Subatomic structure of orthorhombic thaumatin at 0.89 Å reveals that highly flexible conformations are crucial for thaumatin sweetness.

Thaumatin is a sweet-tasting protein that elicits a sweet taste at a threshold of approximately 50 nM. Structure-sweetness relationships in thaumatin suggest that the basicity of two amino acids residues, Arg82 and Lys67, are particularly responsible for sweetness. Using tetragonal crystals, our structural analysis suggested that flexible sidechain conformations of these two residues play an important role in sweetness. However, in tetragonal crystals, Arg82 is adjacent to symmetry-related residues, and its flexibility is relatively restrained by the crystal packing. To reduce and diminish these symmetry-related effects, orthorhombic crystals were prepared, and their structures were successfully determined at a resolution of 0.89 Å. Within the orthorhombic lattice, two alternative conformations were more clearly visible at Lys67 than in a tetragonal system. Interestingly, for the first time, three alternative conformations at Arg82 were only found in an orthorhombic system. These results suggest the importance of flexible conformations in sweetness determinants. Such subtle structural variations might serve to adjust the complementarity of the electrostatic potentials of sweet receptors, thereby eliciting the potent sweet taste of thaumatin.

Columnar Organization of Nonalternant Fluorinated Dehydrobenzannulenes.

Two new partially fluorinated dehydrobenzannulenes have been prepared by inter- and intramolecular oxidative homocoupling of diyne precursors. These systems contain fluorinated and nonfluorinated arene rings in a desymmetrized non-alternant arrangement. Both macrocycles are roughly planar and organize into extended columns in the solid state. The assembly of these columns is mediated by the combination of dispersion interactions, slipped [π⋅⋅⋅π] stacking interactions of the perfluorinated rings with each other, and their association with the nonfluorinated rings in the molecules of the neighboring macrocycles. These results suggest that partial fluorination of dehydrobenzannulenes can serve as a versatile motif for their assembly into columnar superstructures.

Quantitative characterization of fluorine-centered noncovalent interactions in crystalline benzanilides.

Six isomeric molecules, featuring a minimum of three fluorine atoms on either the benzoyl or aniline side, have been synthesized, crystallized and characterized through single crystal X-ray diffraction (SCXRD). In addition, two other compounds, containing six fluorine atoms, three on each of the benzoyl and aniline side of the benzanilide scaffold have also been characterized through SCXRD. This current study aims to augment the capacity for hydrogen bond formation, specifically involving organic fluorine, by elevating the acidity of the involved hydrogens through the incorporation of highly electronegative fluorine atoms, in the presence of strong N-H×××O=C H-bonds. Lattice energy calculations and assessment of intermolecular interaction energies elucidate the contributions of electrostatics and dispersion forces in crystal packing. The topological analysis of the electron density is characterized by the presence of bond critical points (BCPs) involving C-H×××F and F×××F contacts, thus establishing the bonding nature of these interactions which play a crucial role in the crystal packing in addition to the presence of traditional N-H×××O=C H-bonds.

Synthon Approach in Crystal Engineering to Modulate Physicochemical Properties in Organic Salts of Chlorpropamide.

