Response-surface analyses for toxicity to Tetrahymena pyriformis: reactive carbonyl-containing aliphatic chemicals

A response-plane has been developed with Tetrahymena pyriformis population growth impairment toxicity data [log 1/50% growth inhibitory concentration (IGC50)], the 1-octanol/water partition coefficient (log Kow), and the energy of the lowest unoccupied molecular orbital (Elumo). A statistically robust plane [log 1/IGC50 = 0.530 (log Kow) -0.890 (Elumo) -0.271, n = 50, s = 0.295, r2 = 0.855, F = 145] was found for reactive carbonyl-containing aliphatic chemicals. These compounds had a variety of electrophilic mechanisms of action and included aldehydes acting as Schiff-base formers, alpha,beta-unsaturated aldehydes and alpha,beta-unsaturated ketones acting as Michael-type acceptors, and selected alpha-diones acting as selective binders to arganine residues; gamma-diones acting as selective binders to tubulin; and beta-diones with unknown mechanisms of action. Outliers to this model broadly fell into two groups: small reactive molecules (e.g., acrolein) that were more toxic than predicted and molecules in which the reactive center was sterically hindered by an alkyl group (e.g., 2,4-dimethyl-2,6-heptadienal) that were less toxic than predicted.     

Electrospray mass spectrometry of neuac oligomers associated with the c fragment of the tetanus toxin

The Clostridial neurotoxins, botulinum and tetanus, gain entry into motor neurons by binding to the sialic or N-acetylneuraminic acid (NeuAc) residues of gangliosides and specific protein receptors attached to the cell's surface. While the C-fragment of tetanus toxin (TetC) has been identified to be the ganglioside binding domain, remarkably little is known about how this domain discriminates between the structural features of different gangliosides. We have used electrospray ionization mass spectrometry (ESI-MS) to examine the formation of complexes between TetC and carbohydrates containing NeuAc groups to determine how NeuAc residues contribute to ganglioside binding. ESI-MS was used to obtain an estimate of the dissociation constants (KD values) for TetC binding to a number of related NeuAc-containing carbohydrates (sialyllactose and disialyllactose), as well as six (NeuAc)n oligomers (n = 1-6). KD values were found to range between approximately 10-35 microM. The strength of the interactions between the C fragment and (NeuAc)n are consistent with the topography of the targeting domain of tetanus toxin and the nature of its carbohydrate binding sites. These results suggest that the targeting domain of tetanus toxin contains two binding sites that can accommodate NeuAc (or a dimer) and that NeuAc may play an important role in ganglioside binding and molecular recognition, a process critical for normal cell function and one frequently exploited by toxins, bacteria, and viruses to facilitate their entrance into cells.     

An excimer-based, binuclear, on-off switchable calix[4]crown chemosensor

A new fluorescent chemosensor with two different types of cation binding sites on the lower rims of a 1,3-alternate calix[4]arene (1) is synthesized. Two pyrene moieties linked to a cation recognition unit composed of two amide groups form a strong excimer in solution. For 1, the excimer fluorescence is quenched by Pb2+, but revived by addition of K+ to the Pb2+ ligand complex. Thus, metal ion exchange produces an on-off switchable, fluorescent chemosensor. Computational results show that the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbitals (LUMO) of the two pyrene moieties interact under UV irradiation of 1 and its K+ complex, while such HOMO-LUMO interactions are absent in the Pb2+ complex.     

DNA and estrogen receptor interaction revealed by fragment molecular orbital calculations

Molecular orbital calculations of the complex between DNA-ERE (estrogen response element) and ER (estrogen receptor)-DBD (DNA-binding domain) were performed using the fragment molecular orbital (FMO) method, which enables large-scale MO (molecular orbital) calculations by reducing the computational cost and by significantly increasing efficiency for parallel computation. Such a large system, which contains 3354 atoms, is impractical via conventional MO methods due to the immense computational cost. Details of the interaction between DNA-ERE and ER-DBD were revealed in this study as follows by using the FMO calculations to analyze the interfragment interaction energies (IFIEs) and the electrostatic potentials (ESPs). An area with a high positive ESP is identified on the DNA-binding side of ER-DBD and is the main driving force behind access to the DNA. The position of the ER-DBD monomer can be fixed on a phosphate group of DNA-ERE by the strong electrostatic interactions, whereas the rotation cannot be fixed. In contrast, both the position and rotation of the ER-DBD dimer can be fixed and can therefore form the stable (ER-DBD)2...DNA-ERE complex. Dimerization of the ER-DBD monomers, each of which have a charge of +5 , is mainly due to large attractive interaction energies of the second Zn fragments. The base pairs in the consensus sequence of DNA-ERE interact only with the recognition helix located in the major groove due to the large shielding effect of the phosphate groups of DNA. The recognition helix has weaker interactions with the base pairs than the electrostatic interactions with the phosphate groups. Thus, the DNA-binding machinery of the ER-DBD dimer, which can secure the recognition helix in the major groove of DNA, is crucial for interactions between the recognition helix and base pairs.     

