Difference Electron Density Map Research Articles

Mechanism of Ionic Permeation in the Mimics of CNG Channels: A Structural, Functional and Computational Analysis

Using an engineered cyclic nucleotide-gated (CNG) channel mimic based on the bacterial non-selective NaK channel, we examined how different ionic species interact with the pore by means of electrophysiology, all-atoms molecular dynamics simulations and X-ray crystallography.Difference and anomalous difference electron-density maps of high-resolution crystal structures (up to 1.85A) obtained after soaking with different ionic species (Li+, Na+, K+, Rb+, Cs+, Methylammonium) clearly shows the presence of different peaks inside the pore. Depending on these ionic species Glu66 and Thr67, located at the extracellular entrance of the selectivity filter, adopt different rotameric states. In the presence of Methylammonium, Glu66 points towards Tyr55 of the same subunit, while in the presence of Na+, Glu66 forms H-bonds with Thr67 and Thr60 of a neighboring subunit (Derebe et al, 2011, PNAS). Moreover, large-scale molecular dynamics simulations in a hydrated lipid bilayer at 0 mV indicates that Glu66 and Thr67 side chains are capable of large structural fluctuations which are modulated by the nature of the ion residing in the pore. In particular, in presence of Rb+ and Cs+ Glu66 explores at least three different conformations, characterized by a significantly different distribution of the local charge. Single channel recordings from this chimeric ionic channel in symmetrical Rb+ and Cs+ conditions show a strong voltage dependency similar to what observed in the native CNGA1 channel (Marchesi et al, 2012, Nat. Communications). These results indicate that membrane voltage catalyzes a conformational change of these residues, especially of Glu66, perturbing the hydrogen bonding network behind the selectivity filter. Non-selective ionic permeation emerges as a robust feature of an intrinsic flexible pore and is a key microscopic factor controlling ionic selectivity in CNG and possibly in other non-selective channels.

TDDFT studies on electronic structures, chiroptical properties and solvent effect on the CD spectra of diphosphonate-functionalized polyoxomolybdates

The ultraviolet–visible and electronic circular dichroism (UV–vis/ECD) spectra of diphosphonate-functionalized asymmetric cantilever-type chiral polyoxomolybdate (POM) enantiomer R-{Mo2O5[(Mo2O6)NH3CH2CH2CH2C(O)(PO3)2]2}6− (R) were systematically investigated using time-dependent density functional theory (TDDFT) method. From the view of molecular structure and relative energy, we inferred that there is likely a structural conversion from enantiomers R to S-{Mo2O5[(Mo2O6)NH3CH2CH2CH2C(O)(PO3)2]2}6− (S) via the intermediate configuration (IN). The ECD spectra of the enantiomer R were produced over the range of 3.0–6.3eV. The UV–vis and ECD spectra of enantiomer R in the gas phase and different solvents were calculated. The results reveal that the UV–vis and ECD spectra of the chiral POM in gas phase, polar solvent, or non-polar solvent are different. The calculated electron density difference maps (EDDMs) display that the POM cluster is a chiroptical chromophore in studied compound.

Interactions of foreign interstitial and substitutional atoms in bcc iron from ab initio calculations

C and N atoms are the most frequent foreign interstitial atoms (FIAs), and often incorporated into the surface layers of steels to enhance their properties by thermochemical treatments. Al, Si, Ti, V, Cr, Mn, Co, Ni, Cu, Nb and Mo are the most common alloying elements in steels, also can be called foreign substitutional atoms (FSAs). The FIA and FSA interactions play an important role in the diffusion of C and N atoms, and the microstructures and mechanical properties of surface modified layers. Ab initio calculations based on the density functional theory are carried out to investigate FIA interactions with FSA in ferromagnetic bcc iron. The FIA–FSA interactions are analyzed systematically from five aspects, including interaction energies, density of states (DOS), bond populations, electron density difference maps and local magnetic moments.

