Joint host-pathogen genomic analysis identifies hepatitis B virus mutations associated with human NTCP and HLA class I variation.

Evolutionary changes in the hepatitis B virus (HBV) genome could reflect its adaptation to host-induced selective pressure. Leveraging paired human exome and ultra-deep HBV genome-sequencing data from 567 affected individuals with chronic hepatitis B, we comprehensively searched for the signatures of this evolutionary process by conducting "genome-to-genome" association tests between all human genetic variants and viral mutations. We identified significant associations between an East Asian-specific missense variant in the gene encoding the HBV entry receptor NTCP (rs2296651, NTCP S267F) and mutations within the receptor-binding region of HBV preS1. Through in silico modeling and in vitro preS1-NTCP binding assays, we observed that the associated HBV mutations are in proximity to the NTCP variant when bound and together partially increase binding affinity to NTCP S267F. Furthermore, we identified significant associations between HLA-A variation and viral mutations in HLA-A-restricted T cell epitopes. We used in silico binding prediction tools to evaluate the impact of the associated HBV mutations on HLA presentation and observed that mutations that result in weaker binding affinities to their cognate HLA alleles were enriched. Overall, our results suggest the emergence of HBV escape mutations that might alter the interaction between HBV PreS1 and its cellular receptor NTCP during viral entry into hepatocytes and confirm the role of HLA class I restriction in inducing HBV epitope variations.

Self-Replication Without Hydrogen-Bonds: An Exobiotic Design.

Life on Earth uses DNA as the central template for self-replication, genetic encoding, and information transfer. However, there are no physical laws precluding life's existence elsewhere in space, and alternative life forms may not need DNA. In the search for exobiology, knowing what to look for as a biosignature remains a challenge-especially if it is not from the obvious list of biologic building blocks. Clues from chemicals recently discovered on Mars and in the Taurus Molecular Cloud 1 (TMC-1), show that intriguing organic compounds exist beyond Earth, which could provide a starting point for unconventional exobiotic designs. Here we present a new self-replicating system with structural similarities to recently discovered compounds on Mars and TMC-1. Rather than using DNA's hydrogen-bonding motif for reliable base-paring, our design employs sulfur-nitrogen interactions to selectively template unique benzothiadiazole units in sequence. We synthesized and studied two versions of this system, one reversible and the other irreversible, and found experimental evidence of self-replication in d-chloroform solvent. These results are part of a larger pursuit in our lab for developing a basis for a potential exobiological system using starting blocks closely related to these cosmic compounds.

Sequential, Electrochemical-Photochemical Synthesis of 1,2,4-Triazolo-[4,3-a]pyrazines.

1,2,4-triazolo-[4,3-a]pyrazine was prepared via a two-step electrochemical, photochemical process. First, a 5-substituted tetrazole is electrochemically coupled to 2,6-dimethoxypyrazine to yield 1,5- and 2,5- disubstituted tetrazoles. Subsequent photochemical excitation of the 2,5-disubstituted tetrazole species using an ultraviolet lamp releases nitrogen gas and produces a short-lived nitrilimine intermediate. Subsequent cyclization of the nitrilimine intermediate yields a 1,2,4-triazolo-[4,3-a]pyrazine backbone. The scope of this reaction was explored using various tetrazoles and pyrazines. Materials produced were identified using chemical analytical techniques and computationally studied for potential application as an insensitive energetic material.

Direct Oxidations of meso-Tetrakis(pentafluorophenyl)porphyrin: Porphotrilactones and Entry into a Nonbiological Porphyrin Degradation Pathway.

The direct oxidations of meso-tetrakis(pentafluorophenyl)porphyrin using cetyltrimethylammonium permanganate (CTAP), RuCl3/Oxone/base or Ag+/oxalic acid each generate distinctive product mixtures that may contain, inter alia, porpho-mono-, di-, and trilactones. The CTAP and RuCl3/Oxone/base oxidations also generate a unique open chain tripyrrin derived from the degradation of a porpholactone oxazolone moiety. Thus, its formation and structure are distinctly different from all biological or nearly all other nonbiological biliverdin-like linear porphyrinoid degradation products that are derived from ring cleavages between the pyrrolic building blocks.

