Diastereoselective Additions of Allylmagnesium Reagents to α-Substituted Ketones When Stereochemical Models Cannot Be Used.

The stereoselectivities of reactions of allylmagnesium reagents with chiral ketones cannot be easily explained by stereochemical models. Competition experiments indicate that the complexation step is not reversible, so nucleophiles cannot access the widest range of possible encounter complexes and therefore cannot be analyzed easily using available models. Nevertheless, additions of allylmagnesium reagents to a ketone can still be stereoselective provided that the carbonyl group adopts a conformation that leads to one face being completely blocked from the approach of the allylmagnesium reagent.

The influence of external electric fields on proton transfer tautomerism in the guanine-cytosine base pair.

The Watson-Crick base pair proton transfer tautomers would be widely considered as a source of spontaneous mutations in DNA replication if not for their short lifetimes and thermodynamic instability. This work investigates the effects external electric fields have on the stability of the guanine-cytosine proton transfer tautomers within a realistic strand of aqueous DNA using a combination of ensemble-based classical molecular dynamics (MD) coupled to quantum mechanics/molecular mechanics (QM/MM). Performing an ensemble of calculations accounts for the stochastic aspects of the simulations while allowing for easier identification of systematic errors. The methodology applied in this work has previously been shown to estimate base pair proton transfer rate coefficients that are in good agreement with recent experimental data. A range of electric fields in the order of 104 to 109 V m-1 is investigated based on their real-life medicinal applications which include gene therapy and cancer treatments. The MD trajectories confirm that electric fields up to 1.00 × 109 V m-1 have a negligible influence on the structure of the base pairs within DNA. The QM/MM results show that the application of large external electric fields (1.00 × 109 V m-1) parallel to the hydrogen bonds increases the thermodynamic population of the tautomers by up to one order of magnitude; moreover, the lifetimes of the tautomers remain insignificant when compared to the timescale of DNA replication.

Adenine-thymine tautomerization under the influence of strong homogeneous electric fields.

The effect of strong electric fields on the tautomerization of the adenine-thymine (AT) base pair in DNA is explored using density functional theory. It was found that the AT base pair is not likely to undergo a double proton transfer reaction even in the presence of electric fields ranging from 5.14 × 108 to 5.14 × 109 V m-1. This conclusion holds true in Gibbs energies computed at 25 °C or 37 °C. Energy correction terms to the electronic energy, such as total internal energy, Gibbs energy, zero-point energy, enthalpy and entropy corrections, were investigated in detail to pinpoint the major contributors to the low probability of the AT tautomerization. It was found that the entropy corrections are the least significant, while zero-point energy and Gibbs energy corrections can be large enough to thermodynamically inhibit the DPT in AT.

A review on point mutations via proton transfer in DNA base pairs in the absence and presence of electric fields.

This is a comprehensive review that focuses on spontaneous mutations that may occur during DNA replication, the fundamental process responsible for transferring genetic information. In 1963, Löwdin postulated that these mutations are primarily a result of proton transfer reactions within the hydrogen-bonded DNA base pairs. The single and double proton transfer reactions within the base pairs result in zwitterions and rare tautomers, respectively. For persistent mutations, these products must be generated at high rates and should be thermodynamically stable. This review covers the proton transfer reactions studied experimentally and computationally. The review also examines the influence of externally applied electric fields on the thermodynamics and kinetics of proton transfer reactions within DNA base pairs, and their biological implications.

Average Electron Density: A Quantitative Tool for Evaluating Non-Classical Bioisosteres of Amides.