Structures and redox-switchable second-order nonlinear optics properties of N-legged piano stool shaped 12-vertex rhenacarborane half-sandwich complexes

Three sets of n-legged piano stool shaped (–Re(CO)3 or –Re(CO)3I) 12-vertex rhenacarborane half-sandwich complexes (n = 3 or 4) have been investigated by density functional theory (DFT). Natural bond orbital (NBO) analysis shows that introducing iodine (I) atom changes the bond formations between rhenium (Re) ion and carborane cage or 3/4-legged piano stools. The redox-switchable second-order nonlinear optics (NLO) properties of sets 1 and 3 are different, notably, the total first hyperpolarizability (βtot) of complex 231e is about 20 times larger than that of its parent complex 3. Furthermore, time-dependent density functional theory (TDDFT) calculations were employed to account for the redox-switchable NLO properties, the plots of frontier molecular orbitals (FMOs) and electron density difference maps (EDDM) visually indicate that the intramolecular interactions among I atom, Re ion and carborane cage contribute to the redox property of set 3.

Benchmark calculations of metal carbonyl cations: relativistic vs. electron correlation effects

In this paper we present benchmark results for isoelectronic metal carbonyl complexes of the groups 11 and 12 of the periodic table. The focus is on the geometry, vibrational frequencies, bond dissociation energy and chemical bonding. The description of these complexes requires a good balance between electron correlation and relativistic effects. Our results demonstrate that the combination of the effective core potential and the MP2 method gives quantitative results for the first- and the second-row transition metal complexes and only qualitative agreement for the third-row complexes. In order to obtain quantitative results for the whole series the use of four-component or X2C methods is mandatory. The fourth-row transition metal carbonyl complexes from groups 11 and 12 have been studied for the first time. The metal-carbon bond strength pattern along the group is shown to be highly dependent on the correct description of the relativistic effects. Finally, the relativistic effects on the bonding are studied by means of electron density difference maps, the analysis of the bond critical points of the electron density and the mechanism for σ-donation and π-backdonation. Our analysis indicates that the fourth-row complexes exhibit a strong covalent character induced by relativistic effects.

Probing the structural, electronic and magnetic properties of multicenter Fe2S2 0/−, Fe3S4 0/− and Fe4S4 0/− clusters

The structural, electronic and magnetic properties of neutral and anion Fe2S2, Fe3S4 and Fe4S4 have been investigated with the aid of previous photoelectron spectroscopy and density functional theory calculations. Theoretical electron detachment energies (both vertical and adiabatic) of anion clusters for the lowest energy structure were computed and compared with the experimental results to verify the ground states. The optimized structures show that the ground state structures of Fe2S2(0/-), Fe3S4(0/-) and Fe4S4(0/-) favor high spin state and are similar to their structures in proteins. The electron delocalization pattern for all the clusters and the nature of bonding between Fe and S atoms were studied by analyzing molecular orbitals. Natural population analysis demonstrates that Fe atoms act as an electron donor in all clusters, and the electron density difference map clearly shows the direction of the electron flow over the whole complex. Furthermore, the investigated magnetism shows that the Fe atoms carried most of the magnetic moments, which is due mainly to the 3d state, while only very small magnetic moments are found on S atoms.

Density Functional Theory Investigation on the Second‐Order Nonlinear Optical Properties of Chlorobenzyl‐o‐Carborane Derivatives

AbstractThe structures and second‐order nonlinear optical (NLO) properties of a series of chlorobenzyl‐o‐carboranes derivatives (1–12) containing different push‐pull groups have been studied by density functional theory (DFT) calculation. Our theoretical calculations show that the static first hyperpolarizability (βtot) values gradually increase with increasing the π‐conjugation length and the strength of electron donor group. Especially, compound 12 exhibits the largest βtot (62.404×10−30 esu) by introducing tetrathiafulvalene (TTF), which is about 76 times larger than that of compound 1 containing aryl. This means that the appropriate structural modification can substantially increase the first hyperpolarizabilities of the studied compounds. For the sake of understanding the origin of these large NLO responses, the frontier molecular orbitals (FMOs), electron density difference maps (EDDMs), orbital energy and electronic transition energy of the studied compounds are analyzed. According to the two‐state model, the lower transition energy plays an important role in increasing the first hyperpolarizability values. This study may evoke possible ways to design preferable NLO materials.

