The mechanistic insight of a specific interaction between 15d-Prostaglandin-J2 and eIF4A suggests an evolutionary conserved role across species.

15-deoxy-delta 12,14-prostaglandin J2 (15d-PGJ2) is an anti-inflammatory/anti-neoplastic prostaglandin that functions through covalent binding to cysteine residues of various target proteins. We previously showed that 15d-PGJ2 mediated anti-inflammatory responses are dependent on the translational inhibition through its interaction with eIF4A (Kim et al., 2007). Binding of 15d-PGJ2 to eIF4A specifically blocks the interaction between eIF4G and eIF4A, which leads to the formation of stress granules (SGs), which then cluster mRNAs with inhibited translation. Here, we show that the binding between 15d-PGJ2 and eIF4A specifically blocks the interaction between the MIF4G domain of eIF4G and eIF4A. To reveal the mechanism of this interaction, we used computational simulation-based docking studies and identified that the carboxyl tail of 15d-PGJ2 could stabilize the binding of 15d-PGJ2 to eIF4A through arginine 295 of eIF4A, which is the first suggestion that the 15d-PGJ2 tail plays a physiological role. Interestingly, the putative 15d-PGJ2 binding site on eiF4A is conserved across many species, suggesting a biological role. Our data propose that studying 15d-PGJ2 and its targets may uncover new therapeutic approaches in anti-inflammatory drug discovery.

Density functional theory based study of molecular interactions, recognition, engineering, and quantum transport in π molecular systems.

CONSPECTUS: In chemical and biological systems, various interactions that govern the chemical and physical properties of molecules, assembling phenomena, and electronic transport properties compete and control the microscopic structure of materials. The well-controlled manipulation of each component can allow researchers to design receptors or sensors, new molecular architectures, structures with novel morphology, and functional molecules or devices. In this Account, we describe the structures and electronic and spintronic properties of π-molecular systems that are important for controlling the architecture of a variety of carbon-based systems. Although DFT is an important tool for describing molecular interactions, the inability of DFT to accurately represent dispersion interactions has made it difficult to properly describe π-interactions. However, the recently developed dispersion corrections for DFT have allowed us to include these dispersion interactions cost-effectively. We have investigated noncovalent interactions of various π-systems including aromatic-π, aliphatic-π, and non-π systems based on dispersion-corrected DFT (DFT-D). In addition, we have addressed the validity of DFT-D compared with the complete basis set (CBS) limit values of coupled cluster theory with single, double, and perturbative triple excitations [CCSD(T)] and Møller-Plesset second order perturbation theory (MP2). The DFT-D methods are still unable to predict the correct ordering in binding energies within the benzene dimer and the cyclohexane dimer. Nevertheless, the overall DFT-D predicted binding energies are in reasonable agreement with the CCSD(T) results. In most cases, results using the B97-D3 method closely reproduce the CCSD(T) results with the optimized energy-fitting parameters. On the other hand, vdW-DF2 and PBE0-TS methods estimate the dispersion energies from the calculated electron density. In these approximations, the interaction energies around the equilibrium point are reasonably close to the CCSD(T) results but sometimes slightly deviate from them because interaction energies were not particularly optimized with parameters. Nevertheless, because the electron cloud deforms when neighboring atoms/ions induce an electric field, both vdW-DF2 and PBE0-TS seem to properly reproduce the resulting change of dispersion interaction. Thus, improvements are needed in both vdW-DF2 and PBE0-TS to better describe the interaction energies, while the B97-D3 method could benefit from the incorporation of polarization-driven energy changes that show highly anisotropic behavior. Although the current DFT-D methods need further improvement, DFT-D is very useful for computer-aided molecular design. We have used these newly developed DFT-D methods to calculate the interactions between graphene and DNA nucleobases. Using DFT-D, we describe the design of molecular receptors of π-systems, graphene based electronic devices, metalloporphyrin half-metal based spintronic devices as graphene nanoribbon (GNR) analogs, and graphene based molecular electronic devices for DNA sequencing. DFT-D has also helped us understand quantum phenomena in materials and devices of π-systems including graphene.

