On the Characterization and Selection of Diverse Conformational Ensembles
Sébastien Loriot, Sushant Sachdeva, Karine Bastard, Chantal Prévost, Frédéric Cazals · 2008
Abstract—To address challenging flexible docking problems, a number of docking algorithms pre-generate large collections of candidate conformers. To further remove the redundancy from such ensembles, a central question in this context is the following one: report a selection of conformers maximizing some geometric diversity criterion. In this context, we make three contributions. First, we tackle this problem resorting 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 systems above, we show that using the loops selected by our strategy can significantly improve the result of the docking process. Index Terms—Flexibility, conformer selection, flexible docking, geometric optimization, Van der Waals models. Abbreviations: MSA: molecular surface area, VdW: Van