Small Guest Molecules Research Articles

Overview of the SAMPL6 host-guest binding affinity prediction challenge.

Accurately predicting the binding affinities of small organic molecules to biological macromolecules can greatly accelerate drug discovery by reducing the number of compounds that must be synthesized to realize desired potency and selectivity goals. Unfortunately, the process of assessing the accuracy of current computational approaches to affinity prediction against binding data to biological macromolecules is frustrated by several challenges, such as slow conformational dynamics, multiple titratable groups, and the lack of high-quality blinded datasets. Over the last several SAMPL blind challenge exercises, host-guest systems have emerged as a practical and effective way to circumvent these challenges in assessing the predictive performance of current-generation quantitative modeling tools, while still providing systems capable of possessing tight binding affinities. Here, we present an overview of the SAMPL6 host-guest binding affinity prediction challenge, which featured three supramolecular hosts: octa-acid (OA), the closely related tetra-endo-methyl-octa-acid (TEMOA), and cucurbit[8]uril (CB8), along with 21 small organic guest molecules. A total of 119 entries were received from ten participating groups employing a variety of methods that spanned from electronic structure and movable type calculations in implicit solvent to alchemical and potential of mean force strategies using empirical force fields with explicit solvent models. While empirical models tended to obtain better performance than first-principle methods, it was not possible to identify a single approach that consistently provided superior results across all host-guest systems and statistical metrics. Moreover, the accuracy of the methodologies generally displayed a substantial dependence on the system considered, emphasizing the need for host diversity in blind evaluations. Several entries exploited previous experimental measurements of similar host-guest systems in an effort to improve their physical-based predictions via some manner of rudimentary machine learning; while this strategy succeeded in reducing systematic errors, it did not correspond to an improvement in statistical correlation. Comparison to previous rounds of the host-guest binding free energy challenge highlights an overall improvement in the correlation obtained by the affinity predictions for OA and TEMOA systems, but a surprising lack of improvement regarding root mean square error over the past several challenge rounds. The data suggests that further refinement of force field parameters, as well as improved treatment of chemical effects (e.g., buffer salt conditions, protonation states), may be required to further enhance predictive accuracy.

Thermodynamics of H2O and CO2 Absorption and Guest-Induced Phase Transitions in Zeolite RHO

Gas absorption calorimetry at low pressures has been employed to probe the interaction of water and carbon dioxide with several ion-exchanged zeolite RHO samples. It reveals that guest-induced framework flexibility transitions from a less hydrated (initially anhydrous) acentric form to the more hydrated centric phase during water absorption. The differential enthalpy of absorption as a function of water loading directly identifies the strengths of different interactions along with possible water binding mechanisms. Interactions with CO2 are weaker, and no phase transition is seen except in Li,H-RHO. The most negative initial enthalpies have been obtained in both water and CO2 absorption for Cd and Cs-RHO. However, Li,H-RHO shows the strongest capture ability for CO2 despite a less exothermic initial enthalpy of absorption. The derived differential enthalpy, chemical potential, and entropy elucidate the thermodynamic behavior of multiple interactions of small guest molecules (H2O and CO2) and ion-exchanged...

Role of hydrogen-bonds in the crystal packing of three novel strandberg-type polyoxoanion compounds