Novel ionophores with 2n-crown-n topology: anion sensing via pure aliphatic C-H···anion hydrogen bonding.

A series of novel coronands having a 2n-crown-n topology based on trioxane (6-crown-3) derivatives are designed and characterized. These neutral hosts can sense anions through pure aliphatic C-H hydrogen bonding (HB) in condensed phases due to the unusual topology of 2n-crown-n. C-H bonds are strongly polarized by two adjacent oxygen atoms in this scaffold. These hosts provide a rare opportunity to modulate anion binding strength by changing the electronic nature of aliphatic C-H bonds and offer ease of synthesis.

Calix[n]imidazolium as a new class of positively charged homo-calix compounds.

Macrocycles based on neutral calixarenes and calixpyrroles have been extensively explored for ion binding, molecular assembly and related applications. Given that only these two types of calix compounds and their analogs are available, the introduction of new forms of widely usable calix macrocycles is an outstanding challenge. Here we report the quadruply/quintuply charged imidazole-based homo-calix compounds, calix[4/5]imidazolium. The noncovalent (C-H)(+)/π(+)-anion interactions of the imidazolium rings with anions inside and outside the cone are the stabilizing factors for crystal packing, resulting in self-assembled arrays of cone-shaped calix-imidazolium molecules. Calix[4]imidazolium senses fluoride selectively even in aqueous solutions. Calix[5]imidazolium recognizes neutral fullerenes through π(+)-π interactions and makes them soluble in water, which could be useful in fullerene chemistry. Not only derivatization and ring expansion of calix[n]imidazolium, but also their utilization in ionic liquids, carbene chemistry and nanographite/graphene exfoliation could be exploited.

Intercalation of Transition Metals into Stacked Benzene Rings: A Model Study of the Intercalation of Transition Metals into Bilayered Graphene.

Structures of neutral metal-dibenzene complexes, M(C6H6)2 (M = Sc-Zn), are investigated by using Møller-Plesset second order perturbation theory (MP2). The benzene molecules change their conformation and shape upon complexation with the transition metals. We find two types of structures: (i) stacked forms for early transition metal complexes and (ii) distorted forms for late transition metal ones. The benzene molecules and the metal atom are bound together by δ bonds which originate from the interaction of π-MOs and d orbitals. The binding energy shows a maximum for Cr(C6H6)2, which obeys the 18-electron rule. It is noticeable that Mn(C6H6)2, a 19-electron complex, manages to have a stacked structure with an excess electron delocalized. For other late transition metal complexes having more than 19 electrons, the benzene molecules are bent or stray away from each other to reduce the electron density around a metal atom. For the early transition metals, the M(C6H6) complexes are found to be more weakly bound than M(C6H6)2. This is because the M(C6H6) complexes do not have enough electrons to satisfy the 18-electron rule, and so the M(C6H6)2 complexes generally tend to have tighter binding with a shorter benzene-metal length than the M(C6H6) complexes, which is quite unusual. The present results could provide a possible explanation of why on the Ni surface graphene tends to grow in a few layers, while on the Cu surface the weak interaction between the copper surface and graphene allows for the formation of a single layer of graphene, in agreement with chemical vapor deposition experiments.

Anion Binding by Electron-Deficient Arenes Based on Complementary Geometry and Charge Distribution.

Extended electron-deficient arenes are investigated as potential neutral receptors for polyanions. Anion binds via σ interaction with extended arenes, which are composed solely of C and N ring atoms and CN substituents. As a result, the positive charge on the aromatic C is enhanced, consequently maximizing binding strength. Selectivity is achieved because different charge distributions can be obtained for target anions of a particular geometry. The halides F(-) and Cl(-) form the most stable complex with 6, while the linear N3(-) interacts most favorably with 7. The trigonal NO3(-) and tetrahedral ClO4(-) fit the 3-fold rotational axis of 6 but do not form stable complexes with 5 and 7. The Y-shaped HCOO(-) forms complexes with 4, 5, and 7, with the latter being the most stable. Thus, the anion complexes exhibit strong binding and the best geometrical fit between guest and host, reminiscent of Lego blocks.

