ESR, STESR, DFT, and MD Study of the Dynamical Structure of Cucurbituril-Spin Probe Guest-Host Complexes.
ABSTRACT: We study the molecular dynamics and structures of the guest-host complexes of cucurbituril, CB, with spin probes through the conventional electron spin resonance (ESR), saturation transfer ESR (STESR), density functional theory (DFT), and molecular dynamics (MD) computations. Protonated TEMPOamine (I), a derivative of TEMPO having a positive charge and an octyl group on the quaternary nitrogen atom (II), and the neutral spin-labeled indole (III) are used as guests. To eliminate the overall complex rotation, the solutions of complexes in a solid CB matrix were prepared. Resultantly, for all of the spin probes, the combined study of the conventional ESR and STESR spectra indicates the librational character of the rotational motion within the CB cavity as opposed to the diffusional rotation over the whole solid angle. The kinetic accessibilities of the reporter NO groups to the paramagnetic complexes in aqueous solutions, determined by Heisenberg exchange broadening of the ESR spectra, together with the environment polarities from the hyperfine interaction values, as well as DFT computation results and MD simulations, were used to estimate the spin probe location relative to CB. Utilizing the concept of the aqueous clusters surrounding the spin probes and CB molecules and MD simulations has allowed the application of DFT to estimate the aqueous environment effects on the complexation energy and spatial structure of the guest-host complexes.
Project description:Two supramolecular complexes of trans-1?CB and trans-2?CB were successfully achieved by the controlled selective complexation process of cucurbituril (CB) with hetero-guest pair containing azobenzene and bispyridinium moieties in aqueous solution, exhibiting the reversibly light-driven movements of CB upon the photocontrollable isomerization of azophenyl axle components. Significantly, the obtained bistable supramolecular complexes and their corresponding pseudorotaxanes could act as a promising concentrator and cleavage agent to regulate the binding behaviors with DNA molecules.
Project description:Cucurbituril (CB) was found in vitro to sequester the neurotoxins MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and MPP(+) (N-methyl-4-phenylpyridine). The CB/neurotoxin host-guest complexes were studied in detail with (1)H NMR, electrospray ionization mass spectrometry, UV-visible spectroscopic titration, and molecular modeling by density functional theory. The results supported the macrocyclic encapsulation of MPTP and MPP(+), respectively, by CB in aqueous solutions with relatively strong affinities and 1:1 host-guest binding stoichiometries in both cases. More importantly, the progression of MPTP/MPP(+) induced neurodegeneration (often referred to as a Parkinson's disease model) was observed to be strongly inhibited in vivo by the synthetic CB receptor, as shown in zebrafish models. These results show that a supramolecular approach could lead to a new preventive and/or therapeutic strategy for counteracting the deleterious effects of some neurotoxins leading to neurodegeneration.
Project description:In this work, iminyl ?-radical formation in several one-electron-oxidized cytosine analogs, including 1-MeC, cidofovir, 2'-deoxycytidine (dCyd), and 2'-deoxycytidine 5'-monophosphate (5'-dCMP), were investigated in homogeneous, aqueous (D2O or H2O) glassy solutions at low temperatures by employing electron spin resonance (ESR) spectroscopy. Upon employing density functional theory (DFT) (DFT/B3LYP/6-31G* method), the calculated hyperfine coupling constant (HFCC) values of iminyl ?-radical agree quite well with the experimentally observed ones, thus confirming its assignment. ESR and DFT studies show that the cytosine iminyl ?-radical is a tautomer of the deprotonated cytosine ?-cation radical [cytosine ?-aminyl radical, C(N4-H)(•)]. Employing 1-MeC samples at various pHs ranging from ca. 8 to 11, ESR studies show that the tautomeric equilibrium between C(N4-H)(•) and the iminyl ?-radical at low temperature is too slow to be established without added base. ESR and DFT studies agree that, in the iminyl ?-radical, the unpaired spin is localized on the exocyclic nitrogen (N4) in an in-plane pure p-orbital. This gives rise to an anisotropic nitrogen hyperfine coupling (Azz = 40 G) from N4 and a near isotropic ?-nitrogen coupling of 9.7 G from the cytosine ring nitrogen at N3. Iminyl ?-radical should exist in its N3-protonated form, as the N3-protonated iminyl ?-radical is stabilized in solution by over 30 kcal/mol (?G = -32 kcal/mol) over its conjugate base, the N3-deprotonated form. This is the first observation of an isotropic ?-hyperfine ring nitrogen coupling in an N-centered DNA radical. Our theoretical calculations predict that the cytosine iminyl ?-radical can be formed in double-stranded DNA by a radiation-induced ionization-deprotonation process that is only 10 kcal/mol above the lowest energy path.
