Where are the GaPs? A rational approach to monomer acquisition and selection

Gridding and partitioning (GaP) is a computational method for the classification and selection of monomers for combinatorial libraries. The molecules are described in terms of the pharmacophoric groups they contain and where those pharmacophoric groups can be located in three-dimensional space. The approach involves a detailed conformational analysis of each molecule. This conformational analysis is done within a common coordinate frame, thus enabling the monomers to be compared. The use of a partitioned space is central to this particular application as it facilitates the identification of regions of space which are not well represented by existing compounds. Several ways to extend the use of partitioned pharmacophore spaces are described. Applications of the approach in monomer acquisition and in library design are outlined.     

Where are ionic liquid strategies most suited in the pursuit of chemicals and energy from lignocellulosic biomass?

Certain ionic liquids have been shown to dissolve cellulose, other biopolymers, and even raw biomass under relatively mild conditions. This particular ability of some ionic liquids, accompanied by a series of concurrent advantages, enables the development of improved processing strategies for the manufacturing of a plethora of biopolymer-based advanced materials. The more recent discoveries of dissolution of lignocellulosic materials (e.g., wood) in ionic liquids, with at least partial separation of the major constituent biopolymers, suggest further paths towards the achievement of a truly sustainable chemical and energy economy based on the concept of a biorefinery which provides chemicals, materials, and energy. Nonetheless, questions remain about the use of ionic liquids and the advisability of introducing any new process which utilizes bulk synthetic chemicals which have to be made, disposed of, and prevented from entering the environment. In this article, we discuss our own journey from the discovery of the dissolution of cellulose in ionic liquids to the cusp of an enabling technology for a true biorefinery and consider some of the key questions which remain.     

Speciation and legislation – Where are we today and what do we need for tomorrow?

In international legislation concerning trace elements in food, in the environment or in occupational health most regulations are based on the total element contents, and are frequently given as maximum limits or guideline levels. In contrast, only few regulations pay attention to the molecular species in which the elements are bound. The international legislation concerning contaminants in food is presently being established in the Codex Alimentarius, which is an independent United Nations organisation under the joint FAO/WHO Food Standards Programme. Development of the Codex General Standard for Contaminants and Toxins in Food provides the framework for future international legislation on metals as contaminants in food. For certain food additives, which include some essential minerals, speciation is an integral part of the set of specification criteria, because only certain defined chemical compounds are permitted as sources of the essential element. The development of more species-specific analytical and toxicological data, and improved communication with legislators will be necessary before it will become possible to lay down species-specific regulations in all the cases where the specialised scientist will consider it reasonable.     

Emetine and the Alternative Splicing of Bcl-X: Where to next?

Interference with the alternative splicing of apoptotic factors offers an innovative and specific mechanism to target malignant cells. In this issue of Chemistry & Biology, Zhou et al. report on the regulation of the alternative splicing of Bcl-x pre-mRNA in response to emetine, a potent protein synthesis inhibitor, as well as define a major player in the signaling mechanism.     

Where are genes in paulingite? Mathematical principles of formation of inorganic materials on the atomic level

By means of the concept of universal optimum and general principles of inorganic gene, structures of paulingite-related zeolites and minerals have been constructed. The structures of zeolite Rho and paulingite are considered as members of zeolite family generated by the work of 4-colored cellular automaton (CA). The ideal symmetry of the members of the family is cubic, space group $Im \bar 3mBy means of the concept of universal optimum and general principles of inorganic gene, structures of paulingite-related zeolites and minerals have been constructed. The structures of zeolite Rho and paulingite are considered as members of zeolite family generated by the work of 4-colored cellular automaton (CA). The ideal symmetry of the members of the family is cubic, space group , a = 15 + 10n [?], where n is a number of the CA cycle (n = 0 for zeolite Rho and 2 for paulingite). A new hypothetical zeolite of the family with n = 1 is predicted and named ISC-1 (Institute of Silicate Chemistry-1); atomic coordinates and theoretical X-ray powder diffraction pattern have been calculated. It appears to be very probable that universal optimum contains all necessary information for its material realization (sharp configurations) and construction of materials with certain type of interaction potential (even with restrictions existing in theory for this potential).

V. Ya. ShevchenkoEmail:

     

Where is the road to bio-water-saving for the globe?

