Conformational analysis of the eight-membered ring of the oxidized cysteinyl-cysteine unit implicated in nicotinic acetylcholine receptor ligand recognition.

Nicotinic acetylcholine receptors (nAChRs) are membrane-bound, pentameric ligand-gated ion channels associated with a variety of human disorders such as Alzheimer's disease, Parkinson's disease, schizophrenia, and pain. Most known nAChRs contain an unusual eight-membered disulfide-containing cysteinyl-cysteine ring, ox-[Cys-Cys], as does the soluble acetylcholine binding protein (AChBP) found in the snail Lymnaea stagnalis. The cysteinyl-cysteine ring is located in a region implicated in ligand binding, and conformational changes involving this ring may be important for modulation of nAChR function. We have studied the preferred conformations of Ac-ox-[Cys-Cys]-NH2 by NMR in water and computationally by Monte Carlo simulations using the OPLS-AA force field and GB/SA water model. ox-[Cys-Cys] adopts four distinct low-energy conformers at slightly above 0 degrees C in water. Two populations are dependent on the peptide omega2 dihedral angle, with the trans amide favored over the cis amide by a ratio of ca. 60:40. Two ox-[Cys-Cys] conformers with a cis amide bond (C+ and C-) differ from each other primarily by variation of the chi3 dihedral angle, which defines the orientation of the helicity about the S-S bond (+/- 90 degrees ). Two trans amide conformers have the same S-S helicity (chi3 approximately -90 degrees ), but are distinguished by a backbone rotation about phi2 and psi1 (T- and T'-). The ratio of T-/T'-/C+/C- is 47:15:29:9. The orientation of the pendant moieties from the eight-membered ring is more compact for the major trans conformer (T-) than for the extended conformations adopted by T'-, C+, and C-. These conformational preferences are also observed in tetrapeptide and undecapeptide fragments of the human alpha7 subtype of the nAChR that contains the ox-[Cys-Cys] unit. Conformer T- is nearly identical to the conformation seen in the X-ray structure of ox-[Cys(187)-Cys(188)] found in the unliganded AChBP, and is a Type VIII beta-turn.     

An experimental and a DFT study on the synthesis, spectroscopic characterization, and reactivity of the adducts of dimethyl- and diphenyltin(IV) dichlorides with γ-pyrones [4H-pyran-4-one (PYR) and 2,6-dimethyl-4H-pyran-4-one (DMP)]: Crystal structure of Ph2SnCl2(PYR)

The Sn(IV) R₂SnCl₂(γ-pyrone)_n [R = Me or Ph; γ-pyrone = 4H-pyran-4-one (PYR) or 2,6-dimethyl-4H-pyran-4-one (DMP); n = 1 or 2] adducts have been synthesized and investigated. The adducts Ph₂SnCl₂(PYR) (1), Me₂SnCl₂(PYR)₂ (2), Ph₂SnCl₂(DMP) (3) and Me₂SnCl₂(PYR)(PNO) (4), (PNO = 4-methylpyridine N-oxide) have been prepared by the addition of the corresponding γ-pyrone to chloroform solution of R₂SnCl₂. The new compounds have been characterized by elemental analysis and spectroscopic (IR, ¹H, ¹³C NMR and Mössbauer) means. The single-crystal diffraction study of 1 shows the Sn(IV) to be five-coordinate, [Sn-O and Sn-Cl(1), Sn-Cl(2) distances of 2.3190(13) and 2.4312(6), 2.3653(7), respectively], and the Cl-Sn-Cl bond angle to be 91.17°. The reactivity of 2 towards bipy, Ph₃PO, QNO (Q = quinoline) resulted in complete displacement of PYR and formation of already known compounds whereas, the PNO displaced only one equivalent of PYR, causing the preparation of the new mixed complex 4, possibly through a S_N¹ formation mechanism. DFT/B3LYP molecular orbital calculations were carried out for the 1-4 complexes, their precursors, Ph₂SnCl₂, (5) and Me₂SnCl₂, (6) and the ligands, PYR, DMP and PNO in an attempt to explain the structures and reactivity of the complexes. Optimized resulting geometries, vibrational frequencies, and the electron-accepting ability of the complexes and the precursors towards nucleophiles are discussed.     