Thermally stable intermolecular proton bonds in polyaromatic aldehyde crystals.

We have synthesized self-assembled red-colored proton complexes of the aldehyde derivatives of polyaromatic hydrocarbon with strong intermolecular hydrogen bonding. These intermolecularly proton-bonded polyaromatic aldehydes formed as 1-pyrenecarbaldehyde (Py-CHO) reacted with HAuCl(4) to produce [(Py-CHO)(2)H][AuCl(4)] under dry conditions. The formation of [(Py-CHO)(2)H][AuCl(4)] was confirmed by single-crystal structure determination and IR spectral analysis at various temperatures. The compounds are distinctively hydrophobic in nature and are soluble only in a few organic polar solvents. The proton bonds are clearly observed from both the electron density in X-ray analysis and the characteristic IR frequency signature. The proton complex units have an O-H(+)-O distance of the typical Zundel-like cationic hydrogen bond (in which two O atoms share a proton-like H in the midpoint of the short O-O distance of ≈2.4 Å). The proton bonds are thermally stable, even over 100 °C, because the complexes are stabilized in layered structures with π-π intermolecular interactions of the polyaromatic hydrocarbon ligands. The IR signatures at around 900, 1200, and 1700 cm(-1) for the Zundel-like proton bond are clearly characterized.

Mechanistic studies on the oxidation of ascorbic acid and hydroquinone by a {Mn4O6}4+ core in aqueous media.

Described in this work is the kinetics of oxidation of ascorbic acid and hydroquinone by a tetranuclear Mn(IV) oxidant, [Mn(4)(µ-O)(6)(bipy)(6)](4+) (1(4+), bipy =2,2(/)-bipyridine), in aqueous solution over a wide pH range 1.5-6.0. In particular, below pH 3.0, protonation on the oxo-bridge of 1(4+) results in the formation of [Mn(4)(µ-O)(5)(µ-OH)(bipy)(6)](5+) (1H(5+)) as an additional oxidant over 1(4+). Both ascorbic acid and ascorbate whereas only hydroquinone and none of its protolytic species were found to be reactive reducing agents in these reactions. Analysis of the rate data clearly established that the oxo-bridge protonated oxidant 1H(5+) is kinetically far more superior to 1(4+) in oxidizing ascorbic acid and hydroquinone. Rates of these reactions are substantially lowered in D(2)O-enriched media in comparison to that in H(2)O media. An initial one electron one proton transfer electroprotic rate step could be mechanistically conceived. DFT studies established that among the two sets of terminal and central Mn(IV) atoms in the tetranuclear oxidant, one of the two terminal Mn(IV) is reduced to Mn(III) at the rate step that we can intuitively predict considering the probable positive charge distribution on the Mn(IV) atoms.

Induction-driven stabilization of the anion-π interaction in electron-rich aromatics as the key to fluoride inclusion in imidazolium-cage receptors.

Intermolecular interactions that involve aromatic rings are key processes in both chemical and biological recognition. It is common knowledge that the existence of anion-π interactions between anions and electron-deficient (π-acidic) aromatics indicates that electron-rich (π-basic) aromatics are expected to be repulsive to anions due to their electron-donating character. Here we report the first concrete theoretical and experimental evidence of the anion-π interaction between electron-rich alkylbenzene rings and a fluoride ion in CH(3)CN. The cyclophane cavity bridged with three naphthoimidazolium groups selectively complexes a fluoride ion by means of a combination of anion-π interactions and (C-H)(+)···F(-)-type ionic hydrogen bonds. (1)H NMR, (19)F NMR, and fluorescence spectra of 1 and 2 with fluoride ions are examined to show that only 2 can host a fluoride ion in the cavity between two alkylbenzene rings to form a sandwich complex. In addition, the cage compounds can serve as highly selective and ratiometric fluorescent sensors for a fluoride ion. With the addition of 1 equiv of F(-), a strongly increased fluorescence emission centered at 385 nm appears at the expense of the fluorescence emission of 2 centered at 474 nm. Finally, isothermal titration calorimetry (ITC) experiments were performed to obtain the binding constants of the compounds 1 and 2 with F(-) as well as Gibbs free energy. The 2-F(-) complex is more stable than the 1-F(-) complex by 1.87 kcal mol(-1), which is attributable to the stronger anion-π interaction between F(-) and triethylbenzene.

