Skull Modularity in Neotropical Marsupials and Monkeys: Size Variation and Evolutionary Constraint and Flexibility

An organism is built through a series of contingent factors, yet it is determined by historical, physical, and developmental constraints. A constraint should not be understood as an absolute obstacle to evolution, as it may also generate new possibilities for evolutionary change. Modularity is, in this context, an important way of organizing biological information and has been recognized as a central concept in evolutionary biology bridging on developmental, genetics, morphological, biochemical, and physiological studies. In this article, we explore how modularity affects the evolution of a complex system in two mammalian lineages by analyzing correlation, variance/covariance, and residual matrices (without size variation). We use the multivariate response to selection equation to simulate the behavior of Eutheria and Metharia skulls in terms of their evolutionary flexibility and constraints. We relate these results to classical approaches based on morphological integration tests based on functional/developmental hypotheses. Eutherians (Neotropical primates) showed smaller magnitudes of integration compared with Metatheria (didelphids) and also skull modules more clearly delimited. Didelphids showed higher magnitudes of integration and their modularity is strongly influenced by within-groups size variation to a degree that evolutionary responses are basically aligned with size variation. Primates still have a good portion of the total variation based on size; however, their enhanced modularization allows a broader spectrum of responses, more similar to the selection gradients applied (enhanced flexibility). Without size variation, both groups become much more similar in terms of modularity patterns and magnitudes and, consequently, in their evolutionary flexibility. J. Exp. Zool. (Mol. Dev. Evol.) 314B:663-683, 2010. (C) 2010 Wiley-Liss, Inc.

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.