Structural interpretation of a topological index. 1. External factor variable connectivity index (EFVCI)

The external factor variable connectivity index (EFVCI) is interpreted by mining out the structural features hidden in the space spanned by the EFVCI indices through projection pursuit combining with number-theory net (NT-net) on the unit sphere U(Us). Projection pursuit is concerned with "interesting" projections of high-dimensional data sets to machine-pick "interesting" low-dimensional projections of a high-dimensional point cloud by numerically maximizing a certain objective function or projection index. At first, the optimal EFVCI index reaches to -0.80 in the correlation with a retention index of 207 hydrocarbons produced by insects. The EFVCI indices, with regression results of R = 0.99998, s = 3.49, RMSECV = 3.90, and F = 7.9560e+005, obtain high regression quality. The model is proven valid by leave-one-out cross validation. Second, the EFVCI index is interpreted by the structure information, that is, size, branch number, graph center, and branching position of topological structures, which is searched out on the unit sphere U(Us) by projection pursuit. Finally, the interpretation information is used to discover some chemical knowledge concerning the variation of the retention index with the change in chemical structures.     

Multilinear regression and comparative molecular field analysis (CoMFA) of azo dye-fiber affinities. 2. Inclusion of solution-phase molecular orbital descriptors

For a data set with 30 direct azo dyes taken from literature, quantitative structure-activity relationship (QSAR) analyses have been performed to model the affinity of the dye molecules for the cellulose fiber. The electronic structure of the compounds was characterized using quantum chemical gas-phase (AM1) and continuum-solvation molecular orbital parameters. As regards the solution phase, COSMO appears to be better suited than SM2 in quantifying relative trends of the aqueous solvation energy. For the dye-fiber affinity, the leave-one-out prediction capability of multilinear regression equations is superior to CoMFA, with predictive squared correlation coefficients ranging from 0.63 (pure CoMFA) to 0.89. At the same time, solution-phase CoMFA is superior to previously derived AM1-based CoMFA models. As a general trend, the dye-fiber affinity increases with increasing electron donor capacity that corresponds to an increasing hydrogen bond acceptor strength of the azo dyes. The discussion includes the consideration of structural features that are likely to be involved in dye-fiber and dye-dye hydrogen bonding interactions, and possible links between CoMFA electrostatic results and the atomic charge distribution of the compounds.     

Structural interpretation of the topological index. 2. The molecular connectivity index, the Kappa index, and the atom-type E-State index

The structural interpretation is extended to the topological indices describing cyclic structures. Three representatives of the topological index, such as the molecular connectivity index, the Kappa index, and the atom-type E-State index, are interpreted by mining out, through projection pursuit combining with a number theory method generating uniformly distributed directions on unit sphere, the structural features hidden in the spaces spanned by the three series of indices individually. Some interesting results, which can hardly be found by individual index, are obtained from the multidimensional spaces by several topological indices. The results support quantitatively the former studies on the topological indices, and some new insights are obtained during the analysis. The combinations of several molecular connectivity indices describe mainly three general categories of molecular structure information, which include degree of branching, size, and degree of cyclicity. The cyclicity can also be coded by the combination of chi cluster and path/cluster indices. The Kappa shape indices encode, in combination, significant information on size, the degree of cyclicity, and the degree of centralization/separation in branching. The size, branch number, and cyclicity information has also been mined out to interpret atom-type E-State indices. The structural feature such as the number of quaternary atoms is searched out to be an important factor. The results indicate that the collinearity might be a serious problem in the applications of the topological indices.     

A comparative molecular similarity index analysis (CoMSIA) study identifies an HLA-A2 binding supermotif

The 3D-QSAR CoMSIA technique was applied to a set of 458 peptides binding to the five most widespread HLA-A2-like alleles: A^*0201, A^*0202, A^*0203, A^*0206 and A^*6802. Models comprising the main physicochemical properties (steric bulk, electron density, hydrophobicity and hydrogen-bond formation abilities) were obtained with acceptable predictivity (q ² ranged from 0.385 to 0.683). The use of coefficient contour maps allowed an A2-supermotif to be identified based on common favoured and disfavoured areas. The CoMSIA definition for the best HLA-A2 binder is as follows: hydrophobic aromatic amino acid at position 1; hydrophobic bulky side chains at positions 2, 6 and 9; non-hydrogen-bond-forming amino acids at position 3; small aliphatic hydrogen-bond donors at position 4; aliphatic amino acids at position 5; small aliphatic side chains at position 7; and small aliphatic hydrophilic and hydrogen-bond forming amino acids at position 8.     

