Nonpolar Cavity Research Articles

Versatile separation layer for separation and purification of ethanol/cyclohexane mixtures by pervaporation process

Quaternized cyclodextrin (CD) obtained by quaternization reaction of bromine-CD and N, N-Dimethylethylenediamine, are used for preparing PV membranes. Three different kinds of composite membranes are interfacially synthesized on the polyacrylonitrile substrate. The different sequences of piperazine and quaternized CD reacted with trimesoyl trichloride show a great difference in separation of polar/nonpolar mixture. The topmost layer of CD-based polyamide layer shows a higher separation factor, which can be inferred that quaternized CD played the major role during separation. Quaternized CD can integrate cavity size, polar and non-polar characteristics to achieve exceptional screening performance. PV performance of the optimal membrane at 25 °C is measured using the 5 wt% ethanol and cyclohexane mixture, exhibiting the separation factor of 66.7. PV performances of other different organic mixtures prove that nonpolar inner cavity of CD has a stronger inclusion of cyclohexane than other smaller nonpolar molecules, thus enhancing the repulsion of cyclohexane from the mixture. In summary, these outside polar quaternary ammonium salt structures of quaternized CD have a high selectivity for polar solvents. The nonpolar cavity of CD shows the inclusion ability of nonpolar solvents, especially the organic solvent with large molecular volume, which hinders their penetration and improves the separation factor.

Molecular baskets form inclusion complexes with phenethylamine drugs in water.

Molecular basket 16- comprising a nonpolar cavity and an anionic nest of six carboxylates at its rim was found to form inclusion complexes with (1R, 2S)-ephedrine, (1R, 2R)-pseudoephedrine, and (1S, 2R)-tranylcypromine. Experimental results (NMR) and theory (MM/DFT) suggest the basket encapsulates phenethylamines in unique and predictable fashion.

Probing the interaction of cephalosporin antibiotic “cefoperazone” with lysozyme using spectroscopic and in silico methods: Effect of paracetamol on binding

The interaction of lysozyme with cefoperazone was studied by means of spectroscopic and computational approaches. The change in the UV–visible spectrum of lysozyme in presence of cefoperazone was an indication of the complex formation between them. Fluorescence spectroscopy suggested that there was a fair interaction between the protein and drug which was taken place via dynamic quenching mechanism and the binding ratio was approximately 1:1. The binding was energetically feasible and principally supported by the hydrophobic forces. CD spectroscopic studies have shown that cefoperazone induced the secondary structure of lysozyme by increasing the α-helical contents of the latter. In silico studies revealed that the large nonpolar cavity was the preferred binding site of cefoperazone within lysozyme and the interaction was taken place mainly through hydrophobic forces with small involvement of hydrogen bonding and electrostatic interactions which is in good agreement with the experimental analyses. Effect of paracetamol was also seen on the binding and it was found that paracetamol had a negative influence on the binding between cefoperazone and lysozyme.

Rapid Access to Chiral and Tripodal Cavitands from β-Pinene.

We report Pd-catalyzed cyclotrimerization of (+)-α-bromoenone, obtained from monoterpene β-pinene, into an enantiopure cyclotrimer. This C3 symmetric compound has three bicyclo[3.1.1]heptane rings fused to its central benzene with each ring carrying a carbonyl group. The cyclotrimer undergoes diastereoselective threefold alkynylation with the lithium salts of five terminal alkynes (41-63 %, de=4-83 %). The addition enabled a rapid synthesis of a small library of novel chiral cavitands that, in shape, resemble a tripod stand. These molecular tripods include a tris-bicycloannelated benzene head attached to three alkyne legs twisted in one direction to form a nonpolar cavity with polar groups as feet. Tripods with methylpyridinium and methylisoquinolinium legs, respectively, form inclusion complexes with anti-inflammatory and chiral drugs (R)/(S)-ibuprofen and (R)/(S)-naproxen. The mode of binding shows drug molecules docked in the cavity of the host through ion-ion, cation-π, and C-H-π contacts that, in addition of desolvation, give rise to complexes having millimolar to micromolar stability in water. Our findings open the door to creating a myriad of enantiopure tripods with tunable functions that, in the future, might give novel chemosensors, catalysts or sequestering agents.

