Nanoinformatics knowledge infrastructures: bringing efficient information management to nanomedical research

Nanotechnology represents an area of particular promise and significant opportunity across multiple scientific disciplines. Ongoing nanotechnology research ranges from the characterization of nanoparticles and nanomaterials to the analysis and processing of experimental data seeking correlations between nanoparticles and their functionalities and side effects. Due to their special properties, nanoparticles are suitable for cellular-level diagnostics and therapy, offering numerous applications in medicine, e.g. development of biomedical devices, tissue repair, drug delivery systems and biosensors. In nanomedicine, recent studies are producing large amounts of structural and property data, highlighting the role for computational approaches in information management. While in vitro and in vivo assays are expensive, the cost of computing is falling. Furthermore, improvements in the accuracy of computational methods (e.g. data mining, knowledge discovery, modeling and simulation) have enabled effective tools to automate the extraction, management and storage of these vast data volumes. Since this information is widely distributed, one major issue is how to locate and access data where it resides (which also poses data-sharing limitations). The novel discipline of nanoinformatics addresses the information challenges related to nanotechnology research. In this paper, we summarize the needs and challenges in the field and present an overview of extant initiatives and efforts

A Natural Love of Natural Products

Recent research on the chemistry of natural products from the author’s group that led to the receipt of the ACS Ernest Guenther Award in the Chemistry of Natural Products is reviewed. REDOR NMR and synthetic studies established the T-taxol conformation as the bioactive tubulin-binding conformation, and these results were confirmed by the synthesis of compounds which clearly owed their activity or lack of activity to whether or not they could adopt the T-taxol conformation. Similar studies with the epothilones suggest that the current tubulin-binding model needs to be modified. Examples of natural products discovery and biodiversity conservation in Suriname and Madagascar are also presented, and it is concluded that natural products chemistry will continue to make significant contributions to drug discovery. My first real exposure to natural products chemistry came in my third and final year as an undergraduate at Cambridge University, when I attended a course of lectures on the chemistry of natural products by the Nobel Prize-winning chemist Sir Alexander Todd (later to become Lord Todd). The lectures included many references to his own work in the field, with stories of his early work on the structure of cholesterol, th

Ion channels in icosahedral virus: a comparative analysis of the structures and binding sites at their fivefold axes.

An analysis of the crystallographically determined structures of the icosahedral protein coats of Tomato Bushy Stunt Virus, Southern Bean Mosaic Virus, Satellite Tobacco Necrosis Virus, Human Rhinovirus 14 and Mengovirus around their fivefold axes is presented. Accessibilities surfaces, electrostatic energy profile calculations, ion-protein interaction energy calculations, free energy perturbation methods and comparisons with structures of chelating agents are used in this study. It is concluded that the structures built around the viral fivefold axes would be adequate for ion binding and transport. Relative ion preferences are derived for the binding sites, using free energy perturbation methods, which are consistent with the experimental data when available. In the cases where crystallographic studies determined the existence of ions on the fivefold axes, our results indicate that they would correspond to ions in crystallization or purification buffers. The environment of the fivefold axes are rich in polar residues in all icosahedral viral structures whose atomic coordinates are available, including some that are not being analyzed in detail in this work. The fivefold channel-like structures have most of the basic properties expected for real ion channels including a funnel at the entrance, a polar internal environment with frequent alternation of acidic and basic residues, ion binding sites, the capability to induce ion dehydration and ion transit from the external viral surface to the binding sites

Complete basis set and density functional determination of the enthalpy of formation of the controversial HO3 radical: a discrepancy between theory and experiment

Enthalpies of formation of the HOOOH molecule and HOOO radical were determined accurately employing density functional (DFT), coupled-clusters (CC) and complete basis set (CBS) extrapolation methods. The enthalpy of formation of the HO3 radical was determined as 7.1 +/- 2 kcal/mol at 298 K through a series of calculations employing the isodesmic reaction HOOOH + OH - HOH + HOOO. This value is in disagreement with the experimental one of Speranza, -1 +/- 5 kcal/mol. The enthalpy of formation of HOOOH, calculated at the extrapolated CBS/CCSD(T) and CBS-APNO levels, amounts to -21.1 +/- 1 kcal/mol, also in disagreement with the experimentally determined upper limit of -26.0 kcal/mol. Further examination of the procedure used to determine this value from the raw experimental data, suggests that this value is not as reliable as originally thought (by Speranza). The data should be reexamined and perhaps supplemented with additional experiments. (C) 2002 Published by Elsevier Science B.V

Model of the catalytic mechanism of human aldose reductase based on quantum chemical calculations

Aldose Reductase is an enzyme involved in diabetic complications, thoroughly studied for the purpose of inhibitor development. The structure of an enzyme-inhibitor complex solved at sub-atomic resolution has been used to develop a model for the catalytic mechanism. This model has been refined using a combination of Molecular Dynamics and Quantum calculations. It shows that the proton donation, the subject of previous controversies, is the combined effect of three residues : Lys 77, Tyr 48 and His 110. Lys 77 polarises the Tyr 48 OH group, which donates the proton to His 110, which becomes doubly protonated. His 110 then moves and donates the proton to the substrate. The key information from the sub-atomic resolution structure is the orientation of the ring and the single protonation of the His 110 in the enzyme-inhibitor complex. This model is in full agreement with all available experimental data.L'aldose réductase est un enzyme impliqué dans des complications diabétiques. Il fait l'objet d'études approfondies dans le but de développer des inhibiteurs. La structure d'un complexe enzyme-inhibiteur, déterminée à résolution sub-atomique, a été utilisée pour développer un modèle du mécanisme catalytique. Ce modèle a été affiné en utilisant une combinaison de dynamique moléculaire et de calculs quantiques. Il montre que la donation du proton, objet de nombreuses controverses, est due à l'effet combiné de trois résidus : Lys 77, Tyr 48 et His 110. Lys 77 polarise le groupement OH de Tyr 48, dont le proton est donné à His 110, qui est alors doublement protonée. His 110 est alors déplacée et donne le proton au substrat. L'information clé fournie par la structure à résolution sub-atomique est l'orientation du cycle et la protonation simple de His 110 dans le complexe enzyme-inhibiteur. Ce modèle est en complet accord avec toutes les données expérimentales disponibles