Bioisosterism is strategically used in drug design to enhance the pharmacokinetic and pharmacodynamic properties of therapeutic molecules. The average electron density (AED) tool has been used in several studies to quantify similarities among nonclassical bioisosteres of carboxylic acid. In this study, the AED tool is used to quantify the similarities among nonclassical bioisosteres of an amide group. In particular, amide-to-1,2,3-triazole bioisosterism is considered. To evaluate the AED differences exhibited by isomers of nonclassical bioisosteres, both isomers of amide (cis and trans) and 1,2,3-triazole (1,4 and 1,5 disubstituted moieity) were considered. The amide and 1,2,3-triazole bioisosteric moieties were capped with various R groups (R= methyl, hydrogen, and chloro) to account for changes in their environment. Amide-to-triazole bioisosteric substitutions were then explored in a more realistic environment, that is, within the FDA-approved anticancer imatinib drug. The AED tool effectively identified similarities between substantially different moieties, 1,2,3-triazole and amide, showing AED differences of no more than 4%. The AED tool was also proven to be useful in evaluating the contribution of various factors affecting triazole-amide bioisosterism including isomerism and changes in their environment. The AED values of each bioisostere were transferable within a maximum difference of 2.6%, irrespective of the change in environment. The 1,4- and 1,5-disubstituted isomers of 1,2,3-triazole have AED values that differ by less than unity, 0.52%. Similarly, the AED values of the cis- and trans-amide isomers differ by only 1.31%. Overall, the AED quantitative tool not only replicated experimental observations regarding similarities in bioisosteres, but also explained and quantified each contributing factor. This demonstrates the extended utility of the AED tool from nonclassical carboxylic acid bioisosteres to amide equivalents.On the contrary, electrostatic potential maps, usually used in the literature to qualitatively evaluate bioisosterism, were not similar for the 1,2,3-triazole and amide bioisosteres, under different environments. Overall, the AED tool proves to be powerful in quantitatively evaluating and predicting bioisosterism across diverse moieties considering structural and environmental variations, making it valuable in drug design.

Quantum and Classical Evaluations of Carboxylic Acid Bioisosteres: From Capped Moieties to a Drug Molecule.

Using the Quantum Theory of Atoms in Molecules, the average electron density (AED) tool was developed and employed to quantitatively evaluate the similarities between bioisosteric moieties in drug design. Bioisosteric replacements are valuable in drug molecules to fine-tune their pharmacokinetic and pharmacodynamic properties while maintaining their biological activity. This study was performed on non-classical bioisosteres of carboxylic acid. It was found that the AED of a given bioisostere is generally transferable, within less than 5% difference, irrespective of its environment. It was shown that the AED tool succeeds at depicting not only the similarities of bioisosteric groups but also at highlighting, as counter examples, the differences in non-bioisosteric groups. For the first time, the AED was used to evaluate bioisosterism in an FDA-approved drug molecule, furosemide, and in five analogues of this medicine. In one of the analogues, non-bioisosteric moieties were exchanged, and in four of the analogues, carboxylic acid was replaced with either furan or sulfonamide, and vice versa. It was also found that irrespective of the pH, the AED tool consistently reproduced experimental predictions. The distinct power of the AED tool in quantitatively and precisely measuring the similarity among bioisosteric groups is contrasted with the relatively ambiguous bioisosteric evaluations through the classical qualitative electrostatic potential (ESP) maps. The ESP maps were demonstrated to fail, even qualitatively, in depicting the similarities, in some cases.

Assessment of the PW86+PBE+XDM density functional on van der Waals complexes at non-equilibrium geometries.

The deficiency of conventional density-functional theory (DFT) in properly describing van der Waals (vdW) (especially dispersion-bound) complexes has been extensively addressed in the past decade. There are now several new methods published in the literature that are capable of accurately capturing weak dispersion interactions in complexes at equilibrium geometries. However, the performance of these new methods at non-equilibrium geometries remains to be assessed. We have previously published [F. O. Kannemann and A. D. Becke, J. Chem. Theory Comput. 6, 1081 (2010); A. D. Becke, A. A. Arabi, and F. O. Kannemann, Can. J. Chem. 88, 1057 (2010)] that the functional PW86+PBE+XDM for exchange + correlation + dispersion, respectively, is a highly accurate functional for general thermochemistry and vdW complexes at equilibrium geometries. Here, we show that this nonempirical, except for two parameters in the dispersion damping part, functional also performs well for vdW complexes at compressed and stretched intermonomer separations. The mean absolute relative error (MARE) is 9.4% overall for vdW complexes in the "S22×5" database incorporating compressed and stretched geometries [J. Rezac, K. E. Riley, and P. Hobza, J. Chem. Theory Comput. 7, 2427 (2011)]. Our largest MARE on the S22×5 database is 13.3% on the compressed geometry set.

Research performance of the GCC countries: A comparative analysis of quantity and quality.