The First International Conference on the Theory and Practices in Bio-water-saving (ICTPB) was held from May 21 to 25, 2006 in Beijing, China. This indicated that the work related to this hot topic on the globe has been paid more attention to. Most progress in this field has been presented from near 300 participating people worldwide, who were meeting together to discuss about the theory and practices of water-saving biology and how to serve global agricultural and ecological sustainable development. The work related to bio-water-saving has been involved in different scales and soil–plant root biointerfaces. On the basis of this background and in combination with the work from our laboratory and the center, we provided some ideas for global bio-water-saving in this paper, sharing the achievement in this field and advocating true bio-water-saving for the world and promoting the pace of global bio-water-saving.     

What are the relative steric demands of carboxyl and methyl groups?

The relative steric demands of carboxyl and methyl groups are compared by contrasting the difference quantity H _f ^o (g, ArCOOH) — H _f ^o (g, ArCH₃) for a collection of alkylated benzoic acids and toluenes with the value for Ar=C₆H₅, the archetypical (i.e., unsubstituted) benzoic acid and toluene. We conclude that carboxyl and methyl groups are nearly the same size.     

How accurate are the nonlinear chemical Fokker-Planck and chemical Langevin equations?

The chemical Fokker-Planck equation and the corresponding chemical Langevin equation are commonly used approximations of the chemical master equation. These equations are derived from an uncontrolled, second-order truncation of the Kramers-Moyal expansion of the chemical master equation and hence their accuracy remains to be clarified. We use the system-size expansion to show that chemical Fokker-Planck estimates of the mean concentrations and of the variance of the concentration fluctuations about the mean are accurate to order Ω(-3∕2) for reaction systems which do not obey detailed balance and at least accurate to order Ω(-2) for systems obeying detailed balance, where Ω is the characteristic size of the system. Hence, the chemical Fokker-Planck equation turns out to be more accurate than the linear-noise approximation of the chemical master equation (the linear Fokker-Planck equation) which leads to mean concentration estimates accurate to order Ω(-1∕2) and variance estimates accurate to order Ω(-3∕2). This higher accuracy is particularly conspicuous for chemical systems realized in small volumes such as biochemical reactions inside cells. A formula is also obtained for the approximate size of the relative errors in the concentration and variance predictions of the chemical Fokker-Planck equation, where the relative error is defined as the difference between the predictions of the chemical Fokker-Planck equation and the master equation divided by the prediction of the master equation. For dimerization and enzyme-catalyzed reactions, the errors are typically less than few percent even when the steady-state is characterized by merely few tens of molecules.     

Thermal Plasma Technology: Where Do We Stand and Where Are We Going?

In this overview, an attempt is made to assess the present and future research and development in thermal plasma processing of materials restricted to (1) thermal plasma coating technologies, (2) thermal plasma synthesis of fine powders, (3) thermal plasma waste destruction, and (4) thermal plasma spheroidization and densification. Since thermal plasma processing is, in general, governed by a large number of parameters, implementation of controls becomes mandatory. The lack of sufficient controls combined with economic drawbacks in some cases has been the main obstacle for the growth of thermal plasma technology. Present R&D efforts, however, address these problems.     

Where Does the Electron Go? Stable and Metastable Peptide Cation Radicals Formed by Electron Transfer

Electron transfer to doubly and triply charged heptapeptide ions containing polar residues Arg, Lys, and Asp in combination with nonpolar Gly, Ala, and Pro or Leu generates stable and metastable charge-reduced ions, (M + 2H)^+●, in addition to standard electron-transfer dissociation (ETD) fragment ions. The metastable (M + 2H)^+● ions spontaneously dissociate upon resonant ejection from the linear ion trap, giving irregularly shaped peaks with offset m/z values. The fractions of stable and metastable (M + 2H)^+● ions and their mass shifts depend on the presence of Pro-4 and Leu-4 residues in the peptides, with the Pro-4 sequences giving larger fractions of the stable ions while showing smaller mass shifts for the metastables. Conversion of the Asp and C-terminal carboxyl groups to methyl esters further lowers the charge-reduced ion stability. Collisional activation and photodissociation at 355 nm of mass-selected (M + 2H)^+● results in different dissociations that give sequence specific MS³ spectra. With a single exception of charge-reduced (LKGLADR + 2H)^+●, the MS³ spectra do not produce ETD sequence fragments of the c and z type. Hence, these (M + 2H)^+● ions are covalent radicals, not ion–molecule complexes, undergoing dramatically different dissociations in the ground and excited electronic states. The increased stability of the Pro-4 containing (M + 2H)^+● ions is attributed to radicals formed by opening of the Pro ring and undergoing further stabilization by hydrogen atom migrations. UV–VIS photodissociation action spectroscopy and time-dependent density functional theory calculations are used in a case in point study of the stable (LKGPADR + 2H)^+● ion produced by ETD. In contrast to singly-reduced peptide ions, doubly reduced (M + 3H)⁺ ions are stable only when formed from the Pro-4 precursors and show all characteristics of even electron ions regarding no photon absorption at 355 nm or ion-molecule reactions, and exhibiting proton driven collision induced dissociations.