Three new supramolecular compounds [Cu0.5(H3O)2](H2prz)1.5[Mo5P2O23]·H2O (1); [4,4′-bpy]2[4,4′-H2bpy][H4Mo5P2O23]·4H2O (2); [4,4′-Hbpy][4,4′-bpy][H3Mo5P2O23]·2H3O (3); (pyz = pyrazine, bpy = 4,4′-bpyridine) have been hydrothermally synthesized and characterized by IR, UV-Vis spectroscopy, X-ray photoelectron spectroscopy (XPS), powder XRD analyses, TG analyses, cyclic voltammogram analyses, elemental analyses and single crystal X-ray diffraction analyses. Single crystal X-ray diffraction analysis reveals that there are multipoint hydrogen-bonding interactions in compounds 1–3. The structural features of the three compounds are that distinct one-dimensional (1D) chains are firstly formed, then the chains extend to form novel two-dimensional (2D) networks, finally unprecedented three-dimensional (3D) supramolecular host-guest structures were generated by Strandberg-type polyoxometaltes (POMs) and transition metal coordination complexes (TMCs) or organic ligands, and small organic guest molecules are exactly entrapped in void spaces via H-bonding interactions. The formations of the three distinct 3D supramolecular hybrid materials demonstrate the important role of H-bonds (non-covalent bond) in the construction of high dimensional architectures. Compounds 2–3 also show outstanding photocatalysis properties.

Aliphatic Polyester Nanofibers Functionalized with Cyclodextrins and Cyclodextrin-Guest Inclusion Complexes.

The fabrication of nanofibers by electrospinning has gained popularity in the past two decades; however, only in this decade, have polymeric nanofibers been functionalized using cyclodextrins (CDs) or their inclusion complexes (ICs). By combining electrospinning of polymers with free CDs, nanofibers can be fabricated that are capable of capturing small molecules, such as wound odors or environmental toxins in water and air. Likewise, combining polymers with cyclodextrin-inclusion complexes (CD-ICs), has shown promise in enhancing or controlling the delivery of small molecule guests, by minor tweaking in the technique utilized in fabricating these nanofibers, for example, by forming core–shell or multilayered structures and conventional electrospinning, for controlled and rapid delivery, respectively. In addition to small molecule delivery, the thermomechanical properties of the polymers can be significantly improved, as our group has shown recently, by adding non-stoichiometric inclusion complexes to the polymeric nanofibers. We recently reported and thoroughly characterized the fabrication of polypseudorotaxane (PpR) nanofibers without a polymeric carrier. These PpR nanofibers show unusual rheological and thermomechanical properties, even when the coverage of those polymer chains is relatively sparse (~3%). A key advantage of these PpR nanofibers is the presence of relatively stable hydroxyl groups on the outer surface of the nanofibers, which can subsequently be taken advantage of for bioconjugation, making them suitable for biomedical applications. Although the number of studies in this area is limited, initial results suggest significant potential for bone tissue engineering, and with additional bioconjugation in other areas of tissue engineering. In addition, the behaviors and uses of aliphatic polyester nanofibers functionalized with CDs and CD-ICs are briefly described and summarized. Based on these observations, we attempt to draw conclusions for each of these combinations, and the relationships that exist between their presence and the functional behaviors of their nanofibers.

Targeted bottom-up synthesis of 1T-phase MoS2 arrays with high electrocatalytic hydrogen evolution activity by simultaneous structure and morphology engineering

The incorporation of small guest molecules or ions by bottom-up hydrothermal synthesis has recently emerged as a promising new way to engineer 1T-phase MoS2 with high hydrogen evolution reaction (HER) activity. However, the mechanism of the associated structural evolution remains elusive and controversial, leading to a lack of effective routes to prepare 1T-phase MoS2 with controlled structure and morphology, along with high purity and stability. Herein, urea is chosen as precursor of small molecules or ions to simultaneously engineer the phase (~16.4%, ~69.4%, and ~90.2% of 1T phase) and size (~98.8, ~151.6, and ~251.8 nm for the 90.2% 1T phase) of MoS2 nanosheets, which represent an ideal model system for investigating the structural evolution in these materials, as well as developing a new type of 1T-phase MoS2 arrays. Using reaction intermediate monitoring and theoretical calculations, we show that the oriented growth of 1T-phase MoS2 is controlled by ammonia-assisted assembly, recrystallization, and stabilization processes. A superior HER performance in acidic media is obtained, with an overpotential of only 76 mV required to achieve a stable current density of 10 mA·cm–2 for 15 h. This excellent performance is attributed to the unique array structure, involving well-dispersed, edge-terminated, and high-purity 1T-phase MoS2 nanosheets.