Project description:Conspectus This Account focuses on stimuli responsive systems that function in aqueous solution using examples drawn from the work of the Isaacs group using cucurbit[n]uril (CB[n]) molecular containers as key recognition elements. Our entry into the area of stimuli responsive systems began with the preparation of glycoluril derived molecular clips that efficiently distinguish between self and nonself by H-bonds and π-π interactions even within complex mixtures and therefore undergo self-sorting. We concluded that the selectivity of a wide variety of H-bonded supramolecular assemblies was higher than previously appreciated and that self-sorting is not exceptional behavior. This lead us to examine self-sorting within the context of CB[n] host-guest chemistry in water. We discovered that CB[n] homologues (CB and CB) display remarkably high binding affinity (Ka up to 10(17) M(-1)) and selectivity (ΔΔG) toward their guests, which renders CB[n]s prime components for the construction of stimuli responsive host-guest systems. The CB·adamantaneammonium ion complex, which is particularly privileged (Ka = 4.2 × 10(12) M(-1)), was introduced by us as a stimulus to trigger constitutional changes in multicomponent self-sorting systems. For example, we describe how the free energy associated with the formation of host-guest complexes of CB[n]-type receptors can drive conformational changes of included guests like triazene-arylene foldamers and cationic calixarenes, as well as induced conformational changes (e.g., ammonium guest size dependent homotropic allostery, metal ion triggered folding, and heterochiral dimerization) of the hosts themselves. Many guests display large pKa shifts within their CB[n]-guest complexes, which we used to promote pH controlled guest swapping and thermal trans-to-cis isomerization of azobenzene derivatives. We also used the high affinity and selectivity of CB toward its guests to outcompete an enzyme (bovine carbonic anhydrase) for a two-faced inhibitor, which allowed stimuli responsive regulation of enzymatic activity. These results prompted us to examine the use of CB[n]-type receptors in both in vitro and in vivo biological systems. We demonstrated that adamantaneammonium ion can be used to intracellularly sequester CB from gold nanoparticles passivated with hexanediammonium ion·CB complexes and thereby trigger cytotoxicity. CB derivatives bearing a biotin targeting group enhance the cytotoxicity of encapsulated oxaliplatin toward L1210FR cells. Finally, acyclic CB[n]-type receptors function as solubilizing excipients for insoluble drugs for drug delivery purposes and as a broad spectrum reversal agent for the neuromuscular blocking agents rocuronium, vecuronium, and cis-atracurium in rats. The work highlights the great potential for integration of CB[n]-type receptors with biological systems.
Project description:The histamine H?-receptor antagonists cimetidine, famotidine and nizatidine are individually encapsulated by macrocyclic cucurbituril (CB), with binding affinities of 6.57 (±0.19) × 10³ M(-1), 1.30 (±0.27) × 10? M(-1) and 1.05 (±0.33) × 10? M(-1), respectively. These 1:1 host-guest inclusion complexes have been experimentally examined by ¹H-NMR, UV-visible spectroscopic titrations (including Job plots), electrospray ionization mass spectrometry (ESI-MS), and isothermal titration calorimetry (ITC), as well as theoretically by molecular dynamics (MD) computation. This study may provide important insights on the supramolecular formulation of H?-receptor antagonist drugs for potentially enhanced stability and controlled release based on different binding strengths of these host-guest complexes.
Project description:Recognition tunneling technique owns the capability for investigating and characterizing molecules at single molecule level. Here, we investigated the conductance value of cucurbituril (CB) and melphalan@CB (Mel@CB) complex molecular junctions by using recognition tunneling technique. The conductances of CB and Mel@CB with different pH values were studied in aqueous media as well as organic solvent. Both pH value and guest molecule have an impact on the conductance of CB molecular junction. The conductances of CB and Mel@CB both showed slightly difference on the conductance under different measurement systems. This work extends the molecular conductance measurement to aqueous media and provides new insights of pH-responsive host-guest system for single molecule detection through electrical measurements.