Substrate binds in the S1 site of the F253A mutant of LeuT, a neurotransmitter sodium symporter homologue

LeuT serves as the model protein for understanding the relationships between structure, mechanism and pharmacology in neurotransmitter sodium symporters (NSSs). At the present time, however, there is a vigorous debate over whether there is a single high-affinity substrate site (S1) located at the original, crystallographically determined substrate site or whether there are two high-affinity substrates sites, one at the primary or S1 site and the other at a second site (S2) located at the base of the extracellular vestibule. In an effort to address the controversy over the number of high-affinity substrate sites in LeuT, one group studied the F253A mutant of LeuT and asserted that in this mutant substrate binds exclusively to the S2 site and that 1 mM clomipramine entirely ablates substrate binding to the S2 site. Here we study the binding of substrate to the F253A mutant of LeuT using ligand binding and X-ray crystallographic methods. Both experimental methods unambiguously show that substrate binds to the S1 site of the F253A mutant and that binding is retained in the presence of 1 mM clomipramine. These studies, in combination with previous work, are consistent with a mechanism for LeuT that involves a single high-affinity substrate binding site.

Fluorene‐Containing Organic Photosensitizers for Dye‐Sensitized Solar Cells

AbstractSeven new donor–spacer–acceptor metal‐free organic dyes containing a fluorene and/or thiophene unit as a conjugated spacer are prepared and their physicochemical properties as well as photovoltaic performance are studied. The electron transfer from donor to acceptor upon excitation of these dyes is sensitive to the conjugated spacers. If a stronger donor moiety such as (ethylenedioxy)thiophene is used as a spacer, such as in F‐E1 dye, the dye molecule has a better charge separation and therefore high efficiency. Furthermore, for the same donor and acceptor, fluorene is a better conjugated spacer than the bithiophene moiety because of its nonplanar conformation, which avoids the electron–hole recombination of dye upon photoexcitation. Short molecules with planar conformation aggregate easily, and the corresponding device reveals low open‐circuit voltage Voc. On the other hand, dye molecules with long alkyl side chains (large size) adsorb less on the TiO2 electrode, which results in a smaller short‐circuit current density Jsc. The difference in the efficiency of these dyes is small except for F‐1 (owing to its short conjugation length), and electron density difference map analyses reveal that photoexcitation transfer of electron density from the donating moieties toward the acceptor/anchoring units occurs for all molecules. The small difference in the efficiency is attributed partly to the degree of effective charge transfer upon excitation, not totally to the absorption profile of the dye molecules. Furthermore, time‐dependent DFT simulated absorption spectra are in excellent agreement with experimental spectra when the dyes are in their protonated states in THF solution. The transition probability calculated with the electron density difference analyses combined with the absorption data and photovoltaic performance provide useful information for designing organic sensitizers for dye‐sensitized solar cells.

Cation–πvs. π–π interactions: Complexes of 2-pyridinylguanidinium derivatives and aromatic systems

We have theoretically studied, using PCM–water solvation, the cation–π and π–π complexes established by the biologically relevant 5-substituted 2-pyridinylguanidinium derivatives and electron-rich and electron-depleted aromatic systems (benzene and (hexafluoro)benzene). In condensed phase using PCM–water and M06-2X/6-311++G(d,p) different cation–π and π–π complexes were found. The interactions established within these complexes have been analyzed by means of the Atoms in Molecules and Natural Bond Orbital approaches and electron density difference maps have been calculated. Finally, the effect of the cation–π and π–π complexation on the aromaticity of pyridine, benzene and hexafluorobenzene was evaluated by calculating the corresponding aromaticity indexes, NICS0, 1 and 2 as well as the NICS on the 0.001 a.u. isodensity surface.

