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Rapport (Rapport De Recherche) Année : 2008

On the Characterization and Selection of Diverse Conformational Ensembles

Résumé

As of today, a number of flexible docking experiments fail due to the lack of candidate conformations close from the bound ones. To tackle these difficult cases, which usually feature large re-arrangements, the route of choice consists of pre-generating discrete ensembles of conformers. But for a flexible fragment (rotamer, loop, domain), the fact that the generation of such ensembles does not take into account the whole environment of the fragment (in the whole protein or complex), prevents, in general, to directly relate the conformer energy to the thermodynamic equilibrium between the conformations. This observation calls for the development of methods providing a rather uniform sampling of the conformational space of the fragment, so as retain conformers avoiding obvious steric clashes. But such algorithms face one central difficulty: that of characterizing the conformational space coverage, so as to maximize the diversity of the conformers. This paper makes three contributions in this perspective. First, we formulate several conformer selection problems as a geometric optimization problems, so as to maximize spatial coverage in several guises. We propose to solve these problems using greedy algorithms, for which approximation bounds are given. Second, we develop several algorithms for one specific problem, that of optimizing the Molecular Surface Area (MSA) of the selection. Third, we experiment on the loops of four proteins (1BTH, 1CGI, 1OAZ, 3HHR), for dense and sparse conformational ensembles. Third, by focusing on the MSA and the Betti numbers of the union of the selection, we show that our strategy matches the MSA of standard selection methods, but resorting to a number of conformers between {\em one and two orders of magnitude} smaller. We therefore expect our characterization and selection of diverse conformational ensembles to improve the processing of challenging docking experiments.
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Dates et versions

inria-00252046 , version 1 (10-04-2008)
inria-00252046 , version 2 (14-04-2008)
inria-00252046 , version 3 (06-04-2009)

Identifiants

  • HAL Id : inria-00252046 , version 2

Citer

Sebastien Loriot, Sushant Sachdeva, Karine Bastard, Chantal Prevost, Frédéric Cazals. On the Characterization and Selection of Diverse Conformational Ensembles. [Research Report] RR-6503, 2008. ⟨inria-00252046v2⟩

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