Supramolecular Binding of Phosphonate Dianions by Nanojars and Nanojar Clamshells.

Despite the widespread use of phosphonates (RPO32-) in various agricultural, industrial, and household applications and the ensuing eutrophication of polluted water bodies, the capture of phosphonate ions by molecular receptors has been scarcely studied. Herein, we describe a novel approach to phosphonate binding using chemically and thermally robust supramolecular coordination assemblies of the formula [RPO3⊂{cis-CuII(µ-OH)(µ-pz)}n]2- (Cun; n = 27-31; pz = pyrazolate ion, C3H3N2-; R = aliphatic or aromatic group). The neutral receptors, termed nanojars, strongly bind phosphonate anions by a multitude of hydrogen bonds within their highly hydrophilic cavities. These nanojars can be synthesized either directly from their constituents or by depolymerization of [trans-CuII(µ-OH)(µ-pz)]∞ induced by phosphonate anions. Electrospray-ionization mass spectrometry, UV-vis and variable-temperature, paramagnetic 1H and 31P NMR spectroscopy, single-crystal X-ray diffraction, along with chemical stability studies toward NH3 and Ba2+ ions, and thermal stability studies in solution are employed to explore the binding of various phosphonate ions by nanojars. Crystallographic studies of 12 different nanojars offer unprecedented structural characterization of host-guest complexes with doubly charged RPO32- ions and reveal a new motif in nanojar chemistry, nanojar clamshells, which consist of phosphonate anion-bridged pairs of nanojars and double the phosphonate-binding capacity of nanojars.

Conversion of Metal Pyrazolate/(Hydr)oxide Clusters into Nanojars: Solution vs Solid-State Structure and Magnetism.

Nanojars are a class of anion binding and extraction agents composed of a series of [Cu(µ-OH)(µ-pz)]n (pz = pyrazolate; n = 26-36) supramolecular metal-organic complexes. In contrast to other anion binding agents amenable to liquid-liquid extraction, nanojars only form by self-assembly around the target anion, and guest-free nanojar hosts cannot be isolated. An extraordinary binding strength toward highly hydrophilic anions such as carbonate and sulfate was demonstrated by the inability of Ba2+ ions to precipitate the corresponding insoluble barium salts from nanojars. Herein, we provide an additional proof for the superior robustness of the nanojar framework based on competition experiments with other transition metal pyrazolate/(hydr)oxide complexes. In addition to the mass spectrometric characterization, we present variable-temperature nuclear magnetic resonance studies with an emphasis on the influence of the paramagnetic Cu2+ centers on 1H hyperfine shifts, along with X-ray crystallographic analysis of two polymorphs of (MePh3P)2[CO3⊂{Cu(OH)(pz)}27], including the highest (cubic) symmetry nanojar crystal lattice obtained to date as well as magnetism studies for the first time. Furthermore, we provide evidence for the first molybdate-incarcerating nanojars, [MoO4⊂{Cu(µ-OH)(µ-pz)}n]2- (n = 28, 31-33), formed by rearrangement from [MoVI8O12(µ-O)9(µ-pz)6(pzH)6·3pzH] in the presence of Cu2+ ions.

Ternary Complexes of BiI3/CuI and SbI3/CuI with Tetrahydrothiophene.

Reactions of BiI3/CuI mixtures with tetrahydrothiophene (THT) in toluene produce 2-D sheet networks BiCu3I6(THT)n (n = 2, 3, or 4), depending on reaction conditions. All three structures are based on BiI6 octahedra, which share pairs of (µ2-I)2 with Cu3(THT)n units. BiCu3I6(THT)2 features Cu2(µ2-I)2 rhombs with close Cu···Cu interactions and is accompanied by formation of the very complex HBi3Cu12I22(THT)8. Reactions of SbI3/CuI with THT in toluene produced a SbCu3I6(THT)2 network shows Cu3(µ2-THT)2 units, like its Bi congener, but Cu6(µ2-I)6 barrels rather than rhombs. Isolated SbI3 units are stacked above the Cu6I6 barrels. A molecular compound, Sb3Cu3I12(THT)6 consists of a face-sharing Sb3I12 stack, in which the Cu-THT units are bonded in asymmetric fashion about the central SbI6. Metal-halide bonds were investigated via QTAIM and NLMO analyses, demonstrating that these bonds are largely ionic and occur between the Bi/Sb and I p orbitals. Hirshfeld analysis shows significant H···H and H···I interactions. Diffuse reflectance spectroscopy (DRS) reveals band edges for the Bi species of 1.71-1.82 eV, while those for the neutral Sb complexes are in the range of 1.94-2.06 eV. Mapping of the electronic structure via density of state calculations indicates population of antibonding Bi/Sb-I orbitals in the excited state.