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Graphical Abstract ?

     

What are the Implications of Nonequilibrium in the O+OH and O+HO2 Reactions?

Vibrationally excited O2, OH, and HO2 species have been suggested (J. Phys. Chem. A 2004, 108, 758) to provide clues for explaining the "ozone deficit problem" and "HOx dilemma" in the middle atmosphere under conditions of local thermodynamic disequilibrium (LTD), but the question arises of how much LTD will affect the title ozone sink reactions. Besides providing novel kinetic results, it is shown that LTD tends to disfavor ozone depletion relative to traditional atmospheric modeling under Boltzmann equilibration, which is partly due to competition between the various reactive channels. The calculations also suggest that the title LTD processes can be important sources of highly vibrationally excited O2 in the middle atmosphere. Moreover, LTD is shown to offer an explanation for the fact that some down revision of the O + HO2 rate constant, or the ratio of the O + HO2 to O + OH rate constants, is required to improve agreement between the predictions of traditional modeling and observation. This, in turn, provides significant evidence supporting LTD at such altitudes.     

Paradigms and paradoxes: what are the 54 electron affinities of O2?

Only one electron affinity of oxygen, 43(1) kJ mol⁻¹ is generally cited since the molecular orbital theory anion bond order [3/4] gives an electron affinity, 14 kJ mol⁻¹. However, electron correlation rules predict 27 bonding and 27 antibonding spin orbital coupling states. The relative bond orders (RBOs), 12/13 to [1/4] and the 13 valence electrons of superoxide are used to calculate electron affinities 103 to −243 kJ mol⁻¹ consistent with experimental and theoretical values. These are used to construct 54 ionic Morse potentials.     

Where is the spin? Understanding electronic structure and g-tensors for ruthenium complexes with redox-active quinonoid ligands

Understanding the bonding in transition metal complexes with redox-active ligands is a major challenge, for example in redox catalysis or in bioinorganic chemistry. In this work, electronic g-tensors, spin-density distributions, and electronic structure have been studied by different density functional methods for an extended series of complexes [Ru(acac)2(L)]n (n = -1, 0, +1; L = redox-active o-quinonoid ligand). Comparison is made with experimental g-tensors and g-tensor-based oxidation-state assignments for a number of experimentally studied examples, using both gradient-corrected (BP86) and hybrid functionals (B3LYP, BHLYP) representing a range of exact-exchange admixtures. Reasonable, albeit not perfect, agreement with experimental g-tensors is obtained in one-component DFT calculations with hybrid functionals. Analyses of spin densities confirm the assignment of the cationic complexes as predominantly d5-Ru(III) with a neutral quinonoid ligand. However, this conclusion is obtained only after inclusion of the appreciable spin polarization of the unrestricted determinant, while the singly occupied molecular orbital (SOMO) is localized more on the acac ligands. The anionic complexes turn out to be approximately halfway between a d6-Ru(II)/semiquinone and a d5-Ru(III)/catecholate formulation, but again only after taking into account the extensive spin polarization. Even the previous assignment of the neutral parent systems as d5-Ru(III)/semiquinone is not accurate, as a d6-Ru(II)/quinone resonance structure contributes to some extent. Very unusual trends in the spin contamination of the Kohn-Sham determinant with increasing exact-exchange admixture in some of the cationic complexes have been traced to an interplay between spin delocalization and spin polarization.     

The reductionist paradox: are the laws of chemistry and physics sufficient for the discovery of new drugs?

Reductionism is alive and well in drug-discovery research. In that tradition, we continually improve experimental and computational methods for studying smaller and smaller aspects of biological systems. Although significant improvements continue to be made, are our efforts too narrowly focused? Suppose all error could be removed from these methods, would we then understand biological systems sufficiently well to design effective drugs? Currently, almost all drug research focuses on single targets. Should the process be expanded to include multiple targets? Recent efforts in this direction have lead to the emerging field of polypharmacology. This appears to be a move in the right direction, but how much polypharmacology is enough? As the complexity of the processes underlying polypharmacology increase will we be able to understand them and their inter-relationships? Is “new” mathematics unfamiliar in much of physics and chemistry research needed to accomplish this task? A number of these questions will be addressed in this paper, which focuses on issues and questions not answers to the drug-discovery conundrum.     