(Acetylacetonato-κ2O,O′)[(2-bromophenyl)diphenylphosphane-κP]carbonylrhodium(I)

In the title compound, [Rh(C5H7O2)(C18H14BrP)(CO)], the RhI atom adopts a slightly distorted square-planar geometry involving two O atoms [Rh—O = 2.077 (2) and 2.033 (2) Å] of the acetyl­acetonate ligand, one carbonyl C atom [Rh—C = 1.813 (2) Å] and one P atom [Rh—P = 2.242 (5) Å] of the PPh2(2-BrC6H4) phosphane ligand. Difference electron density maps indicate a disorder of the Br atom over two positions in an approximate 0.95:0.05 ratio. However, this disorder could not be resolved satisfactorily with the present data.

Binding of viologen derivatives to cucurbit[8]uril

Molecular interactions between cucurbit[8]uril host and methyl -(MV2+), ethyl -(EV2+), propyl -(PV2+) and butyl -(BV2+) viologen have been analyzed employing the density functional theory. The complexation of viologen guests with CB[8] favors complete encapsulation of guest within host cavity over lateral interactions from host portals. The lowest energy complex reveals that both α- and methylene protons of alkyl substituent interact with hydrophilic exterior of CB[8] via hydrogen bond interactions. These host–guest interactions are analyzed using quantum theory of atoms in molecules. It has been shown that amongst viologen derivatives, methyl viologen binds strongly to CB[8] and strength of binding decreases steadily with increasing aliphatic chain length of the substituent. Normal vibration analyses reveal that CO stretching vibrations from CB[8] (1788cm−1) downshifts to 1754cm−1 when ureido oxygens interact with viologen guest. The CO vibrations from hydrogen bonded interactions (1754cm−1) and those from noninteracting ones (1792cm−1) engender distinct vibrations in the complex. The CN stretching vibration of viologen cation exhibits a blue shift of 22cm−1 on encapsulation within CB[8] cavity. The direction of frequency shift of CO and CN stretching vibrations has been explained by combining MED topography with difference electron density maps and further been supported by natural bond orbital analysis. Calculated 1H NMR chemical shifts predict that β-protons of bipyridinium moiety are shielded due to encapsulation within the host cavity unlike α- or methylene protons participating in CO⋯H interactions which exhibit deshielding. These inferences are in consonant with 1H NMR experiments.

Crystal structure of the uranium oxo borohydride complex U2(μ-O)(BH4)6(dme)2 (dme = 1,2-dimethoxyethane) and reformulation of U2(μ-H)2(BH4)6(dme)2

The reaction of uranium tetrachloride, UCl4, with sodium N,N-dimethylaminodiboranate, Na(H3BNMe2BH3), in refluxing 1,2-dimethoxyethane (dme) yields small amounts of a new complex, which we formulate as (μ-oxo)hexakis(tetrahydroborato)bis(1,2-dimethoxyethane)diuranium(IV), toluene solvate, U2(μ-O)(BH4)6(dme)2·C7H8, 1. Most likely, the formation of BH4− groups from H3BNMe2BH3− occurs with the elimination of [Me2NBH2]2, and the formation of the oxo group involves adventitious hydrolysis. Each uranium center in 1 adopts a fac octahedral geometry (counting the BH4− groups as occupying one coordination site); the bridging oxygen atom and the two coordinated oxygen atoms of the dme ligand occupy positions trans to the three BH4− groups. The hydrogen atom positions were located in the electron density difference maps and reveal that all three BH4− groups are bound in a κ3H fashion. The U⋯B distances to the two BH4− groups that are cis to the bridging oxygen atom are 2.574(6) and 2.584(6)Å, whereas the U⋯B distance of 2.635(7)Å to the BH4− group that is trans to the bridging oxygen is distinctly longer. Thus, the bridging oxygen atom exerts a noticeable trans influence. The crystallographic and 1H NMR data strongly suggest that the previously reported uranium hydride complex U2(μ-H)2(BH4)6(dme)2 should be reformulated as this oxo complex U2(μ-O)(BH4)6(dme)2.

