Detecting similarities among distant homologous proteins by comparison of domain flexibilities

Aim of this work is to assess the informativeness of protein dynamics in the detection of similarities among distant homologous proteins. To this end, an approach to perform large-scale comparisons of protein domain flexibilities is proposed. CONCOORD is confirmed as a reliable method for fast conformational sampling. The root mean square fluctuation of alpha carbon positions in the essential dynamics subspace is employed as a measure of local flexibility and a synthetic index of similarity is presented. The dynamics of a large collection of protein domains from ASTRAL/SCOP40 is analyzed and the possibility to identify relationships, at both the family and the superfamily levels, on the basis of the dynamical features is discussed. The obtained picture is in agreement with the SCOP classification, and furthermore suggests the presence of a distinguishable familiar trend in the flexibility profiles. The results support the complementarity of the dynamical and the structural information, suggesting that information from dynamics analysis can arise from functional similarities, often partially hidden by a static comparison. On the basis of this first test, flexibility annotation can be expected to help in automatically detecting functional similarities otherwise unrecoverable. © 2007 The Author(s)

Le phénomène des badanti en Italie. Caractéristiques et spécificités

Cet article analyse le phénomène des auxiliaires de vie (appelées badanti dans le langage commun) dans le contexte italien, en soulignant sa complexité et ses spécificités. En particulier, il prend en compte les facteurs qui sont à l’origine d’une telle présence, les changements et les impacts que cette figure détermine sur l’État-providence italien, sur les dynamiques familiales et sur la demande d’assistance. Sur la base des données d’une recherche empirique, l’attention est portée sur les effets positifs et négatifs que la présence des auxiliaires de vie produit sur l’offre de services et sur leur rôle positif, au sein du système de Welfare

New Aryl Hydrocarbon Receptor Homology Model Targeted To Improve Docking Reliability

The aryl hydrocarbon receptor (AhR) is a ligand-dependent, basic helix–loop–helix Per-ARNT-Sim (PAS) containing transcription factor that can bind and be activated by structurally diverse chemicals, including the toxic environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). As no experimentally determined structures of the AhR ligand binding domain (LBD) are available and previous homology models were only derived from <i>apo</i> template structures, we developed a new model based on <i>holo</i> X-ray structures of the hypoxia-inducible factor 2α (HIF-2α) PAS B domain, targeted to improve the accuracy of the binding site for molecular docking applications. We experimentally confirmed the ability of two HIF-2α crystallographic ligands to bind to the mAhR with relatively high affinity and demonstrated that they are AhR agonists, thus justifying the use of the <i>holo</i> HIF-2α structures as templates. A specific modeling/docking approach was proposed to predict the binding modes of AhR ligands in the modeled LBD. It was validated by comparison of the calculated and the experimental binding affinities of active THS ligands and TCDD for the mAhR and by functional activity analysis using several mAhR mutants generated on the basis of the modeling results. Finally the ability of the proposed approach to reproduce the different affinities of TCDD for AhRs of different species was confirmed, and a first test of its reliability in virtual screening is carried out by analyzing the correlation between the calculated and experimental binding affinities of a set of 14 PCDDs