Neutralization-Reionization of alkenylammonium cations: An experimental and ab initio study of intramolecular N-H … C=C interactions in cations and hypervalent ammonium radicals

A series of isomeric hexenylammonium and hexenyldimethylammonium cations were neutralized by collisional electron transfer in the gas phase in an attempt to generate hypervalent ammonium radicals. The radicals dissociated completely on the 4.8–5.4 µs time scale. Radicals in which the hexene double bond was in the 3-, 4-, and 5-positions dissociated by competitive N-H and N=C bond cleavages. Allylic 2-hexen-1-ylammonium and 2-hexen-1-yldimethylammonium radicals underwent predominant cleavages of allylic N-C bonds. Deuterium labeling experiments revealed no intramolecular hydrogen transfer from the hypervalent ammonium group to the hexene double bond. Ab initio and density functional theory calculations showed that alkenylammonium and alkenylmethyloxonium ions preferred hydrogen bonded structures in the gas phase. The stabilization through intramolecular H bonding in 3-buten-1-ylammonium and 3-buten-1-yl methyloxonium ions was calculated by B3LYP/6-311G(2d,p) at 26 and 18 kJ mol^?1, respectively. No intramolecular hydrogen bonding was found for the allylammonium ion. The hypervalent 3-buten-1-yl-methyloxonium radical was calculated to be unbound and predicted to dissociate exothermically by O-H bond cleavage. This dissociation may provide kinetic energy for the hydrogen atom to overcome a small energy barrier for exothermic addition to the double bond. The 3-butten-1-ylammonium and allylammonium radicals were found to be bound and preferred gauche conformations without intramolecular hydrogen bonding. Vertical neutralization of alkenylammonium ions was accompanied by small Franck-Condon effects. The failure to detect stable or metastable hypervalent alkenylammonium radicals was ascribed to the low activation barriers to exothermic dissociations by N-H and N-C bond cleavages.     

Molecular dynamics and free energy perturbation study of hydride-ion transfer step in dihydrofolate reductase using combined quantum and molecular mechanical model

We used molecular dynamics simulation and free energy perturbation (FEP) methods to investigate the hydride-ion transfer step in the mechanism for the nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of a novel substrate by the enzyme dihydrofolate reductase (DHFR). The system is represented by a coupled quantum mechanical and molecular mechanical (QM/MM) model based on the AM1 semiempirical molecular orbital method for the reacting substrate and NADPH cofactor fragments, the AMBER force field for DHFR, and the TIP3P model for solvent water. The FEP calculations were performed for a number of choices for the QM system. The substrate, 8-methylpterin, was treated quantum mechanically in all the calculations, while the larger cofactor molecule was partitioned into various QM and MM regions with the addition of “link” atoms (F, CH₃, and H). Calculations were also carried out with the entire NADPH molecule treated by QM. The free energies of reaction and the net charges on the NADPH fragments were used to determine the most appropriate QM/MM model. The hydride-ion transfer was also carried out over several FEP pathways, and the QM and QM/MM component free energies thus calculated were found to be state functions (i.e., independent of pathway). A ca. 10 kcal/mol increase in free energy for the hydride-ion transfer with an activation barrier of ca. 30 kcal/mol was calculated. The increase in free energy on the hydride-ion transfer arose largely from the QM/MM component. Analysis of the QM/MM energy components suggests that, although a number of charged residues may contribute to the free energy change through long-range electrostatic interactions, the only interaction that can account for the 10 kcal/mol increase in free energy is the hydrogen bond between the carboxylate side chain of Glu30 (avian DHFR) and the activated (protonated) substrate. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 977–988, 1998     

Numerical calculation of molecular surface area. I. Assessment of errors

Several points distributions have been used to calculate van der Waals surface areas of a set of molecules. It is shown that there is no strict correlation between the global statistical characteristics of the points distribution, such as deviation and standard deviation, and the accuracy of the calculation of molecular surface. Information about details of the points distribution is needed for predicting the precision of the results. The results show that points distributions produced by optimization of the U function of Le Grand and Merz [J. Comput. Chem., 14 , 349 (1993)] give the most accurate estimation of the molecular surface in numerical calculations. The precision of the numerical evaluation of the van der Waals surface areas has been assessed for 256, 512, 1024, and 2048 points on a single sphere. © 1996 by John Wiley & Sons, Inc.     

