The effect of salt concentration on DNA conformation transition: a molecular-dynamics study

We performed three 3-ns molecular dynamics simulations of d(CGCGAATTCGCG)₂ using the AMBER 8 package to determine the effect of salt concentration on DNA conformational transitions. All the simulations were started with A-DNA, with different salt concentrations, and converged with B-DNA with similar conformational parameters. However, the dynamic processes of the three MD simulations were very different. We found that the conformation transition was slow in the solution with higher salt concentration. To determine the cause of this retardation, we performed three additional 1.5-ns simulations starting with B-DNA and with the salt concentrations corresponding to the simulations mentioned above. However, astonishingly, there was no delayed conformation evolution found in any of the three simulations. Thus, our simulation conclusion is that higher salt concentrations slows the A → B conformation transition, but have no effect on the final stable structure. Figure A-DNA and B-DNA. (a) is the canonical A-DNA, and (b) is the canonical B-DNA. Looking from the central major groove     

Aromaticity and electronic properties of Heterosuperbenzene (Heterohexabenzocoronene)

A global electrophilicity parameter and the aromaticity of some heterocyclic polyaromatic hydrocarbons were evaluated on the basis of DFT calculations. The substitution of carbon atoms by nitrogen atoms dramatically changes the global electrophilicity of the molecules, with the fully substituted molecule being the most electrophilic with a reactivity very close to that of fullerene. Figure Fully substituted heterohexabenzocoronene Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Electrostatic interactions play an essential role in DNA repair and cold-adaptation of Uracil DNA glycosylase

Life has adapted to most environments on earth, including low and high temperature niches. The increased catalytic efficiency and thermoliability observed for enzymes from organisms living in constantly cold regions when compared to their mesophilic and thermophilic cousins are poorly understood at the molecular level. Uracil DNA glycosylase (UNG) from cod (cUNG) catalyzes removal of uracil from DNA with an increased k_cat and reduced K_m relative to its warm-active human (hUNG) counterpart. Specific issues related to DNA repair and substrate binding/recognition (K_m) are here investigated by continuum electrostatics calculations, MD simulations and free energy calculations. Continuum electrostatic calculations reveal that cUNG has surface potentials that are more complementary to the DNA potential at and around the catalytic site when compared to hUNG, indicating improved substrate binding. Comparative MD simulations combined with free energy calculations using the molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) method show that large opposing energies are involved when forming the enzyme-substrate complexes. Furthermore, the binding free energies obtained reveal that the Michaelis-Menten complex is more stable for cUNG, primarily due to enhanced electrostatic properties, suggesting that energetic fine-tuning of electrostatics can be utilized for enzymatic temperature adaptation. Energy decomposition pinpoints the residual determinants responsible for this adaptation. Figure Electrostatic isosurfaces of cod uracil DNA glycosylase in complex with double stranded DNA     

Rotational model for nematic phase stability of fluorinated phenylbicyclohexane liquid crystals

A mechanical molecular rotation model for liquid crystal (LC) systems is employed to evaluate phase transition temperature of fluorinated phenylbicyclohexane isomeric LC compounds. Results show that when a fluorine atom is substituted along the molecular long axis, an LC molecule acquires high rotational speed and its rotation becomes stable, thereby resulting in a better thermal stability of the nematic phase. A novel explanation is proposed for the behavior of the nematic-isotropic phase of the LC system when a heavy atom is substituted along the molecular long axis. Figure Molecular conformation of fluorinated bicyclohexylphenyl compounds. . The fluorine atoms are substituted in different positions 2, 3, 4, and 5 of the phenyl ring, respectively. The axis expresses molecular long rotation axis.     

