How large does a compound screening collection need to be?

Increasingly, chemical libraries are being produced which are focused on a biological target or group of related targets, rather than simply being constructed in a combinatorial fashion. A screening collection compiled from such libraries will contain multiple analogues of a number of discrete series of compounds. The question arises as to how many analogues are necessary to represent each series in order to ensure that an active series will be identified. Based on a simple probabilistic argument and supported by in-house screening data, guidelines are given for the number of compounds necessary to achieve a "hit", or series of hits, at various levels of certainty. Obtaining more than one hit from the same series is useful since this gives early acquisition of SAR (structure-activity relationship) and confirms a hit is not a singleton. We show that screening collections composed of only small numbers of analogues of each series are sub-optimal for SAR acquisition. Based on these studies, we recommend a minimum series size of about 200 compounds. This gives a high probability of confirmatory SAR (i.e. at least two hits from the same series). More substantial early SAR (at least 5 hits from the same series) can be gained by using series of about 650 compounds each. With this level of information being generated, more accurate assessment of the likely success of the series in hit-to-lead and later stage development becomes possible.     

How close to two dimensions does a Lennard-Jones system need to be to produce a hexatic phase?

We report on a computer simulation study of a Lennard-Jones liquid confined in a narrow slit pore with tunable attractive walls. In order to investigate how freezing in this system occurs, we perform an analysis using different order parameters. Although some of the parameters indicate that the system goes through a hexatic phase, other parameters do not. This shows that to be certain whether a system of a finite particle number has a hexatic phase, one needs to study not only a large system, but also several order parameters to check all necessary properties. We find that the Binder cumulant is the most reliable one to prove the existence of a hexatic phase. We observe an intermediate hexatic phase only in a monolayer of particles confined such that the fluctuations in the positions perpendicular to the walls are less than 0.15 particle diameters, i.e., if the system is practically perfectly 2D.     

How does the nickel pincer complex catalyze the conversion of CO2 to a methanol derivative? A computational mechanistic study

The mechanistic details of nickel-catalyzed reduction of CO(2) with catecholborane (HBcat) have been studied by DFT calculations. The nickel pincer hydride complex ({2,6-C(6)H(3)(OP(t)Bu(2))(2)}NiH = [Ni]H) has been shown to catalyze the sequential reduction from CO(2) to HCOOBcat, then to CH(2)O, and finally to CH(3)OBcat. Each process is accomplished by a two-step sequence at the nickel center: the insertion of a C═O bond into [Ni]H, followed by the reaction of the insertion product with HBcat. Calculations have predicted the difficulties of observing the possible intermediates such as [Ni]OCH(2)OBcat, [Ni]OBcat, and [Ni]OCH(3), based on the low kinetic barriers and favorable thermodynamics for the decomposition of [Ni]OCH(2)OBcat, as well as the reactions of [Ni]OBcat and [Ni]OCH(3) with HBcat. Compared to the uncatalyzed reactions of HBcat with CO(2), HCOOBcat, and CH(2)O, the nickel hydride catalyst accelerates the H(δ-) transfer by lowering the barriers by 30.1, 12.4, and 19.6 kcal/mol, respectively. In general, the catalytic role of the nickel hydride is similar to that of N-heterocyclic carbene (NHC) catalyst in the hydrosilylation of CO(2). However, the H(δ-) transfer mechanisms used by the two catalysts are completely different. The H(δ-) transfer catalyzed by [Ni]H can be described as hydrogen being shuttled from HBcat to nickel center and then to the C═O bond, and the catalyst changes its integrity during catalysis. In contrast, the NHC catalyst simply exerts an electronic influence to activate either the silane or CO(2), and the integrity of the catalyst remains intact throughout the catalytic cycle. The comparison between [Ni]H and Cp(2)Zr(H)Cl in the stoichiometric reduction of CO(2) has suggested that ligand sterics and metal electronic properties play critical roles in controlling the outcome of the reaction. A bridging methylene diolate complex has been previously observed in the zirconium system, whereas the analogous [Ni]OCH(2)O[Ni] is not a viable intermediate, both kinetically and thermodynamically. Replacing HBcat with PhSiH(3) in the nickel-catalyzed reduction of CO(2) results in a high kinetic barrier for the reaction of [Ni]OOCH with PhSiH(3). Switching silanes to HBcat in NHC-catalyzed reduction of CO(2) generates a very stable NHC adduct of HCOOBcat, which makes the release of NHC less favorable.     

