Encapsulated Water Molecules Research Articles

Molecular localization and exchange kinetics in pharmaceutical liposome and mRNA lipoplex nanoparticle products determined by small angle X-ray scattering and pulsed field gradient NMR diffusion measurements

We have used pulsed field gradient (PFG)-NMR diffusion experiments, also known as DOSY, in combination with small angle X-ray scattering measurements to investigate structure and molecular exchange dynamics between pharmaceutical lipid nanoparticles and the bulk phase. Using liposomes and lipoplexes formed after complexation of the liposomes with messenger mRNA as test systems, information on dynamics of encapsulated water molecules, lipids and excipients was obtained. The encapsulated fraction, having a diffusivity similar to that of the liposomes, could be clearly identified and quantified by the NMR diffusion measurements. The unilamellar liposome membranes allowed a fast exchange of water molecules, while sucrose, used as an osmolyte and model solute, showed very slow exchange. Upon interactions with mRNA a topological transition from a vesicular to a lamellar organization took place, where the mRNA was inserted in repeating lipid bilayer stacks. In the lipoplexes, a small fraction of tightly bound water molecules was present, with a diffusivity that was influenced by the additional presence of sucrose. This extended information on dynamic coherencies inside pharmaceutical nanoparticle products, provided by the combined application of SAXS and PFG-NMR diffusion measurements, can be valuable for evaluation of quality and comparability of nanoscaled pharmaceuticals.

Synthesis of Open‐Cage Fullerenes Containing a H‐Bond between the Encapsulated Water Molecule and the Amide Moiety on the Rim of the Orifice

AbstractFurther hydrolysis of an open‐cage fullerene derivative with an epoxy moiety on the rim of the orifice led to the formation of a new open‐cage fullerene with a 17‐membered orifice and an amide group directly above the orifice. The water encapsulation ratio in the new open‐cage compound reached 100 % as a result of heating with water at 80 °C. The amide group above the orifice completely blocks the opening and forms H‐bond with the trapped water molecule. Single crystal X‐ray structure shows that the bond length between the trapped water oxygen and the amide oxygen is 2.859 Å. The H‐bond energy is about −3.83 kcal/mol as shown by theoretical calculation.

Doubly chiral pseudopeptidic macrobicyclic molecular cages: Water-assisted dynamic covalent self-assembly and chiral self-sorting

<h2>Summary</h2> Taking advantage of the dynamic covalent chemistry approach, four different cages were synthesized by condensation of tripodal pseudopeptides with 4,4′-biphenyldicarboxyaldehyde. Whereas undesired products of polymeric nature were obtained in polar solvents, the [3+2] cryptand-type macrobicyclic architectures were obtained in excellent yields using chloroform as solvent, even at relatively high concentrations. The presence of two encapsulated water molecules may provide a positive template effect in the low polarity medium. The final macrobicycles display a combination of two types of chirality: d,l chirality due to the asymmetric α-C centers and P,M helical chirality. The homochiral helicity found for all the enantiomerically pure molecular cages indicates strong chirality induction by the asymmetric α-C. Besides, the self-sorting properties of the different chiral pseudopeptides have been studied, resulting in high-fidelity homo-self-sorting. DFT calculations point out that the self-sorting outcome may also be a direct result of the encapsulation of two water molecules within the cavity.

Unraveling the Origin of Symmetry Breaking in H2 O@C60 Endofullerene Through Quantum Computations.

We explore the origin of the anomalous splitting of the 101 levels reported experimentally for the H2O@C60 endofullerene, in order to give some insight about the physical interpretations of the symmetry breaking observed. We performed fully‐coupled quantum computations within the multiconfiguration time‐dependent Hartree approach employing a rigorous procedure to handle such computationally challenging problems. We introduce two competing physical models, and discuss the observed unconventional quantum patterns in terms of anisotropy in the interfullerene interactions, caused by the change in the off‐center position of the encapsulated water molecules inside the cage or the uniaxial C60‐cage distortion, arising from noncovalent bonding upon water's encapsulation, or exohedral fullerene perturbations. Our results show that both scenarios could reproduce the experimentally observed rotational degeneracy pattern, although quantitative agreement with the available experimental rotational levels splitting value has been achieved by the model that considers an uniaxial elongation of the C60‐cage. Such finding supports that the observed symmetry breaking could be mainly caused by the distortion of the fullerene cage. However, as nuclear quantum treatments rely on the underlying interactions, a decisive conclusion hinges on the availability of their improved description, taken into account both endofullerene and exohedral environments, from forthcoming highly demanding electronic structure many‐body interaction studies.