Relating Trp‐Glu dipeptide fluorescence to molecular conformation: The role of the discrete chi 1 and chi 2 angles

Molecular dynamics (MD), coupled with fluorescence data for charged dipeptides of tryptophanyl glutamic acid (Trp‐Glu), reveal a detailed picture of how specific conformation affects fluorescence. Fluorescence emission spectra and time‐resolved emission measurements have been collected for all four charged species. MD simulations 20 to 30 ns in length have also been carried out for the Trp‐Glu species, as simulation provides aqueous phase conformational data that can be correlated with the fluorescence data. The calculations show that each dipeptide species is characterized by a similar set of six, discrete Chi 1, Chi 2 dihedral angle pairs. The preferred Chi 1 angles—60°, 180°, and 300°—play the significant role in positioning the terminal amine relative to the indole ring. A Chi 1 angle of 60° results in the arching of the backbone over the indole ring and no interaction of the ring with the terminal amine. Chi 1 values of 180° and 300° result in an extension of the backbone away from the indole ring and a NH₃ cation‐π interaction with indole. This interaction is believed responsible for charge transfer quenching. Two fluorescence lifetimes and their corresponding amplitudes correlate with the Chi 1 angle probability distribution for all four charged Trp‐Glu dipeptides. Fluorescence emission band maxima are also consistent with the proposed pattern of terminal amine cation quenching of fluorescence. © 2013 Wiley Periodicals, Inc.     

The comparative molecular surface analysis (CoMSA) with modified uniformative variable elimination-PLS (UVE-PLS) method: application to the steroids binding the aromatase enzyme

The application of the CoMSA method to analyze 3D QSAR of 50 steroid aromatase inhibitors is described. The 3D QSAR model obtained, reaching a value of cross-validated q(2) = 0.96 (s = 0.31), significantly outperforms those reported in the literature for the CoMFA or CoSA (CoSASA). It is shown that the Uniformative Variable Elimination UVE-PLS or modified iterative UVE procedure (IVE-PLS) can be used for indicating the regions contributing to the binding activity. Thus, after separating the series into two groups of the training and test molecules quite correct external predictions result from the processing of the training set. We proved that the procedure of the data elimination provides stable results, if tested in 50 random runs of the IVE-PLS-CoMSA with different training/test sets. Depending upon the procedure used the quality of the predictions for 25 test molecules is given by SDEP = sum(y(pred)-y(obs))(2)/n)(1/2) = 0.321 - 0.782.     

Development of single-chain variable fragment (scFv) antibodies against hapten benzo[a]pyrene: a binding study

Due to its highly carcinogenic and mutagenic effect on humans, a maximum tolerable limit of 10 ng/L of benzo[a]pyrene (B[a]P) in drinking water was set by the European Commission (Council Directive 98/83/EC). Although several polyclonal and monoclonal antibodies (mAb) for the detection of B[a]P and other polycyclic aromatic hydrocarbons (PAH) have been developed by others, a traditional enzyme-linked immunosorbent assay (ELISA) with a limit of quantification of 10 ng/L for monitoring B[a]P has not been developed. With this in mind, several single-chain variable fragment (scFv) antibodies were created using existing mAbs against the extremely hydrophobic hapten B[a]P, and their heavy and light chains recombined to make unique variable light (V_L) and heavy (V_H) chain combinations. Their binding behaviour was investigated using microtiter plate ELISA and surface plasmon resonance techniques. Specifically, the coding sequences for V_L and V_H chains of 10 murine anti-B[a]P antibody producing hybridoma cell lines were isolated by degenerate oligonucleotide primer sets, cloned in phagemid pIT2 and transferred into Escherichia coli HB2151. To systematically investigate the interaction of the V_L and V_H domains, three high-affinity B[a]P-specific and one nonspecific clone were selected and recombined to build a set of 16 different V_L and V_H combinations. On the basis of our data, it was shown that the V_H plays the major role for specific binding of B[a]P, whilst the V_L can, in some cases, increase the final sensitivity of the assay by one order of magnitude. Furthermore, the sequence analysis of scFvs indicates that the complementarity determining region H3 plays a major role in affinity, whilst cross-reactivity to seven other PAHs demonstrates the importance of the V_L in providing cross-reactivity.     

