Understanding alkali metal cation affinities of multi-layer guanine quadruplex DNA.

To gain better understanding of the stabilizing interactions between metal ions and DNA quadruplexes, dispersion-corrected density functional theory (DFT-D) based calculations were performed on double-, triple- and four-layer guanine tetrads interacting with alkali metal cations. All computations were performed in aqueous solution that mimics artificial supramolecular conditions where guanine bases assemble into stacked quartets as well as biological environments in which telomeric quadruplexes are formed. To facilitate the computations on these significant larger systems, optimization of the DFT description was performed first by evaluating the performance of partial reduced basis sets. Analysis of the stabilizing interactions between alkali cations and the DNA bases in double and triple-layer guanine quadruplex DNA reproduced the experimental affinity trend of the order Li+< Rb+ < Na+ < K+. The desolvation and the size of alkali metal cations are thought to be responsible for the order of affinity. Nevertheless, for the alkali metal cation species individually, the magnitude of the bond energy stays equal for binding as first, second or third cation in double, triple and four-layer guanine quadruplexes, respectively. This is the result of an interplay between a decreasingly stabilizing interaction energy and increasingly stabilizing solvation effects, along the consecutive binding events. This diminished interaction energy is the result of destabilizing electrostatic repulsion between the hosted alkali metal cations. This work emphasizes the stabilizing effect of aqueous solvent on large highly charged biomolecules.

The role of alkali metal cations in the stabilization of guanine quadruplexes: why K(+) is the best.

The alkali metal ion affinity of guanine quadruplexes has been studied using dispersion-corrected density functional theory (DFT-D). We have done computational investigations in aqueous solution that mimics artificial supramolecular conditions where guanine bases assemble into stacked quartets as well as biological environments in which telomeric quadruplexes are formed. In both cases, an alkali metal cation is needed to assist self-assembly. Our quantum chemical computations on these supramolecular systems are able to reproduce the experimental order of affinity of the guanine quadruplexes for the cations Li(+), Na(+), K(+), Rb(+), and Cs(+). The strongest binding is computed between the potassium cation and the quadruplex as it occurs in nature. The desolvation and the size of alkali metal cations are thought to be responsible for the order of affinity. Until now, the relative importance of these two factors has remained unclear and debated. By assessing the quantum chemical 'size' of the cation, determining the amount of deformation of the quadruplex needed to accommodate the cation and through the energy decomposition analysis (EDA) of the interaction energy between the cation and the guanines, we reveal that the desolvation and size of the alkali metal cation are both almost equally responsible for the order of affinity.

How amino and nitro substituents direct electrophilic aromatic substitution in benzene: an explanation with Kohn-Sham molecular orbital theory and Voronoi deformation density analysis.

The substituent effect of the amino and nitro groups on the electronic system of benzene has been investigated quantum chemically using quantitative Kohn-Sham molecular orbital theory and a corresponding energy decomposition analysis (EDA). The directionality of electrophilic substitution in aniline can accurately be explained with the amount of contribution of the 2pz orbitals on the unsubstituted carbon atoms to the highest occupied π orbital. For nitrobenzene, the molecular π orbitals cannot explain the regioselectivity of electrophilic substitution as there are two almost degenerate π orbitals with nearly the same 2pz contributions on the unsubstituted carbon atoms. The Voronoi deformation density analysis has been applied to aniline and nitrobenzene to obtain an insight into the charge rearrangements due to the substituent. This analysis method identified the orbitals involved in the C-N bond formation of the π system as the cause for the π charge accumulation at the ortho and para positions in the case of the NH2 group and the largest charge depletion at these same positions for the NO2 substituent. Furthermore, we showed that it is the repulsive interaction between the πHOMO of the phenyl radical and the πHOMO of the NH2 radical that is responsible for pushing up the πHOMO of aniline and therefore activating this π orbital of the phenyl ring towards electrophilic substitution.

The Role of Aromaticity, Hybridization, Electrostatics, and Covalency in Resonance-Assisted Hydrogen Bonds of Adenine-Thymine (AT) Base Pairs and Their Mimics.