Electric fields control water-gated proton transfer in cytochrome c oxidase

Aerobic life is powered by membrane-bound enzymes that catalyze the transfer of electrons to oxygen and protons across a biological membrane. Cytochrome c oxidase (CcO) functions as a terminal electron acceptor in mitochondrial and bacterial respiratory chains, driving cellular respiration and transducing the free energy from O2 reduction into proton pumping. Here we show that CcO creates orientated electric fields around a nonpolar cavity next to the active site, establishing a molecular switch that directs the protons along distinct pathways. By combining large-scale quantum chemical density functional theory (DFT) calculations with hybrid quantum mechanics/molecular mechanics (QM/MM) simulations and atomistic molecular dynamics (MD) explorations, we find that reduction of the electron donor, heme a, leads to dissociation of an arginine (Arg438)-heme a3 D-propionate ion-pair. This ion-pair dissociation creates a strong electric field of up to 1 V Å-1 along a water-mediated proton array leading to a transient proton loading site (PLS) near the active site. Protonation of the PLS triggers the reduction of the active site, which in turn aligns the electric field vectors along a second, "chemical," proton pathway. We find a linear energy relationship of the proton transfer barrier with the electric field strength that explains the effectivity of the gating process. Our mechanism shows distinct similarities to principles also found in other energy-converting enzymes, suggesting that orientated electric fields generally control enzyme catalysis.

Adaptive Binding of Alkyl Glycosides by Nonpeptidic Helix Bundles in Water: Toward Artificial Glycolipid Binding Proteins.

Amphipathic water-soluble helices formed from synthetic peptides or foldamers are promising building blocks for the creation of self-assembled architectures with non-natural shapes and functions. While rationally designed artificial quaternary structures such as helix bundles have been shown to contain preformed cavities suitable for guest binding, there are no examples of adaptive binding of guest molecules by such assemblies in aqueous conditions. We have previously reported a foldamer 6-helix bundle that contains an internal nonpolar cavity able to bind primary alcohols as guest molecules. Here, we show that this 6-helix bundle can also interact with larger, more complex guests such as n-alkyl glycosides. X-ray diffraction analysis of co-crystals using a diverse set of guests together with solution and gas-phase studies reveals an adaptive binding mode whereby the apo form of the 6-helix bundle undergoes substantial conformational change to accommodate the hydrocarbon chain in a manner reminiscent of glycolipid transfer proteins in which the cavity forms upon lipid uptake. The dynamic nature of the self-assembling and molecular recognition processes reported here marks a step forward in the design of functional proteomimetic molecular assemblies.

Prediction of local thermodynamics of water in and around endo-functionalized molecular tube receptors: An approach using grid inhomogeneous solvation theory

Water molecules in and around a receptor play a significant role in the guest/ligand binding process. Here, we discuss the waters’ role in the guest binding process of small miniature receptor endo-functionalized molecular tubes (host-1a and host-1b). We have portrayed this using classical molecular dynamics (MD) simulation and GIST methodology. Trajectories from MD simulation have been utilized in GIST methodology to estimate different localized thermodynamic parameters at different regions of these receptors. These small receptors reveal a surprisingly detailed solvation structure, thermodynamic pattern and offer comprehensive insights. The torus site with high water density is especially relevant within the receptor binding sites in the solvation structure. Water molecules are energetically unstable inside (i.e., torus and cavity regions) of these host molecules. This water instability offers some guest molecules extremely high binding affinities inside these host cavities. Also, we are curious to see the effect of electrostatic on these thermodynamic parameters. For this, we have used a nonpolar version of these host molecules in which all partial charges of the atomic sites of both these receptors are artificially set to zero. Every energetic and entropic solvation parameters are less perturbed for nonpolar host molecules than the corresponding regular host molecules. The water molecules inside the nonpolar host cavity are less strongly bound than the corresponding regular host molecules. Thus, the value of free energy for removing water molecules from a particular region of a purely nonpolar host molecule is more favorable than the corresponding regular host molecule.

