What does the future hold for top down mass spectrometry?

Mass spectrometry (MS) research has revolutionized modern biological and biomedical fields. At the heart of the majority of mass spectrometry experiments is the use of Bottom Up mass spectrometry methods where proteins are first proteolyzed into smaller fragments before MS interrogation. The advent of electron capture dissociation and, more recently, electron-transfer dissociation, however, has allowed Top Down (analysis of intact proteins) or middle down (analysis of large polypeptides) mass spectrometry to both experience large increases in development, growth, and overall usage. Nevertheless, for high-throughput large-scale proteomic studies, Bottom Up mass spectrometry has easily dominated the field. As Top Down mass spectrometry methodology and technology continue to develop, will it genuinely be able to compete with Bottom Up mass spectrometry for whole proteome analysis? Discussed here are the current approaches, applications, issues, and future view of high-throughput Top Down mass spectrometry.     

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.     

What does an ionic liquid surface really look like? Unprecedented details from molecular simulations

We present the first intrinsic analysis of the surface of the [bmim][PF(6)] room-temperature ionic liquid. Our detailed analysis reveals unprecedented details about the structure of the interface by providing the relative prevalence of different molecular orientations. These results suggest that experimental data should be reinterpreted considering a distribution of molecular arrangements.     

Metal bioavailability: how does its significance change in the time?

The significance of terms "metal bioavailability" and "bioavailable metal fraction" is evolved in the time, passing from a very simple concept to a complex concept bound to abiotic and biotic aspects. At the beginning metal toxicity was related to metal fraction present in water phase, than only free metal ion activity was considered and the free ion activity model (FIAM) was proposed. Successively, due to the exceptions observed and to the consciousness that metal bioavailability could be considered as dynamic characteristic the concept of metal bioavailability became very complex, depending on physical, chemical and biological factors.     

Synthesis of α‐Hydroxy Ketones from Terpene Aldehydes

Abstract

Unsymmetrically substituted α‐hydroxy ketones possessing isoprenoid units within the molecule were synthesised from commercially available terpene aldehydes. The synthesis was applicable to α,β‐unsaturated aldehydes and afforded the respective α‐hydroxy‐methyl ketones in overall good yield. Tautomerisation of these products did not occur under the conditions of reaction but was observed upon heating. Diastereoisomeric α‐hydroxy ketones have been resolved, and X‐ray analysis on one of these analogues allowed for the elucidation of the stereochemistry after conversion into its camphanate ester.     

1,3-Dipolar reactions involving corannulene: how does its rim and spoke addition vary?

[reaction: see text] Corannulene undergoes 1,3-dipolar reactions with the dipoles, diazomethane, nitrile oxide, and nitrone through its rim and spoke pi bonds; the rim addition yields "one possible" adduct whereas two "regioselective" adducts are formed by spoke addition. Mechanisms of these reactions have been investigated at the B3LYP/6-31G(d) level. Computations show that both rim and spoke additions prefer concerted pathways that lie 2-5 kcal/mol lower in energy than stepwise paths. Stepwise additions can take place in two ways and the activation energies of these two modes differ by 1-2 kcal/mol. A close inspection of the energy profiles reveals that rim addition is more favorable kinetically and thermodynamically than spoke addition in view of lower activation energy and higher exothermicity observed for rim addition. The rim bond of corannulene is more flexible for distortion and also has a stronger double bond (i.e. pi-character) than the spoke bond and this facilitates rim addition over spoke addition. Deformation energy analysis also confirms the above through higher deformation in corannulene from the spoke addition when compared to rim addition. In the spoke addition, regio1 reaction is kinetically more favored than regio2 reaction. Attempts to react corannulene in an endohedral fashion have led to the exohedral adduct. Computed activation energies suggest that corannulene acts as a deactivated dipolarophile compared to ethylene. Even more striking is the observation that rim and spoke double bonds in corannulene are part of the local aromatic system but it shows remarkable reactivity compared to benzene despite the loss of aromaticity during the reaction. This is well indicated by computed NICS values. Inclusion of acetonitrile as solvent through the PCM model increases the reaction rate and exothermicity.     

The life of an anise-flavored alcoholic beverage: does its stability cloud or confirm theory?

The well-known alcoholic beverage Pastis becomes turbid when mixed with water due to the poor solubility of trans-anethol, the anise-flavored component of Pastis in the water solution formed. This destabilization appears as the formation of micrometer-sized droplets that only very slowly grow in size, thus expanding the life of the anise-flavored beverage. The slow growth has been attributed to an extremely low interfacial tension of the droplets. Fitting experimental droplet growth rates to an Ostwald ripening model, interfacial tensions were deduced in the past. Direct determination of the interfacial tensions was not yet reported on these systems. We have measured the interfacial tensions and used these data to predict droplet growth rates using an Ostwald ripening model and a model for creaming of the droplets. The interfacial tension was measured to be about 11 mN/m for a 30/70 w/w % ethanol/water mixture, and it decreases slightly to a value of 1.4 mN/m in the case of a 70/30 w/w % ethanol/water mixture. These values are not as low as those deduced in the past. The theoretical predictions for both the Ostwald ripening rates and the creaming rates, using the directly measured interfacial tensions, are found to contradict with the experimental results on Ostwald ripening and creaming. While the experiments on Ostwald ripening show an increase in stability with increasing ethanol concentration, the results based on our interfacial tension measurements in combination with the same Ostwald ripening model show a decrease in stability with an increase in ethanol concentration. Further research is needed to understand fully which parameters play a role in both droplet growth and the stability of these three-component emulsions to elucidate the current discrepancy between model and experiment. This could be useful for a better control of "spontaneous emulsification" processes.     