Mechanistic appraisal of the charge-transfer complexes of promethazine with chloranil: a modelling approach.

Various mechanisms are often used to explain the interaction between electron donors and acceptors. Commonly proposed mechanisms are those in which the acceptor interacts with the aromatic pi-systems in the donor molecule or the acceptor forms a weak interaction of the Lewis acid with Lewis base type. In this study, the above mechanisms were examined as well as other possible mechanisms. Promethazine was chosen as the model drug containing aromatic systems capable of pi-pi interaction as well as N-methyl group capable of forming a complex with the weak Lewis acid, p-chloranil. Our modelling studies revealed that the situation where the p-chloranil interacts with a protonated N-methyl group is the most significant mechanism of interaction, based on the calculated energies for the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO), the Tripos force field energy terms and also the stability of the complexes during molecular dynamics simulations.     

Improved method for large-scale purification of brain gangliosides by Q-sepharose column chromatography. Immunochemical detection of C-series polysialogangliosides in adult bovine brains

A new chromatographic method for separation of bovine brain gangliosides has been developed using Q-Sepharose. Gangliosides were separated based not only on their sialic acid numbers but also on the sialic acid molecular species and chain lengths of the skeletal oligosaccharide portions. The following results indicate that this column chromatography has practical advantages in separating mixtures of gangliosides, especially positional isomers and molecular species with N-acetyl- or N-glycolylneuraminic acid. (1) the loading capacity of Q-Sepharose for gangliosides was very high; (2) most major gangliosides such as GM1, GD1a, GD1b, GT1b and GQ1b were isolated in a single step; (3) these major gangliosides were clearly separated from gangliosides containing, N-glycolylneuraminic acid when examined using Hanganutziu-Deicher antibody; (4) polysialogangliosides that have four or more sialic acid residues were isolated efficiently. It was shown by the combination of Q-Sepharose column chromatography with thin-layer chromatography/enzyme immunostaining that adult bovine brains possess C-series polysialogangliosides as minor components which are known as embryonic molecules in avian and mammalian brains.     

Theoretical Study on the Transition State of N-nitropyrazoles Rearrangement Reaction

Theoretical studies on the rearrangement reactions of nitropyrazoles have been investigated. In order to gain a better understanding of the intermediate process of rearrangement reactions, the transition states of the rearrangement reactions were obtained by TS method at the B3 LYP/6-311 G(d, p) level of theory. The natural bond orbital charge, electrostatic potential and frontier molecular orbital of the molecules in the process of rearrangement were analyzed, and the solvent effect was also discussed. The rearrangement of nitropyrazoles involves two transition states and one intermediate, and the nitro group and hydrogen atom are two transfer groups for rearrangement reactions. The migration of these two groups leads to the change of charge distribution and molecular structure. The structural changes of the molecules in different solvents are not significant, but the dipole moment of the molecule has obvious change.     

Reaction ergodography for the additions of HLi and its dimer to acetylene

The ab initio calculation has been performed with the addition pathways of HLi and its dimer to acetylene at the RHF/3-21G basis set. It shows that the reaction mechanisms of these two reactions are rather similar. In either of two reaction pathways, there is a meta-stable molecular complex near the isolated reactant state. This kind of addition can be treated approximately as the unimolecular reaction in which the molecular complex rearranges into the product. We have estimated the activation entropies and the statistical A factors of these two reactions by the use of RRKM theory. Frontier molecular orbital analysis of these two transition states reveals their HOMOS to be formed from both HOMO-LUMO and HOMO-HOMO interactions.     

Innate immunity probed by lipopolysaccharides affinity strategy and proteomics

Lipopolysaccharides (LPSs) are ubiquitous and vital components of the cell surface of Gram-negative bacteria that have been shown to play a relevant role in the induction of the immune-system response. In animal and plant cells, innate immune defenses toward microorganisms are triggered by the perception of pathogen associated molecular patterns. These are conserved and generally indispensable microbial structures such as LPSs that are fundamental in the Gram-negative immunity recognition. This paper reports the development of an integrated strategy based on lipopolysaccharide affinity methodology that represents a new starting point to elucidate the molecular mechanisms elicited by bacterial LPS and involved in the different steps of innate immunity response. Biotin-tagged LPS was immobilized on streptavidin column and used as a bait in an affinity capture procedure to identify protein partners from human serum specifically interacting with this effector. The complex proteins/lipopolysaccharide was isolated and the protein partners were fractionated by gel electrophoresis and identified by mass spectrometry. This procedure proved to be very effective in specifically binding proteins functionally correlated with the biological role of LPS. Proteins specifically bound to LPS essentially gathered within two functional groups, regulation of the complement system (factor H, C4b, C4BP, and alpha 2 macroglobulin) and inhibition of LPS-induced inflammation (HRG and Apolipoproteins). The reported strategy might have important applications in the elucidation of biological mechanisms involved in the LPSs-mediated molecular recognition and anti-infection responses.     