Cucurbiturils in supramolecular catalysis

Nearly 80 years following the initial synthesis of cucurbiturils, its structure was finally revealed in 1981, which discovery opened the field for further investigation. As a result, the scope of available sizes and varieties of cucurbiturils has grown profoundly in the last four decades, leading to a large number of potential applications, including cucurbiturils in catalysis as supramolecular additives due to the capability of supramolecular binding to certain substrates. Owing to their polar portals and non-polar cavity, cucurbiturils can have an eclectic range of binding versatile guests of different shapes and electronic structures, making them especially attractive for supramolecular catalysis with a wide range of possible reaction types. This review concisely discusses the unique structure and properties of cucurbiturils, and highlights their use as molecular containers in terms of supramolecular interactions in catalytic reactions such as photoreaction, solvolysis, oxidation, metal-assisted catalysis, bromination, Diels–Alder, xanthene synthesis, and Schiff base reaction.

Twist-Turn-Twist Motif Chaperoned Inside Molecular Baskets.

Two molecular baskets 16-, each with three (S)-glutamic acids at its rim, were found (NMR, ITC) to complex diammonium alkanes 22+-52+ (+H3N(CH2)nNH3+, n = 7-10) giving ternary [2-5⊂12]10- assemblies (K = 107-109 M-2). From the magnetic perturbation of proton nuclei (1H NMR, NICS), we deduced that each guest assumed a U shape within the binary complex, [2-5⊂1]4-. Two ammonium groups were bound in the "anionic nest" at the top of 16-, while the hydrocarbon chain resided in its nonpolar cavity. From detailed ITC analyses, we showed that the binary complex [2-5⊂1]4- forms first and then another 16- capped [2-5⊂1]4- to give [2-5⊂12]10-, via interactions of the carboxylates at the rims with ammoniums on the guest. Long-range NOEs revealed that U-shaped 22+ and 52+ coiled into highly strained twist-turn-twist formations, for the first time observed within an abiotic host while curiously resembling helix-turn-helix motif found in DNA binding proteins.

Investigation of inclusion complexes of ametryne and atrazine with cucurbit[n]urils (n = 6–8) using experimental and theoretical techniques

Inclusion complexes of cucurbit[n]uril, CBn, with atrazine (ATZ) and ametryne (AME) herbicides were investigated in aqueous media and solid state. Mass spectrometry using matrix assisted laser desorption time-of-flight, MALDI-TOF, and 1HNMR techniques were used to characterize the inclusion complexes prepared in aqueous media. The solid complexes between the triazine herbicides and CBn hosts were prepared by lyophilization and were characterized by Fourier transform infrared spectroscopy (FT-IR) and powder X-ray diffraction (PXRD) technique. Molecular dynamics (MD) simulations were used to study the mechanism of inclusion and to monitor the stability of these complexes in aqueous media. Analysis of the MD trajectories has shown that both triazines form stable complexes with CBn in aqueous media throughout the simulation time. The stability of these complexes was found to originate from the hydrophobic effects where both hosts prefer to accommodate the nonpolar cavity of the hosts. It was observed that CB6 is capable of encapsulating only the isopropyl side chain of the guests, whereas the other two hosts were able to accommodate the major parts of the guests. A number of strong hydrogen bonds between the hosts and the guests further increased the stability of the complexes.

