A comprehensive classification and nomenclature of carboxyl-carboxyl(ate) supramolecular motifs and related catemers: implications for biomolecular systems.:

Carboxyl and carboxylate groups form important supramolecular motifs (synthons). Besides carboxyl cyclic dimers, carboxyl and carboxylate groups can associate through a single hydrogen bond. Carboxylic groups can further form polymeric-like catemer chains within crystals. To date, no exhaustive classification of these motifs has been established. In this work, 17 association types were identified (13 carboxyl-carboxyl and 4 carboxyl-carboxylate motifs) by taking into account the syn and anti carboxyl conformers, as well as the syn and anti lone pairs of the O atoms. From these data, a simple rule was derived stating that only eight distinct catemer motifs involving repetitive combinations of syn and anti carboxyl groups can be formed. Examples extracted from the Cambridge Structural Database (CSD) for all identified dimers and catemers are presented, as well as statistical data related to their occurrence and conformational preferences. The inter-carboxyl(ate) and carboxyl(ate)-water hydrogen-bond properties are described, stressing the occurrence of very short (strong) hydrogen bonds. The precise characterization and classification of these supramolecular motifs should be of interest in crystal engineering, pharmaceutical and also biomolecular sciences, where similar motifs occur in the form of pairs of Asp/Glu amino acids or motifs involving ligands bearing carboxyl(ate) groups. Hence, we present data emphasizing how the analysis of hydrogen-containing small molecules of high resolution can help understand structural aspects of larger and more complex biomolecular systems of lower resolution

MINAS—a database of Metal Ions in Nucleic AcidS

Correctly folded into the respective native 3D structure, RNA and DNA are responsible for uncountable key functions in any viable organism. In order to exert their function, metal ion cofactors are closely involved in folding, structure formation and, e.g. in ribozymes, also the catalytic mechanism. The database MINAS, Metal Ions in Nucleic AcidS (http://www.minas.uzh.ch), compiles the detailed information on innersphere, outersphere and larger coordination environment of >70 000 metal ions of 36 elements found in >2000 structures of nucleic acids contained today in the PDB and NDB. MINAS is updated monthly with new structures and offers a multitude of search functions, e.g. the kind of metal ion, metal-ligand distance, innersphere and outersphere ligands defined by element or functional group, residue, experimental method, as well as PDB entry-related information. The results of each search can be saved individually for later use with so-called miniPDB files containing the respective metal ion together with the coordination environment within a 15 Å radius. MINAS thus offers a unique way to explore the coordination geometries and ligands of metal ions together with the respective binding pockets in nucleic acids

Simulations de la dynamique moleculaire de cryptands et cruptates cationiques: de la phase gazeuse a la phase liquide

SIGLEAvailable from INIST (FR), Document Supply Service, under shelf-number : TD 80827 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Simulations de dynamique moléculaires d'ARN – Structures et environnements

RNA's, the only type of biomolecules that are at the same time informative and catalytic, play a role at all levels of cellular life. For some RNA's, the function is inscribed in their sequence. For others like transfer RNA's, the function resides in the formation and maintenance of their compact three-dimensional folds. These last RNA's, called structured RNA's, need Mg2+ cations to maintain their tertiary structure and participate to catalytic functions. In Eric WESTHOF's team, numerous three-dimensional models of structured RNA systems have been build through the use of phylogeny and chemical mapping techniques. These models gather almost all available experimental data for a given system and allowed to propose pertinent catalytic and molecular recognition mechanisms. Yet, these models do not allow to access to atomic resolution. This is why molecular dynamics simulation techniques have been developed in order to refine model structures and better understand structure-function relationships. Recent progress in MD simulation techniques obtained in our laboratory, allows us now to simulate the dynamics of molecules of the tRNA or small ribozymes size with an unprecedented level of precision. For better understanding RNA functions, that are by nature dynamical processes, we developed MD techniques in order to complement fragmentary structural information available on RNA hydration and on the structural role played by ions such as : mono- and divalent cations as well as anions. This knowledge is essential for the comprehension of the folding and stability of RNA systems and should lead to more elaborate three-dimensional models. Among the systems that we propose to investigate, we can cite transfer RNAs, ribosomal fragments as well as RNA/antibiotic and RNA/protein complexes.Les ARN, seules molécules à la fois informatives et catalytiques, interviennent à tous les niveaux de la vie cellulaire. Pour certaines molécules d'ARN, comme les ARN messagers, la fonction réside dans la séquence. Pour d'autres, comme les ARN de transfert, la fonction réside dans l'adoption et le maintien d'une structure tridimensionnelle compacte. Ces derniers, dits ARN structurés, nécessitent des ions Mg2+ pour maintenir leur structure tertiaire et assurer leur fonction de catalyse. Dans l'équipe d'Eric WESTHOF, de nombreux modèles tridimensionnels de ces ARN structurés, élaborés à partir de contraintes fournies par des méthodes de cartographie chimique en solution et de comparaison de séquences, ont été construits. Ces modèles regroupent l'ensemble des données expérimentales existantes pour un système donné et permettent ainsi de proposer des mécanismes de réaction ou de reconnaissance pertinents. Toutefois, ces modèles ne prétendent pas atteindre la résolution atomique de structures cristallographiques. C'est pourquoi des méthodes de simulations de dynamique moléculaire (DM) sont développées afin d'affiner les structures modélisées et, ultérieurement, de mieux comprendre les relations structure-fonction de ces ARN. Les progrès récents dans les techniques de simulation de DM réalisés au laboratoire, nous permettent maintenant de simuler la dynamique de molécules de la taille d'un ARN de transfert ou de petits ribozymes avec un degré de précision jusqu'alors rarement atteint. Pour mieux comprendre les fonctions des ARN, qui sont par nature des processus dynamiques, nous utilisons les méthodes de DM pour compléter les informations structurales fragmentaires qui sont disponibles sur l'hydratation de ces ARN et le rôle d'agents structurants (ions monovalents, divalents et anions). En effet, cette connaissance préalable est indispensable pour la compréhension du repliement et de la stabilité de ces ARN. De plus, elle contribuera à la construction de modèles structuraux plus précis. Parmi les systèmes que nous nous proposons d'étudier se trouvent les ARN de transfert ainsi que des fragments d'ARN ribosomaux. Des complexes entre ARN et antibiotiques ainsi que des complexes ARN/protéines sont en cours d'étude