The formulation of drug with improved bioavailability is always challenging and indispensable in the field of pharmaceutics. The control of intermolecular interactions via crystal engineering approach and solid-state molecular recognition results in the formation of active drug molecules with modulated pharmacological benefits. Therefore, with the aim to improve the solubility and dissolution rate of the drug chlorpropamide (CPA), the mechanochemical liquid-assisted grinding (LAG) of the drug with several pharmaceutically accepted excipients was performed. This contributed to the discovery of six novel solid phases, namely salts, salt cocrystals and salt cocrystal hydrate─the salt of CPA with 3, 4-diaminopyridine (DAP); salt and salt cocrystal (SC) polymorph (Z″=3) with 1, 4-diazabicyclo [2.2.2] octane (DABCO); a salt, SC polymorph (Z″=9), and a SC hydrate (Z″=9) with piperazine (PIP). The formation of these salts and salt cocrystals are mainly guided by the strong hydrogen bonds with tunable strength having high electrostatic contribution. This attractive interaction brings the donor and the acceptor atoms close to each other for a facile proton transfer. Furthermore, the conformational constraints on the drug molecules, provided by the excipients via strong and directional hydrogen bonds, are quite impressive as this leads to the identification and characterization of "new conformational isomers" for the CPA molecules. The new crystalline phases exhibit enhanced intrinsic dissolution rate in comparison to that of the pure drug, the magnitude being 7, 131, and 120 folds for CPADAP, CPADABCO_II, and CPAPIP_III, respectively. Furthermore, it is interesting to note that the order of solubility is enhanced by 2.7-, 3-, and 7-fold, respectively, for the abovementioned salts. This also mirrors the trends in the magnitude of the binding energy, the higher magnitude being reflected in the lower solubility. Additionally, the in vivo experiments performed in SD rats results in the enhancement of the magnitude of the pharmacokinetic properties, when compared to the pristine drug. The concentration of the drug in CPADABCO_II and CPAPIP_III formulations exhibits 6- and 4-fold increments, respectively. Indeed, these results corroborate to the trends observed in the structural characterization, intermolecular energy calculations, solubility, and in vitro dissolution assessments.

A Novel Homoconjugated Propellane Triimide: Synthesis, Structural Analyses, and Gas Separation.

Rigid three-dimensional (3D) polycyclic propellanes have garnered interest due to their unique conformational spaces, which display great potential use in selectivity, separation and as models to study through-space electronic interactions. Herein we report the synthesis of a novel rigid propellane, trinaphtho[3.3.3]propellane triimide, which comprises three imide groups embedded on a trinaphtho[3.3.3]propellane. This propellane triimide exhibits large bathochromic shift, amplified molar absorptivity, enhanced fluorescence, and lower reduction potential when compared to the subunits. Computational and experimental studies reveal that the effective through-space π-orbitals interacting (homoconjugation) occurs between the subunits. Single-crystal XRD analysis reveals that the propellane triimide has a highly quasi-D3h symmetric skeleton and readily crystallizes into different superstructures by changing alkyl chains at the imide positions. In particular, the porous 3D superstructure with S-shaped channels is promising for taking up ethane (C2H6) with very good selectivity over ethylene (C2H4), which can purify C2H4 from C2H6/C2H4 in a single separation step. This work showcases a new class of rare 3D polycyclic propellane with intriguing electronic and supramolecular properties.

An Asymmetric Coumarin-Anthracene Conjugate as Efficient Fullerene-Free Acceptor for Organic Solar Cells.

Asymmetric wide-band gap fullerene-free acceptors (FFAs) play a crucial role in organic solar cells (OSCs). Here, we designed and synthesized a simple asymmetric coumarin-anthracene conjugate named CA-CN with optical band gap of 2.1 eV in a single-step condensation reaction. Single crystal X-ray structure analysis confirms various multiple intermolecular non-covalent interactions. The molecular orbital energy levels of CA-CN estimated from cyclic voltammetry were found to be suitable for its use as an acceptor for OSCs. Binary OSCs fabricated using CA-CN as acceptor and PTB7-Th as the donor achieve a power conversion efficiency (PCE) of 11.13 %. We further demonstrate that the insertion of 20 wt % of CA-CN as a third component in ternary OSCs with PTB7-Th : DICTF as the host material achieved an impressive PCE of 14.91 %, an improvement of ~43 % compared to the PTB7-Th : DICTF binary device (10.38 %). Importantly, the ternary blend enhances the absorption coverage from 400 to 800 nm and improves the morphology of the active layer. The findings highlight the efficacy of an asymmetric design approach for FFAs, which paves the way for developing high-efficiency OSCs at low cost.

A Direct Route to closo-SBnCln Thiaboranes from Simple Electron-Precise Synthons: The Different Role of Chalcogen Bonding in SB5Cl5 and SB11Cl11 Crystals.