Energetics of Storage and Diffusion of Water and Cyclo-Octasulfur for a Nonpolar Cavity of RHCC Tetrabrachion by Molecular Dynamics Simulations

Tetrabrachion forms the key component of the S-layer of Staphylothermus marinus. Molecular dynamics simulations have been used to study the energetics of occupancy of cavity 3 of the right-handed coiled-coil stalk of tetrabrachion by both water molecules and cyclooctasulfur S8 crowns, as well as to determine possible pathways and free energy barriers for the diffusion of both water and cyclooctasulfur through the peptide walls of RHCC tetrabrachion between cavity 3 and bulk solvent. Calculations of the transfer free energy from solvent to cavity show that clusters of six, seven and eight water molecules are marginally stable in cavity 3, but that occupancy of the cavity by a cyclooctasulfur ring is favoured significantly over water clusters of all sizes. Thermal activation simulations at T = 400K revealed that water molecules diffusing through the wall pass through a sequence of metastable configurations where they are temporarily immobilized by forming networks of hydrogen bonds with specific wall residues. Calculations of the free energy of these metastable configurations using multi-configurational thermodynamic integration yielded a free energy profile with a principal free energy maximum ∆G~50 kJ/mol and a slight activation asymmetry in favour of the direction from cavity to solvent. Potential exit pathways for cyclooctasulfur were investigated with the methods of steered molecular dynamics and umbrella sampling. The cyclooctasulfur was steered through a gap in the tetrabrachion wall along a linear path from cavity 3 into the solvent and the resulting trajectory was subdivided into 22 sampling windows. The free energy profile created for the trajectory by umbrella sampling showed a sharp principal maximum as a function of the reaction coordinate with asymmetric free energy barriers ∆Gexit~220 kJ/mol and ∆Gentrance~100 kJ/mol for cavity exit and entrance, respectively.

Molecular polarity effect on the association constant of cyclodextrin-pyrimidine nucleobases in water

Host:guest interactions of 2-hydroxypropyl-beta-cyclodextrin:nucleobases derivatives have been studied via absorption and fluorescence spectroscopy in aqueous medium. The effect of the polarity of guests (pyrimidine nucleobases such as uracil, thymine and 5-fluorouracil) on the binding constant of the cyclodextrin-nucleobases complexes has been investigated. Benesi-Hildebrand method and nonlinear regression analysis were applied to determine the association constants of the formed complexes at room temperature. The formation constants derived from absorption titration experiments suggest that 1:1 host:guest complexes are formed and the least polar molecules in the ground state, 5-fluourouracil and thymine, are more strongly bound to the hydrophobic nonpolar cavity of the cyclodextrin compared to uracil. Similarly, excited state association constants derived from fluorescence titration experiments suggest that 2:1 host:guest complexes are formed and the least polar molecule in the excited state, uracil, is more strongly bound to the cyclodextrin. In addition, the emission spectra of bound pyrimidine nucleobases are blue shifted relative to the spectra of their counterpart, unbound pyrimidine nucleobases. The latter indicates a change in the environment of the guest molecule as it is displaced from the polar environment, water, into the nonpolar environment, cavity of the 2-hydroxypropyl-beta-cyclodextrin.

Reduced Free Energy Perturbation/Hamiltonian Replica Exchange Molecular Dynamics Method with Unbiased Alchemical Thermodynamic Axis.

Replica-exchange molecular dynamics (REMD) has been proven to efficiently improve the convergence of free-energy perturbation (FEP) calculations involving considerable reorganization of their surrounding. We previously introduced the FEP/(λ,H)-REMD algorithm for ligand binding, in which replicas along the alchemical thermodynamic coupling axis λ were expanded as a series of Hamiltonian boosted replicas along a second axis to form a two-dimensional replica-exchange exchange map [Jiang, W.; Roux, B., J. Chem. Theory Comput. 2010, 6 (9), 2559-2565]. Aiming to achieve a similar performance at a lower computational cost, we propose here a modified version of this algorithm in which only the end-states along the alchemical axis are augmented by boosted replicas. The reduced FEP/(λ,H)-REMD method with one-dimensional unbiased alchemical thermodynamic coupling axis λ is implemented on the basis of generic multiple copy algorithm (MCA) module of the biomolecular simulation program NAMD. The flexible MCA framework of NAMD enables a user to design customized replica-exchange patterns through Tcl scripting in the context of a highly parallelized simulation program without touching the source code. Two Hamiltonian tempering boosting scheme were examined with the new algorithm: a first one based on potential energy rescaling of a preidentified "solute" and a second one via the introduction of flattening torsional free-energy barriers. As two illustrative examples with reliable experiment data, the absolute binding free energies of p-xylene and n-butylbenzene to the nonpolar cavity of the L99A mutant of T4 lysozyme were calculated. The tests demonstrate that the new protocol efficiently enhances the sampling of torsional motions for backbone and side chains around the binding pocket and accelerates the convergence of the free-energy computations.