Computational studies of the binding site of α<Subscript>1A</Subscript>-adrenoceptor antagonists

Aimed at achieving a good understanding of the 3-dimensional structures of human α_1A-adrenoceptor (α_1A-AR), we have successfully developed its homology model based on the crystal structure of β₂-AR. Subsequent structural refinements were performed to mimic the receptor’s natural membrane environment by using molecular mechanics (MM) and molecular dynamics (MD) simulations in the GBSW implicit membrane model. Through molecular docking and further simulations, possible binding modes of subtype-selective α_1A-AR antagonists, Silodosin, RWJ-69736 and (+)SNAP-7915, were examined. Results of the modeling and docking studies are qualitatively consistent with available experimental data from mutagenesis studies. The homology model built should be very useful for designing more potent subtype-selective α_1A-AR antagonists and for guiding further mutagenesis studies. Figure The superposition of β₂-AR crystal structure (gold ribbons) and α_1A-AR homology model (blue ribbons)     

Alpha particle chemistry. On the formation of stable complexes between He2+ and other simple species: implications for atmospheric and interstellar chemistry

The possibility that stable complexes may be formed between alpha particles (He²⁺) and small molecules is investigated using QCISD quantum mechanical calculations. Implications for their presence in the terrestrial atmosphere and/or in interstellar space are discussed. Figure Optimized structure of a stable H₂OHe²⁺ complex     

G2, G3, and complete basis set calculations on the thermodynamic properties of triazane

As a follow-up study to our study on tetrazane (N₄H₆), we present computed thermodynamic properties of triazane (N₃H₅). Calculated properties include optimized geometries, infrared vibrations, enthalpy of formation, enthalpy of combustion, and proton affinities. We have also mapped the potential energy surface as the molecule is rotated about the N-N bond. We have predicted a specific enthalpy of combustion for triazane of about -20 kJ g⁻¹. Figure Schematic diagram of the dielectric barrier discharge (left) and typical temporal profiles of voltage and current, as obtained from the simulations (right)     

Synthesis, DFT calculations, linear and nonlinear optical properties of binuclear phthalocyanine gallium chloride

The axially substituted binuclear GaCl/GaCl phthalocyanine 1 with an unsymmetrical pattern of substitution has been prepared and its nonlinear optical (NLO) properties determined. The resulting binuclear complex retains approximately the same transition energies of monomeric (RO)₈PcGaCl as far as the linear optical spectrum is concerned, although 1 has a double concentration of central atoms per molecule and an enlarged conjugated ligand. The lack of significant spectral shifts in passing from mononuclear to binuclear complexes has been rationalized theoretically by means of density functional theory calculations. The purpose of the present study is to determine whether binuclearity affects the optical limiting behavior of 1 with respect to monomeric (RO)₈PcGaCl in the NLO regime determined by nanosecond laser pulses. Figure Bis axially substituted binuclear phthalocyanine: synthesis, DFT calculations and NLO properties Dedicated to Professor Dr. Paul von Ragué Schleyer on the occasion of his 75th birthday.     

A computational approach to the synthesis of 1,3,5-thiadiazinane-2-thiones in aqueous medium: theoretical evidence for water-promoted heterocyclization

Based on experimental evidence and DFT studies, a probable cyclization route to 1,3,5-thiadiazinanes-2-thiones in aqueous medium is proposed. Experimental facts suggest the formation of a {[hydroxymethyl (substituted) carbamothioyl] sulfanyl}methanol intermediate via reaction of dithiocarbamate (DTC) and formaldehyde. Nucleophilic addition of glycine to this intermediate generates an adduct that undergoes intramolecular heterocyclization via an S_N2 reaction. Computational calculations predict an active role of water in the reaction mechanism that promotes intramolecular cyclization. Figure Energy profile of the proposed reaction mechanism for the synthesis of thiadiazinane-2-thione ring 11 in aqueous medium from a (hydroxymethylcarbamothioyl)sulfanylmethanol intermediate, 9     

The decomposition of α-aminophosphine oxides to phosphonic acid derivatives (P<Superscript>III</Superscript>)