Given the increased focus on scientific research in the Gulf Cooperation Council (GCC) countries, it is important to have a thorough bibliometric study about their research productivity and its progress over a long period of time. Using the world's largest bibliometric database (Scival/Scopus), we analyzed the research output of the GCC countries, from 1996 to 2020, in various disciplines. We considered raw metrics of quantity (number of articles) and quality (citations, citations/article, and Field-Weighted Citation Impact -FWCI), and then normalized them to population size, Gross Domestic Product (GDP), Gross Expenditure on Research and Development (GERD), and number of researchers. Over the past 25 years, the GCC countries have witnessed an increase in research productivity, with Saudi Arabia having the highest research output (ca. 38,000 articles for 2020) and Qatar having the highest fold growth (77.6-fold increase). The GCC countries had diverse research portfolios with varying growth over the years across almost all disciplines. When normalized to population size or GDP, growth rates were dampened for all GCC countries. The increased research output in the GCC was coupled with a high percentage of international collaborations and a reasonable increase in the quality of publications. While the research performance in the GCC countries has promisingly enhanced, it remains low compared to that of international countries (Switzerland, Singapore, and Canada) which have remarkable research productivity. Considering the GCC's economic standings and the potential for further growth, the GCC countries would need increased investment in scientific research and in human capital to be able to catch up with the highest international standards in research.

Effects of external electric fields on double proton transfer kinetics in the formic acid dimer.

Molecules can be exposed to strong local electric fields of the order of 10(8)-10(10) V m(-1) in the biological milieu. The effects of such fields on the rate constant (k) of a model reaction, the double-proton transfer reaction in the formic acid dimer (FAD), are investigated. The barrier heights and shapes are calculated in the absence and presence of several static homogenous external fields ranging from 5.14 × 10(8) to 5.14 × 10(9) V m(-1) using density functional theory (DFT/B3LYP) and second order Møller-Plesset perturbation theory (MP2) in conjunction with the 6-311++G(d,p) Pople basis set. Conventional transition state theory (CTST) followed by Wigner tunneling correction is then applied to estimate the rate constants at 25 °C. It is found that electric fields parallel to the long axis of the dimer (the line joining the two carbon atoms) lower the uncorrected barrier height, and hence increase the raw k. These fields also flatten the potential energy surface near the transition state region and, hence, decrease the multiplicative tunneling correction factor. The net result of these two opposing effects is that fields increase k(corrected) by a factor of ca. 3-4 (DFT-MP2, respectively) compared to the field-free k. Field strengths of ∼3 × 10(9) V m(-1) are found to be sufficient to double the tunneling-corrected double proton transfer rate constant at 25 °C. Field strengths of similar orders of magnitudes are encountered in the scanning tunneling microscope (STM), in the microenvironment of a DNA base-pair, in an enzyme active site, and in intense laser radiation fields. It is shown that the net (tunneling corrected) effect of the field on k can be closely fitted to an exponential relationship of the form k = aexp(bE), where a and b are constants and E the electric field strength.

Atomic and molecular properties of nonclassical bioisosteric replacements of the carboxylic acid group.

Aim: Drug design is fraught with challenges as small differences in the structure of a drug molecule can significantly affect its biological activity. Bioisosteres are interchangeably used to adjust pharmacokinetic and pharmacodynamic properties without affecting the biological activity of the drug. While electrostatic potential maps (EPMs) are typically used to show the similarity in the 'key and lock' interactions between a drug and its receptor, they are limited to qualitative comparisons. Methodology & results: Using the quantum theory of atoms in molecules, quantitative similarities among nonclassical bioisosteres of carboxylic acid were evaluated. Conclusion: The similarity in the bioisosteric groups was captured with the average electron density tool which generated remarkably close average electron densities regardless of the capping group, the isodensity values or the protonation state of the molecule. The similarities among bioisosteres was less obvious using the EPM tool.

Where is electronic energy stored in adenosine triphosphate?

The gas-phase electronic energy of the hydrolysis of methyl triphosphate, a model of adenosine 5'-triphosphate (ATP), is partitioned into local (atomic and group) contributions. A modified definition of Lipmann's "group transfer potential" is proposed on the basis of the partitioning of the total electronic energy into atomic contributions within the framework of the quantum theory of atoms in molecules (QTAIM). The group transfer potential is defined here as the sum of the atomic energies forming the group in ATP minus the sum of the energies of the same atoms in inorganic phosphate. It is found that the transfer potential of the terminal phosphate group in ATP is significantly reduced, from +241.7 to +73.1 kcal/mol, as a result of complexation with magnesium. This is accompanied by a concomitant change in the energy of reaction from -168.6 to -24.9 kcal/mol. Regions within ATP where the electronic energy changes the most upon hydrolysis are identified. The study is conducted at the DFT/B3LYP/6-31+G(d,p) level of theory.

Effects of Intense Electric Fields on the Double Proton Transfer in the Watson-Crick Guanine-Cytosine Base Pair.