Tuning Light Emission towards White Light from a Naphthalenediimide-Based Entangled Metal-Organic Framework by Mixing Aromatic Guest Molecules

Taking advantage of the outstanding properties of a naphthalenediimide-based entangled porous coordination polymer, a simple strategy for the achievement of white light emission is herein presented. The dynamic structural transformation of the [Zn2(bdc)2(dpNDI)]n metal-organic framework enhances the interactions with aryl-guests giving rise to different luminescence colors upon UV (ultraviolet) illumination. Thus, through the rational selection of those small aromatic guest molecules with different electron donor substituents at the appropriate proportion, the emission color was tuned by mixture ratio of guest molecules and even white light emission was achieved. Furthermore, domains in large crystals with a complementary response to linearly polarized light were noticed.

Chemically Modified Silica Materials as Model Systems for the Characterization of Water-Surface Interactions

Abstract A series of novel functionalized mesoporous silica-based materials with well-defined pore diameters, surface functionalization and surface morphology is synthesized by co-condensation or grafting techniques and characterized by solid-state NMR spectroscopy, DNP enhanced solid state-NMR and thermodynamic techniques. These materials are employed as host-systems for small-guest molecules like water, small alcohols, carbonic acids, small aromatic molecules, binary mixtures and others. The phase-behavior of these confined guests is studied by combinations of one dimensional solid-state NMR techniques (1H MAS, 2H-line shape analysis, 13C CPMAS) and two-dimensional correlation experiments like 1H-29Si- solid-state HETCOR.

An Examination of the Prediction of Hydrate Formation Conditions in the Presence of Thermodynamic Inhibitors

Abstract Gas hydrates are crystalline compounds, solid structures where water traps small guest molecules, typically light gases, in cages formed by hydrogen bonds. They are notorious for causing problems in oil and gas production, transportation and processing. Gas hydrates may form at pressures and temperatures commonly found in natural gas and oil production pipelines, thus causing partial or complete pipe blockages. In order to inhibit hydrate formation, chemicals such as alcohols (e.g., ethanol, methanol, mono-ethylene glycol) and salts (sodium, magnesium or potassium chloride) are injected into the produced stream. The purpose of this work is to briefly review the literature on hydrate formation in mixtures containing light gases (hydrocarbons and carbon dioxide) and water in the presence of thermodynamic inhibitors. Four calculation methods to predict hydrate formation in those systems were examined and compared. Three commercial packages (Multiflash®, PVTSim® and CSMGem) and a hydrate prediction routine in Fortran90 using the van der Waals and Platteeuw theory and the Peng-Robinson equation of state were tested. Predictions given by the four methods were compared to independent experimental data from the literature. In general, the four methods were found to be reasonably accurate. CSMGem and Multiflash® showed the best results.

Trapping White Phosphorus within a Purely Organic Molecular Container Produced by Imine Condensation.

Three tetrahedral organic cages have been obtained by condensing a triamino linker with a set of three ostensibly analogous triformyl precursors. Despite the large number of imine bonds formed, the corresponding cages were obtained in exceptionally high yields. Both theory and experimental results demonstrate that intramolecular CH⋅⋅⋅π interactions within all of the cage frameworks play an important role in abetting the condensations and contributing to the near-quantitative synthetic yields. The three cages of this study exhibit high thermodynamic and kinetic stability. A variety of small neutral guest molecules with complementary sizes and geometries may be used as templates in the cage forming reactions. Among the guests that may be used in this way is white phosphorus (P4 ), whose inherent reactivity towards oxygen is almost fully attenuated when bound within one of the cages.