Quencher-free molecular beacon: Enhancement of the signal-to-background ratio with graphene oxide.

We report the highly improved version of quencher-free molecular beacon (QF-MB) system by using graphene oxide (GO) as an external quencher. This QF-MB/GO system provided a higher S/B ratio (31.0) relative to that (2.2) of the same system in the absence of GO, while retaining a high selectivity for fully matched over single-base-mismatched targets.

Differences in structure, energy, and spectrum between neutral, protonated, and deprotonated phenol dimers: comparison of various density functionals with ab initio theory.

We have carried out extensive calculations for neutral, cationic protonated, anionic deprotonated phenol dimers. The structures and energetics of this system are determined by the delicate competition between H-bonding, H-π interaction and π-π interaction. Thus, the structures, binding energies and frequencies of the dimers are studied by using a variety of functionals of density functional theory (DFT) and Møller-Plesset second order perturbation theory (MP2) with medium and extended basis sets. The binding energies are compared with those of highly reliable coupled cluster theory with single, double, and perturbative triple excitations (CCSD(T)) at the complete basis set (CBS) limit. The neutral phenol dimer is unique in the sense that its experimental rotational constants have been measured. The geometry of the neutral phenol dimer is governed by the hydrogen bond formed by two hydroxyl groups and the H-π interaction between two aromatic rings, while the structure of the protonated/deprotonated phenol dimers is additionally governed by the electrostatic and induction effects due to the short strong hydrogen bond (SSHB) and the charges populated in the aromatic rings in the ionic systems. Our salient finding is the substantial differences in structure between neutral, protonated, and deprotonated phenol dimers. This is because the neutral dimer involves in both H(π)···O and H(π)···π interactions, the protonated dimer involves in H(π)···π interactions, and the deprotonated dimer involves in a strong H(π)···O interaction. It is important to compare the reliability of diverse computational approaches employed in quantum chemistry on the basis of the calculational results of this system. MP2 calculations using a small cc-pVDZ basis set give reasonable structures, but those using extended basis sets predict wrong π-stacked structures due to the overestimation of the dispersion energies of the π-π interactions. A few new DFT functionals with the empirical dispersion give reliable results consistent with the CCSD(T)/CBS results. The binding energies of the neutral, cationic protonated, and anionic deprotonated phenol dimers are estimated to be more than 28.5, 118.2, and 118.3 kJ mol(-1), respectively. The energy components of the intermolecular interactions for the neutral, protonated and deprotonated dimers are analyzed.

Structural basis of triclosan resistance.

Triclosan (5-chloro-2-(2,4-dichloro-phenoxy)-phenol, TCL) is a well known inhibitor against enoyl-acyl carrier protein reductase (ENR), an enzyme critical for cell-wall synthesis of bacteria. The inhibitory concentration at 50% inhibition (IC(50)) of TCL against the Escherichia coli ENR is 150nM for wild type (WT), 380, 470 and 68,500nM for Ala, Ser and Val mutants, respectively. To understand this high TCL resistance in the G93V mutant, we obtained the crystal structures of mutated ENRs complexed with TCL and NAD(+). The X-ray structural analysis along with the ab initio calculations and molecular dynamics simulations explains the serious consequence in the G93V mutant complex. The major interactions around TCL due to the aromatic(cation)-aromatic and hydrogen bonding interactions are found to be conserved both in WT and mutant complexes. Thus, the overall structural change of protein is minimal except that a flexible α-helical turn around TCL is slightly pushed away due to the presence of the bulky valine group. However, TCL shows substantial edge-to-face aromatic (π)-interactions with both the flexible R192-F203 region and the residues in the close vicinity of G93. The weakening of some edge-to-face aromatic interactions around TCL in the G93V mutant results in serious resistance to TCL. This understanding is beneficial to design new generation of antibiotics which will effectively act on the mutant ENRs.