What does polycondensation mean?

This contribution has the function of an introduction to the entire volume. It deals with several fundamental definitions and classifications related to the chemistry of polycondensation processes, and it includes modifications of the classical theory of step-growth polymerizations.     

Aptasensors – the future of biosensing?

Aptamers are artificial nucleic acid ligands that can be generated against amino acids, drugs, proteins and other molecules. They are isolated from combinatorial libraries of synthetic nucleic acid by an iterative process of adsorption, recovery and reamplification. Aptamers, first reported in 1990, are attracting interest in the areas of therapeutics and diagnostics and offer themselves as ideal candidates for use as biocomponents in biosensors (aptasensors), possessing many advantages over state of the art affinity sensors. The properties of aptamers, their applicability to biosensor technology, current research and future prospects are addressed in this short review.     

A future for nuclear analytical techniques? Why not?

The choices of universities and national research institutions in supporting scientific research are increasingly justified on the basis of, amongst others, the relevance that has to be reflected by external, preferably sustainable funding of the research programs. Many traditional fields of application such as environmental sciences do not offer a promising outlook in this respect. As a consequence, university research reactors face closure because of reallocations of university funds to more contemporary sciences such as molecular biology and nanotechnology. Therefore, laboratories operating nuclear analytical techniques (NAA, (TR)XRF, and PIXE) need to use their creativity in finding ways for participation in, for example, nanotechnology, cancer research, or genomics. This requires an open mind in terms of the opportunities, strengths, and weaknesses of the techniques, and a departure of technique-oriented research towards problem-oriented research in which other nuclear techniques can be used. The unique features of radiotracers, nuclear imaging, and nuclear beam techniques are discussed in view of the new areas mentioned above. Some examples of opportunities for nuclear analytical techniques in the above-mentioned fields are given.     

What does shape a topological atom?

In this pedagogical communication after demonstrating the legitimacy for using the quantum theory of atoms in molecules (QTAIM) to non-Coulombic systems, Hookean H₂ ⁺/H₃ ²⁺ species are used for AIM analysis. In these systems, in contrast to their Coulombic counterparts, electron density is atom-like and instead of expected two/three topological atoms, just a single topological atom emerges. This observation is used to demonstrate that what is really “seen” by the topological analysis of electron densities is the clustering of electrons. The very trait of monotonic decay of electron density around the “centers” of clustering guarantees the appearance of topological atoms as basin of attraction of the gradient vector field of the electron density. Although observations with Hookean molecules may seem disappointing at first glance, a careful reasoning points to the fact that the QTAIM methodology is extendable to novel domains, by a knowledge of the morphology of underlying densities, beyond the typical Coulombic systems.     

Targeted alpha-therapy: past, present, future?

Monoclonal antibodies have become a viable strategy for the delivery of therapeutic, particle emitting radionuclides specifically to tumor cells to either augment anti-tumor action of the native antibodies or to solely take advantage of their action as targeting vectors. Proper and rational selection of radionuclide and antibody combinations is critical to making radioimmunotherapy (RIT) a standard therapeutic modality due to the fundamental and significant differences in the emission of either alpha- and beta-particles. The alpha-particle has a short path length (50-80 microm) that is characterized by high linear energy transfer (100 keV microm(-1)). Actively targeted alpha-therapy potentially offers a more specific tumor cell killing action with less collateral damage to the surrounding normal tissues than beta-emitters. These properties make targeted alpha-therapy an appropriate therapy to eliminate minimal residual or micrometastatic disease. RIT using alpha-emitters such as (213)Bi, (211)At, (225)Ac, and others has demonstrated significant activity in both in vitro and in vivo model systems. Limited numbers of clinical trials have progressed to demonstrate safety, feasibility, and therapeutic activity of targeted alpha-therapy, despite having to traverse complex obstacles. Further advances may require more potent isotopes, additional sources and more efficient means of isotope production. Refinements in chelation and/or radiolabeling chemistry combined with rational improvements of isotope delivery, targeting vectors, molecular targets, and identification of appropriate clinical applications remain as active areas of research. Ultimately, randomized trials comparing targeted alpha-therapy combined with integration into existing standards of care treatment regimens will determine the clinical utility of this modality.     

Is there a future for sequential chemical extraction?

Since their introduction in the late 1970s, sequential extraction procedures have experienced a rapid increase in use. They are now applied for a large number of potentially toxic elements in a wide range of sample types. This review uses evidence from the literature to consider the usefulness and limitations of sequential extraction and thereby to assess its future role in environmental chemical analysis. It is not the intention to provide a comprehensive survey of all applications of sequential extractions or to consider the merits and disadvantages of individual schemes. These aspects have been covered adequately in other, recent reviews. This review focuses in particular on various key issues surrounding sequential extractions such as nomenclature, methodologies, presentation of data and interpretation of data, and discusses typical applications from the recent literature for which sequential extraction can provide useful and meaningful information. Also covered are emerging developments such as accelerated procedures using ultrasound- or microwave energy-assisted extractions, dynamic extractions, the use of chemometrics, the combination of sequential extraction with isotope analysis, and the extension of the approach to non-traditional analytes such as arsenic, mercury, selenium and radionuclides.     

Bidentate ligands by supramolecular chemistry--the future for catalysis?

In this Frontier Article we give our view on recent developments in transition-metal catalyst development that evolve from a combination of supramolecular strategies and traditional ligand design and development.