How does a thin volatile film move?

When a water film evaporates from a mica substrate, an interface similar to a solidification front develops, separating two films of different thicknesses. We show experimentally that the evolution dynamics is controlled mainly by material diffusion through the vapor phase rather than by hydrodynamic flow through the film. Our results illustrate the role of different contributions to pattern formation of volatile liquid films.     

How does CO capture process on microporous NaY zeolites? A FTIR and DFT combined study

Reliable experimental IR and theoretical approaches, both investigating CO adsorption on NaY faujasites, are supporting that CO capture occurs through the completion of the vacant coordination of Na(+) cations located in the accessible S(II) sites. As a result, carbonyl adsorbed species are formed by the capture of one, two or three CO molecules and are experimentally discernable by their respective IR positions that are down-shifted by an average 11-12 cm(-1) value for each captured CO molecule. DFT analysis is proposed for comparison and reproduces well the observed experimental shift of the ν(CO) positions of the different polycarbonyls of interest. In addition, the effect of Si or Al composition surrounding the SII Na(+) cation is investigated and results suggest that polycarbonyls that are formed might be in connection with the acidic strength of the cationic sites. This combined study completes and improves the understanding of the complex issue of CO adsorption at 80 K widely used as a model to explain how physical adsorption takes place in NaY faujasites working as an efficient industrial adsorbent in gas separation or gas purification processes.     

How to revise the GUM?

The announcement of a revision of the Guide to the expression of uncertainty in measurement has renewed the debate about the topic of measurement uncertainty. In this paper the author, chairman of Working Group 1 of the Joint Committee for Guides in Metrology, replies to the theses given in two recent papers by Semion Rabinovich. His opinions are personal, and are not necessarily shared by the JCGM/WG1. They are to be intended as a further contribution to the present discussion. Papers published in this section do not necessarily reflect the opinion of the Editors, the Editorial Board and the Publisher.     

How does the solvent guide the hydration process?

The hydration numbers are investigated of the glycine amino acid in solutions of substances with different effects on the structure of water: urea, monomethylurea, and 1,3-dimethylurea. Glycine loses a half of its hydration water in a 20m urea solution and only a quarter of it in a 20m dimethylurea solution. The constancy of the hydration number of glycine in concentrated dimethylurea solutions is due to the compensatory effect of the interactions in the ternary and binary systems.     

How does a hydrocarbon staple affect peptide hydrophobicity?

Water is essential for the proper folding of proteins and the assembly of protein–protein/ligand complexes. How water regulates complex formation depends on the chemical and topological details of the interface. The dynamics of water in the interdomain region between an E3 ubiquitin ligase (MDM2) and three different peptides derived from the tumor suppressor protein p53 are studied using molecular dynamics. The peptides show bimodal distributions of interdomain water densities across a range of distances. The addition of a hydrocarbon chain to rigidify the peptides (in a process known as stapling) results in an increase in average hydrophobicity of the peptide–protein interface. Additionally, the hydrophobic staple shields a network of water molecules, kinetically stabilizing a water chain hydrogen‐bonded between the peptide and MDM2. These properties could result in a decrease in the energy barrier associated with dehydrating the peptide–protein interface, thereby regulating the kinetics of peptide binding. © 2015 Wiley Periodicals, Inc.     