Metal-Ligand Redox Cooperativity in Cerium Amine-/Amido-Phenolate-Type Complexes.

The synthesis and characterization of two cerium complexes of redox-active amine/amido-phenolate-type ligands are reported. A tripodal framework comprising the tris(2-(3',5'-di-tert-butyl-2'-hydroxyphenyl)amino-phenyl) amine (H6Clamp) proligand was synthesized for comparison of its cerium complex with a potassium-cerium heterobimetallic complex of the 4,6-di-tert-butyl-2-[(2,6-diisopropylphenyl)imino]quinone (dippap) proligand. Structural studies indicate differences in the cerium(III) cation coordination spheres, where CeIII(CH3CN)1.5(H3Clamp) (1-Ce(H3Clamp)) exhibits shorter Ce-O distances and longer Ce-N bond distances compared to the analogous distances in K3(THF)3CeIII(dippap)3 (2-Ce(ap)), due to the gross structural differences between the systems. Differences are also evident in the temperature-dependent magnetic properties, where smaller χT products were observed for 2-Ce(ap) compared to 1-Ce(H3Clamp). Solution electrochemical studies for the complexes were interpreted based on ligand- and metal-based oxidation events, and the cerium(III) oxidation of 2-Ce(ap) was observed to be more facile than that of 1-Ce(H3Clamp), behavior that was cautiously attributed to the rigidity of the encrypted 1-Ce(H3Clamp) complex compared to the heterobimetallic framework of 2-Ce(ap). These results contribute to the understanding of how ligand designs can promote facile redox cycling for cerium complexes of redox-active ligands, given the large contraction of cerium-ligand bonds upon oxidation.

Anion-π interaction with alkenes: persistent complexes vs. irreversible reactions of anions with tetracyanoethylene.

The interaction of the tetracyanoethylene (TCNE) π-acceptor with oxo- and fluoro-anions (BF4-, PF6-, ClO4-, NO3-) led to the formation of anion-π complexes in which these polyatomic anions were located over the face of alkenes, with multiple contacts being shorter than the van der Waals separations. The anion-π associations of TCNE with halides were delimited by the electron-donor strengths and nucleophilicity of the anions. Specifically, while bromides formed persistent anion-π associations with TCNE in the solid state and in solutions, only transient anion-π complexes with iodides and chlorides were observed. In the case of iodide (strong 1e reducing agent), the formation of anion-π complexes was followed by the reduction of the π-acceptor to the TCNE-˙ anion-radical. The interaction of TCNE with Cl- (and F-) anions (which are better nucleophiles in the aprotic solvents) led to the formation of 1,1,2,3,3-pentacyanoprop-2-en-1-ide anions. Thermodynamics, UV-Vis spectra, and structures, as well as contributions of electrostatics, orbital interactions, and dispersion to the interaction energies in the complexes of TCNE with various anions were closely related to the characteristics of the corresponding associations with the aromatic and p-benzoquinone acceptors. This points out the general equivalence of the interactions in the anion-π complexes with different π-acceptors and the critical role of the nature of the anions in these bindings.

Complexes of Zinc-Coordinated Heteroaromatic N-Oxides with Pyrene: Lewis Acid Effects on the Multicenter Donor-Acceptor Bonding.