What are the practical limits for the specific surface area and capacitance of bulk sp~2 carbon materials?

The possible practical limits for the specific surface area and capacitance performance of bulk sp~2 carbon materials were investigated experimentally and theoretically using a variety of carbon materials. We find the limit for the specific surface area to be 3500–3700 m~2 g~(-1), and based on this, the corresponding best capacitance was predicted for various electrolyte systems. A model using an effective ionic diameter for the electrolyte ions was proposed and used to calculate the theoretical capacitance. A linear dependence of experimental capacitance versus effective specific surface area of various sp~2 carbon materials was obtained for all studied ionic liquid, organic and aqueous electrolyte systems. Furthermore, excellent agreement between the theoretical and experimental capacitance was observed for all the tested sp~2 carbon materials in these electrolyte systems, indicating that this model can be applied widely in the evaluation of various carbon materials for supercapacitors.     

Where does the electron go? Electron distribution and reactivity of peptide cation radicals formed by electron transfer in the gas phase

We report the first detailed analysis at correlated levels of ab initio theory of experimentally studied peptide cations undergoing charge reduction by collisional electron transfer and competitive dissociations by loss of H atoms, ammonia, and N-C alpha bond cleavage in the gas phase. Doubly protonated Gly-Lys, (GK + 2H) (2+), and Lys-Lys, (KK + 2H) (2+), are each calculated to exist as two major conformers in the gas phase. Electron transfer to conformers with an extended lysine chain triggers highly exothermic dissociation by loss of ammonia from the Gly residue, which occurs from the ground ( X ) electronic state of the cation radical. Loss of Lys ammonium H atoms is predicted to occur from the first excited ( A ) state of the charge-reduced ions. The X and A states are nearly degenerate and show extensive delocalization of unpaired electron density over spatially remote groups. This delocalization indicates that the captured electron cannot be assigned to reduce a particular charged group in the peptide cation and that superposition of remote local Rydberg-like orbitals plays a critical role in affecting the cation-radical reactivity. Electron attachment to ion conformers with carboxyl-solvated Lys ammonium groups results in spontaneous isomerization by proton-coupled electron transfer to the carboxyl group forming dihydroxymethyl radical intermediates. This directs the peptide dissociation toward NC alpha bond cleavage that can proceed by multiple mechanisms involving reversible proton migrations in the reactants or ion-molecule complexes. The experimentally observed formations of Lys z (+*) fragments from (GK + 2H) (2+) and Lys c (+) fragments from (KK + 2H) (2+) correlate with the product thermochemistry but are independent of charge distribution in the transition states for NC alpha bond cleavage. This emphasizes the role of ion-molecule complexes in affecting the charge distribution between backbone fragments produced upon electron transfer or capture.     

Mono- and Di-Fucosylated Glycans of the Parasitic Worm S. mansoni are Recognized Differently by the Innate Immune Receptor DC-SIGN

The parasitic worm, Schistosoma mansoni, expresses unusual fucosylated glycans in a stage-dependent manner that can be recognized by the human innate immune receptor DC-SIGN, thereby shaping host immune responses. We have developed a synthetic approach for mono- and bis-fucosylated LacdiNAc (LDN-F and LDN-DF, respectively), which are epitopes expressed on glycolipids and glycoproteins of S. mansoni. It is based on the use of monosaccharide building blocks having carefully selected amino-protecting groups, facilitating high yielding and stereoselective glycosylations. The molecular interaction between the synthetic glycans and DC-SIGN was studied by NMR and molecular modeling, which demonstrated that the α1,3-fucoside of LDN-F can coordinate with the Ca²⁺-ion of the canonical binding site of DC-SIGN allowing for additional interactions with the underlying LDN backbone. The 1,2-fucoside of LDN-DF can be complexed in a similar manner, however, in this binding mode GlcNAc and GalNAc of the LDN backbone are placed away from the protein surface resulting in a substantially lower binding affinity. Glycan microarray binding studies showed that the avidity and selectivity of binding is greatly enhanced when the glycans are presented multivalently, and in this format Le^x and LDN-F gave strong responsiveness, whereas no binding was detected for LDN-DF. The data indicates that S. mansoni has developed a strategy to avoid detection by DC-SIGN in a stage-dependent manner by the addition of a fucoside to a number of its ligands.