Aminophosphine oxides and aminophosphonates are, in general, very stable compounds. However, following phosphorus–carbon bond cleavage in aqueous acidic media these compounds sometimes decompose to phosphonic acids derivatives (P^III). Despite some controversy in the literature, careful analysis supported by theoretical studies leads to the conclusion that decomposition to P^III derivatives proceeds via an elimination reaction. Figure The decomposition of α-aminophosphine oxides to phosphonic acid derivatives (P^III)     

A theoretical investigation of cytotoxic activity of celastroid triterpenoids

Quantum chemical calculations at the B3LYP/6-31G* level of theory have been carried out on 20 celastroid triterpenoids to obtain a set of molecular electronic properties and to correlate these with cytotoxic activities. The cytotoxic activities of these compounds can be roughly correlated with electronic effects related to nucleophilic addition to C(6) of the compounds: The energies of the frontier molecular orbitals (E _HOMO and E _LUMO), the HOMO-LUMO energy gap, the dipole moment, the charge on C(6), and the electrophilicity on C(6). Figure LUMO of Pristimerin.     

Molecular dynamics studies of the Nafion®, Dow® and Aciplex® fuel-cell polymer membrane systems

The Nafion, Dow and Aciplex systems – where the prime differences lies in the side-chain length – have been studied by molecular dynamics (MD) simulation under standard pressure and temperature conditions for two different levels of hydration: 5 and 15 water molecules per (H)SO₃ end-group. Structural features such as water clustering, water-channel dimensions and topology, and the dynamics of the hydronium ions and water molecules have all been analysed in relation to the dynamical properties of the polymer backbone and side-chains. It is generally found that mobility is promoted by a high water content, with the side-chains participating actively in the H₃O⁺/H₂O transport mechanism. Nafion, whose side-chain length is intermediate of the three polymers studied, is found to have the most mobile polymer side-chains at the higher level of hydration, suggesting that there could be an optimal side-chain length in these systems. There are also some indications that the water-channel network connectivity is optimal for high water-content Nafion system, and that this could explain why Nafion appears to exhibit the most favourable overall hydronium/water mobility. Figure The simulation box for Aciplex with 5 water molecules per sulphonate end-group (yellow spheres). The polymer backbone is black; while side-chains are brown. The water-channel iso-surfaces are represented as blue clouds     

Adsorption and phase transitions in adsorbed systems: structural properties of CCl<Subscript>4</Subscript> layers adsorbed on a graphite surface

We present the results of simulations of a CCl₄ monolayer adsorbed on a graphite surface. The CCl₄ molecule was represented either by a shapeless superatom or by its atomic sites. The simulations were carried out over a large range of temperatures, from 20 K up to 340 K. We address the following problems: (1) the influence of molecular shape on the structure and stability of phases (particularly at low temperatures), and (2) the influence of the graphite corrugation on layer stability and mechanism of phase transitions. In particular, we discuss the possibility and conditions of the appearance of hexatic phase in the system. Figure Temperature dependence of Φ6 order parameter for CCl₄ monolayer adsorbed onsmooth and corrugated surfaces, in the spherical Lennard Jones (LJ) approximation.For comparison, the order parameter calculated for MacDonald’s five-site potential is also presented     

Design of Benzene-1,2-diamines as selective inducible nitric oxide synthase inhibitors: a combined de novo design and docking analysis

Selective inhibition of inducible nitric oxide synthases (iNOS) has been a challenging problem for researchers pursuing work in finding methods to treat inflammatory disorders, shock, etc. Though many inhibitors have been studied to date, all are associated with selectivity or potency problems. Additionally, most of the reported compounds have several similarities and fewer number of novel structures are being tried. There is an increasing need to design novel molecules for this target. In this work, de novo design using LUDI, combined with docking analysis using FlexX has been employed in an attempt to identify novel scaffolds. Benzene-1,2-diamines were identified which could mimic the interactions of the substrate analogs and other inhibitors. Comparative docking scores in each of the isoforms of nitric oxide synthase were employed to recognize hits for iNOS selectivity. Figure Figure shows the docked poses of the ligand M226 along with that of the reference GW274150. (FlexX analysis)     