Six-vertex closo-SB5Cl5 (1) and ten-vertex closo-1-SB9Cl9 (2) thiaboranes have been prepared, besides the already known 12-vertex closo-SB11Cl11 (3), from the co-pyrolysis reaction of B2Cl4 with S2Cl2 at 280 °C in vacuo. The compounds are sublimable, off-white solids. Their elemental composition has been determined by high-resolution mass spectrometry. They were further characterized by one- and two-dimensional 11B NMR spectroscopy and X-ray structure determination for 1 and 3. Ab initio/GIAO/NMR computations support octahedral, bicapped square-antiprismatic, and icosahedral geometries for 1, 2 and 3, respectively, as expected based on their closo-electron counts. 1 is the first isolated example of a neutral polyhedral closo-thiaborane with a cluster size smaller than ten vertices. The solid-state structure of 3 is one of the rare examples of a single-crystal X-ray structure determination of an icosahedral heteroborane reported. The corresponding crystal-packing forces show the different role of chalcogen bonding in these octahedral and icosahedral crystals. In addition, there is a mass-spectrometry evidence for the recurrent formation of further thiaborane homologs of closo-SBnCln with n=4, 6, 10, and supra-icosahedral 12.

Perfluoroalkyl Chain Length Effect on Crystal Packing and [LnO8] Coordination Geometry in Lanthanide-Lithium ß-Diketonates: Luminescence and Single-Ion Magnet Behavior.

Functionalized perfluoroalkyl lithium ß-diketonates (LiL) react with lanthanide(III) salts (Ln = Eu, Gd, Tb, Dy) in methanol to give heterobimetallic Ln-Li complexes of general formula [(LnL3)(LiL)(MeOH)]. The length of fluoroalkyl substituent in ligand was found to affect the crystal packing of complexes. Photoluminescent and magnetic properties of heterobimetallic ß-diketonates in the solid state are reported. The effect of the geometry of the [LnO8] coordination environment of heterometallic ß-diketonates on the luminescent properties (quantum yields, phosphorescence lifetimes for Eu, Tb, Dy complexes) and single-ion magnet behavior (Ueff for Dy complexes) is revealed.

Spin-Distribution-Directed Regioselective Substitution Strategy for Highly Stable Olympicenyl Radicals.

The synthesis of bench-stable conjugated π-radicals is challenging owing to the lack of modular approaches, which greatly hampers their practical material screens and applications. Here, we demonstrate a spin-distribution-directed regioselective substitution strategy to introduce substituents into the specific positions of an olympicenyl radical in a stepwise manner, resulting in a series of highly stable radical species. The substituents can also adjust the crystal packing by means of steric and electronic factors, enabling the changing from a π-dimer to a pseudo-one-dimensional chain. The first single crystal organic field-effect transistor device based on a graphenic radical is fabricated in air, showing a hole mobility of up to 0.021 cm2 V-1 s-1 and excellent device stability. This approach may be generalized to diverse spin-delocalized open-shell organic radicals.

Mitoxantrone stacking does not define the active or inactive state of USP15 catalytic domain.

Ubiquitin specific protease USP15 is a deubiquitinating enzyme reported to regulate several biological and cellular processes, including TGF-ß signaling, regulation of immune response, neuro-inflammation and mRNA splicing. Here we study the USP15 D1D2 catalytic domain and present the crystal structure in its catalytically-competent conformation. We compare this apo-structure to a previous misaligned state in the same crystal lattice. In both structures, mitoxantrone, an FDA approved antineoplastic drug and a weak inhibitor of USP15 is bound, indicating that it is not responsible for inducing a switch in the conformation of active site cysteine in the USP15 D1D2 structure. Instead, mitoxantrone contributes to crystal packing, by forming a stack of 12 mitoxantrone molecules. We believe this reflects how mitoxantrone can be responsible for e.g. nuclear condensate partitioning. We conclude that USP15 can switch between active and inactive states in the absence of ubiquitin, and that this is independent of mitoxantrone binding. These insights can be important for future drug discovery targeting USP15.

Surface Engineering of Top7 to Facilitate Structure Determination.