The molecular orientation of CO on Pd(1 1 1): a polarization-dependent SFG study

The molecular orientation of carbon monoxide adsorbed on Pd(1 1 1) was examined by sum frequency generation (SFG) vibrational spectroscopy utilizing different polarization combinations of the visible and SFG light. This allows to determine the CO tilt angle with respect to the substrate, provided that a proper optical model for the interface can be defined. It is demonstrated that it is essential to invoke the β_aac hyperpolarizability into the analysis and that polarization-dependent SFG of CO/Pd(1 1 1) yields information on β_aac/β_ccc rather than the tilt angle.     

分子连接性指数(mZh)与烷基苯理化性质的相关性研究

定义有机物分子中成键原子点价δiz.基于δiz和分子图的邻接矩阵,建构一种新的分子连接性指数mZh(m=0,1),并研究了0Zh,1Zh与烷基苯的燃烧热、等张比容、沸点、汽化热、标准生成自由能、标准熵、摩尔体积、溶解度、正辛醇/水分配系数等10种物理化学性质的相关性.结果表明:0Zh,1Zh与烷基苯的物理化学性质具有优良的性质相关性,二元相关系数均在0.99以上;以0Zh,1Zh和分子中C原子数NC为自变量的三元线性回归方程对烷基苯理化性质的预测结果相当令人满意.     

Mass connectivity index,a new molecular parameter for the estimation of ionic liquid properties

A new concept named mass connectivity index (MCI) to encode bond contributions and to allow quantifying the extent of branching in a molecule, especially of ionic liquids, is proposed. The concept is based on the molecular connectivity concept first introduced by Randic in 1975 and modified in different forms by several authors. The proposed concept is much easier to calculate than any of the connectivity indexes available in the literature. Thus the only data required for determining the MCI are the groups forming the molecule and the mass of the groups. The groups forming the molecule are defined as commonly done in group contribution methods. The index is used as a variable in generalized correlations to accurately estimate the density and the heat capacity of ionic liquids.     

Fluorescence of cis-1-amino-2-(3-indolyl)cyclohexane-1-carboxylic acid: a single tryptophan chi(1) rotamer model

A constrained derivative, cis-1-amino-2-(3-indolyl)cyclohexane-1-carboxylic acid, cis-W3, was designed to test the rotamer model of tryptophan photophysics. The conformational constraint enforces a single chi(1) conformation, analogous to the chi(1) = 60 degrees rotamer of tryptophan. The side-chain torsion angles in the X-ray structure of cis-W3 were chi(1) = 58.5 degrees and chi(2) = -88.7 degrees. Molecular mechanics calculations suggested two chi(2) rotamers for cis-W3 in solution, -100 degrees and 80 degrees, analogous to the chi(2) = +/-90 degrees rotamers of tryptophan. The fluorescence decay of the cis-W3 zwitterion was biexponential with lifetimes of 3.1 and 0.3 ns at 25 degrees C. The relative amplitudes of the lifetime components match the chi(2) rotamer populations predicted by molecular mechanics. The longer lifetime represents the major chi(2) = -100 degrees rotamer. The shorter lifetime represents the minor chi(2) = 80 degrees rotamer having the ammonium group closer to C4 of the indole ring (labeled C5 in the cis-W3 X-ray structure). Intramolecular excited-state proton transfer occurs at indole C4 in the tryptophan zwitterion (Saito, I.; Sugiyama, H.; Yamamoto, A.; Muramatsu, S.; Matsuura,T. J. Am. Chem. Soc. 1984, 106, 4286-4287). Photochemical isotope exchange experiments showed that H-D exchange occurs exclusively at C5 in the cis-W3 zwitterion, consistent with the presence of the chi(2) = 80 degrees rotamer in solution. The rates of two nonradiative processes, excited-state proton and electron transfer, were measured for individual chi(2) rotamers. The excited-state proton-transfer rate was determined from H-D exchange and fluorescence lifetime data. The excited-state electron-transfer rate was determined from the temperature dependence of the fluorescence lifetime. The major quenching process in the -100 degrees rotamer is electron transfer from the excited indole to carboxylate. Electron transfer also occurs in the 80 degrees rotamer, but the major quenching process is intramolecular proton transfer. Both quenching processes are suppressed by deprotonation of the amino group. The results for cis-W3 provide compelling evidence that the complex fluorescence decay of the tryptophan zwitterion originates in ground-state heterogeneity with the different lifetimes primarily reflecting different intramolecular excited-state proton- and electron-transfer rates in various rotamers.     