Inelastic Electron Transport and Ortho-Para Fluctuation of Water Molecule in H2O@C60 Single Molecule Transistors.

Light molecules such as H2O are the systems in which we can have access to quantum mechanical information on their constituent atoms. Here, we have investigated electron transport through H2O@C60 single molecule transistors (SMTs). The H2O@C60 SMTs exhibit Coulomb stability diagrams that show multiple tunneling-induced excited states below 30 meV. Furthermore, we have performed terahertz (THz) photocurrent spectroscopy on H2O@C60 SMTs and confirmed the same excitations. From comparison between experiment and theory, the excitations observed below 10 meV are identified to be the quantum rotational excitations of the water molecule. Surprisingly, the quantum rotational excitations of both para- and ortho-water molecule are observed simultaneously even for a single water molecule, indicating that the fluctuation between the ortho- and para-water states takes place in a time scale shorter than our measurement time (∼1 min), probably by the interaction between the encapsulated water molecule and conducting electrons.

Encapsulation of a Water Molecule inside C60 Fullerene: The Impact of Confinement on Quantum Features.

We introduce an efficient quantum fully coupled computational scheme within the multiconfiguration time-dependent Hartree (MCTDH) approach to handle the otherwise extremely costly computations of translational–rotational–vibrational states and energies of light-molecule endofullenes. Quantum calculations on energy levels are reported for a water molecule inside C60 fullerene by means of such a systematic approach that includes all nine degrees of freedom of H2O@C60 and does not consider restrictions above them. The potential energy operator is represented as a sum of natural potentials employing the n-mode expansion, along with the exact kinetic energy operator, by introducing a set of Radau internal coordinates for the H2O molecule. On the basis of the present rigorous computations, various aspects of the quantized intermolecular dynamics upon confinement of H2O@C60 are discussed, such as the rotational energy level splitting and the significant frequency shifts of the encapsulated water molecule vibrations. The impact of water encapsulation on quantum features is explored, and insights into the nature of the underlying forces are provided, highlighting the importance of a reliable first-principles description of the guest–host interactions.

Reactions on a 1,2-Dicarbonyl Moiety of a Fullerene Skeleton.

A 1,2-dicarbonyl moiety on a cage-opened fullerene skeleton is one of suitable building blocks for the further derivatization. Herein, we discuss the chemical transformation of a 1,2-dicarbonyl compound into β-oxo-phosphorus ylide, acid anhydride, and α-methylene carbonyl derivatives. Despite possessing a sterically small methylene unit in the last one, the release of an encapsulated water molecule was significantly supressed whereas the β-oxo-phosphorus ylide bearing three bulky p-tolyl groups on the P-atom enabled the faster insertion/release dynamics, implying the flexibility of the phosphonium substituent. The replacement of the carbonyl group with phosphorus ylide and methylene units largely varied electrochemical properties of the fullerene skeleton, likely arising from the anionic charge delocalized over the entire molecule and removal of an electron-withdrawable carbonyl group, respectively.

Interplay of water and a supramolecular capsule for catalysis of reductive elimination reaction from gold

Supramolecular assemblies have gained tremendous attention due to their ability to catalyze reactions with the efficiencies of natural enzymes. Using ab initio molecular dynamics, we identify the origin of the catalysis by the supramolecular capsule Ga4L612− on the reductive elimination reaction from gold complexes and assess their similarity to natural enzymes. By comparing the free energies of the reactants and transition states for the catalyzed and uncatalyzed reactions, we determine that an encapsulated water molecule generates electric fields that contributes the most to the reduction in the activation free energy. Although this is unlike the biomimetic scenario of catalysis through direct host-guest interactions, the electric fields from the nanocage also supports the transition state to complete the reductive elimination reaction with greater catalytic efficiency. However it is also shown that the nanocage poorly organizes the interfacial water, which in turn creates electric fields that misalign with the breaking bonds of the substrate, thus identifying new opportunities for catalytic design improvements in nanocage assemblies.

Probing the interaction between the encapsulated water molecule and the fullerene cages in H2O@C60- and H2O@C59N.

