Intestinal absorption of drugs II. The effect of inclusion in cyclodextrins on the absorption of dantrolene

The inclusion of dantrolene sodium, a muscle relaxant with poor water-solubility, in-,- and-cyclodextrins was determined. Subsequently, the influence of the cyclodextrins on the absorption of the drug from aqueous solutions was investigated in a chronically isolated internal loop in the small intestine of the rat.A good correlation was found between the inclusion of dantrolene in the various cyclodextrins and the decrease in the absorption rate resulting from a reduction of the thermodynamically active dantrolene according to the phase-separation model. It was concluded that the cyclodextrins do not have a significant influence on the passage of dantrolene across the absorption barrier. Furthermore, experimental evidence was collected to support the fact that-cyclodextrin was absorbed to a limited, if not negligible, extent in the small intestine of the rat.     

Lipid-based mechanisms for vesicle fission

Shape transformations and topological changes of lipid vesicles, such as fusion, budding, and fission, have important chemical physical and biological significance. In this paper, we study the fission process of lipid vesicles. Two distinct routes are considered that are both based on an asymmetry of the lipid distribution within the membrane. This asymmetry consists of a nonuniform distribution of two types of lipids. In the first mechanism, the two types of lipids are equally distributed over both leaflets of the membrane. Phase separation of the lipids within both leaflets, however, results in the formation of rafts, which form buds that can split off. In the second mechanism, the asymmetry consists of a difference in composition between the two monolayers of the membrane. This difference in composition yields a spontaneous curvature, reshaping the vesicle into a dumbbell such that it can split. Both pathways are studied with molecular dynamics simulations using a coarse-grained lipid model. For each of the pathways, the conditions required to obtain complete fission are investigated, and it is shown that for the second pathway, much smaller differences between the lipids are needed to obtain fission than for the first pathway. Furthermore, the lipid composition of the resulting split vesicles is shown to be completely different for both pathways, and essential differences between the fission pathway and the pathway of the inverse process, i.e., fusion, are shown to exist.     

Solution Structure of a RNA Decamer Duplex,Containing 9‐[2‐O‐(β‐D‐ribofuranosyl)‐β‐D‐ribofuranosyl]adenine,a Special Residue in Lower Eukaryotic Initiator tRNAs

The solution structure of the self‐complementary deca‐ribonucleotide 5′‐r(GCGA*AUUCGC)‐3′ containing 9‐[2‐O‐(β‐D ‐ribofuranosyl)‐β‐D ‐ribofuranosyl]adenine (A*), a modified nucleotide that occurs in lower eukaryotic methionine initiator tRNAs (tRNAs_i^Met), was determined by NMR spectroscopy. Unexpectedly, the modification has no effect on the thermal stability of the duplex. However, the extra ribose moiety is in the C(3′)‐endo conformation and takes up a well‐defined position in the minor groove, which is in agreement with its position in tRNAs_i^Met as determined by X‐ray crystallography. Molecular‐dynamics simulations on the RNA duplex in H₂O show that the position of the extra ribofuranose moiety seems to be stabilized by bridged H‐bonds (mediated by two H₂O molecules) to the backbone of the complementary chain.     

Chemical shifts in nucleic acids studied by density functional theory calculations and comparison with experiment

NMR chemical shifts are highly sensitive probes of local molecular conformation and environment and form an important source of structural information. In this study, the relationship between the NMR chemical shifts of nucleic acids and the glycosidic torsion angle, χ, has been investigated for the two commonly occurring sugar conformations. We have calculated by means of DFT the chemical shifts of all atoms in the eight DNA and RNA mono-nucleosides as a function of these two variables. From the DFT calculations, structures and potential energy surfaces were determined by using constrained geometry optimizations at the BP86/TZ2P level of theory. The NMR parameters were subsequently calculated by single-point calculations at the SAOP/TZ2P level of theory. Comparison of the (1) H and (13) C?NMR shifts calculated for the mono-nucleosides with the shifts determined by NMR spectroscopy for nucleic acids demonstrates that the theoretical shifts are valuable for the characterization of nucleic acid conformation. For example, a clear distinction can be made between χ angles in the anti and syn domains. Furthermore, a quantitative determination of the χ angle in the syn domain is possible, in particular when (13) C and (1) H chemical shift data are combined. The approximate linear dependence of the C1' shift on the χ angle in the anti domain provides a good estimate of the angle in this region. It is also possible to derive the sugar conformation from the chemical shift information. The DFT calculations reported herein were performed on mono-nucleosides, but examples are also provided to estimate intramolecularly induced shifts as a result of hydrogen bonding, polarization effects, or ring-current effects.     

Estimating ground-state properties of quantum dot arrays using a local Thomas-Fermi-Dirac approximation

An exactly solvable local Thomas-Fermi-Dirac approximation is applied to the calculation of the ground-state density of three-dimensional quantum dot arrays, where we give estimates to properties like total energy, chemical potential, and differential capacitance. Numeric examples are calculated for pairs of quantum dots using a Gaussian confining potential. The computational complexity of the present method is linear in the number of electrons and centers of the system.