Trapping White Phosphorus within a Purely Organic Molecular Container Produced by Imine Condensation

AbstractThree tetrahedral organic cages have been obtained by condensing a triamino linker with a set of three ostensibly analogous triformyl precursors. Despite the large number of imine bonds formed, the corresponding cages were obtained in exceptionally high yields. Both theory and experimental results demonstrate that intramolecular CH⋅⋅⋅π interactions within all of the cage frameworks play an important role in abetting the condensations and contributing to the near‐quantitative synthetic yields. The three cages of this study exhibit high thermodynamic and kinetic stability. A variety of small neutral guest molecules with complementary sizes and geometries may be used as templates in the cage forming reactions. Among the guests that may be used in this way is white phosphorus (P4), whose inherent reactivity towards oxygen is almost fully attenuated when bound within one of the cages.

Systematic Study of the Effect of Lower-Rim Methylation on Small Guest Binding within the Host Cavity of Calix[4]arene.

The efficacy of calixarenes for the storage and/or detection of small guest molecules at the upper-rim is well-known. As part of our continuing efforts to investigate the ability to fine-tune the structure and hence host-guest binding characteristics of calixarenes, we present a systematic investigation of the effect of methylation of the lower-rim tetraphenolic pocket of calix[4]arene (C[4]) on binding at the upper-rim for a test-suite of guest molecules consisting of H2, O2, N2, H2O, CO2, NH3, H2S, N2O, HCN, and SO2. Results of the effects on the host-guest binding for all permutations of single, double, triple and quadruple methylations are presented. It was found that while a tetraphenolic C[4] host does not discriminate between many of the guest molecules in terms of binding energies, progressively methylated lower-rim C[4] hosts introduce differences in guest binding energies within the upper cavity to the extent where it may be possible to competitively bind one guest over another over a wide range of guests. In this regard, this family of methylated C[4] hosts show promise as gas separation devices.

Temperature responsive fluorescent polymer nanoparticles (TRFNPs) for cellular imaging and controlled releasing of drug to living cells

Recent studies have demonstrated that drug delivery by using functional nanomaterials with imaging capability could afford plenty of insightful information for the better control of the delivery process. In this work, we developed temperature responsive fluorescent nanoparticles (TRFNPs) for drug delivery and cellular imaging. The TRFNP was fabricated by one-pot co-precipitation of thermal sensitive amphiphilic block copolymers polystyrene-b-poly(N-isopropyl acrylamide) (PS-b-PNIPAM) and fluorescent conjugated polymer poly [(9,9-dioctylfluorenyl-2,7-diyl)-alt-co-(1,4-benzo(2,1′,3)-thiadiazole)] (PFBT) in the presence of desired small guest molecules. The dynamic light scattering (DLS) measurements verified that this functional nanoparticle exhibited temperature dependent size variation, which could therefore regulate the releasing rate of loaded guest molecules (e.g. drugs) inside the polymer core. Besides, the TRFNPs displayed good photostability in terms of optical characterization. The cellular cytotoxicity characterization demonstrated that this nanoparticle exhibited good biocompatibility even under the mass concentration of 10μg/mL. By using Nile Red as a model molecule, the temperature-controlled releasing process from TRFNPs in solution as well as inside living cells was monitored directly according to the spectroscopic and microscopic characterizations. Furthermore, anti-cancer drug was successfully delivered into living cells via TRFNPs and released in a temperature dependent manner. As a consequence, owing the attractive merits as mentioned above, this nanostructure would find broad applications in nanomedicine in the future.

BILP-19-An Ultramicroporous Organic Network with Exceptional Carbon Dioxide Uptake.