Co–Cu–La catalysts for selective CO2 hydrogenation to higher hydrocarbons

Copper and lanthanum promoted cobalt catalysts for CO₂ hydrogenation to higher hydrocarbons are described. The catalysts were prepared by the self-propagating high-temperature synthesis followed by alkaline leaching. They are active in CO₂ hydrogenation at 200 °C under 10 bar pressure (CO₂ : H₂ = 1 : 3) with selectivity to C₂₊ alkanes up to 39%; no alkenes and alcohols are formed under these experimental conditions.     

Vanadium nitrogenase: a two-hit wonder?

Nitrogenase catalyzes the biological conversion of atmospheric dinitrogen to bioavailable ammonia. The molybdenum (Mo)- and vanadium (V)-dependent nitrogenases are two homologous members of this metalloenzyme family. However, despite their similarities in structure and function, the characterization of V-nitrogenase has taken a much longer and more winding path than that of its Mo-counterpart. From the initial discovery of this nitrogen-fixing system, to the recent finding of its CO-reducing capacity, V-nitrogenase has proven to be a two-hit wonder in the over-a-century-long research of nitrogen fixation. This perspective provides a brief account of the catalytic function and structural basis of V-nitrogenase, as well as a short discussion of the theoretical and practical potentials of this unique metalloenzyme.     

How does the first water shell fold proteins so fast?

First shells of hydration and bulk solvent play a crucial role in the folding of proteins. Here, the role of water in the dynamics of proteins has been investigated using a theoretical protein-solvent model and a statistical physics approach. We formulate a hydration model where the hydrogen bonds between water molecules pertaining to the first shell of the protein conformation may be either mainly formed or broken. At thermal equilibrium, hydrogen bonds are formed at low temperature and are broken at high temperature. To explore the solvent effect, we follow the folding of a large sampling of protein chains, using a master-equation evolution. The dynamics shows a clear mechanism. Above the glass-transition temperature, a large ratio of chains fold very rapidly into the native structure irrespective of the temperature, following pathways of high transition rates through structures surrounded by the solvent with broken hydrogen bonds. Although these states have an infinitesimal probability, they act as strong dynamical attractors and fast folding proceeds along these routes rather than pathways with small transition rates between configurations of much higher equilibrium probabilities. At a given low temperature, a broad jump in the folding times is observed. Below this glass temperature, the pathways where hydrogen bonds are mainly formed become those of highest rates although with conformational changes of huge relaxation times. The present results reveal that folding obeys a double-funnel mechanism.     

How does dielectric solvation affect the size of an ion?

The effect of solvation by a continuum dielectric on the size of an ion is examined using electronic structure calculations. Various measures correlated with size are considered, including the root-mean-square radius of the electronic charge density, the amount of solute charge penetrating outside the cavity, the electronic radial distribution function, the nucleus-electron potential energy, and the electron-electron potential energy. Calculations are made on several representative ionic solutes, and it is found that every measure indicates that the application of a dielectric makes the cations larger and the anions smaller. These counterintuitive trends are examined, and a plausible explanation is offered for the observed behavior.     

How does a drug molecule find its target binding site?

Although the thermodynamic principles that control the binding of drug molecules to their protein targets are well understood, detailed experimental characterization of the process by which such binding occurs has proven challenging. We conducted relatively long, unguided molecular dynamics simulations in which a ligand (the cancer drug dasatinib or the kinase inhibitor PP1) was initially placed at a random location within a box that also contained a protein (Src kinase) to which that ligand was known to bind. In several of these simulations, the ligand correctly identified its target binding site, forming a complex virtually identical to the crystallographically determined bound structure. The simulated trajectories provide a continuous, atomic-level view of the entire binding process, revealing persistent and noteworthy intermediate conformations and shedding light on the role of water molecules. The technique we employed, which does not assume any prior knowledge of the binding site's location, may prove particularly useful in the development of allosteric inhibitors that target previously undiscovered binding sites.     

How does trimethylamine N-oxide counteract the denaturing activity of urea?

