SIMCOMP/SUBCOMP: chemical structure search servers for network analyses

One of the greatest challenges in bioinformatics is to shed light on the relationship between genomic and chemical significances of metabolic pathways. Here, we demonstrate two types of chemical structure search servers: SIMCOMP (http://www.genome.jp/tools/simcomp/) for the chemical similarity search and SUBCOMP (http://www.genome.jp/tools/subcomp/) for the chemical substructure search, where both servers provide links to the KEGG PATHWAY and BRITE databases. The SIMCOMP is a graph-based method for searching the maximal common subgraph isomorphism by finding the maximal cliques in the association graph. In contrast, the SUBCOMP is an extended method for solving the subgraph isomorphism problem. The obtained links to PATHWAY or BRITE databases can be used to interpret as the biological meanings of chemical structures from the viewpoint of the various biological functions including metabolic networks

Protein sequences insight into heavy metal tolerance in Cronobacter sakazakii BAA-894 encoded by plasmid pESA3

The recently annotated genome of the bacterium Cronobacter sakazakii BAA-894 suggests the organism has the ability to bind heavy metals. This study demonstrates heavy metal tolerance in Cronobacter sakazakii, in which proteins with the heavy metal interaction were recognized by computational and experimental study. As the result, approximately one fourth of proteins encoded on the plasmid pESA3 are proposed to have potential interaction with heavy metals. Interaction between heavy metals and predicted proteins was further corroborated using protein crystal structures from protein data bank database and comparison of metal-binding ligands. In addition with, a phylogenetic study was undertaken for most toxic heavy metals, like arsenic, cadmium, lead and mercury and obtained related tree pattern for lead, cadmium and arsenic. Laboratory studies confirmed the organism's tolerance to tellurite, copper and silver. These experimental and computational study data extend our understanding of the genes encoding for proteins of this important neonatal pathogen and provides further insights into the genotypes associated with features that can contribute to its persistence in the environment. The information will be of value for future environmental protection from heavy toxic metals

The Need for a New Generation of Substructure Searching Software

Advances in synthetic chemistry mean that the molecules now synthesized include increasingly complex entities with mechanical bonds or extensive frameworks. For these complex molecular and supramolecular species, single-crystal X-ray crystallography has proved to be the optimal technique for determining full three-dimensional structures in the solid state. These structures are curated and placed in structural databases, the most comprehensive of which (for organic and metallo-organic structures) is the Cambridge Structural Database (CSD). A question of increasing importance is how users can search such databases effectively for these structures. In this Opinion we highlight some of the classes of complex molecules and supramolecules and the challenges associated with searching for them. We develop the idea of substructure searches that involve topological searches as well as searches for molecular fragments, and propose significant enhancements to substructure-search programs that are both achievable and highly beneficial for both the database user community and the broader chemistry community

PDBe: Protein Data Bank in Europe

The Protein Data Bank in Europe (PDBe) (http://www.ebi.ac.uk/pdbe/) is actively working with its Worldwide Protein Data Bank partners to enhance the quality and consistency of the international archive of bio-macromolecular structure data, the Protein Data Bank (PDB). PDBe also works closely with its collaborators at the European Bioinformatics Institute and the scientific community around the world to enhance its databases and services by adding curated and actively maintained derived data to the existing structural data in the PDB. We have developed a new database infrastructure based on the remediated PDB archive data and a specially designed database for storing information on interactions between proteins and bound molecules. The group has developed new services that allow users to carry out simple textual queries or more complex 3D structure-based queries. The newly designed ‘PDBeView Atlas pages’ provide an overview of an individual PDB entry in a user-friendly layout and serve as a starting point to further explore the information available in the PDBe database. PDBe’s active involvement with the X-ray crystallography, Nuclear Magnetic Resonance spectroscopy and cryo-Electron Microscopy communities have resulted in improved tools for structure deposition and analysis

Modélisation moléculaire de complexes Tubuline-Ligand

Les microtubules sont des polymères cylindriques de tubuline-ab, membres du cytosquelette eucaryote. Ils possèdent une dynamique intrinsèque nécessaire à de nombreuses fonctions cellulaires telle que la mitose. L hydrolyse du nucléotide GTP dans les polymères de tubuline-ab ainsi que les interactions entre la tubuline et les protéines partenaires ou les molécules à visées pharmacologiques, jouent un rôle critique sur la dynamique des microtubules. Durant cette thèse, des approches de modélisation moléculaire ont été utilisées pour mieux appréhender les interactions tubuline-ligand à l échelle atomique et contribuer au développement de nouvelles molécules actives. Des simulations de dynamiques moléculaires ont été réalisées pour étudier l effet de différents nucléotides dans la tubuline-b sur la structure et la dynamique du protofilament de tubuline. Nous proposons un rôle du résidu aE254 dans la coordination du magnésium catalytique. Nous observons également des changements conformationnels aux interfaces latérales et un réarrangement de structure aux interfaces longitudinales qui peuvent affecter la stabilisation du microtubule. Des travaux menés au laboratoire ont montré que la colchicine et le carbendazime se fixent dans des poches voisines dans la sous-unité tubuline-b et inhibent la prolifération cellulaire. Nous avons proposé un site de fixation du carbendazime dans les complexes tubuline-colchicine à l aide de l amarrage moléculaire et de simulations de dynamiques moléculaires. Ces expériences ont mené au design de molécules hybrides composées des noyaux colchicine et carbendazime reliés par un linker. Une de ces molécules hybrides a été synthétisée et testée avec succès sur des lignées de cellules HeLa. Enfin, nous avons construit des peptides cycliques dérivées d I19L, un peptide anti-microtubule identifié au laboratoire. Des simulations de dynamique moléculaire et des calculs d énergie libre de liaisons ont permis d évaluer ces peptides. Enfin, des mutations ont été proposées afin d optimiser l interaction entre le meilleur peptide et la tubuline.Microtubules are cylindrical polymers of ab-tubulin heterodimers, members of the eukaryotic cytoskeleton. They possess an intrinsic dynamics which is necessary to any cellular functions such as the mitosis. It has long been recognized that GTP hydrolysis in ab-tubulin polymers plays a critical role in this dynamics as well as the interactions between tubulin and the protein partners or the drugs. In this thesis, molecular modeling approaches are applied to three theoretical studies to gain insight at the atomic scale about tubulin-ligand interactions and to contribute to the development of new active compounds. Molecular dynamics simulations were used to study the effect of the different nucleotide states at b-tubulin on the protofilament structure and dynamics. We propose a role for residue aE254 in catalytic magnesium coordination. We also observe conformational changes and structure rearrangement at lateral and longitudinal interfaces that can affect the microtubule stabilization. Previous work carried out in the laboratory showed that colchicine and carbendazime bind neighboring pockets in the b-tubulin subunit and inhibit cell proliferation. We proposed a binding site of carbendazime on the tubulin-colchicine complex, using docking and molecular dynamics simulation, which lead to the design of hybrid molecules composed of both colchicines and carbendazime moieties attached with a linker. One of these hybrid molecules has been synthesized and successfully tested on HeLa cells. Finally, we designed four cyclic peptides based on I19L, an anti-microtubule peptide identified at the laboratory. Molecular dynamic simulations and binding free energy calculations were used to evaluate these peptides. Mutations were then proposed on the best peptide to increase its interactions with tubulin.EVRY-Bib. électronique (912289901) / SudocSudocFranceF