High temperature annealed molecular dynamics simulations as a tool for conformational sampling. Application to the bicyclic "222" cryptand

International audienceWe have performed “High Temperature Annealed Molecular Dynamics Simulations” (HTAMDS) on the bicyclic 222 cryptand, and on model M’l222 cryptates with different representations of M’. The analysis of four sets of 500 structures allows assessment of the ability of HTAMDS to: (1) interconvert experimentally known conformers starting from one of them, (2) locate the energy minima, (3) generate new conformers of low energy, and (4) account for the average structure observed on the NMR time scale. In view of the ionophoric behavior of 222, structures are also analyzed in terms of the “inlout” orientation of the binding sites. It is found that simulations on the free molecule, although widely sampling the conformational space, do not give structures adequate for cation inclusion. They generate however the lowest energy structure known experimentally and other new closely related ones. Inclusion of the substrate in the simulation (either as a purely electrostatic “driver,” or as a charged sphere) is required to generate conformations found in several complexes. These results suggest that in the field of drug design, conformation of drugs suitable for binding to a given receptor may not be found when the simulations are performed on the isolated drug or substrate

Molecular dynamics simulations on the protonated 222. H+ and 222.2H+ cryptands in water: Endo versus exo conformations

International audienceMD simulations on the 222 cryptand, monoprotonated 222.H+ and diprotonated 222.2H+ in the endo-endo and exo-exo conformations have been performed in vacuo and in a bath of water molecules. It is found that intrinsically endo protonation is favoured over exo protonation due to internal N--H+...O hydrogen bonding which makes the cage more rigid. On the other hand, endo protonated forms display 'hydrophobic' hydration compared to exo forms. For the monoprotonated 222. H + endo conformer, one water molecule is hydrogen bonded inside the cage thereby forming a 'water cryptate'. From the hydration pattern found previously for the neutral 222 cryptand and for its cation complexes, we suggest mechanisms (not involving exo to endo conversions) for the protonation of 222 and for acid catalysed decomplexation of cryptates in the endo-endo form

Vers une meilleure compréhension des interactions ARN/ligands (méthodes, outils et applications)

L objectif de cette thèse est d essayer de mieux comprendre les interactions ARN/ligand, et plus particulièrement, les interactions entre le site-A de l ARN ribosomal bactérien 16S et différents antibiotiques de la famille des aminoglycosides, en utilisant les données théoriques et expérimentales des simulations de DM et de bases de données structurales. Ainsi, un ensemble d outils et de méthodes ont été développés visant, entre autres, à mettre en relation les données des simulations de DM avec les données structurales issues des expériences de diffraction de rayons X. Cette mise en relation permet de valider les données des simulations de DM ainsi que de combler certaines des carences des structures expérimentales. En effet, ce travail prend en compte un certain nombre d aspects de développement et d aspects méthodologiques comprenant, entre autres, la conception du web service SwS, l élaboration de méthodes de détection des positions des atomes d hydrogène et de techniques de cartographie des sites de solvatation basées sur les données expérimentales (structures RX) et théoriques (simulations de DM). Les outils et méthodes développés ont été mis à profit dans l étude de différents complexes site-A/aminoglycosides, révélant, entre autres, certains de leurs aspects dynamiques intéressants.The objective of this thesis is to try to better understand RNA/ligands interactions and especially the interactions between the A-site, part of the bacterial 16S ribosomal RNA, and various antibiotics of the aminoglycosides family, using theoretical MD simulations data and experimental structural databases. Thus, a set of tools and methods have been developed aiming, among other things, to link data from MD simulations with the structural data derived from X-ray diffraction experiments. This link allows validating MD simulations data and addressing some of experimental structures shortcomings. Indeed, this work involves a number of development and methodological aspects including, among other things, the programming of the SwS web service, the development of methods for detecting hydrogen atoms positions and mapping techniques of solvation sites based on experimental (structures RX) and theoretical data (MD simulations). The tools and methods developed have been used in the study of various A-site/aminoglycosides complexes revealing, among other things, some of their interesting dynamic aspects.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Anions in Nucleic Acid Crystallography

International audienc

Silver-wired DNA

International audienc

Quantitative studies on molecular recognition : free energy perturbation simulations on M + ⊂222 cryptates in water and in methanol

International audienceRelative free energies of complexation of Na+, K+ and Rb+ cations by the 222 cryptand have been calculated in water and in methanol. This was achieved by "slow growth MD mutations" using the perturbation thermodynamic cycle. Starting with the experimental structure of the K+C222 cryptate we calculate that, in gas phase and in solution, 222 prefers intrinsically Na+. In solution, taking into account the relative solvation free energies, we find a peak of binding selectivity for K+, in qualitative agreement with experiment. Calculated relative free energies of transfer from water to methanol of the free cations and of their cryptates compare also reasonably well with experiment. However, calculations starting from another cryptate type structure give rather different energies, which questions the predictive power of FEP calculations when restricted to small simulation times, and when the experimental structures are not available