4-Nitroquinoline-N-oxide (NQO) and 4-nitropyridine-N-oxide (NPO) are important precursors for the synthesis of substituted heterocycles while NQO is a popular model mutagen and carcinogen broadly used in cancer research; intermolecular interactions are critical for their reactions or functioning in vivo. Herein, the effects of the coordination of N-oxide's oxygen atom to Lewis acids on multicenter donor-acceptor bonding were explored via a combination of experimental and computational studies of the complexes of NQO and NPO with a typical π-electron donor, pyrene. Coordination with ZnCl2 increased the positive electrostatic potentials on the surfaces of these π-acceptors and lowered the energy of their LUMO. Analogous effects were observed upon the protonation of the N-oxides' oxygen or bonding with boron trifluoride. The interaction of ZnCl2, NPO, or NQO and pyrene resulted in the formation of dark co-crystals comprising π-stacked Zn-coordinated N-oxides and pyrene similar to that found with protonated or (reported earlier) BF3-bonded N-oxides. Computational studies indicated that the coordination of N-oxides to zinc(II), BF3, or protonation led to the strengthening of the multicenter bonding of the nitro-heterocycle with pyrene, and this effect was related both to the increased electrostatic attraction and molecular-orbital interactions in their complexes.

Electrostatic CH-π Interactions Can Override Fluorine Gauche Effects To Exert Conformational Control.

Fluorine gauche effects are conformational properties of 2-fluoroethanes often applied in modern molecular designs. However, the physical origins of fluorine gauche effects are not well understood, with the consensus favoring the established hyperconjugation theory over an emerging electrostatic model. Using a series of model systems, we show that a shift to fluorine gauche effects can be influenced by intramolecular CH⋅⋅⋅π aromatic interactions, a through-space event. Modulating the π-ring (forming the aromatic interaction) with substituent groups resulted in a linear Hammett relationship, thus indicating that the CH⋅⋅⋅π interaction has electrostatic features. For instance, attaching a nitro group (an electron-withdrawing substituent) to the π-ring weakened the CH⋅⋅⋅π interaction and led to a gauche preference, whereas an anti conformer is preferred with amine as substituent. The experimental results performed by using proton NMR spectroscopy are corroborated by gas-phase DFT calculations and solid-state X-ray crystallography.

Bridging the crystal and solution structure of a series of lipid-inspired ionic liquids.

A series of 1,2-dimethylimidazolium ionic liquids bearing a hexadecyl alkyl chain are thoroughly examined via X-ray crystallography. The crystal structures reveal several key variations in the non-covalent interactions in the lipid-like salts. Specifically, distinct cation-cation π interactions are observed when comparing the bromide and iodide structures. Changing the anion to bis(trifluoromethane)sulfonimide (Tf2N-) changes these cation-cation π interactions with anion⋯π interactions. Additionally, several well-defined geometries of the cations are noted based on torsion and core-plane angles of the alkyl chains. Hirshfeld surface analysis is used to distinguish the interactions and geometries in the solid state, helping to reveal characteristic structural fingerprints for the compounds. The solid-state structures of the ionic liquids are correlated with the solution-state structures through UV-vis spectroscopic studies, further emphasizing the importance of the π interactions in the formation of aggregates. Finally, we investigated the thermal properties of the ionic liquids, revealing complex phase transitions for the iodide-containing species. These phase transitions are further rationalized via the analysis of the data gathered from the structures of the other crystallized salts.

Chromate Incarceration by Nanojars and Its Removal from Water by Liquid-Liquid Extraction.

The unprecedented liquid-liquid extraction of the dinegative chromate ion (CrO42-) from neutral aqueous solutions into aliphatic hydrocarbon solvents using nanojars as extraction agents is demonstrated. Transferring chromate from water into an organic solvent is extremely challenging due to its large hydration energy (ΔGh° = -950 kJ/mol) and strong oxidizing ability. Owing to their highly hydrophilic anion binding pockets lined by a multitude of hydrogen bond donor OH groups, neutral nanojars of the formula [cis-CuII(µ-OH)(µ-4-Rpz)]n (n = 27-33; pz = pyrazolate anion; R = H or n-octyl) strongly bind the CrO42- ion and efficiently transfer it from water into n-heptane or C11 - C13 isoalkanes (when R = n-octyl). The extracted chromate can easily be recovered from the organic layer by stripping with an aqueous acid solution. Electrospray ionization mass spectrometric, UV-vis and paramagnetic 1H NMR spectroscopic, X-ray crystallographic, and thermal stability studies in solution and chemical stability studies toward NH3, methanol, and Ba2+ ions are employed to explore the binding of the CrO42- ion by nanojars. Titration of carbonate nanojars [CO3 ⊂ {Cu(OH)(pz)}n]2- with H2CrO4 leads to anion exchange and the formation of chromate nanojars [CrO4 ⊂ {Cu(OH)(pz)}n]2-. Details of chromate binding by H-bonding based on single-crystal structures of (Bu4N)2[CrO4 ⊂ {Cu(OH)(pz)}28], four pseudopolymorphs of (Bu4N)2[CrO4 ⊂ {Cu(OH)(pz)}31], and also the methoxy-substituted derivative (Bu4N)2[CrO4 ⊂ {Cu31(OH)30(OCH3)(pz)31}] are presented.