Cancer-Related Somatic Mutations in Transmembrane Helices Alter Adenosine A1 Receptor Pharmacology

Overexpression of the adenosine A₁ receptor (A₁AR) has been detected in various cancer cell lines. However, the role of A₁AR in tumor development is still unclear. Thirteen A₁AR mutations were identified in the Cancer Genome Atlas from cancer patient samples. We have investigated the pharmacology of the mutations located at the 7-transmembrane domain using a yeast system. Concentration–growth curves were obtained with the full agonist CPA and compared to the wild type hA₁AR. H78L^3.23 and S246T^6.47 showed increased constitutive activity, while only the constitutive activity of S246T^6.47 could be reduced to wild type levels by the inverse agonist DPCPX. Decreased constitutive activity was observed on five mutant receptors, among which A52V^2.47 and W188C^5.46 showed a diminished potency for CPA. Lastly, a complete loss of activation was observed in five mutant receptors. A selection of mutations was also investigated in a mammalian system, showing comparable effects on receptor activation as in the yeast system, except for residues pointing toward the membrane. Taken together, this study will enrich the view of the receptor structure and function of A₁AR, enlightening the consequences of these mutations in cancer. Ultimately, this may provide an opportunity for precision medicine for cancer patients with pathological phenotypes involving these mutations.     

Axial Imidazole Binding Strengths in Porphyrinoid Cobalt(III) Complexes as Studied by Tandem Mass Spectrometry

The Co(II) complexes of twelve meso-tetraaryl-porphyrins, -chlorins, and chlorin analogues containing non-pyrrolic heterocycles were synthesized and converted in situ to the corresponding Co(III) complexes coordinated to one or two imidazoles. Electrospray ionization tandem mass spectrometry (ESI-MS/MS) in conjunction with the energy-variable collision-induced dissociation (CID) technique was used to compare the relative gas-phase binding strength of the axially coordinated imidazoles to the octahedral and square planar Co(III) porphyrinoid complex ions. The observed binding energies of these ligands were rationalized in terms of the effects of porphyrinoid core structure and meso-substitution on the electron density on the central Co(III) centers. Some of these trends were supported by DFT-based computational studies. The study highlights to which extend porphyrins vary from chlorins and chlorin analogues in their coordination abilities and to which extraordinary degree meso-thienyl-substituents influence the electronic structure of porphyrins. The study also defines further the scope and limits CID experiments can be used to interrogate the electronic structures of metalloporphyrin complexes.     

Secondary organic aerosol formation from low-NO(x) photooxidation of dodecane: evolution of multigeneration gas-phase chemistry and aerosol composition

The extended photooxidation of and secondary organic aerosol (SOA) formation from dodecane (C(12)H(26)) under low-NO(x) conditions, such that RO(2) + HO(2) chemistry dominates the fate of the peroxy radicals, is studied in the Caltech Environmental Chamber based on simultaneous gas and particle-phase measurements. A mechanism simulation indicates that greater than 67% of the initial carbon ends up as fourth and higher generation products after 10 h of reaction, and simulated trends for seven species are supported by gas-phase measurements. A characteristic set of hydroperoxide gas-phase products are formed under these low-NO(x) conditions. Production of semivolatile hydroperoxide species within three generations of chemistry is consistent with observed initial aerosol growth. Continued gas-phase oxidation of these semivolatile species produces multifunctional low volatility compounds. This study elucidates the complex evolution of the gas-phase photooxidation chemistry and subsequent SOA formation through a novel approach comparing molecular level information from a chemical ionization mass spectrometer (CIMS) and high m/z ion fragments from an Aerodyne high-resolution time-of-flight aerosol mass spectrometer (HR-ToF-AMS). Combination of these techniques reveals that particle-phase chemistry leading to peroxyhemiacetal formation is the likely mechanism by which these species are incorporated in the particle phase. The current findings are relevant toward understanding atmospheric SOA formation and aging from the "unresolved complex mixture," comprising, in part, long-chain alkanes.     