The double proton transfer reaction in the guanine-cytosine (GC) base pair is studied, using density functional theory, to understand the chances of mutations under the effect of uniform electric fields in the order of 108 to 109 V m-1. On the basis of potential energy surfaces, reaction Gibbs energies, equilibrium constants, imaginary frequencies, forward and reverse barrier heights, tunneling-corrected rate constants, half-lives of the forward and reverse reactions, percent tautomerization, and Boltzmann distributions, it was found that fields ≥+3.60 × 109 V m-1 facilitate the mutation in the GC base pair and reduce the rectification of point mutations. Fields applied along the double proton transfer in the - x (defined in the C to G direction) direction favor the canonical over the rare tautomers. Tunneling-corrected rate constants of the forward reaction increase exponentially with stronger fields in the - x direction and follow a Gaussian curve for the reverse reaction.

Routes to drug design via bioisosterism of carboxyl and sulfonamide groups.

AIM: The similarity in the biological function of the bioisosteric pair, carboxyl and sulfonamide functional groups, is studied using the quantitative tool, average electron density of the bioisosteric moiety in drug molecules and the qualitative tool, electrostatic potential. Results/methodology: Five different capping groups (methyl, phenyl, chlorine, hydrogen and amine) were considered to investigate the effect of the environment on the properties of the bioisosteres. The molecules were considered in their neutral and anionic forms to account for the change in pH depending on the medium of the drug-receptor interactions. CONCLUSION: The new developed approach, average electron density, is not only advantageous as a qualitative descriptor, it is also more consistent compared with the conventionally accepted method, electrostatic potential, especially for the anions.

Distribution of heavy metals around the Barakah nuclear power plant in the United Arab Emirates.

Inductively coupled plasma emission spectroscopy was used to measure the concentrations of heavy metals in 58 samples collected from the Barakah nuclear power plant (BNPP) area, UAE. The grain size distribution was symmetric, but the samples ranged from fine to coarse sand. The inverse relationship between grain size and heavy metal contaminations was validated. The pre-operational average heavy metal contaminations around the BNPP were 0.03, 0.40, 1.2, 2.05, 1.66, 1.6, 5.9, 7.3, 7, 8.8, 60, and 2521 ppm for Cd, Mo, Co, Cu, Pb, As, Zn, Ni, V, Cr, Mn, and Fe, respectively. The spatial distribution was more compact in the south compared to the north, with less severe contaminations in the east and west. The negative geoaccumulation indices suggest an uncontaminated area, and the BNPP has minor enrichments. All concentrations were significantly below the safe limits set by the Dutch guidelines. The levels of heavy metals reported in the UAE were lower than levels reported in countries around the world.

Evaluating dispersion forces for optimization of van der Waals complexes using a non-empirical functional.

Modelling dispersion interactions with traditional density functional theory (DFT) is a challenge that has been extensively addressed in the past decade. The exchange-dipole moment (XDM), among others, is a non-empirical add-on dispersion correction model in DFT. The functional PW86+PBE+XDM for exchange, correlation and dispersion, respectively, compromises an accurate functional for thermochemistry and for van der Waals (vdW) complexes at equilibrium and non-equilibrium geometries. To use this functional in optimizing vdW complexes, rather than computing single point energies, it is necessary to evaluate accurate forces. The purpose of this paper is to validate that, along the potential energy surface, the distance at which the energy is minimum is commensurate with the distance at which the forces vanish to zero. This test was validated for 10 rare gas diatomic molecules using various integration grids and different convergence criteria. It was found that the use of either convergence criterion, 10-6 or 10-8, in Gaussian09, does not affect the accuracy of computed optimal distances and binding energies. An ultra-fine grid needs to be used when computing accurate energies using generalized gradient approximation functionals.This article is part of the themed issue 'Multiscale modelling at the physics-chemistry-biology interface'.

Electrostatic potentials and average electron densities of bioisosteres in methylsquarate and acetic acid.

BACKGROUND: The bioisosterism in -CO2H and -C4HO3 is exploited using the quantum theory of atoms in molecules and molecular electrostatic potentials (ESP). RESULTS & DISCUSSION: Bioisosteres in methylsquarate and acetic acid, in the neutral/anionic forms, have average electron densities that differ by less than 2% (i.e., ∼0.01 atomic units) while irrespective of the capping group. The topography of the ESP reveals similarities in the case of the neutral species but not in the anionic forms. CONCLUSION: The nonclassical bioisosteres in methylsquarate and acetic acid have average electron densities that are similar and relatively insensitive to the ionization state (neutral or anionic) or its studied capping group (H, CH3, Cl or phenyl). The ESP reveals similarities in the topography of neutral molecules.