Halogen Bonding and/or Covalent Bond: Analogy of 3c-4e N···I···X (X = Cl, Br, I, and N) Interactions in Neutral, Cationic, and Anionic Complexes.

X-ray structural measurements and computational analysis demonstrated the similarity of the geometries and electronic structures of the X-I···N (X = Cl, Br, I, and N) bonding in strong halogen-bonded (HaB) complexes and in the anionic or cationic halonium ions. In particular, I···N bond lengths in the solid-state associations formed by strong HaB donors (e.g., I2, IBr, ICl, and N-iodosuccinimide) and acceptors (e.g., quinuclidine or pyridines) were in the same range of 2.3 ± 0.1 Å as those in the halonium ions [e.g., the bis(quinuclidine)iodonium cation or the 1,1'-iodanylbis(pyrrolidine-2,5-dione) anion]. In all cases, bond lengths were much closer to those of the N-I covalent bond than to the van der Waals separations of these atoms. The strong N···I bonding in the HaB complexes led to a substantial charge transfer, lengthening and weakening of the I···X bonds, and polarization of the HaB donors. As a result, the central iodine atoms in the strong HaB complexes bear partial positive charges akin to those in the halonium ions. The energies and Mayer bond orders for both N···I and I···X bonds in such associations are also comparable to those in the halonium ions. The similarity of the bonding in such complexes and in halonium ions was further supported by the analysis of electron densities and energies at bond critical (3, -1) points in the framework of the quantum theory of atoms in molecules and by the density overlap region indicator. Overall, all these data point out the analogy of the symmetric N···I···N bonding in the halonium ions and the asymmetric X···I···N bonding in the strong HaB complexes, as well as the weakly covalent character of these 3c-4e interactions.

Dinickel-Catalyzed N═N Bond Rotation.

Azoarenes function as molecular switches that can be triggered by external stimuli, such as heat, light, and electrochemical potential. Here, we show that a dinickel catalyst can induce cis/trans isomerization in azoarenes through a N═N bond rotation mechanism. Catalytic intermediates containing azoarenes bound in both the cis and trans forms are characterized. Solid-state structures reveal the importance of π-back-bonding interactions from the dinickel active site in lowering the N═N bond order and accelerating bond rotation. The scope of the catalytic isomerization includes high-performance acyclic, cyclic, and polymeric azoarene switches.

Mechanistic Investigation of the Synthesis of Dianionic In-Derived Coordination Polymers.

The mechanism of formation of crystalline coordination polymers is as complex as the architectures themselves. In this Communication, we detail a three-tiered approach using density functional theory (DFT) analysis, synthesis, and in situ Raman spectroscopy to study the formation of coordination polymers. Specifically, the previously reported coordination polymers YCM-22 and YCM-51 containing the [In(CO2R)2X3]2- (X = halogen) molecular building unit (MBU) were investigated. DFT revealed two potential pathways of formation, involving the initial formation of either [InCl4]- or [In(CO2R)Cl3]-. A molecular dimeric In species (8a) containing two [In(CO2R)Cl4]2- centers bridged by 2,5-thiophenedicarboxylic acid was isolated. When a suspension of 8a was treated with a solution of 2,5-thiophenedicarboxylic acid, an isomer of the coordination polymer YCM-22 (denoted as YCM-22') was formed. In situ Raman analysis of the formation of YCM-22 confirms that [InCl4]- forms at the onset of the reaction and that the [In(CO2R)2X3]2- MBU forms at its expense. The totality of the data presented support a mechanism of formation of one-dimensional In-derived coordination polymers and present a roadmap for future investigations into the formation of other crystalline coordination polymers.

