Flexibility and inhibitor binding in Cdc25 phosphatases

Cdc25 phosphatases involved in cell cycle checkpoints are now active targets for the development of anti-cancer therapies. Rational drug design would certainly benefit from detailed structural information for Cdc25s. However, only apo- or sulfate-bound crystal structures of the Cdc25 catalytic domain have been described so far. Together with previously available crystalographic data, results from molecular dynamics simulations, bioinformatic analysis, and computer-generated conformational ensembles shown here indicate that the last 30-40 residues in the C-terminus of Cdc25B are partially unfolded or disordered in solution. The effect of C-terminal flexibility upon binding of two potent small molecule inhibitors to Cdc25B is then analyzed by using three structural models with variable levels of flexibility, including an equilibrium distributed ensemble of Cdc25B backbone conformations. The three Cdc25B structural models are used in combination with flexible docking, clustering, and calculation of binding free energies by the linear interaction energy approximation to construct and validate Cdc25B-inhibitor complexes. Two binding sites are identified on top and beside the Cdc25B active site. The diversity of interaction modes found increases with receptor flexibility. Backbone flexibility allows the formation of transient cavities or compact hydrophobic units on the surface of the stable, folded protein core that are unexposed or unavailable for ligand binding in rigid and densely packed crystal structures. The present results may help to speculate on the mechanisms of small molecule complexation to partially unfolded or locally disordered proteins.

Texture analysis using graphs generated by deterministic partially self-avoiding walks

Texture is one of the most important visual attributes for image analysis. It has been widely used in image analysis and pattern recognition. A partially self-avoiding deterministic walk has recently been proposed as an approach for texture analysis with promising results. This approach uses walkers (called tourists) to exploit the gray scale image contexts in several levels. Here, we present an approach to generate graphs out of the trajectories produced by the tourist walks. The generated graphs embody important characteristics related to tourist transitivity in the image. Computed from these graphs, the statistical position (degree mean) and dispersion (entropy of two vertices with the same degree) measures are used as texture descriptors. A comparison with traditional texture analysis methods is performed to illustrate the high performance of this novel approach. (C) 2011 Elsevier Ltd. All rights reserved.

Analytic Methods for the Logic of Proofs

The logic of proofs (lp) was proposed as Gdels missed link between Intuitionistic and S4-proofs, but so far the tableau-based methods proposed for lp have not explored this closeness with S4 and contain rules whose analycity is not immediately evident. We study possible formulations of analytic tableau proof methods for lp that preserve the subformula property. Two sound and complete tableau decision methods of increasing degree of analycity are proposed, KELP and preKELP. The latter is particularly inspired on S4-proofs. The crucial role of proof constants in the structure of lp-proofs methods is analysed. In particular, a method for the abduction of proof constant specifications in strongly analytic preKELP proofs is presented; abduction heuristics and the complexity of the method are discussed.