Analysis of the topology of the electron density and underlying local orbital interactions of the fully optimized structure of the molecular cage of the in-bicyclo[4.4.4]-1-tetradecyl cation reveals that the inside 3c2e C-H...C hydrogen bond is not only unusual but also strong. The inside C-H bond of the unsaturated, neutral precursor bicyclo[4.4.4]-1-tetradecene is involved in an intramolecular C-H/pi interaction with the transannular double bond. Known and calculated (1)H and (13)C NMR properties, including diamagnetic and paramagnetic contributions to shielding tensors, are accounted for in terms of electron density redistributions and the unusual electronic environment within these hydrocarbon cages.

The mechanism of thiamin diphosphate-dependent enzyme reactions requires two carbanion intermediates 1a and 1b. Neither has been isolated nor detected, but resonance stabilization is assumed to occur with the thiazolium quaternary nitrogen being the electron sink. We have questioned the electronic nature of these carbanion intermediates and, in a broader sense, the role of sulfur in the thiazolium moiety. To address these issues the theory of atoms in molecules (AIM) was used to acquire quantitative electron distributions in thiazolium 2, oxazolium 3, and imidazolium 4 as cations and zwitterions. Among the heteroatoms, only sulfur acts as an electron sink. This is corroborated by a similar behavior in phosphorothioates. Further, the formal carbanion at C2 and Calpha of the intermediates are positively charged and their nucleophilic character is explained with AIM theory by comparison with the sigmaC(-) of model 5a and piC(-) of model 6a. C2 of 2a excels in lone-pair coverage in the sigma-plane, surpassing the sigmaC(-) in acyclic 5a and other cyclic ylidenes, and hence, is a more effective nucleophile. The piC(-) of 6a reveals a depletion area centered in the sigma-plane but shows lone-pair concentration above and below the plane. Unlike 6a, the AIM properties, bond length, and bond order of 2b indicate no lone-pair on Calpha but essentially a double bond across C2-Calpha. Thus, the nucleophilic behavior at Calpha of 1b is based on the enamine chemistry induced by an electrophile.

Analysis using the theory of atoms in molecules and natural bond orbital theory of the fully optimized structure of the inside-protonated form of 1,6-diazabicyclo[4.4.4]tetradecane reveals that the encapsulated proton is engaged in a short-strong though asymmetric H-bond with covalent character. The symmetric conformer with the proton in the center of the cage was found to be a transition state with a very low barrier to proton transfer along the N...N axis. Both an implicit reaction field model (IEF-PCM) and explicit placements of chloride counterions, suggested by a published X-ray crystal structure, were found to modify the position of the proton and the strength of the H-bond. An external counterion placed along the N...N axis and near one of the bridgehead nitrogens is most effective in weakening this very hydrophobically shielded diamine H-bond. The results of this study are relevant to ongoing issues about the possible participation of unusually strong H-bonds in enzymatic catalysis.

In passing through the lens, light crosses thousands of cell membranes. To explore the possible contribution of lipids to the scattering properties of the lens, we have carried out in vitro studies with lipids extracted from human lenses 1–90 years of age. Sphingomyelin and human lens lipids were extruded into large unilamellar vesicles (LUVs). The intensity of light scattered by human lens LUVs increased with age and lipid hydrocarbon chain order. Hydrocarbon chain order also correlated with light scattering intensity by sphingomyelin LUVs. Light scattered by LUVs composed of sphingomyelin (1–30mgml−1) was 20 to 100 times more intense than that scattered by the same concentration of α-crystallin in aqueous media. Increased lipid hydrocarbon chain order as well as variations in the headgroup and interfacial region of bilayers resulting from lipid compositional changes can influence membrane light scattering properties. In vitro measurements suggest that the contribution to light scattering by lipids may be significant and should not be disregarded in the investigation of factors and components that lead to the increase in light scattering by human lenses with age and cataract.

piH-bonded complexes of water and the water dimer with ethene, propene, trans-2-butene, and allyl alcohol were examined in structures calculated ab initio at MP2/6-311++G(2d,2p). Cooperative enhancement of piH and sigmaH bonds is observed in the presence of hydroxy groups either from the second water or the alcohol. These interactions are analyzed in terms of structural changes, binding energies, normal-mode frequency shifts and intensity increases, and donor-acceptor charge transfers among local (natural bond) orbitals that nonadditively polarize participating bonds. The field effect of electron-releasing methyl groups attached to the double bond is also shown to strengthen the piH bond.

The changes induced by Ca2+ on human lens sphingolipids, sphingomyelin (SM), and dihydrosphingomyelin were investigated by infrared spectroscopy. Ca2+-concentration-dependent studies of the head group region revealed that, for both sphingolipids, Ca2+ partially dehydrates some of the phosphate groups and binds to others. Ca2+ affects the interface of each sphingolipid differently. In SM, Ca2+ shifts the amide I' band to frequencies lower than those in dehydrated samples of SM alone. This could be attributed to the direct binding of Ca2+ to carbonyl groups and/or strong tightening of interlipid H-bonds to levels beyond those in dehydrated samples of SM only. In contrast, Ca2+ induces relatively minor dehydration around the amide groups of dihydrosphingomyelin and a slight enhancement of direct lipid-lipid interactions. Temperature-dependent studies reveal that 0.2 M Ca2+ increases the transition temperature T-m from 31.6 +/- 1.0degreesC to 35.7 +/- 1.1degreesC for SM and from 45.5 +/- 1.1degreesC to 48.2 +/- 1.0degreesC for dihydrosphingomyelin. Binding of Ca2+ to some phosphate groups remains above T-m. The strength of the interaction is, however, weaker. This allows for the partial rehydration of these moieties. Similarly, above T-m, Ca2+-lipid and/or direct inter-lipid interactions are weakened and lead to the rehydration of amide groups.