We report a high-resolution photoelectron imaging study of cryogenically-cooled H2O@C60- and H2O@C59N- endohedral fullerene anions. The electron affinity (EA) of H2O@C60 is measured to be 2.6923 ± 0.0008 eV, which is 0.0088 eV higher than the EA of C60, while the EA of H2O@C59N is measured to be 3.0058 eV ± 0.0007 eV, which is 0.0092 eV lower than the EA of C59N. The opposite shifts are found to be due to the different electrostatic interactions between the encapsulated water molecule and the fullerene cages in the two systems. There is a net coulombic attraction between the guest and host in H2O@C60-, but a repulsive interaction in H2O@C59N-. We have also observed low-frequency features in the photoelectron spectra tentatively attributed to the hindered rotational excitations of the encapsulated H2O molecule, providing further insights into the guest-host interactions in H2O@C60- and H2O@C59N-.

Hydration-induced crystalline transformation of starch polymer under ambient conditions

With synchrotron small/wide-angle X-ray scattering (SAXS/WAXS), we revealed that post-harvest hydration at ambient conditions can further alter the starch crystalline structure. The hydration process induced the alignment of starch helices into crystalline lamellae, irrespective of the starch type (A- or B-). In this process, non-crystalline helices were probably packed with water molecules to form new crystal units, thereby enhancing the overall concentration of starch crystallinity. In particular, a fraction of the monoclinic crystal units of the A-type starches encapsulated water molecules during hydration, leading to the outward movement of starch helices. Such movement resulted in the transformation of monoclinic units into hexagonal units, which was associated with the B-type crystallites. Hence, the hydration under ambient conditions could enhance the B-polymorphic features for both A-type and B-type starches. The new knowledge obtained here may guide the design of biopolymer-based liquid crystal materials with controlled lattice regularity and demanded features.

A Cyanide-Bridged Magnetically Switchable Cage with Encapsulated Water Molecules.

A cage complex, H2O@[Co5Fe4], was found to encapsulate two water molecules during its self-assembly. The complex exhibited remarkable multifunctionality, combining magnetic switching from the thermal electron-transfer-coupled spin transition of the cage host and dipolar reorientational motion of the confined water, as evidenced by permittivity measurements, density functional theory calculations, and solid-state 2H NMR spectra.

Transport properties of the H2O@C60-dimer-based junction

Theoretical predictions play an important role in finding potential applications in molecular electronics. Fullerenes have a number of potential applications, and the charge flow from a single C60 molecule to another becomes more versatile and more interesting after doping. Here, we report the conductance of two H2O@C60 molecules in series order and how the number of encapsulated water molecules influences the transport properties of the junction. Encapsulating an H2O molecule into one of the C60 cages increases the conductance of the dimer. Negative differential resistance is found in the dimer systems, and its peak-to-valley current ratio depends on the number of encapsulated H2O molecules. The conductance of the C60 dimer and the H2O@C60 dimer is two orders of magnitude smaller than that of the C60 monomer. Furthermore, we demonstrate that the conductance of the molecular junctions based on the H2O@C60 dimer can be tuned by moving the encapsulated H2O molecules. The conductance is H2O-position dependent. Our findings indicate that H2O@C60 can be used as a building block in C60-based molecular electronic devices and sensors.

Probing Thermal Conductivity of Fullerene C60 Hosting a Single Water Molecule

Encapsulation of a single water molecule inside the fullerene C60 can yield a significant change on its fundamental properties. Through comprehensive reverse nonequilibrium molecular dynamics (RNEMD) simulations, we investigate the thermal conductivity of endohedral C60 fullerene containing a single water molecule. The encapsulated single water molecule enhances the thermal phonon propagation resistance of the fullerene C60 due to its interaction with carbon atoms and brings down the thermal conductivity of the fullerene C60. Further simulations indicate that the thermal conductivity will depend on the external electrical field due to the polarity of the encapsulated water molecule. A larger electrical intensity will lead to a smaller thermal conductivity. A hierarchical model is proposed to quantitatively understand thermal behavior of the single endohedral fullerene and its enabled single-chain structures and shows good agreement with simulations.

Electrical detection of ortho-para conversion in fullerene-encapsulated water.