Synthesis, characterization, and ab initio theoretical study of a molecularly imprinted polymer selective for biosensor materials

Despite the complex phenomena involved in encoding template molecule information within stable synthetic polymers to yield selective and efficient molecular recognition processes, molecularly imprinted polymers (MIP) are increasingly finding broad areas of application. Molecular interactions, both during the polymerization of the functional monomers in the presence of the template and during the processes of specific recognition after template removal, are key determinants of an effective MIP. Covalent and noncovalent template imprinting have been employed to achieve specific recognition sites. In the present study, a molecularly imprinted biocompatible polymer, having a high capacity and affinity for the dye template, nickel(II) phthalocyanine tetrasulfonic acid, has been prepared. UV-visible spectroscopy, FTIR spectroscopy, and ICP analysis were used to investigate the aspects of the synthesis, binding capacity, and adsorption kinetics of the system. Poly(allylamine) cross-linked with epichlorohydrin has been used to represent an amino-functional receptor. Binding isotherms and capacities were correlated with the degree of template removal. Kinetic studies of binding allowed diffusion mechanisms to be evaluated for the fine particulate MIP. Ab initio molecular orbital calculations were performed using Hartree-Fock, MP2, and density functional theory methods to determine the most likely mechanisms of molecular imprinting. Suitable theoretical models have been constructed to mimic the interactions between the template molecule and the polymer. Simulation of the vibrational spectra was also undertaken to make meaningful assignments to experimentally determined spectral bands resulting from these template MIP receptor interactions.     

How Ionization Catalyzes Diels-Alder Reactions

The catalytic effect of ionization on the Diels-Alder reaction between 1,3-butadiene and acrylaldehyde has been studied using relativistic density functional theory (DFT). Removal of an electron from the dienophile, acrylaldehyde, significantly accelerates the Diels-Alder reaction and shifts the reaction mechanism from concerted asynchronous for the neutral Diels-Alder reaction to stepwise for the radical-cation Diels-Alder reaction. Our detailed activation strain and Kohn-Sham molecular orbital analyses reveal how ionization of the dienophile enhances the Diels-Alder reactivity via two mechanisms: (i) by amplifying the asymmetry in the dienophile's occupied π-orbitals to such an extent that the reaction goes from concerted asynchronous to stepwise and thus with substantially less steric (Pauli) repulsion per reaction step; (ii) by enhancing the stabilizing orbital interactions that result from the ability of the singly occupied molecular orbital of the radical-cation dienophile to engage in an additional three-electron bonding interaction with the highest occupied molecular orbital of the diene.     

Low energy (e,2e) measurements of CH4 and neon in the perpendicular plane

Low energy experimental and theoretical triple differential cross sections for the highest occupied molecular orbital of methane (1t(2)) and for the 2p atomic orbital of neon are presented and compared. These targets are iso-electronic, each containing 10 electrons and the chosen orbital within each target has p-electron character. Observation of the differences and similarities of the cross sections for these two species hence gives insight into the different scattering mechanisms occurring for atomic and molecular targets. The experiments used perpendicular, symmetric kinematics with outgoing electron energies between 1.5 eV and 30 eV for CH(4) and 2.5 eV and 25 eV for neon. The experimental data from these targets are compared with theoretical predictions using a distorted-wave Born approximation. Reasonably good agreement is seen between the experiment and theory for neon while mixed results are observed for CH(4). This is most likely due to approximations of the target orientation made within the model.     

化学及生物体系中的分别识别*

分子识别的目标是研究分子间专一性地相互作用, 这在化学及生命过程中起着非常重要的作用。本文综述了分子识别的机制及其在化学、生命科学、材料、信息等有关学科中的应用。     

Charge transmission through a molecular wire: the role of terminal sites for the current-voltage behavior

The current-voltage and the conductance-voltage characteristics are analyzed for a particular type of molecular wire embedded between two electrodes. The wire is characterized by internal molecular units where the lowest occupied molecular orbital (LUMO) levels are positioned much above the Fermi energy of the electrodes, as well as above the LUMO levels of the terminal wire units. The latter act as specific intermediate donor and acceptor sites which in turn control the current formation via the superexchange and sequential electron transfer mechanisms. According to the chosen wire structure, intramolecular multiphonon processes may block the superexchange component of the interelectrode current, resulting in a negative differential resistance of the molecular wire. A pronounced current rectification appears if (i) the superexchange component dominates the electron transfer between the terminal sites and if (ii) the multiphonon suppression of distant superexchange charge hopping events between those sites is nonsymmetric.     