NH4(+) Resides Inside the Water 20-mer Cage As Opposed to H3O(+), Which Resides on the Surface: A First Principles Molecular Dynamics Simulation Study.

Experimental vibrational predissociation spectra of the magic NH4(+)(H2O)20 clusters are close to those of the magic H3O(+)(H2O)20 clusters. It has been assumed that the geometric features of NH4(+)(H2O)20 clusters might be close to those of H3O(+)(H2O)20 clusters, in which H3O(+) resides on the surface. Car-Parrinello molecular dynamics simulations in conjunction with density functional theory calculations are performed to generate the infrared spectra of the magic NH4(+)(H2O)20 clusters. In comparison with the experimental vibrational predissociation spectra of NH4(+)(H2O)20, we find that NH4(+) is inside the cage structure of NH4(+)(H2O)20 as opposed to on the surface structure. This shows a clear distinction between the structures of NH4(+)(H2O)20 and H3O(+)(H2O)20 as well as between the hydration phenomena of NH4(+) and H3O(+).

How Different Are Aromatic π Interactions from Aliphatic π Interactions and Non-π Stacking Interactions?

We compare aromatic π interactions with aliphatic π interactions of double- and triple-bonded π systems and non-π stacking interactions of single-bonded σ systems. The model dimer systems of acetylene (C2H2)2, ethylene (C2H4)2, ethane (C2H6)2, benzene (C6H6)2, and cyclohexane (C6H12)2 are investigated. The ethylene dimer has large dispersion energy, while the acetylene dimer has strong electrostatic energy. The aromatic π interactions are strong with particularly large dispersion and electrostatic energies, which would explain why aromatic compounds are frequently found in crystal packing and molecular self-engineering. It should be noted that the difference in binding energy between the benzene dimer (aromatic-aromatic interactions) and the cyclohexane dimer (aliphatic-aliphatic interactions) is not properly described in most density functionals.

Can Electron-Rich π Systems Bind Anions?

In general, anion-π interactions exist between anions and aromatics with a positive quadrupole moment. The interaction between anions and aromatics with a negative quadrupole moment is expected to be unstable due to Coulombic repulsion. However, here we investigated the cases of aromatics with a negative quadrupole moment such as electron-rich alkyl/alkenyl/alkynyl-substituted benzenes and triphenylene, which interact with halides. Favorable binding was demonstrated with coupled cluster theory with singles, doubles, and perturbative triples excitations [CCSD(T)] at the complete basis set (CBS) limit. Stability increases with chain length, unsaturation, and halogenation. Energy decomposition analysis based on symmetry adapted perturbation theory (SAPT) shows that electrostatic repulsion is overcome by induction effects arising from the alkyl substituents.

H2-Binding by Neutral and Multiply Charged Titaniums: Hydrogen Storage Capacity of Titanium Mono- and Dications.

Given that transition metal-hydrogen systems have been studied as a predecessor for hydrogen storage materials, we have investigated the neutral and multiply charged titanium-H2 systems (Ti-H2, Ti(+)-H2, Ti(2+)-H2, Ti(3+)-H2, and Ti(4+)-H2) using density functional theory (DFT) and high-level ab initio calculations, including coupled cluster theory with single, double, and perturbatively triple excitations [CCSD(T)]. These systems show different types of hydrogenation depending on their charged state. The neutral Ti-H2 system shows dihydride structure with covalent interaction where the Ti-H distance is 1.76 Å, while H2 is dissociated into two neigboring hydride ions by withdrawing electrons from Ti. The charged Ti(+)-H2, Ti(2+)-H2, and Ti(3+)-H2 systems show dihydrogen structures with noncovalent interaction, where the Ti(+)-H, Ti(2+)-H, and Ti(3+)-H distances are 2.00, 2.14, and 2.12 Å, respectively. The main binding energies in these systems arise from the hydrogen polarizability driven interaction by the positive charge of Ti(n+) (n = 1-3). Among Ti(n+)-H2 (n = 1-3) the Ti(+)-H2 has the shortest distance against our common expectation, while Ti(2+)-H2 has the longest distance. The Ti(+)-H2 distance is the shortest because of the d-σ* molecular orbital (MO) interaction which is not present in Ti(2+)-H2 and Ti(3+)-H2. The Ti(4+) ion does not bind H2. In this regard, we have investigated the maximal hydrogen binding capacity by Ti complexes. The coordination of titanium mono- and dications complexed with dihydrogen (H2) [Ti(+)(H2)n and Ti(2+)(H2)m] is studied along with their structures, binding energies, electronic properties, and spectra. The titanium monocations of the quartet ground state have up to the hexacoordinaton, while titanium dications of the triplet ground state have up to the octacoordination at very low temperatures. At room temperature, the monocations favor penta- to hexacoordination, while the dications favor hexacoordination. This information would be useful for the design of hydrogen storage devices of Ti complexes, such as Ti-decorated/dispersed polymer-graphene hybrid materials.