Energetic Salts of a Tri-Annulated Ring System.

Energetic salts of a triazolyl-tetrazinyl-aminotriazine ring system are characterized as energetic materials. Previously known sodium, ammonium, hydrazinium, barium, and triaminoguanidinium salts as well as the parent free acid were synthesized according to literature procedures and fully characterized for the first time as energetic materials. The silver salt was also synthesized and characterized for the first time as an energetic material. Generally, these materials form hydrates that are insensitive to mechanical stimuli; however, in cases in which anhydrous materials can be obtained, high sensitivities are possible.

Synthesis, Characterization, and Reduction of Thorium Pyridinediimine Complexes.

A family of thorium complexes featuring the redox-noninnocent pyridinediimine ligand MesPDIMe was synthesized, including (MesPDIMe)ThCl4 (1-Th), (MesPDIMe)ThCl3(THF) (2-Th), (MesPDIMe)ThCl2(THF)2 (3-Th) and [(MesPDIMe)Th(THF)]2 (5-Th) Full characterization of these species shows that these complexes feature MesPDIMe in four different oxidation states. The electronic structures of these complexes have been explored using 1H NMR and electronic absorption spectroscopies, X-ray crystallography, and SQUID magnetometry where appropriate.

Physical and Electrochemical Analysis of N-Alkylpyrrolidinium-Substituted Boronium Ionic Liquids.

In this work, a series of novel boronium-bis(trifluoromethylsulfonyl)imide [TFSI-] ionic liquids (IL) are introduced and investigated. The boronium cations were designed with specific structural motifs that delivered improved electrochemical and physical properties, as evaluated through cyclic voltammetry, broadband dielectric spectroscopy, densitometry, thermogravimetric analysis, and differential scanning calorimetry. Boronium cations, which were appended with N-alkylpyrrolidinium substituents, exhibited superior physicochemical properties, including high conductivity, low viscosity, and electrochemical windows surpassing 6 V. Remarkably, the boronium ionic liquid functionalized with both an ethyl-substituted pyrrolidinium and trimethylamine, [(1-e-pyrr)N111BH2][TFSI], exhibited a 6.3 V window, surpassing previously published boronium-, pyrrolidinium-, and imidazolium-based IL electrolytes. Favorable physical properties and straightforward tunability make boronium ionic liquids promising candidates to replace conventional organic electrolytes for electrochemical applications requiring high voltages.

Exploring the Nature of Anion-π Interactions: Complexes of π-Acceptors with Fluoro- or Oxoanions Compared to the Associations with Halides.

The variations in the nature and properties of the anion-π complexes with different types of anions are identified via experimental (UV-vis and X-ray crystallographic) measurements and computational analysis of the associations of tetracyanopyrazine, tetrafluoro-, or dichlorodicyano-p-benzoquinone. Co-crystals of these π-acceptors with the salts of fluoro- and oxoanions (PF6-, BF4-, CF3SO3-, or ClO4-) comprised anion-π bonded alternating chains or 1:2 complexes showing interatomic contacts of up to 15% shorter than the van der Waals separations. DFT computations confirmed that binding energies between the neutral π-acceptors and polyatomic noncoordinating oxo- and fluoroanions are comparable to those in the previously reported anion-π complexes with more nucleophilic halides. Yet, while the latter show distinct charge-transfer bands in the UV-vis range, the absorption spectra of the solutions containing oxo- and fluoroanions and the π-acceptors were close to those of the individual reactants. The natural bond orbital (NBO) analysis revealed a very small charge transfer of Δq = 0.01-0.02 e in the complexes with oxo- or fluoroanions as compared to the Δq = 0.05-0.22 e found for analogous complexes with halides. These distinctions were related to the smaller frontier orbital energy gap and better overlap in the complexes with halides (since the highest occupied orbitals of these monoatomic anions are closer in energy to the lowest unoccupied orbitals of the π-acceptors) as compared to that in the multicenter-bonded associations with polyatomic oxo- and fluoroanions. In accordance with these data, the energy decomposition analysis showed that while the complexes of neutral π-acceptors with the fluoro- and oxoanions are formed predominantly via electrostatic interaction, the associations with halides comprised significant orbital (charge-transfer) interactions and they explain their spectral and structural features.