Ceramide (Cer) has been identified as an active lipid second messenger in the regulation of cell growth, differentiation, and apoptosis. Its analog, dihydroceramide, without the 4 to 5 trans double bond in the sphingoid backbone lacks these biological effects. To establish the conformational features that distinguish ceramide from its analogs, nuclear magnetic resonance spectral data were acquired for diluted samples of ceramides (C2- and C18-Cer), dihydroceramide (C16-DHCer), and deoxydihydroceramide (C18-DODHCer). Our results suggest that in both C2- and C18-Cer, an H-bond network is formed in which the amide proton NH is donated to the OH groups on carbons C1 and C3 of the sphingosine backbone. Two tightly bound water molecules appear to stabilize this network by participating in flip-flop interactions with the hydroxyl groups. In DHCer, the lack of the trans double bond leads to a conformational distortion of this H-bonding motif. Without the critical double bond, the degree with which water molecules stabilize the H bonds between the two OH groups of the sphingolipid is reduced. This structural alteration might preclude the participation of DHCer in signaling-related interactions with cellular targets.

Equilibrium structures of monomers and dimers of 2-aminoethanol (AE) exhibiting different intramolecular and intermolecular hydrogen bonds between the OH and NH2 groups were optimized and analyzed in theoretical density functional B3LYP/6-311++G(2d,2p) calculations. Natural bond orbital (NBO) theory was applied to quantify the relative strength of these interactions and to account for their effect on stability, structural, and vibrational parameters of both monomers and dimers. It is shown that the charge transferred from the lone pair of the hydrogen bond acceptor to the antibonding orbital of the donor provides the substantial stabilizing component of the hydrogen bond. NBO energetic analysis demonstrates that the OH···N interaction is the strongest one for both monomers (intramolecular) and dimers (intermolecular). The intramolecular hydrogen bond in AE monomers is relatively weak, in part, because of its bent nature. The formation of a stronger and more linear intermolecular hydrogen bond between mole...

Natural bond orbital (NBO) theory has been applied to analyze stereoelectronic preferences of the gg, tg and tt stationary states and two connecting transition states of the dimethylphosphate (DMP−) anion. In going from the compact gg to the extended tt state, the Oa–P–Oa angle closes as phosphoryl anionic oxygen, P–Oa, bonds are weakened by negative hyperconjugation. Phosphoryl ester oxygen, P–Oe, bonds are strengthened, however, due to increased π-overreach, largely a result of delocalization of ester oxygen lone pair density. In a ‘closing scissors effect’, contraction of the Oe–P–Oe angle between these stronger bonds also results, in this case due to the dominance of repulsive forces among the lone pairs. Counterintuitive arrangements in the transition states between gg and tg, and between two equivalent, twisted tt stationary states result, again, from dominant repulsions of oxygen lone pairs. Complexation of DMP− with water, Na+, or Mg+2 ions is accompanied by significant charge transfer to the ligand, thus imparting a degree of covalency to the anion–ligand bond. H-bonds between water and the two Oa oxygens lead to delocalization of charge through lone pairs at the docking site of DMP− into σ∗(Ow–H) antibonds. For the ion-pairs, charge is transferred by a similar mechanism into Rydberg orbitals on the cation. Rearrangement of electron density within DMP− in the complexes replenishes losses from Oa lone pairs and increases the magnitude of the anomeric effect involving Oe lone pairs. NBO theory provides a quantitative description of the complex balance of interactions that dictate the conformational features of this biologically significant molecular functionality.

The conformational features of dihydrosphingomyelin (DHSM), the major phospholipid of human lens membranes, were investigated by 1H and 31P nuclear magnetic resonance spectroscopy. Several postulates emerge from the observed trends: (a) in partially hydrated samples of DHSM in CDCl3 above 13 mM, at which lipid–lipid interactions prevail, the amide proton is mostly involved in intermolecular H-bonds that link neighboring phospholipids through bridging water molecules. In the absence of water, the NH group is involved in an intramolecular H-bond that restricts the mobility of the phosphate group. (b) In the monomeric form of the lipid molecule, the amide proton of the major conformer is bound intramolecularly with one of the anionic and/or ester oxygens of the phosphate group. A minor conformer may also be present in which the NH proton participates in an intramolecular H-bond linking to the OH group of the sphingoid base. (c) Complete hydration leads to an extension of the head group as water molecules bind to the phosphate and NH groups via H-bonds, thus disrupting the intramolecular H-bonds prevalent at low concentrations.

Force field parameters were developed for the phosphodiester linkage and introduced into the molecular mechanics program MM3 to simulate conformational states of phosphosphingolipids. The modified MM3 parameter set was tested with the dimethylphosphate anion and the methylphosphorylcholine zwitterion. The results compare well with established conformational preferences of these important functionalities in lipid head groups. At a dielectric constant of ϵ=4.0, generally taken to represent the electrostatic environment of the membrane surface, the diesterphosphate dihedral angles α2 and α3 are predicted to be primarily +sc, +sc in both species. The outer dihedral angles α4 and α5 of the choline functionality are predominantly ap and ±sc, respectively, in the lowest energy structures. Increase of the dielectric constant reveals an extension of these partially folded structures as might occur under the influence of an aqueous environment. This parameter set was then applied to a phosphorylated dihydroceramide to investigate conformational preferences of the head group with respect to the lipid interface. Three of the most probable conformations are compatible with liquid crystalline, bilayer organizations. These conformations exhibit intramolecular hydrogen bonds involving the NH and OH moieties as donors and an ester and/or anionic phosphate oxygen as acceptors. Features of the Boltzmann-distributed conformations are confirmed by known experimental results from NMR spectroscopy.