Project description:Supramolecular host-guest interactions of trityl-nitroxide (TN) biradicals CT02-VT, CT02-AT and CT02-GT with methyl-?-cyclodextrin (M-?-CD), hydroxypropyl-?-cyclodextrin (H-?-CD) and ?-cyclodextrin (?-CD) were investigated by EPR spectroscopy. In the presence of cyclodextrins (i.e., ?-CD, M-?-CD and H-?-CD), host-guest complexes of CT02-VT are formed where the nitroxide and linker parts possibly interact with the cyclodextrins' cavities. Complexation with cyclodextrins leads to suppression of the intramolecular through-space spin-spin exchange coupling in CT02-VT, thus allowing the determination of the through-bond spin-spin exchange coupling which was calculated to be 1.6 G using EPR simulations. Different types of cyclodextrins have different binding affinities with CT02-VT in the order of ?-CD (95 M(-1)) > M-?-CD (70 M(-1)) > H-?-CD (32 M(-1)). In addition, the effect of the linkers in TN biradicals on the host-guest interactions was also investigated. Among the three TN biradicals studied, CT02-VT has the highest association constant with one designated cyclodextrin derivative. On the other hand, the complexes of CT02-GT (? 22 G) and CT02-AT (7.7-9.0 G) with cyclodextrins have much higher through-bond spin-spin exchange couplings than those of CT02-VT (1.6 G) due to the shorter linkers than those of CT02-VT. Furthermore, the stability of TN biradicals towards ascorbate was significantly enhanced after the complexation with CDs, with an almost 2-fold attenuation of the second-order rate constants for all the biradicals. Therefore, the supramolecular host-guest interactions with cyclodextrins will be an alternative method to modulate the magnitude of the spin-spin interactions and redox sensitivity of TN biradicals, and the resulting complexes are promising as highly efficient DNP polarizing agents as well as EPR redox probes.
Project description:The self-assembly of a stimuli-responsive aqueous supramolecular hyperbranched polymer from small molecules is reported. This system is composed of ditopic and tritopic guest-functionalised molecules that are able to form heteroternary supramolecular complexes with the macrocyclic host cucurbituril (CB). We demonstrate that the supramolecular hyperbranched polymer formed is responsive to both photo- and chemical stimuli, exhibiting reversibility. Furthermore, this system is shown to assemble at liquid-liquid interfaces, which upon gelation, is observable on the micrometre scale. This self-healing supramolecular network can act as a soft matter barrier for aqueous microdroplets, inhibiting their coalescence.
Project description:The molecular dynamics of spin-labeled compounds included into the solid phase of cyclodextrins (CDs) has been studied using conventional (X-band) ESR at 9 GHz and high-field high-frequency (HFHF) ESR at 240 and 170 GHz. The patterns of axial rotation at these higher frequencies are clear just by inspection of the spectrum, unlike the case for 9 GHz spectra. That is HFHF ESR is sensitive to molecular motion about the diffusion axis collinear with the X, Y or Z-direction of the magnetic g- and A-tensors of the nitroxide moiety (referred to, respectively, as X, Y or Z-rotation). For doxyl stearic acids (Z-rotation) and TEMPOyl caprylate (X-rotation) included in beta- and gamma-CDs we were able to determine the rate of molecular motion and the corresponding potential barriers. We emphasize that determining the rate of Z-rotation by ESR is feasible only using HFHF ESR. For the X-rotation case we suggest that the motion of the nitroxide moiety consists of fast small-angle librations about the magnetic X-axis superimposed by rotational diffusion about the same axis. The potential barrier of 1.7 Kcal mol(-1) for this rotational diffusion is unusually low. A fascinating feature of TEMPO derivatives included in beta-CD is the detectable molecular motion at temperatures below 77 K. For the other CD-spin probe systems, we used multifrequency analysis to assign the conformations of spin-labeled molecules. A dramatic spectral change for 16-sasl in beta- and gamma-CDs at approximately 260 K corresponds to a tilting of the position of the nitroxide moiety on the rotating molecule relative to the long diffusion axis, while for TEMPO derivatives in gamma-cyclodextrin below 200 K, we observe a rapid transition from fast to very slow rotational motion. More complex features are best studied by means of multifrequency ESR experiments. The visual clarity and the simplicity of analysis of the ESR spectra shown in this work should provide a benchmark for future studies of molecular motion by HFHF ESR.
Project description:Practical applications of guest-host liquid crystal systems are critically dependent on the alignment of the guest species within the liquid crystal host. UV/Vis absorption spectroscopy shows that the 1,5-dihydroxy-2,6-bis-(4-propylphenyl)-9,10-anthraquinone dye aligns within the E7 nematic host, giving an experimental dichroic ratio of 9.40 and dye order parameter of 0.74. This alignment was modelled by using a combination of density functional theory (DFT) and molecular dynamics (MD) computational approaches that do not require the input of experimental data. Time-dependent DFT calculations show that the electronic transition dipole moment is highly aligned with the long molecular axis of the dye. Fully atomistic MD simulations show that the long axis of the dye is less highly aligned within the E7 host, indicating that this contribution limits the overall dye alignment and, thereby, the potential practical applications of this particular system. Importantly, this study demonstrates an experimental and combined DFT and MD computational approach that may be applied generally to guest-host systems, providing a potential route to their rational design.