Trimethylamine N-oxide, TMAO, stabilizes globular proteins and is able to counteract the denaturing activity of urea. The mechanism of this counteraction has remained elusive up to now. A rationalization is proposed grounded on the same theoretical model used to clarify the origin of cold denaturation, and the denaturing activity of GdmCl versus the stabilizing one of Gdm(2)SO(4) [G. Graziano, Phys. Chem. Chem. Phys., 2010, 12, 14245-14252; G. Graziano, Phys. Chem. Chem. Phys., 2011, 13, 12008-12014]. The fundamental quantities are: (a) the difference in the solvent-excluded volume on passing from the N-state to the D-state, calculated in water and in aqueous osmolyte solution; (b) the difference in energetic attractions of the N-state and the D-state with the surrounding solvent molecules, calculated in water and in aqueous osmolyte solution. In aqueous 8 M urea + 4 M TMAO solution, the first quantity is so large and positive to counteract the second one that is large and negative due to preferential binding of urea molecules to the protein surface. This happens because aqueous 8 M urea + 4 M TMAO solution has a volume packing density markedly larger than that of water, rendering the cavity creation process much more costly. The volume packing density increase reflects the strength of the attractions of water molecules with both urea and TMAO molecules. This mechanism readily explains why TMAO counteraction is operative even though urea molecules are preferentially located on the protein surface.     

How does water-nanotube interaction influence water flow through the nanochannel?

Water permeation across various nitrogen-doped double-walled carbon nanotubes (N-DWCNT) has been studied with molecular dynamics simulations to better understand the influence of water-nanopore interaction on the water permeation rate. There exists a threshold interaction energy at around -34.1 kJ/mol. Over the threshold energy, the water flow through N-DWCNT decreases monotonically with the strengthening of the water-nanotube interaction. The effect on the water flow across the channel is found to be negligible when the interaction energy is weaker than the threshold. The water-nanotube interaction energy can be controlled by doping nitrogen atoms into the nanotube walls. Although the van der Waals interaction energy is much stronger than the electrostatic interaction energy, it is less sensitive to the proportion of doped nitrogen atoms. On the other hand, the electrostatic interaction energy weakens after the initial strengthening when the percentage of doped nitrogen atoms increases to ~25%. The doped nitrogen atoms make less influence on the overall electrostatic interaction energy when the proportion is over 25%, due to the repulsions among themselves. Thus, the monotonous strengthening of the van der Waals interaction energy seems to dominate the overall trend of the total interaction energy, whereas the change of the long-range electrostatic interaction energy characterizes the shape of the correlation curve, as the percentage of doped nitrogen atoms increases.     

How does column packing microstructure affect column efficiency in liquid chromatography?

Full three-dimensional computer simulations of the fluid flow and dispersion characteristics of model nonporous chromatographic packings are reported. Interstitial porosity and packing defects are varied in an attempt to understand the chromatographic consequences of the packing microstructure. The tracer zone dispersion is calculated in the form of plate height as a function of fluid velocity for seven model particle packs where particles are selectively removed from the packs in clusters of varying size and topology. In an attempt to examine the consequences of loose but random packs, the velocities and zone dispersion of seven defect-free packs are simulated over the range 0.36< or =epsilon< or =0.50, where epsilon is the interstitial porosity. The results indicate that defect-free loose packings can give good chromatographic efficiency but the efficiency can vary depending on subtle details of the pack. When the defect population increases, the zone dispersion increases accordingly. For a particle pack where 6% of the particles are removed from an epsilon=0.36 pack, approximately 33% of the column efficiency is lost. These results show that it is far more important in column packing to prevent defect sites leading to inhomogeneous packing rather than obtaining the highest density pack with the smallest interstitial void volume.     

How does tack depend on time of contact and contact pressure?