Cover Picture: On the Function and Structure of Synthetically Modified Porins (Angew. Chem. Int. Ed. 26/2009)

Synthetic Modulators are introduced into the trimeric porin OmpF by protein semisynthesis/click chemistry or by S‐alkylation, as U. Koert, L.‐O. Essen et al. report in their Communication on page 4853 ff. The choice of synthetic modulator and the type of covalent attachment significantly affect the blockage efficiency. A model for the functional properties is postulated on the basis of an X‐ray structure analysis of a crown ether/OmpF hybrid.

     

Enabling the exploration of biochemical pathways

The Biochemical Pathways Wall Chart (http://www.expasy.org/tools/pathways/ref.1) has been converted into a molecule and reaction database. Major features of this database are that each molecule is represented by lists of all atoms and bonds (as connection tables), and in the reactions the reaction centre, the atoms and bonds directly involved in the bond rearrangement process, are marked. The information in the database has been enriched by a set of diverse 3D structure conformations generated by the programs CORINA and ROTATE. The web-based structure and reaction retrieval system C@ROL provides a wide range of search methods to mine this rich database. The database is accessible at http://www2.chemie.uni-erlangen.de/services/biopath/index.html and http://www.mol-net.de/databases/biopath.html .     

Deuteration of Non-Stabilized Phosphorus Ylides With DMSO-d6: Convenient Synthesis of Mono-Deuterated Alkenes

The use of DMSO-d₆ as a solvent or cosolvent in the Wittig reaction results in the incorporation of deuterium into the phosphorus ylide and the alkene product.     

Acceleration of the chemistry solver for modeling DI engine combustion using dynamic adaptive chemistry (DAC) schemes

Acceleration of the chemistry solver for engine combustion is of much interest due to the fact that in practical engine simulations extensive computational time is spent solving the fuel oxidation and emission formation chemistry. A dynamic adaptive chemistry (DAC) scheme based on a directed relation graph error propagation (DRGEP) method has been applied to study homogeneous charge compression ignition (HCCI) engine combustion with detailed chemistry (over 500 species) previously using an R-value-based breadth-first search (RBFS) algorithm, which significantly reduced computational times (by as much as 30-fold). The present paper extends the use of this on-the-fly kinetic mechanism reduction scheme to model combustion in direct-injection (DI) engines. It was found that the DAC scheme becomes less efficient when applied to DI engine simulations using a kinetic mechanism of relatively small size and the accuracy of the original DAC scheme decreases for conventional non-premixed combustion engine. The present study also focuses on determination of search-initiating species, involvement of the NO_x chemistry, selection of a proper error tolerance, as well as treatment of the interaction of chemical heat release and the fuel spray. Both the DAC schemes were integrated into the ERC KIVA-3v2 code, and simulations were conducted to compare the two schemes. In general, the present DAC scheme has better efficiency and similar accuracy compared to the previous DAC scheme. The efficiency depends on the size of the chemical kinetics mechanism used and the engine operating conditions. For cases using a small n-heptane kinetic mechanism of 34 species, 30% of the computational time is saved, and 50% for a larger n-heptane kinetic mechanism of 61 species. The paper also demonstrates that by combining the present DAC scheme with an adaptive multi-grid chemistry (AMC) solver, it is feasible to simulate a direct-injection engine using a detailed n-heptane mechanism with 543 species with practical computer time.     

Dosimetry inside MIR station using a silicon detector telescope (DOSTEL)

The dosimetry telescope (DOSTEL) was flown on the MIR orbital station during October 1997-January 1998. The mission average contributions to the absorbed dose rates (in water) were 126 +/- 4 microGy/d and 121 +/- 13 microGy/d for the GCR and the SAA component, respectively. The mean quality factors (ICRP60) deduced from the LET-spectra are 3.5 +/- 0.2 (GCR) and 1.3 +/- 0.1 (SAA). Separate LET spectra and temporal variations of the absorbed dose rates and of the mean quality factors are presented for these two radiation components as well as for solar energetic particles of the November 6, 1997 event.