Distribution of heavy metals in the coastal area of Abu Dhabi in the United Arab Emirates.

Fifty-seven sediment samples were collected from Abu Dhabi coastal area, United Arab Emirates (UAE). The concentrations of heavy metals including antimony, arsenic, barium, cadmium, cobalt, copper, mercury, lead, molybdenum, nickel and zinc were obtained using Inductively Coupled Plasma-Mass Spectroscopy (ICP-MS) and X-ray fluorescence. Heavy metal contaminations in Abu Dhabi had increased since 2004. Nevertheless, the enrichment factors, geoaccumulation indices and the pollution load index of 0.3 showed no pollution with any of the measured metals except arsenic.

Electron-density descriptors as predictors in quantitative structure--activity/property relationships and drug design.

The use of electron density-based molecular descriptors in drug research, particularly in quantitative structure--activity relationships/quantitative structure--property relationships studies, is reviewed. The exposition starts by a discussion of molecular similarity and transferability in terms of the underlying electron density, which leads to a qualitative introduction to the quantum theory of atoms in molecules (QTAIM). The starting point of QTAIM is the topological analysis of the molecular electron-density distributions to extract atomic and bond properties that characterize every atom and bond in the molecule. These atomic and bond properties have considerable potential as bases for the construction of robust quantitative structure--activity/property relationships models as shown by selected examples in this review. QTAIM is applicable to the electron density calculated from quantum-chemical calculations and/or that obtained from ultra-high resolution x-ray diffraction experiments followed by nonspherical refinement. Atomic and bond properties are introduced followed by examples of application of each of these two families of descriptors. The review ends with a study whereby the molecular electrostatic potential, uniquely determined by the density, is used in conjunction with atomic properties to elucidate the reasons for the biological similarity of bioisosteres.

The bioisosteric similarity of the tetrazole and carboxylate anions: clues from the topologies of the electrostatic potential and of the electron density.

There is a need for an a priori method with which to demonstrate the physical similarities between non-classical bioisosteres. In this study we explore the utility of the electron density and the electrostatic potential as the basis for a systematic investigation of the physical and chemical similarities between bioisosteres. The tetrazole and carboxylate bioisosteric pair is used as an illustrative example. It is shown that tetrazole and carboxylate anions give rise to electrostatic potentials (ESP) that exhibit a remarkable local similarity in the disposition of four coplanar local minima at positions consistent with lone pairs. The similarity of the disposition of these ESP minima generated by the two bioisosteres is in sharp contrast with their differences in the number and types of atoms, their nuclear geometrical arrangements, their total volumes, their partial charges, and their electron populations. The topology and geometrical disposition of these minima are shown to be independent of the capping group used in the model, and thus an inherent property of this bioisosteric pair. A model of the receptor region responsible for binding to either of these bioisosteres is proposed on the basis of an electrostatic "lock-and-key".

Atomic partitioning of the dissociation energy of the P-O(H) bond in hydrogen phosphate anion (HPO4(2-)): disentangling the effect of Mg2+.

This paper has three goals: (1) to provide a first step in understanding the atomic basis of the role of magnesium in facilitating the dissociation of the P-O bond in phosphorylated biochemical fuel molecules (such as ATP or GTP), (2) to compare second-order Møller-Plesset perturbation theory (MP2) results with those obtained at the more economical density functional theory (DFT) level for a future study of larger more realistic models of ATP/GTP, and (3) to examine the calculation of atomic total energies from atomic kinetic energies within a Kohn-Sham implemention of DFT, as compared to ab initio methods. A newly described method based on the quantum theory of atoms in molecules (QTAIM), which is termed the "atomic partitioning of the bond dissociation energy" (APBDE), is applied to a simple model of phosphorylated biological molecules (HPO42-). The APBDE approach is applied in the presence and in the absence of magnesium. It is found that the P-O(H) bond in the magnesium complex is shorter, exhibits a higher stretching frequency, and has a higher electron density at the bond critical point than in the magnesium-free hydrogen phosphate anion. Though these data would seem to suggest a stronger P-O(H) bond in the magnesium complex compared to the magnesium-free case, the homolytic breaking of the P-O(H) bond in the complex is found to be easier, i.e., has a lower BDE. This effect is the result of the balance of several atomic contributions to the BDE induced by the magnesium cation, which stabilizes the dissociation product more than it stabilizes the intact model molecule.