GridMol2.0: Implementation and application of linear-scale quantum mechanics methods and molecular visualization

GridMol is a “one-stop” platform for molecular structure building, scientific computing, and molecular visualization aided by a high-performance computing environment. GridMol version 2.0 introduces two unique features: the first is fragment-based linear-scaling quantum chemistry methods, such as molecular fractionation with conjugate caps and fragment molecular orbital methods; the second is that GridMol enables users to visualize molecular geometries along a geometry optimization and an intrinsic reaction coordinate calculation. Compared with version 1.0, fragment-based linear-scaling quantum chemistry methods implemented in GridMol version 2.0 can be used as a useful tool for performing quantum calculations for large molecular systems to explore the mechanisms involved in protein-ligand or targeted drug interactions.     

Dual conductance, negative differential resistance, and rectifying behavior in a molecular device modulated by side groups

We investigate the electronic transport properties for a molecular device model constructed by a phenylene ethynylene oligomer molecular with different side groups embedding in a carbon chain between two graphene electrodes. Using the first-principles method, the unusual dual conductance, negative differential resistance (NDR) behavior with large peak to valley ratio, and obvious rectifying performance are numerically observed in such proposed molecular device. The analysis of the molecular projected self-consistent Hamiltonian and the evolution of the frontier molecular orbitals (MOs) as well as transmission coefficients under various external voltage biases gives an inside view of the observed results, which suggests that the dual conductance behavior and rectifying performance are due to the asymmetry distribution of the frontier MOs as well as the corresponding coupling between the molecule and electrodes. But the NDR behavior comes from the conduction orbital being suppressed at certain bias. Interestingly, the conduction properties can be tuned by introducing side groups to the molecule and the rectification as well as the NDR behavior (peak to valley ratio) can be improved by adding different side groups in the device model.     

On obtaining localized bonding schemes from delocalized molecular-orbital wave functions

A straightforward procedure is proposed for expanding a molecular orbital determinantal wave function into a set of determinantal wave functions composed of atomic orbitals localized at the atoms of a molecule. By employing this method, atomic orbital determinants and their weights can be derived for a molecule from the computed molecular-orbital wave function. The procedure permits the interpretation of a molecular orbital determinantal wave function in terms of bonding schemes related to the classic resonance structures used by organic chemists. By using the unrestricted molecular orbital determinant, bonding schemes and their weights are obtained for butadiene, the butadiene radical cation and the acrylonitrile radical anion. Their dominant bonding schemes are in accord with the relevant resonance structures for these molecules. For the butadiene radical cation and the acrylonitrile anion they are shown to be compatible with the accepted mechanisms of the electrochemical coupling reactions of butadiene and acrylonitrile. Received: 7 August 1996 / Accepted: 18 March 1997     

氟硼二吡咯类pH荧光探针PET光谱特性的理论计算

氟硼二吡咯(BODIPY)类pH荧光探针分子是基于光诱导电子转移(PET)的荧光探针分子, 识别基团氮原子上引入不同取代基可呈现不同的光学灵敏度. 本文应用密度泛函理论(DFT)及含时密度泛函理论(TD-DFT)方法对六种含不同取代基的探针分子进行了几何构型优化及激发态计算, 探讨了不同取代基对PET效应影响. 计算结果表明: 基态时这些探针分子的最高占有分子轨道(HOMO)和最低未占有分子轨道(LUMO)都在荧光母体BODIPY的π, π^*轨道, 而识别基团上氮原子孤对电子所在的轨道为HOMO-1轨道. 但是在激发态, 当氮原子上有两个取代基时, HOMO-1→LUMO跃迁的激发能都小于荧光团的HOMO→LUMO跃迁, 这将有可能产生PET效应并导致荧光熄灭, 而当氮原子上有一个取代基时不会出现这种现象. 通过激发态结构优化可以发现, 无论识别基团氮原子上有一个还是两个取代基, N原子的轨道对称性都发生变化, 由sp³→sp², 孤对电子占据在p轨道上, 其轨道能级升高至荧光团的HOMO和LUMO轨道之间, 将导致不同程度的PET效应, 与实验结果一致.