Water exists in two spin isomers, ortho and para, that have different nuclear spin states. In bulk water, rapid proton exchange and hindered molecular rotation obscure the direct observation of two spin isomers. The supramolecular endofullerene H2O@C60 provides freely rotating, isolated water molecules even at cryogenic temperatures. Here we show that the bulk dielectric constant of this substance depends on the ortho/para ratio, and changes slowly in time after a sudden temperature jump, due to nuclear spin conversion. The attribution of the effect to ortho–para conversion is validated by comparison with nuclear magnetic resonance and quantum theory. The change in dielectric constant is consistent with an electric dipole moment of 0.51±0.05 Debye for an encapsulated water molecule, indicating the partial shielding of the water dipole by the encapsulating cage. The dependence of bulk dielectric constant on nuclear spin isomer composition appears to be a previously unreported physical phenomenon.

Insights into the Partitioning Behavior of Secondary Surfactants in a Microemulsion-Based Synthesis of Metal Nanoparticles: A DLS and 2D NMR Spectroscopic Investigation.

Diffusion-ordered NMR spectroscopy (DOSY) and nuclear Overhauser effect spectroscopy (NOESY) have been used to explore the diffusion and partitioning behavior of secondary surfactants added to suspensions of reverse micelles (RMs) containing either silver or gold nanoparticles (NPs), with an aim of advancing our understanding of the mechanism of metal NP extraction and/or surface functionalization with specific capping agents as performed during a microemulsion-based synthesis. We have coupled these NMR techniques with corresponding dynamic light scattering (DLS) measurements of RMs, with and without encapsulated metal NPs, upon addition of secondary surfactants. Using oleylamine (OAm), oleic acid (OA), dodecylamine (DDAm), and dodecanethiol (DDT), we show that all four secondary surfactants can rapidly diffuse into/out of the RM environment with their head groups in close proximity to the RM interior and encapsulated water molecules; however, surfactant molecules containing a terminal -NH2 or -COOH group undergo a persistent association with the molecules of the RMs, thus solubilizing and partially sequestering a portion of the total concentration of these secondary agents within the RM interface for a lengthened period of time (in relation to the time frame of the DOSY experiments) and slowing their rate of exchange with freely diffusing molecules in the bulk solvent. The extraction of Ag or Au NPs from RMs into organic phase was determined to be critically dependent on the type and concentration of secondary surfactant added to the system, with DDT proving to be most efficient for the extraction of Ag NPs, while OA was shown to be most efficient for Au NPs. Consideration of the results obtained from this particular combination of techniques has provided new knowledge with respect to dynamic metal NP-containing microemulsion systems.

Testing the vesicular morphology to destruction: birth and death of diblock copolymer vesicles prepared via polymerization-induced self-assembly.

Small angle X-ray scattering (SAXS), electrospray ionization charge detection mass spectrometry (CD-MS), dynamic light scattering (DLS), and transmission electron microscopy (TEM) are used to characterize poly(glycerol monomethacrylate)55-poly(2-hydroxypropyl methacrylate)x (G55-Hx) vesicles prepared by polymerization-induced self-assembly (PISA) using a reversible addition–fragmentation chain transfer (RAFT) aqueous dispersion polymerization formulation. A G55 chain transfer agent is utilized to prepare a series of G55-Hx diblock copolymers, where the mean degree of polymerization (DP) of the membrane-forming block (x) is varied from 200 to 2000. TEM confirms that vesicles with progressively thicker membranes are produced for x = 200–1000, while SAXS indicates a gradual reduction in mean aggregation number for higher x values, which is consistent with CD-MS studies. Both DLS and SAXS studies indicate minimal change in the overall vesicle diameter between x = 400 and 800. Fitting SAXS patterns to a vesicle model enables calculation of the membrane thickness, degree of hydration of the membrane, and the mean vesicle aggregation number. The membrane thickness increases at higher x values, hence the vesicle lumen must become smaller if the external vesicle dimensions remain constant. Geometric considerations indicate that this growth mechanism lowers the total vesicle interfacial area and hence reduces the free energy of the system. However, it also inevitably leads to gradual ingress of the encapsulated water molecules into the vesicle membrane, as confirmed by SAXS analysis. Ultimately, the highly plasticized membranes become insufficiently hydrophobic to stabilize the vesicle morphology when x exceeds 1000, thus this PISA growth mechanism ultimately leads to vesicle “death”.