Protonation and electronic structure of 2,6-dichlorophenolindophenolate during reduction. A theoretical study including explicit solvent

Protonation in the two-electron/two-proton reduction processes of 2,6-dichlorophenolindophenolate (DCIP) is investigated combining density functional theory (DFT) and molecular dynamics (MD) methods. DCIP (anion), DCIP^?– (radical anion), and DCIP^2? (dianion) are considered, including the electronic structure analysis from the prospective of quantum theory of atoms and molecules (QTAIM). It is shown that oxygen on the indophenolate moiety and nitrogen are the first and/or the second proton acceptor sites and their energetic order depends on the total charge of the system. MD simulations of differently charged species interacting with the solvent molecules have been performed for methanol, water, and oxonium cation (H₃O⁺). Methanol and water molecules are found to form only hydrogen bonds with the solute irrespective of its charge. The calculated pK_a values show that the imino group of DCIPH^? is a weaker acid than water. While in the case of DCIP (and DCIP^?–) plus oxonium cation, proton transfer from the solvent to the solute was evidenced for both aforementioned acceptor sites. In addition, MD simulations of bulks containing 15 and 43 molecules of water around the DCIP molecule have been performed, revealing the formation of 2–4 hydrogen bonds.

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Graphical Abstract 2,6-Dichlorophenolindophenolate interacts with solvent molecules (water, oxonium cation and methanol). Hydrogen transfer and electronic structure are studied by DFT and molecular dynamics methods

     

Adsorption into the MFI zeolite of aromatic molecule of biological relevance. Investigations by Monte Carlo simulations

Adsorption of paracresol and water into the silicalite-1 (MFI) zeolite has been investigated using canonical and grand-canonical Monte Carlo simulations. The most stable sites of adsorption of paracresol are found to be located at the channel intersections. Grand-canonical simulations have shown that at low loading, water molecules adsorb preferably at the vicinity of paracresol molecules, whereas they are also located in the sinusoidal channels as the loading increases. In order to explain the experimental adsorption isotherm observed for the coadsorption of water and paracresol in the MFI zeolite we propose a new concept of apparent adsorption enthalpy that varies with the concentration of the solution. The mathematical expression for the apparent enthalpy is introduced in an adsorption isotherm model. We shall refer to this theoretical isotherm as a non-langmuirian isotherm. The non-linear expression for the apparent adsorption enthalpy accounts for a variable accessibility of the sites of adsorption with respect to the concentration of the solution. Figure Co-adsorption of paracresol and water in silicalite-1 zeolite and comparison between experimental and modelled adsorption isotherms.     

Molecular electrostatic potentials in aromatic substituted 4-hydroxyquino-2-lones: Glycine/NMDA receptor antagonists

Hydroxyquinolone derivatives have proven to be useful for inhibition at the glycine binding site of N-methyl-D-aspartate (NMDA) receptor. In this work the electronic structure, molecular electrostatic potential (MESP) and vibrational characteristics of a set of C₃ substituted 4-hydroxyquino-2-lone (HQ) derivatives, which act as Glycine/NMDA receptor antagonists, have been investigated using the density functional calculations. In the optimized structures a substituent at the C₃ site of HQ tends to adopt a helical structure. MESP investigations reveal that the ligands showing better inhibition activity should possess electron-rich regions extending over the substituent and carbonyl group of HQ. A correlation of inhibitory activity to the molecular electrostatic potential topography at the carbonyl oxygen as well as to the molecular electron density topography turns out to be a significant output of the investigation. Figure Quantam chemical approach has been employed to understand the reactivity of a set of hydroxyquinolone derivatives known for their inhibition activity towards Glycine/NMDA receptor. Molecular electrostatic potential topography has been used as a tool to understand the reactivity pattern     