Top7 is a de novo designed protein whose amino acid sequence has no evolutional trace. Such a property makes Top7 a suitable scaffold for studying the pure nature of protein and protein engineering applications. To use Top7 as an engineering scaffold, we initially attempted structure determination and found that crystals of our construct, which lacked the terminal hexahistidine tag, showed weak diffraction in X-ray structure determination. Thus, we decided to introduce surface residue mutations to facilitate crystal structure determination. The resulting surface mutants, Top7sm1 and Top7sm2, crystallized easily and diffracted to the resolution around 1.7 Å. Despite the improved data, we could not finalize the structures due to high R values. Although we could not identify the origin of the high R values of the surface mutants, we found that all the structures shared common packing architecture with consecutive intermolecular ß-sheet formation aligned in one direction. Thus, we mutated the intermolecular interface to disrupt the intermolecular ß-sheet formation, expecting to form a new crystal packing. The resulting mutant, Top7sm2-I68R, formed new crystal packing interactions as intended and diffracted to the resolution of 1.4 Å. The surface mutations contributed to crystal packing and high resolution. We finalized the structure model with the R/Rfree values of 0.20/0.24. Top7sm2-I68R can be a useful model protein due to its convenient structure determination.

Synthesis and Structural Characterization of Pyridine-2,6-dicarboxamide and Furan-2,5-dicarboxamide Derivatives.

Derivatives based on pyridine-2-6- and furan-2,5-dicarboxamide scaffolds reveal numerous chemical properties and biological activities. This fact makes them an exciting research topic in supramolecular and coordination chemistry and in discovering new pharmacologically-active compounds. This work aimed to obtain a series of symmetrical pyridine-2-6- and furan-2,5-dicarboxamides through a condensation reaction of the appropriate acyl chlorides and aromatic amides. Successful syntheses were confirmed with NMR spectroscopy. We solved their crystal structures for seven compounds; two pyridine and five furan derivatives. Based on our crystallographic studies, we were able to indicate supramolecular features of the crystals under investigation. Additionally, Hirshfeld surface analysis allowed us to calculate a distribution of intermolecular contacts in the dicarboxamide crystals.

Comparison of Proton Acceptor and Proton Donor Properties of H2O and H2O2 in Organic Crystals of Drug-like Compounds: Peroxosolvates vs. Crystallohydrates.

Two new peroxosolvates of drug-like compounds were synthesized and studied by a combination of X-ray crystallographic, Raman spectroscopic methods, and periodic DFT computations. The enthalpies of H-bonds formed by hydrogen peroxide (H2O2) as a donor and an acceptor of protons were compared with the enthalpies of analogous H-bonds formed by water (H2O) in isomorphic (isostructural) hydrates. The enthalpies of H-bonds formed by H2O2 as a proton donor turned out to be higher than the values of the corresponding H-bonds formed by H2O. In the case of H2O2 as a proton acceptor in H-bonds, the ratio appeared reversed. The neutral O∙∙∙H-O/O∙∙∙H-N bonds formed by the lone electron pair of the oxygen atom of water were the strongest H-bonds in the considered crystals. In the paper, it was found out that the low-frequency Raman spectra of isomorphous crystalline hydrate and peroxosolvate of N-(5-Nitro-2-furfurylidene)-1-aminohydantoin are similar. As for the isostructural hydrate and peroxosolvate of the salt of protonated 2-amino-nicotinic acid and maleic acid monoanion, the Raman spectra are different.

Diastereomeric resolution of 3-chloromandelic acid with threo-(1S,2S)-2-amino-l-p-nitrophenyl-1,3-propanediol.