Crystallographic Complexes of Surfactant Protein A and Carbohydrates Reveal Ligand-induced Conformational Change

Surfactant protein A (SP-A), a C-type lectin, plays an important role in innate lung host defense against inhaled pathogens. Crystallographic SP-A·ligand complexes have not been reported to date, limiting available molecular information about SP-A interactions with microbial surface components. This study describes crystal structures of calcium-dependent complexes of the C-terminal neck and carbohydrate recognition domain of SP-A with d-mannose, D-α-methylmannose, and glycerol, which represent subdomains of glycans on pathogen surfaces. Comparison of these complexes with the unliganded SP-A neck and carbohydrate recognition domain revealed an unexpected ligand-associated conformational change in the loop region surrounding the lectin site, one not previously reported for the lectin homologs SP-D and mannan-binding lectin. The net result of the conformational change is that the SP-A lectin site and the surrounding loop region become more compact. The Glu-202 side chain of unliganded SP-A extends out into the solvent and away from the calcium ion; however, in the complexes, the Glu-202 side chain translocates 12.8 Å to bind the calcium. The availability of Glu-202, together with positional changes involving water molecules, creates a more favorable hydrogen bonding environment for carbohydrate ligands. The Lys-203 side chain reorients as well, extending outward into the solvent in the complexes, thereby opening up a small cation-friendly cavity occupied by a sodium ion. Binding of this cation brings the large loop, which forms one wall of the lectin site, and the adjacent small loop closer together. The ability to undergo conformational changes may help SP-A adapt to different ligand classes, including microbial glycolipids and surfactant lipids.

Electronic structure ofLaNiO3−xthin films studied by x-ray photoelectron spectroscopy and density functional theory

We present the experimental and theoretical study of x-ray photoelectron spectroscopy spectrum of ${\text{LaNiO}}_{3\ensuremath{-}x}$ thin films deposited onto a (100)-plane oriented ${\text{NdGaO}}_{3}$ substrate by applying a reactive dc magnetron sputtering technique. The crystal calculations carried out within pure density functional theory (DFT) approximation properly reproduce the delocalized valence band showing the suitability of homogeneous electron gas model, whereas hybrid DFT/Hartree-Fock (HF) calculations work out in the core region indicating the localized nature of core electrons. The significance of spin-orbit coupling to the electronic structure of ${\text{LaNiO}}_{3}$ is revealed by relativistic molecular HF study allowing to theoretically identify the doublet splitting of $\text{La}\text{ }5p$. Electron-density difference map indicates a different nature of La-O and Ni-O chemical bonds in ${\text{LaNiO}}_{3}$ while the Mulliken population analysis adds information about the charge distributions and overlap populations between separate atoms.

Structural properties and the effect of 2,6‐diaminoanthraquinone on G‐tetrad, non‐G‐tetrads, and mixed tetrads—A density functional theory study

AbstractTelomerase inhibitor causes the attrition of telomere length and consequently leading to senescence which require a lag period for cancer cells to stop proliferating. Telomeric sequences form quadruplex structures stabilized by tetrads. The structural and electronic properties related with interaction of 2,6‐diaminoanthraquinone and tetrads are the key step to elucidate the anticancer activity. The present study has been focused on the stability of the isolated tetrads and the effect of interaction of 2,6‐diaminoanthraquinone with G‐tetrad, non‐G‐tetrads, and mixed tetrads using density functional theory method in both gas and aqueous phases. The solvent interaction with the molecular systems has increased the stability of the isolated tetrads and complexes. The sharing of electron density between the interacting molecules is shown through electron density difference maps. The atoms in molecules theory and natural bond orbital analysis have been performed to study the nature of hydrogen bonds in the inhibitor interacting complexes. The linear correlation is shown between electron density [ρ(r)], and its Laplacian [(2ρ(r)] at the bond critical points. The strong binding nature of 2,6‐diaminoanthraquinone with studied tetrads reveals that this inhibitor is suitable to stabilize the above tetrads and inhibit the telomerase activity. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2011

A Strong Second-Harmonic Generation Material Cd4BiO(BO3)3 Originating from 3-Chromophore Asymmetric Structures

In this communication, the novel nonlinear optical crystal material Cd(4)BiO(BO(3))(3) with 3-chromophore asymmetric structures of CdO(n), BiO(6), and BO(3) groups has been prepared by a flux method, and the single crystal structure has been determined with the space group Cm. It is the largest NLO coefficient for Cd(4)BiO(BO(3))(3) among borate systems, and the strong NLO response originates from cooperation effects of the 3-chromophore asymmetric structures composed of the polar displacement of d(10) Cd(2+) ion, stereochemically active lone pair of Bi(3+), and pi-delocalization of BO(3). These evidence are provided in view of evaluations of calculated density of states and electron-density difference maps. The experimental measurements show that the features of a large SHG effect, phase-match, and high thermal stability will be favorable in industrial production and applications for Cd(4)BiO(BO(3))(3).