Supramolecular self-assembly of water-soluble cavitands: investigated by molecular dynamics simulation

In this study, we have examined supramolecular self-assembly process of a hydrophobic guest with a water-soluble host known by the trivial name octa acid (OA). Two octa acids form a capsular assembly only in presence of a nonpolar guest(s). Size and shape of the guest control the stoichiometry of the capsular complex. Here, all atom molecular dynamics simulation has been utilized to investigate complex formation mechanisms of a nonpolar guest (nonylbenzene) with two OA cavitands. Nonylbenzene was encapsulated into the nonpolar cavity of OA capsule owing to solvophobic interactions. Upon encapsulation it was twisted and bent due to lack of free space within the capsule. These unusual forms obtained from the simulation study were in accord with experimental findings. The post-complexation attributes of the guest were regulated by the available free space within the OA and favorable non-covalent interactions between the guest and the walls of the OA capsule. In the identical simulation condition two OA cavitands did not form a capsule without a guest, thus indicating requirement of a guest during the self-assembly of OA cavitands.

β-CD assisted aqueous dissolution of cetylpicolinium dichromates (CPDC)—Evolution of a class of green water compatible lipopathic Cr(VI) oxidants

Water-insoluble lipopathic dichromates have been successfully solubilized in aqueous phase by the entrapment of their hydrophobic tails in β-cyclodextrin (β-CD) non-polar cavity. Aqueous solubility of α-, β-, and γ- cetylpicolinium dichromate (CPDC) molecules, synthesized in our lab, has been studied to find their suitability for Cr(VI) oxidation purposes in water medium. The analysis of phase solubility shows the existence of a Bs type curve and its significance has been fully deciphered through dynamic light scattering (DLS) analysis. The limiting concentration of β-CD up to which it can induce 1:1 host-guest complexation with the CPDC entities, has been determined and the stoichiometry has been confirmed from Job’s plot. The binding constant and complexation efficiency of the β-CD-CPDC complexes have been determined and temperature effect on these parameters has been discussed through thermodynamic calculations. Analyses of viscosity variation of the aqueous solutions of the complexes have been done and correlated with the solubilization phenomenon.

Predicting conformations and orientations of guests within a water soluble host: a molecular docking approach

In this study we have examined conformations and orientations of guests within a water-soluble host known by the trivial name Octa Acid (OA). Docking program Vina, which was originally developed for screening drug-like molecules, has been used to identify binding modes and affinities of select guest molecules with OA. Hydrophobic guests were encapsulated into the nonpolar cavity of OA capsule owing to solvophobic interactions. Amphiphilic guests were bound by keeping the nonpolar part within the cavity of OA, while pointing the polar anionic group out of the cavity. All these results obtained from the docking study were in accord with experimental findings. The post-complexation attributes of the guests were regulated by available free space and the specific interactions between guest–OA pair, which led to unusual conformations and orientations. This study showed that scoring function available with Vina, which was derived from protein–ligand data set, could successfully predict post-complexed structural features of guests within OA, thus opening opportunities to modulate physical and chemical behavior of guest molecules.

Factors Governing the Host-Guest Interactions between IIA/IIB Group Metal Cations and α-Cyclodextrin: A DFT/CDM Study.