An optical resolution of 3-chloromandelic acid (3-ClMA) using threo-(1S,2S)-2-amino-l-p-nitrophenyl-1,3-propanediol ([S,S]-SA) as a resolving agent was presented. The effects of the type of solvents, the amount of solvent, molar ratio of the resolving agent to racemate and filtration temperature on resolution were investigated. Under the optimal resolution conditions, the content of less soluble salt reached 98%, and the resolution efficiency was as high as 94%. The weak intermolecular interactions (such as hydrogen bond, halogen bond, CH/π and van der Waals interactions) and molecular packing mode in crystal structure of the less soluble salt (R)-3-ClMA(S,S)-SA were investigated. A wall-like 2-D hydrogen-bonding network and hydrophobic structure between hydrogen-bonding walls were revealed. (S,S)-SA was also used to resolve 2-ClMA and 4-ClMA respectively and the corresponding less soluble salts (R)-2-ClMA·(R,R)-SA and (R)-4-ClMA·(R,R)-SA were obtained using threo-(1R,2R)-2-amino-l-p-nitrophenyl-1,3-propanediol ((R,R)-SA) as a resolving agent. In addition, two other resolving agents, (R)-ɑ-phenethylamine ((R)-PEA) and (R)-N-benzyl phenethylamine ((R)-BPA) reported in the literature for the resolution of 3-ClMA were examined along with the newly proposed resolving agent, (S,S)-SA. The crystal structures of the resulting less soluble salts (R)-3-ClMA·(S,S)-SA, (R)-3-ClMA·(R)-PEA and (R)-3-ClMA·(R)-BPA were compared and examined.

Energetic Co-Crystal of a Primary Metal-Free Explosive with BTF. Ideal Pair for Co-Crystallization.

Co-crystallization is an elegant technique to tune the physical properties of crystalline solids. In the field of energetic materials, co-crystallization is currently playing an important role in the engineering of crystals with improved performance. Here, based on an analysis of the structural features of the green primary explosive, tetramethylammonium salt of 7-oxo-5-(trinitromethyl)-4,5,6,7-tetrahydrotetrazolo[1,5-a][1,3,5]triazin-5-ide (1), a co-former such as the powerful secondary explosive, benzotrifuroxan (BTF, 2), has been proposed to improve it. Compared to the original 1, its co-crystal with BTF has a higher detonation pressure and velocity, as well as an initiating ability, while the impact sensitivity and thermal stability remained at about the same level. Both co-formers, 1 and 2, and co-crystal 3 were characterized by single-crystal X-ray diffraction and their crystal packing was analyzed in detail by the set of approaches, including periodic calculations. In the co-crystal 3, all intermolecular interactions were significantly redistributed. However, no new types of intermolecular interactions were formed during co-crystallization. Moreover, the interaction energies of structural units in crystals before and after co-crystallization were approximately the same. A similar trend was observed for the volumes occupied by structural units and their densifications. The similar nature of the organization of the crystals of the co-formers and the co-crystal gives grounds to assert that the selected co-formers are an ideal pair for co-crystallization, and the invariability of the organization of the crystals was probably responsible for the preservation of some of their properties.

Noble Gas Bonding Interactions Involving Xenon Oxides and Fluorides.

Noble gas (or aerogen) bond (NgB) can be outlined as the attractive interaction between an electron-rich atom or group of atoms and any element of Group-18 acting as an electron acceptor. The IUPAC already recommended systematic nomenclature for the interactions of groups 17 and 16 (halogen and chalcogen bonds, respectively). Investigations dealing with noncovalent interactions involving main group elements (acting as Lewis acids) have rapidly grown in recent years. They are becoming acting players in essential fields such as crystal engineering, supramolecular chemistry, and catalysis. For obvious reasons, the works devoted to the study of noncovalent Ng-bonding interactions are significantly less abundant than halogen, chalcogen, pnictogen, and tetrel bonding. Nevertheless, in this short review, relevant theoretical and experimental investigations on noncovalent interactions involving Xenon are emphasized. Several theoretical works have described the physical nature of NgB and their interplay with other noncovalent interactions, which are discussed herein. Moreover, exploring the Cambridge Structural Database (CSD) and Inorganic Crystal Structure Database (ICSD), it is demonstrated that NgB interactions are crucial in governing the X-ray packing of xenon derivatives. Concretely, special attention is given to xenon fluorides and xenon oxides, since they exhibit a strong tendency to establish NgBs.