Hydrogen bonds play a crucial role in many biochemical processes and in supramolecular chemistry. In this study, we show quantum chemically that neither aromaticity nor other forms of π assistance are responsible for the enhanced stability of the hydrogen bonds in adenine-thymine (AT) DNA base pairs. This follows from extensive bonding analyses of AT and smaller analogs thereof, based on dispersion-corrected density functional theory (DFT). Removing the aromatic rings of either A or T has no effect on the Watson-Crick bond strength. Only when the smaller mimics become saturated, that is, when the hydrogen-bond acceptor and donor groups go from sp (2) to sp (3), does the stability of the resulting model complexes suddenly drop. Bonding analyses based on quantitative Kohn-Sham molecular orbital theory and corresponding energy decomposition analyses (EDA) show that the stronger hydrogen bonds in the unsaturated model complexes and in AT stem from stronger electrostatic interactions as well as enhanced donor-acceptor interactions in the σ-electron system, with the covalency being responsible for shortening the hydrogen bonds in these dimers.

Charge Transfer and Environment Effects Responsible for Characteristics of DNA Base Pairing.

A hitherto unresolved discrepancy between theory and experiment is unraveled. Charge transfer and the influence of the environment in the crystal are vital for understanding the nature and for reproducing the structure of hydrogen bonds in DNA base pairs. The introduction of water molecules and a sodium counterion into the theoretical model (see picture) deforms the geometry of AT and GC in such a way that excellent agreement with the experimental structures is obtained.

Synthesis and structural characterisation of neutral pentacoordinate silicon(IV) complexes with a tridentate dianionic N,N,S chelate ligand.

A series of novel neutral pentacoordinate silicon(IV) complexes with SiClSN(2)C, SiBrSN(2)C, SiSN(3)C, SiSON(2)C, SiS(2)N(2)C, SiSeSN(2)C and SiTeSN(2)C skeletons (compounds 1-12) was synthesised, starting from PhSiCl(3), PhSiBr(3), PhSi(NCO)(3), MeSiCl(3) or C(6)F(5)SiCl(3). Compounds 1-12 contain (i) a tridentate dianionic N,N,S chelate ligand (derived from 2-{[(pyridin-2-yl)methyl]amino}benzenethiol), (ii) a phenyl, methyl or pentafluorophenyl group and (iii) a monodentate monoanionic ligand (Cl, Br, NCO, NCS, N(3), OS(O)(2)CF(3), OPh, SPh, SePh, TePh). The pentacoordinate silicon(iv) complexes 1-12 were characterised by elemental analyses, NMR spectroscopic studies in the solid state and in solution and crystal structure analyses. These experimental investigations were complemented by computational studies.

Adenine tautomers: relative stabilities, ionization energies, and mismatch with cytosine.

In this study, we have investigated 12 tautomers of the DNA base adenine at the BP86/TZ2P and BP86/QZ4P levels of density functional theory. The vertical and adiabatic ionization energies of all tautomers were determined as the difference in energy between the radical cation and the corresponding neutral system. Furthermore, an evaluation is made for the eigenvalue spectra calculated with the SAOP functional, which is shown to lead to substantial improvements for orbital energies compared to BP86. We have also explored the correlations between the Kohn-Sham orbitals of the different tautomers at the BP86/QZ4P and SAOP/QZ4P levels. Finally, we discuss implications of the existence of the tautomeric forms of adenine for the DNA replication.

Extension of a predictive substrate model for human cytochrome P4502D6.

1. Metoprolol, indoramine, codeine, tamoxifen and prodipine, compounds which are clinically used, and MDMA (ecstasy) were fitted in a small molecule model for substrates of human cytochrome P4502D6. 2. For both the R- and S-enantiomer of metoprolol, the R- and S-enantiomer of MDMA, and for indoramine and codeine (all proven substrates of cytochrome P4502D6) an acceptable fit in the substrate model was obtained. 3. For tamoxifen, for which the involvement of cytochrome P4502D6 in the 4-hydroxylation is uncertain, no acceptable fit could be obtained in the substrate model. 4. For prodipine, a competitive inhibitor of P4502D6, for which the involvement of P4502D6 in the metabolism is uncertain, no acceptable fit in the substrate model could be obtained. 5. The substrate model was extended in a direction in which two large known substrates extend from the original substrate model. This extension did not change the flat hydrophobic region of the original substrate model.