Porous benzimidazole-based polymers (BILPs) have proven to be promising for carbon dioxide capture and storage. The polarity of their chemical structure in combination with an inherent porosity allows for adsorbing large amounts of carbon dioxide in combination with high selectivities over unpolar guest molecules such as methane and nitrogen. For this reason, among purely organic polymers, BILPs contain some of the most effective networks to date. Nevertheless, they are still outperformed by competitive materials such as metal-organic frameworks (MOFs) or metal doped porous polymers. Here, we report the synthesis of BILP-19 and its exceptional carbon dioxide uptake of up to 6 mmol·g−1 at 273 K, making the network comparable to state-of-the-art materials. BILP-19 precipitates in a particulate structure with a strongly anisotropic growth into platelets, indicating a sheet-like structure for the network. It exhibits only a small microporous but a remarkable ultra-microporous surface area of 144 m2·g−1 and 1325 m2·g−1, respectively. We attribute the exceptional uptake of small guest molecules such as carbon dioxide and water to the distinct ultra-microporosity. Additionally, a pronounced hysteresis for both guests is observed, which in combination with the platelet character is probably caused by an expansion of the interparticle space, creating additional accessible ultra-microporous pore volume. For nitrogen and methane, this effect does not occur which explains their low affinity. In consequence, Henry selectivities of 123 for CO2/N2 at 298 K and 12 for CO2/CH4 at 273 K were determined. The network was carefully characterized with solid-state nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy, thermal gravimetry (TG) and elemental analyses as well as physisorption experiments with Ar, N2, CO2, CH4 and water.

Analytical techniques for characterizing cyclodextrins and their inclusion complexes with large and small molecular weight guest molecules

Cyclodextrins are oligosaccharides that have truncated cone like structures, making them capable of forming non-covalent bonds with a large variety of molecules (especially hydrophobic molecules). Additionally, as the outer rims of their truncated cones are lined with several hydroxyl groups, secondary interactions with and functionalization of these hydroxyl groups are also possible. Current techniques available to analyze and characterize these interactions, although somewhat limited, can be accomplished by judicious selection of analytical tools. However, for emerging applications, the currently utilized techniques summarized in this review may not be sufficient. The purpose of this review is to provide an overview, including their possible limitations, of current techniques commonly employed to investigate such interactions. In view of CD-based materials for emerging applications, wherever possible, analytical tools used for these studies are also discussed.

Flexible Force Field Parameterization through Fitting on the Ab Initio-Derived Elastic Tensor.

Constructing functional forms and their corresponding force field parameters for the metal–linker interface of metal–organic frameworks is challenging. We propose fitting these parameters on the elastic tensor, computed from ab initio density functional theory calculations. The advantage of this top-down approach is that it becomes evident if functional forms are missing when components of the elastic tensor are off. As a proof-of-concept, a new flexible force field for MIL-47(V) is derived. Negative thermal expansion is observed and framework flexibility has a negligible effect on adsorption and transport properties for small guest molecules. We believe that this force field parametrization approach can serve as a useful tool for developing accurate flexible force field models that capture the correct mechanical behavior of the full periodic structure.

Using Predefined M3(μ3-O) Clusters as Building Blocks for an Isostructural Series of Metal-Organic Frameworks.

Metal-organic frameworks (MOFs) have attracted much attention in the past decade owing to their unprecedented internal surface areas, tunable topologies, designable surfaces, and various potential applications. One bottleneck in the field regarding MOF synthesis is controlling the metal-containing secondary building unit (SBU) incorporated into the structure. In this work we report the synthesis and characterization of five trimeric [M3(μ3-O)(CH3CO2)6]x clusters (where M = Fe3+, Cr3+, Fe3+/Cr3+, Fe3+/Co2+, or Fe3+/Ni2+ and x = +1 or 0). The monocarboxylate capping ligand, acetate in this case, readily undergoes exchange with several difunctional counterparts, including 1,4-benzenedicarboxylic acid (H2-BDC) and biphenyl-4,4'-dicarboxylic acid (H2-BPDC), for the formation of an isostructural series of MOFs, several of which are newly reported (for M = Fe3+/Cr3+, Fe3+/Co2+, and Fe3+/Ni2+) and show excellent CO2 adsorption properties. In this report, a host of techniques including NMR, ICP, and ESI-MS are used to probe the ligand exchange process and composition of the SBUs, and XAS is used to monitor the Fe3+ and Cr3+ environment throughout the reactions, giving strong evidence that the clusters stay intact throughout the MOF synthesis. This work reveals that predefined SBUs is an effective means to create metal-substituted analogues of known frameworks. Further, CO adsorption and in situ IR are used to probe accessibility of the metals after solvent removal. We show for the first time that the incorporation of the neutral clusters, containing weaker Lewis acids like Ni2+ and Co2+, can promote the formation of open metal sites in the MOF frameworks, structural features known to enhance the binding energy of small guest molecules like CO2.