DFT Computed Dielectric Response and THz Spectra of Organic Co-Crystals and Their Constituent Components.

Terahertz (THz) spectroscopy has been put forth as a non-contact, analytical probe to characterize the intermolecular interactions of biologically active molecules, specifically as a way to understand, better develop, and use active pharmaceutical ingredients. An obstacle towards fully utilizing this technique as a probe is the need to couple features in the THz regions to specific vibrational modes and interactions. One solution is to use density functional theory (DFT) methods to assign specific vibrational modes to signals in the THz region, coupling atomistic insights to spectral features. Here, we use open source planewave DFT packages that employ ultrasoft pseudopotentials to assess the infrared (IR) response of organic compounds and complex co-crystal formulations in the solid state, with and without dispersion corrections. We compare our DFT computed lattice parameters and vibrational modes to experiment and comment on how to improve the agreement between theory and modeling to allow for THz spectroscopy to be used as an analytical probe in complex biologically relevant systems.

Structural and biophysical characterization of Rv3716c, a hypothetical protein from Mycobacterium tuberculosis.

Latent tuberculosis (TB) is the main hurdle in reaching the goal of "Stop TB 2050". Tuberculin skin and Interferon-gamma release assay tests used currently for the diagnosis of TB infection cannot distinguish between active disease and latent tuberculosis infection (LTBI) and hence new and sensitive protein markers need to be identified for the diagnosis. A protein Rv3716c from Mycobacterium tuberculosis (MtbRv3716c) has been identified as a potential surrogate marker for the diagnosis of LTBI. Here, we present characterization of MtbRv3716c (∼13 kDa) using both biophysical and X-Ray crystallographic methods. EMSA study showed that MtbRv3716c binds to double stranded DNA. X-ray diffraction data collected on a crystal of MtbRv3716c at 1.9 Å resolution was used for structure determination using the molecular replacement method. Significant electron density was not observed for the N-terminal 21 and C-terminal 41 residues in the final electron density map. The C- terminal disordered region is proline rich and displays characteristics of intrinsically disordered proteins. Although the crystal asymmetric unit contained a protomer, a tight dimer could be generated by the application of the crystal two-fold symmetry parallel to the b axis. Packing of dimers in the crystal is mediated by a cadmium ion (Cd2+) occurring at the interface of two dimers. Molecular packing analysis reveals large cavities that are probably occupied by the disordered segments of the N- and C-termini. Structural comparison with other homologous hypothetical DNA binding proteins (PDB codes: 1PUG, 1YBX) highlights structural features that might be significant for DNA binding.

Stable 2D Bisthienoacenes: Synthesis, Crystal Packing, and Photophysical Properties.

Two novel 2D bisthienoacenes with annulated thiophene units at different positions were developed. Both 1,2- and 1,4-addition of the α,ß-unsaturated ketone moieties lead to the major formation of four-fold alkylsilylethynyl substituted 2D heteroacenes (namely BTT-4TIPS and BTP-4TIPS). The photophysical, electrochemical properties, crystal packing structures, and charge carrier transport performances were investigated in detail.

A new crystal form of human transthyretin obtained with a curcumin derived ligand.

Transthyretin (TTR), a 54kDa homotetrameric protein that transports thyroxine (T4), has been associated with clinical cases of TTR amyloidosis for its tendency to aggregate to form fibrils. Many ligands with a potential to inhibit fibril formation have been studied by X-ray crystallography in complex with TTR. Unfortunately, the ligand is often found in ambiguous electron density that is difficult to interpret. The ligand validation statistics suggest over-interpretation, even for the most active compounds like diflunisal. The primary technical reason is its position on a crystallographic 2-fold axis in the most common crystal form. Further investigations with the use of polyethylene glycol (PEG) to crystallize TTR complexes have resulted in a new trigonal polymorph with two tetramers in the asymmetric unit. The ligand used to obtain this new polymorph, 4-hydroxychalcone, is related to curcumin. Here we evaluate this crystal form to understand the contribution it may bring to the study of TTR ligands complexes, which are often asymmetric.