Cyclodextrins' unique molecular structure with hydrophilic exterior surface and nonpolar cavity interior is responsible for their specific complexation properties. Although a wealth of information about these molecules has been accumulated, many aspects of their coordination chemistry remain unknown. For example, there are no systematic studies on the key factors controlling the processes of metal binding and selectivity in these systems. In the computational study herein, DFT molecular modeling has been employed to study the interactions of either hydrated or nonhydrated IIA/IIB group metal cations (Be2+, Mg2+, Ca2+, Sr2+, Ba2+, Zn2+, Cd2+, Hg2+) with the host α-cyclodextrin molecules. The thermodynamic descriptors (Gibbs free energies in the gas phase and in water medium) of the metal binding to α-cyclodextrin have been evaluated, and the effect of various factors (metal's radius, electron configuration and coordination number, and host molecule flexibility and binding site locality) on the interactions between the two binding partners has been assessed. The results obtained shed light on the intimate mechanism of the metal binding to α-cyclodextrin and disclose the key factors governing the process.

Room-Temperature Observation of Trapped Exciton-Polariton Emission in GaN/AlGaN Microcavities with Air-Gap/III-Nitride Distributed Bragg Reflectors

We demonstrate trapped exciton-polariton emission at room temperature from nonpolar GaN/AlGaN cavities sandwiched between air/AlGaN distributed Bragg reflectors. Nanoscale thickness fluctuations characteristic to the nonpolar AlGaN cavity layer create deep potential traps, giving rise to a strong (in-plane) localization of exciton-polaritons. The observed quantized exciton-polariton states exhibit a large quantized energy of up to 6 meV, which benefits from the wide bandgap of III-nitrides. The experimental results are well explained by numerical simulations. III-Nitride exciton-polaritons in such deep traps will be useful for practical exciton-polariton lasers with high degrees of coherence and high-repetition rate Josephson oscillators with multicomponent condensates.

The impact of pressure on β-Cyclodextrin·acetaminophen inclusion complexes

Cyclodextrins (CDs) have attracted considerable interest as model systems in supramolecular host-guest chemistry. They are described as hollow truncated cones with a hydrophilic outer surface and a nonpolar inner cavity suitable for small molecules' encapsulation.[1] By virtue of their character, CDs are used as excipients to improve the aqueous solubility of active pharmaceutical ingredients (APIs). High-pressure crystallisation techniques have been established as a suitable tool for exploring the phenomenon of polymorphism and solvate formation of pharmaceutical compounds throughout numerous examples reported in the literature.[2] Thus, exploring the inclusion-complex formation and the polymorphic behaviour of CDs with APIs at high pressure would be an interesting extension of the technique. The present work describes the attempt of an in-situ crystallisation of β-CD·acetaminophen inclusion complex and compression studies of the known β-CD·acetaminophen complex[3] in different crystallisation media at pressures up to 1.0 GPa. A new high-pressure crystal form observed at 0.8 GPa as well as unexpected results are presented herein. The crystals have been characterised by means of polarised optical microscopy, Raman spectroscopy and single-crystal X-ray diffraction using both home and synchrotron sources.

β-CD assisted dissolution of quaternary ammonium permanganates in aqueous medium

The non-polar internal cavity of β-cyclodextrin (β-CD) has been exploited for the entrapment of the hydrophobic tails of two water insoluble quaternary ammonium permanganates (QAPs): cetyltrimethylammonium permanganate (CTAP) and tetrabutylammonium permanganate (TBAP), for solubilization in aqueous medium. The solubilization and organizational behavior of the QAPs in aqueous β-CD solution have been determined from the comparison of their rates of self-oxidation in presence and in absence of β-CD. Effect of QAP concentration on their observed rate constants (kobs) at a fixed β-CD concentration, phase solubility analysis in varying β-CD concentration, impact of quaternary ammonium bromides (QABs) on the kobs values of CTAP and TBAP at fixed QAP and β-CD concentrations, and the temperature effect have been reported. A scheme to explain the solvation of QAPs in aqueous β-CD has been proposed based on dynamic light scattering (DLS) analysis of the samples.