Ageing of enteric neurons: oxidative stress, neurotrophic factors and antioxidant enzymes

ABSTRACT: BACKGROUND: Ageing is associated with gastrointestinal dysfunction, which can have a major impact on quality of life of the elderly. A number of changes in the innervation of the gut during ageing have been reported, including neuronal loss and degenerative changes. Evidence indicates that reactive oxygen species (ROS) are elevated in ageing enteric neurons, but that neurotrophic factors may reduce generation of neuronal ROS. Two such factors, glial cell line derived neurotrophic factor (GDNF) and neurotrophin-3 (NT-3) have also been found to protect enteric neurons against oxidative stress induced cell death of enteric ganglion cells in vitro. We have investigated the possible roles of neurotrophic factors further, by examining their expression in the gut during ageing, and by analysing their effects on antioxidant enzyme production in cultures of enteric ganglion cells. RESULTS: Analysis of the expression of GDNF and its receptors c-Ret and GFR alpha 1in rat gut by RTPCR showed that expression continues throughout life and into ageing, in both ad libitum(AL) and calorically-restricted (CR) animals. Levels of expression of GDNF and GFR alpha 1 were elevated in 24 month AL animals compared to 24 month CR animals, and to 24 CR and 6 month control animals respectively.The related factor Neurturin and its receptorGFR alpha 2 were also expressed throughout life, the levels of the GFR - alpha-2B isoform were reduced in 24 m AL animals. Immunolabelling showed that c-Ret and GFR alpha 1 proteins were expressed by myenteric neurons in ageing animals. GDNF, but not NT-3, was found to increase expression of Cu/Zn superoxide dismutase and catalase by cultured enteric ganglion cells. CONCLUSIONS: The neurotrophic factors GDNF and neurturin and their receptors continue to be expressed in the ageing gut. Changes in the levels of expression of GDNF , GFR alpha-1 and GFR alpha-2b isoform occurred in 24 m AL animals. GDNF, but not NT-3, increased the levels of antioxidant enzymes in cultured enteric ganglion cells, indicating a possible mechanism for the reported protective effect of GDNF against menadione-induced neuronal apoptosis in the ageing gut. Together these data suggest that GDNF family members may play a protective role in the gut throughout life, and support the suggestion that dysregulation of neurotrophic factor support could contribute to neuronal ageing in the gut.     

Automorphism Groups of Semi-Direct Products

Let G = A ? B be a semi-direct product of two groups. We investigate conditions under which the subgroup of Aut(G) fixing A as a set is also a semi-direct product. If A is characteristic in G, then we have conditions under which Aut(G) itself is a semi-direct product.     

Aggregation and adhesion of gold nanoparticles in phosphate buffered saline

In applications in medicine and more specifically drug delivery, the dispersion stability of nanoparticles plays a significant role on their final performances. In this study, with the use of two laser technologies, dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA), we report a simple method to estimate the stability of nanoparticles dispersed in phosphate buffered saline (PBS). Stability has two features: (1) self-aggregation as the particles tend to stick to each other; (2) disappearance of particles as they adhere to surrounding substrate surfaces such as glass, metal, or polymer. By investigating the effects of sonication treatment and surface modification by five types of surfactants, including nonylphenol ethoxylate (NP9), polyvinyl pyrrolidone (PVP), human serum albumin (HSA), sodium dodecyl sulfate (SDS) and citrate ions on the dispersion stability, the varying self-aggregation and adhesion of gold nanoparticles dispersed in PBS are demonstrated. The results showed that PVP effectively prevented aggregation, while HSA exhibited the best performance in avoiding the adhesion of gold nanoparticle in PBS onto glass and metal. The simple principle of this method makes it a high potential to be applied to other nanoparticles, including virus particles, used in dispersing and processing.