology. Dover, 1994.
[34] C. Delfinado and H. Edelsbrunner, "An Incremental Algorithm for Betti Numbers of Simplicial Complexes on the 3-Sphere," Computer Aided Geometric Design, vol. 12, no. 7, pp. 771-784, 1995.
[35] C. Chen and D. Freedman, "Quantifying Homology Classes ii: Localization and Stability," Preprint, arXiv:0709.2512v2, 2007.
[36] N. London and O. Schueler-Furman, "Funnel Hunting in a Rough Terrain: Learning and Discriminating Native Energy Funnels," Structure, vol. 16, no. 2, pp. 269-279, 2008.
[37] D.W.L. Delano, "The PyMOL Molecular Graphics System," http:/, 2010.
[38] N. Akkiraju and H. Edelsbrunner, "Triangulating the Surface of a Molecule," Discrete Applied Math., vol. 71, nos. 1-3, pp. 5-22, 1996.
[39] B. de Groot, D. van Aalten, R. Scheek, A. Amadei, G. Vriend, and H. Berendsen, "Prediction of Protein Conformational Freedom from Distance Constraints," Proteins Structure Function and Genetics, vol. 29, no. 2, pp. 240-251, 1997.
414 ms
(Ver 2.0)

Marketing Automation Platform Marketing Automation Tool