A density functional study towards substituent effects on anion sensing with urea receptors

Effects of substituents on anion binding in different urea based receptors have been examined using density functional (B3LYP/6-311+G**) level of theory. The complexes formed by a variety of substituted urea with a halide anion (fluoride) and an oxy-anion (acetate) have been calculated. The stronger complexes were predicted for receptors with fluoride ion than that of acetate ion, however, in water the preference was found to be reversed. The pK _a calculations showed the preferred sites of deprotonation for positional isomers, while interacting with anions. The position of the substituent in the receptor, however, could change the preferred sites of deprotonation compared to the site predicted with pK _a values.      

Molecular geometry,vibrations and electrode potentials of 2-(4,5-dihydroxy-2-methylphenyl)-2-phenyl-2H-indene-1,3-dione; experimental and theoretical attempts

The electrode potential of 2-(4,5-dihydroxy-2-methylphenyl)-2-phenyl-2H-indene-1,3-dione (DMPID) in acetonitrile has been calculated. The calculations were performed using ab initio molecular orbital calculations (HF), and density functional theory (DFT) with the inclusion of entropic and thermochemical corrections to yield free energies of redox reactions. The electrode potential of DMPID was also obtained experimentally with the aid of an electrochemical technique (cyclic voltammetry). The values for geometric parameters and the vibrational frequencies of DMPID and 2-(6-methyl-3,4-dioxocyclohexa-1,5-dienyl)-2-phenyl-2H-indene-1,3-dione (MDPID) were also computed using the same levels with the basis set of 6-31G(d). The calculated IR spectrum of DMPID used for the assignment of IR frequencies was observed in the experimental FT-IR spectrum and the calculated IR and FT-IR observed spectra of DMPID were compared with correlation factor of 0.996. It should be mentioned that the present work is the first research on coagulant derivative molecules in which the electrode potential of a molecule is calculated. Optimized structures of 2-(6-methyl-3,4-dioxocyclohexa-1,5-dienyl)-2-phenyl-2H-indene-1,3-dione (MDPID)     

Regulatory phosphorylation of cyclin-dependent kinase 2: insights from molecular dynamics simulations

The structures of fully active cyclin-dependent kinase-2 (CDK2) complexed with ATP and peptide substrate, CDK2 after the catalytic reaction, and CDK2 inhibited by phosphorylation at Thr14/Tyr15 were studied using molecular dynamics (MD) simulations. The structural details of the CDK2 catalytic site and CDK2 substrate binding box were described. Comparison of MD simulations of inhibited complexes of CDK2 was used to help understand the role of inhibitory phosphorylation at Thr14/Tyr15. Phosphorylation at Thr14/Tyr15 causes ATP misalignment for the phosphate-group transfer, changes in the Mg²⁺ coordination sphere, and changes in the H-bond network formed by CDK2 catalytic residues (Asp127, Lys129, Asn132). The inhibitory phosphorylation causes the G-loop to shift from the ATP binding site, which leads to opening of the CDK2 substrate binding box, thus probably weakening substrate binding. All these effects explain the decrease in kinase activity observed after inhibitory phosphorylation at Thr14/Tyr15 in the G-loop. Interaction of the peptide substrate, and the phosphorylated peptide product, with CDK2 was also studied and compared. These results broaden hypotheses drawn from our previous MD studies as to why a basic residue (Arg/Lys) is preferred at the P₊₂ substrate position. Figure View of the substrate binding site of the fully active cyclin-dependent kinase-2 (CDK2) (pT160-CDK2/cyclin A/ATP). The pThr160 activation site is located in the T-loop (yellow secondary structure). The G-loop, which partly forms the ATP binding site, is shown in blue. The Thr14 and Tyr15 inhibitory phosphorylation sites located in the G-loop are shown in licorice representation