Electron-mediating Cu(A) centers in proteins: a comparative high field (1)H ENDOR study

High field (W-band, 95 GHz) pulsed electron-nuclear double resonance (ENDOR) measurements were carried out on a number of proteins that contain the mixed-valence, binuclear electron-mediating Cu(A) center. These include nitrous oxide reductase (N(2)OR), the recombinant water-soluble fragment of subunit II of Thermus thermophilus cytochrome c oxidase (COX) ba(3) (M160T9), its M160QT0 mutant, where the weak axial methionine ligand has been replaced by a glutamine, and the engineered "purple" azurin (purpAz). The three-dimensional (3-D) structures of these proteins, apart from the mutant, are known. The EPR spectra of all samples showed the presence of a mononuclear Cu(II) impurity with EPR characteristics of a type II copper. At W-band, the g( perpendicular) features of this center and of Cu(A) are well resolved, thus allowing us to obtain a clean Cu(A) ENDOR spectrum. The latter consists of two types of ENDOR signals. The first includes the signals of the four strongly coupled cysteine beta-protons, with isotropic hyperfine couplings, A(iso), in the 7-15 MHz range. The second group consists of weakly coupled protons with a primarily anisotropic character with A(zz) < 3 MHz. Orientation selective ENDOR spectra were collected for N(2)OR, M160QT0, and purpAz, and simulations of the cysteine beta-protons signals provided their isotropic and anisotropic hyperfine interactions. A linear correlation with a negative slope was found between the maximum A(iso) value of the beta-protons and the copper hyperfine interaction. Comparison of the best-fit anisotropic hyperfine parameters with those calculated from dipolar interactions extracted from the available 3-D structures sets limit to the sulfur spin densities. Similarly, the small coupling spectral region was simulated on the basis of the 3-D structures and compared with the experimental spectra. It was found that the width of the powder patterns of the weakly coupled protons recorded at g(perpendicular) is mainly determined by the histidine H(epsilon)(1) protons. Furthermore, the splitting in the outer wings of these powder patterns indicates differences in the positions of the imidazole rings relative to the Cu(2)S(2) core. Comparison of the spectral features of the weakly coupled protons of M160QT0 with those of the other investigated proteins shows that they are very similar to those of purpAz, where the Cu(A) center is the most symmetric, but the copper spin density and the H(epsilon)(1)-Cu distances are somewhat smaller. All proteins show the presence of a proton with a significantly negative A(iso) value which is assigned to an amide proton of one of the cysteines. The simulations of both strongly and weakly coupled protons, along with the known copper hyperfine couplings, were used to estimate and compare the spin density distribution in the various Cu(A) centers. The largest sulfur spin density was found in M160T9, and the lowest was found in purpAz. In addition, using the relation between the A(iso) values of the four cysteine beta-protons and the H-C-S-S dihedral angles, the relative contribution of the hyperconjugation mechanism to A(iso) was determined. The largest contribution was found for M160T9, and the lowest was found for purpAz. Possible correlations between the spin density distribution, structural features, and electron-transfer functionality are finally suggested.