Molecular separation with carbon nanotubes

The feasibility of molecular separation with carbon nanotubes is studied by investigating a separation of water molecules and lead nanoparticles with a carbon nanotube-based nanopore system from molecular dynamics simulations. The nanopore system is comprised of a single-walled carbon nanotube and two graphene sheets placed at two ends of the nanotube. The nanotube is subjected to impact loads on a local portion on the wall to generate the propagation of impulse waves in the tube for pumping the encapsulated water molecules out of the tube, while blocking lead nanoparticles by the two graphenes. Studies indicate that the separation is a result of van der Waals interactions between the nanotube and the encapsulated molecules through the propagation of impulse waves in the nanotube. The efficiency of the molecular separation is found to be dependent on the amount of impact loads and the size of the impacted portion of the tube.

Single-crystal 1H NMR data and hydrogen atom disorder in lawsonite, CaAl2[Si2O7](OH)2·H2O

The dynamic structure of hydrogen sublattice in lawsonite, CaAl2[Si2O7](OH)2·H2O is studied by the solidstate proton magnetic resonance (1H NMR) spectroscopy of single crystal at room temperature. It is shown that both encapsulated water molecules, and hydroxyl OH-groups undergoes the rocking librations of the amplitudes of ∼20° for H2O, and ∼40° for hydroxyls.

Conformationally Controlled Oligocholate Membrane Transporters: Learning through Water Play

Controlled translocation of molecules and ions across lipid membranes is the basis of numerous biological functions. Because synthetic systems can help researchers understand the more complex biological ones, many chemists have developed synthetic mimics of biological transporters. Both systems need to deal with similar fundamental challenges. In addition to providing mechanistic insights into transport mechanisms, synthetic transporters are useful in a number of applications including separation, sensing, drug delivery, and catalysis. In this Account, we present several classes of membrane transporters constructed in our laboratory from a facially amphiphilic building block, cholic acid. Our "molecular baskets" can selectively shuttle glucose across lipid membranes without transporting smaller sodium ions. We have also built oligocholate foldamers that transiently fold into helices with internal hydrophilic binding pockets to transport polar guests. Lastly, we describe amphiphilic macrocycles, which form transmembrane nanopores in lipid bilayers through the strong associative interactions of encapsulated water molecules. In addition to presenting the different transport properties of these oligocholate transporters, we illustrate how fundamental studies of molecular behavior in solution facilitate the creation of new and useful membrane transporters, despite the large difference between the two environments. We highlight the strong conformational effect of transporters. Because the conformation of a molecule often alters its size and shape, and the distribution of functional groups, conformational control can be used rationally to tune the property of a transporter. Finally, we emphasize that, whenever water is the solvent, its unique properties--small size, strong solvation for ionic functionalities, and an extraordinary cohesive energy density (i.e., total intermolecular interactions per unit volume)--tend to become critical factors to be considered. Purposeful exploitation of these solvent properties may be essential to the success of the supramolecular process involved--this is also the reason for the "learning through water play" in the title of this Account.

Vibrational Raman spectra of hydrogen clathrate hydrates from density functional theory

Hydrogen clathrate hydrates are promising sources of clean energy and are known to exist in a sII hydrate lattice, which consists of H2 molecules in dodecahedron (5(12)) and hexakaidecahedron (5(12)6(4)) water cages. The formation of these hydrates which occur in extreme thermodynamic conditions is known to be considerably reduced by an inclusion of tetrahydrofuran (THF) in cages of these hydrate lattice. In this present work, we employ the density functional theory with a dispersion corrected (B97-D) functional to characterize vibrational Raman modes in the cages of pure and THF doped hydrogen clathrate hydrates. Our calculations show that the symmetric stretch of the H2 molecule in the 5(12)6(4)H2·THF cage is blueshifted compared to the 5(12)6(4)H2 cage. However, all vibrational modes of water molecules are redshifted which suggest reduced interaction between the H2 molecule and water molecules in the 5(12)6(4)H2·THF cage. The symmetric and asymmetric O-H stretch of water molecules in 5(12)H2, 5(12)6(4)H2, and 5(12)6(4)H2·THF cages are redshifted compared with the corresponding guest free cages due to interactions between encapsulated H2 molecules and water molecules of the cages. The low frequency modes contain contributions from contraction and expansion of water cages and vibration of water molecules due to hydrogen bonding and these modes could possibly play an important role in the formation of the hydrate lattice.