A radical polymer as a two-dimensional organic half metal.

Given that half-metals are promising futuristic materials for spintronics, organic materials showing half-metal character are highly desirable for spintronic devices, not only owing to their weak spin-orbit and hyperfine interactions, but also their light and flexible properties. We predict that a two-dimensional organic 2,4,6-tri-(1,3,5-triazinyl)methyl radical polymer has half-metallic properties as well as a spontaneous magnetic ordering at ambient temperature. The quantum transmission is studied based on the nonequilibrium Green function theory coupled with density functional theory. The half-metallic property in the triazine-based polymer depends mainly on the nature of the p-band in contrast to of conventional half metals in which the nature of the d-band is more important.

Chiral transformation in protonated and deprotonated adipic acids through multistep internal proton transfer.

Protonated and deprotonated adipic acids (PAA: HOOC-(CH(2))(4)--COOH(2) (+) and DAA: HOOC-(CH(2))(4)-COO(-)) have a charged hydrogen bond under the influence of steric constraint due to the molecular skeleton of a circular ring. Despite the similarity between PAA and DAA, it is surprising that the lowest energy structure of PAA is predicted to have (H(2)O...H...OH(2))(+) Zundel-like symmetric hydrogen bonding, whereas that of DAA has H(3)O(+) Eigen-like asymmetric hydrogen bonding. The energy profiles show that direct proton transfer between mirror image structures is unfavorable. Instead, the chiral transformation is possible by subsequent backbone twistings through stepwise proton transfer along multistep intermediate structures, which are Zundel-like ions for PAA and Eigen-like ions for DAA. This type of chiral transformation by multistep intramolecular proton transfers is unprecedented. Several prominent OH...O short hydrogen-bond stretching peaks are predicted in the range of 1000-1700 cm(-1) in the Car-Parrinello molecular dynamics (CPMD) simulations, which show distinctive signatures different from ordinary hydrogen-bond peaks. The O-H-O stretching peaks in the range of 1800-2700 cm(-1) become insignificant above around 150 K and are almost washed out at about 300 K.

Aromatic pi-pi interaction mediated by a metal atom: structure and ionization of the bis(eta(6)-benzene)chromium-benzene cluster.

Aromatic pi-pi interaction in the presence of a metal atom has been investigated experimentally and theoretically with the model system of bis(eta(6)-benzene)chromium-benzene cluster (Cr(Bz)(2)-Bz) in which a free solvating benzene is non-covalently attached to the benzene moiety of Cr(Bz)(2). One-photon mass-analyzed threshold ionization (MATI) spectroscopy and first principles calculations are employed to identify the structure of Cr(Bz)(2)-Bz which adopts the parallel-displaced configuration. The decrease in ionization potential for Cr(Bz)(2)-Bz compared with Cr(Bz)(2), resulting from the increase of the cation-pi stabilization energy upon ionization, is consistent with the parallel-displaced structure of the cluster. Theoretical calculations give the detailed cluster structures with associated energetics, thus revealing the nature of pi-pi-metal or pi-pi-cation interactions at the molecular level.