The tack of polymer melts on rigid substrates under conditions of short contact times and low pressures is examined. The substrate is modeled as a random rough surface with a distribution of asperities heights. The true contact area between the adhesive and the substrate is calculated for a given total load and elastic modulus of the substrate. The dependence of tack on contact time is accounted for by introducing the relaxation of the adhesive through a time-dependent elastic modulus. For relatively high pressures the tack is predicted to scale with 1/E so that for short contact times, t_c, the tack is predicted to scale with (t_c/τ_e)^1/2, where τ_e is the entanglement time. For lower pressures this simple scaling law is no longer valid and we predict a complex variation of tack with contact time and molecular parameters. © 1996 John Wiley & Sons, Inc.     

How does the synthesis temperature impact hybrid organic-inorganic molybdate material design?

We investigate the reactivity of MoO(4)(2-) toward six organoammonium cations (+)(Me(3-x)H(x)N)(CH(2))(2)(NH(y)Me(3-y))(+) (x, y = 1-3) at different synthesis temperatures ranging from 70 to 180 °C. A total of 16 hybrid organic-inorganic materials have been synthesized at an initial pH of 2, via ambient pressure and hydrothermal routes, namely, (H(2)en)[Mo(3)O(10)]·H(2)O (1), (H(2)en)[Mo(3)O(10)] (2), (H(2)en)[Mo(5)O(16)] (3), (H(2)MED)(2)[Mo(8)O(26)]·2H(2)O (4), (H(2)MED)[Mo(5)O(16)] (5), (N,N-H(2)DMED)(2)[Mo(8)O(26)]·2H(2)O (6), (N,N-H(2)DMED)(2)[Mo(8)O(26)]·2H(2)O (7), (N,N'-H(2)DMED)(2)[Mo(8)O(26)] (8), (N,N'-H(2)DMED)[Mo(5)O(16)] (9), (H(2)TriMED)(2)[Mo(8)O(26)]·4H(2)O (10), (H(2)TriMED)(2)[Mo(8)O(26)]·2H(2)O (11), (H(2)TriMED)[Mo(7)O(22)] (12), (H(2)TMED)(2)[Mo(8)O(26)]·2H(2)O (13), (H(2)TMED)(2)[Mo(8)O(26)] (14), (H(2)TMED)(2)[Mo(8)O(26)] (15), and (H(2)TMED)[Mo(7)O(22)] (16). All of these compounds contain different polyoxomolybdate (Mo-POM) blocks, i.e., discrete β-[Mo(8)O(26)](4-) blocks in 6, 10, 13, 14, (1)/(∞)[Mo(3)O(10)](2-), and (1)/(∞)[Mo(8)O(26)](4-) polymeric chains in 1, 2, 4, 7, 8, and 15, respectively, and (2)/(∞)[Mo(5)O(16)](2-) and (2)/(∞)[Mo(7)O(22)](2-) layers in 3, 5, 9, 12, and 16, respectively. The structures of 5, 9, and 14 have been resolved by single-crystal X-ray analyses. The characterization of the different Mo-POM blocks in 1-16 by Fourier transform Raman spectroscopy is reported. The impact of the synthesis temperature on both the composition and topology of the Mo-POM blocks is highlighted.     

How does surface modification aid in the dispersion of carbon nanofibers?

Small-angle light scattering is used to assess the dispersion behavior of vapor-grown carbon nanofibers suspended in water. These data provide the first insights into the mechanism by which surface treatment promotes dispersion. Both acid-treated and untreated nanofibers exhibit hierarchical morphology consisting of small-scale aggregates (small bundles) that agglomerate to form fractal clusters that eventually precipitate. Although the morphology of the aggregates and agglomerates is nearly independent of surface treatment, their time evolution is quite different. The time evolution of the small-scale bundles is studied by extracting the size distribution from the angle-dependence of the scattered intensity, using the maximum entropy method in conjunction with a simplified tube form factor. The bundles consist of multiple tubes possibly aggregated side-by-side. Acid oxidation has little effect on this bundle morphology. Rather acid treatment inhibits agglomeration of the bundles. The time evolution of agglomeration is followed by fitting the scattering data to a generalized fractal model. Agglomerates appear immediately after cessation of sonication for untreated fibers but only after hours for treated fibers. Eventually, however, both systems precipitate.