HostDesigner: a program for the de novo structure-based design of molecular receptors with binding sites that complement metal ion guests

This paper describes a novel approach to the discovery of host structures with binding sites that complement targeted metal ion guests. This approach uses a de novo structure-based design strategy that couples molecular building algorithms with scoring functions to prioritize candidate structures. The algorithms described herein have been implemented in a program called HostDesigner, the first structure-based design software specifically created for the discovery of metal ion receptors. HostDesigner generates and evaluates millions of candidate structures within minutes, rapidly identifying three-dimensional architectures that position binding sites to provide an optimal interaction with the metal ion.     

Mechanistic Insights into RNA Transphosphorylation from Kinetic Isotope Effects and Linear Free Energy Relationships of Model Reactions

Phosphoryl transfer reactions are ubiquitous in biology and the understanding of the mechanisms whereby these reactions are catalyzed by protein and RNA enzymes is central to reveal design principles for new therapeutics. Two of the most powerful experimental probes of chemical mechanism involve the analysis of linear free energy relations (LFERs) and the measurement of kinetic isotope effects (KIEs). These experimental data report directly on differences in bonding between the ground state and the rate‐controlling transition state, which is the most critical point along the reaction free energy pathway. However, interpretation of LFER and KIE data in terms of transition‐state structure and bonding optimally requires the use of theoretical models. In this work, we apply density‐functional calculations to determine KIEs for a series of phosphoryl transfer reactions of direct relevance to the 2′‐O‐transphosphorylation that leads to cleavage of the phosphodiester backbone of RNA. We first examine a well‐studied series of phosphate and phosphorothioate mono‐, di‐ and triesters that are useful as mechanistic probes and for which KIEs have been measured. Close agreement is demonstrated between the calculated and measured KIEs, establishing the reliability of our quantum model calculations. Next, we examine a series of RNA transesterification model reactions with a wide range of leaving groups in order to provide a direct connection between observed Brønsted coefficients and KIEs with the structure and bonding in the transition state. These relations can be used for prediction or to aid in the interpretation of experimental data for similar non‐enzymatic and enzymatic reactions. Finally, we apply these relations to RNA phosphoryl transfer catalyzed by ribonuclease A, and demonstrate the reaction coordinate–KIE correlation is reasonably preserved. A prediction of the secondary deuterium KIE in this reaction is also provided. These results demonstrate the utility of building up knowledge of mechanism through the systematic study of model systems to provide insight into more complex biological systems such as phosphoryl transfer enzymes and ribozymes.     

Synthesis of alkylpyrroles by use of a vinamidinium salt

The synthesis of alkyl-substituted 2-pyrrolecarboxylate esters has been accomplished by the condensation reaction of a symmetrical vinamidinium salt and glycine ester derivatives.     

Qualitative assessment of nanofiller dispersion in poly(ε-caprolactone) nanocomposites by mechanical testing, dynamic rheometry and advanced thermal analysis

A comprehensive overview of available methods for assessing nanofiller dispersion is presented for a wide range of layered silicate-based poly(ε-caprolactone) (PCL) nanocomposites. Focusing on their respective strengths and weaknesses, rheological, mechanical and thermal characterization approaches are evaluated in direct relation to morphological information. Pronounced changes in the rheological and mechanical properties of the materials are only observed for nanocomposites displaying the highest nanofiller dispersion levels, as confirmed by an innovative and highly reliable thermal analysis approach based on quasi-isothermal crystallization. As such, the data obtained from the different methods also allow a detailed investigation of the crucial factors affecting nanofiller dispersion, evidencing the importance of specific matrix/filler interactions and the need for proper melt processing conditions when targeting significant property enhancements. Finally, the wide potential of the developed methodologies for the characterization of polymeric nanocomposites in general is illustrated by an extension to carbon nanotube-based PCL composites, unambiguously demonstrating their complementarity and broad applicability.     

Laboratory Flow Experiments for Visualizing Carbon Dioxide-Induced,Density-Driven Brine Convection

Injection of carbon dioxide (CO₂) into saline aquifers confined by low- permeability cap rock will result in a layer of CO₂ overlying the brine. Dissolution of CO₂ into the brine increases the brine density, resulting in an unstable situation in which more-dense brine overlies less-dense brine. This gravitational instability could give rise to density-driven convection of the fluid, which is a favorable process of practical interest for CO₂ storage security because it accelerates the transfer of buoyant CO₂ into the aqueous phase, where it is no longer subject to an upward buoyant drive. Laboratory flow visualization tests in transparent Hele-Shaw cells have been performed to elucidate the processes and rates of this CO₂ solute-driven convection (CSC). Upon introduction of CO₂ into the system, a layer of CO₂-laden brine forms at the CO₂-water interface. Subsequently, small convective fingers form, which coalesce, broaden, and penetrate into the test cell. Images and time-series data of finger lengths and wavelengths are presented. Observed CO₂ uptake of the convection system indicates that the CO₂ dissolution rate is approximately constant for each test and is far greater than expected for a diffusion-only scenario. Numerical simulations of our system show good agreement with the experiments for onset time of convection and advancement of convective fingers. There are differences as well, the most prominent being the absence of cell-scale convection in the numerical simulations. This cell-scale convection observed in the experiments may be an artifact of a small temperature gradient induced by the cell illumination.