Structure and Mechanism of the Lincosamide Antibiotic Adenylyltransferase LinB

Lincosamides make up an important class of antibiotics used against a wide range of pathogens, including methicillin-resistant Staphylococcus aureus. Predictably, lincosamide-resistant microorganisms have emerged with antibiotic modification as one of their major resistance strategies. Inactivating enzymes LinB/A catalyze adenylylation of the drug; however, little is known about their mechanistic and structural properties. We determined two X-ray structures of LinB: ternary substrate- and binary product-bound complexes. Structural and kinetic characterization of LinB, mutagenesis, solvent isotope effect, and product inhibition studies are consistent with a mechanism involving direct in-line nucleotidyl transfer. The characterization of LinB enabled its classification as a member of a nucleotidyltransferase superfamily, along with nucleotide polymerases and aminoglycoside nucleotidyltransferases, and this relationship offers further support for the LinB mechanism. The LinB structure provides an evolutionary link to ancient nucleotide polymerases and suggests that, like protein kinases and acetyltransferases, these are proto-resistance elements from which drug resistance can evolve.

Ligand Migration and Cavities within Scapharca Dimeric HbI: Studies by Time-Resolved Crystallo- graphy, Xe Binding, and Computational Analysis

As in many other hemoglobins, no direct route for migration of ligands between solvent and active site is evident from crystal structures of Scapharca inaequivalvis dimeric HbI. Xenon (Xe) and organic halide binding experiments, along with computational analysis presented here, reveal protein cavities as potential ligand migration routes. Time-resolved crystallographic experiments show that photodissociated carbon monoxide (CO) docks within 5 ns at the distal pocket B site and at more remote Xe4 and Xe2 cavities. CO rebinding is not affected by the presence of dichloroethane within the major Xe4 protein cavity, demonstrating that this cavity is not on the major exit pathway. The crystal lattice has a substantial influence on ligand migration, suggesting that significant conformational rearrangements may be required for ligand exit. Taken together, these results are consistent with a distal histidine gate as one important ligand entry and exit route, despite its participation in the dimeric interface.

Structural Basis for Enzymatic Evolution from a Dedicated ADP-ribosyl Cyclase to a Multifunctional NAD Hydrolase

Cyclic ADP-ribose (cADPR) is a universal calcium messenger molecule that regulates many physiological processes. The production and degradation of cADPR are catalyzed by a family of related enzymes, including the ADP-ribosyl cyclase from Aplysia california (ADPRAC) and CD38 from human. Although ADPRC and CD38 share a common evolutionary ancestor, their enzymatic functions toward NAD and cADPR homeostasis have evolved divergently. Thus, ADPRC can only generate cADPR from NAD (cyclase), whereas CD38, in contrast, has multiple activities, i.e. in cADPR production and degradation, as well as NAD hydrolysis (NADase). In this study, we determined a number of ADPRC and CD38 structures bound with various nucleotides. From these complexes, we elucidated the structural features required for the cyclization (cyclase) reaction of ADPRC and the NADase reaction of CD38. Using the structural approach in combination with site-directed mutagenesis, we identified Phe-174 in ADPRC as a critical residue in directing the folding of the substrate during the cyclization reaction. Thus, a point mutation of Phe-174 to glycine can turn ADPRC from a cyclase toward an NADase. The equivalent residue in CD38, Thr-221, is shown to disfavor the cyclizing folding of the substrate, resulting in NADase being the dominant activity. The comprehensive structural comparison of CD38 and APDRC presented in this study thus provides insights into the structural determinants for the functional evolution from a cyclase to a hydrolase.