Synthesis of polyglycerol-citric acid nanoparticles as biocompatible vectors for biomedical applications

Citric acid and glycerol play an important role in the food and drug industries. In this work, we present for the first time a facile and gram scale method for the preparation of polyglycerol-citric acid nanoparticles (PGCN) in the presence of silica gel blue as both catalyst and water removal agent. PGCN are highly biocompatible without significant toxicity up to 1mg/ml. They are able to load small guest molecules and transfer them through the cell membrane, efficiently. Taking advantage of their straightforward synthesis and high biocompatibility as well as their ability to load and transfer small guest molecules, PGCN could be used for a variety of future biomedical applications.

NH3 as unique non-classical content-former within clathrate hydrates.

High quality FTIR spectra of aerosols of NH3-THF and NH3-TMO binary clathrate hydrates (CHs) have been measured. Our recently developed all-vapor sub-second approach to clathrate-hydrate formation combined with computational studies has been used to identify vibrational spectroscopic signatures of NH3 within the gas hydrates. The present study shows that there are three distinct NH3 types, namely, classical small-cage NH3, nonclassical small-cage NH3, and NH3 within the hydrate network. The network ammonia does not directly trigger the non-classical CH structure. Rather, the ammonia within the network structure perturbs the water bonding, introducing orientational defects that are stabilized by small and/or large cage guest molecules through H-bonding. This unusual behavior of NH3 within CHs opens a possibility for catalytic action of NH3 during CH-formation. Furthermore, impacts over time of the small-cage NH3-replacement molecules CO2 and CH4 on the structure and composition of the ternary CHs have been noted.

Inclusion Crystal Growth and Optical Properties of Organic Charge-transfer Complexes Built from Small Aromatic Guest Molecules and Naphthalenediimide Derivatives

Inclusion crystals were effectively formed from a simple naphthalenediimide derivative with toluene, 4-fluorotoluene, and p-xylene by the aid of cooperative intermolecular interactions, such as charge-transfer interactions and inclusion phenomena. The crystals showed intense guest-dependent solid-state emission based on ground state CT complexes between naphthalenediimide and small aromatic guests.

Poly-cyclodextrin cryogels with aligned porous structure for removal of polycyclic aromatic hydrocarbons (PAHs) from water

Cyclodextrins (CDs) are sugar-based cyclic oligosaccharides, which form inclusion complexes with small guest molecules through their hydrophobic cavity. Here we successfully synthesized highly porous poly-cyclodextrin (poly-CD) cryogels, which were produced under cryogenic conditions by the cross-linking of amine-functional CDs with PEG-based diepoxide cross-linker. The poly-CD cryogels showed aligned porous network structures owing to the directional freezing of the matrix, of which the pore size and architecture exposed variations depending on the composition of the reactants. The cryogels were employed for the removal of genotoxic polycyclic aromatic hydrocarbons (PAHs) from aqueous solutions. They reached PAH sorption capacities as high as 1.25mg PAH per gram cryogel. This high sorption performance is due to interactions between PAHs and the complete swollen network, and thus, is not restricted by interfacial adsorption. Given that the hydrophilic nature of the components, the sorption performance could only be attributed to the inclusion complex formation of CDs with PAH molecules. The poly-CD cryogels could be recycled with an exposure to ethanol and reused without any significant loss in the sorption capacity of PAHs.