一些全氟(及多氟)有机化合物蒸汽压的QSPR研究

全氟(及多氟)化合物(PFCs)是环境中普遍存在的新一类持久性有机污染物。对其中有蒸汽压数据的35个全氟(及多氟)化合物进行了HF/6-31G*水平上的结构优化,并在优化结构的基础上进行分子表面静电势及其导出参数的计算。分别用"留一法"交叉验证及外部测试集对模型进行检验。结果表明,分子表面静电势参数结合分子表面积可以很好地表达全氟(及多氟)化合物与其分子结构间的定量关系,所建立的QSPR模型具有较强的稳健性和预测能力,同时也证明了分子静电势在全氟化合物QSPR研究中的适用性。     

QSPR generalization of activity coefficient models for predicting vapor–liquid equilibrium behavior

Multiphase equilibrium calculations are an integral part of the design and optimization of numerous chemical processes. Several accurate experimental techniques have been developed for measuring phase equilibrium data. However, experimental techniques are time consuming and costly. Hence, a need exists for reliable thermodynamic models capable of giving a priori predictions of the phase behavior of diverse systems in the absence of experimental data.     

Measurement error models and variance estimation in the presence of rounding error effects

An approach to estimating measurement error variances for any instrument having round-off effects that might also have instrument bias is presented. Recently finite instrument resolution effects on error variances have been studied, but negligible instrument bias was assumed and the contexts were different than considered here. Our intent is to use repeated measurements on several standards to estimate the instrument’s random and systematic error variances. Recognizing that rounding impacts item bias and variance in a manner that depends on the true value, an approach is presented to estimate random error variance and instrument systematic error variance. The key finding is that item-specific bias can interfere with the estimation of overall instrument bias unless appropriate error modeling and associated inference steps are taken.     

Surface-integral QSPR models: local energy properties

Surface-integral models based on AM1 semiempirical molecular orbital calculations are presented for the free energies of solvation in water, n-octanol, and chloroform and for the enthalpy of solvation in water. A parametrized function of four local properties calculated at the isodensity surface (the molecular electrostatic potential, local ionization energy, electron affinity, and polarizability) is integrated over the triangulated surface area to obtain the target quantity. The resulting models give results only slightly less accurate than those reported for parametrized generalized Born/polar surface area models despite relying only on gas-phase calculations. The water and octanol free-energy models were validated by calculating the water-octanol partition coefficient for a test set of organic compounds with moderate success. The models lead to a local solvation energy, which can be projected onto the molecular isodensity surface and provides insight into "hot" areas for solvation in water or the other solvents.     

Electronic and geometric properties of ETS-10: QM/MM studies of cluster models

Hybrid DFT/MM methods have been used to investigate the electronic and geometric properties of the microporous titanosilicate ETS-10. A comparison of finite length and periodic models demonstrates that band gap energies for ETS-10 can be well represented with relatively small cluster models. Optimization of finite clusters leads to different local geometries for bulk and end sites, where the local bulk TiO6 geometry is in good agreement with recent experimental results. Geometry optimizations reveal that any asymmetry within the axial O-Ti-O chain is negligible. The band gap in the optimized model corresponds to a O(2p) --> Tibulk(3d) transition. The results suggest that the three Ti atom, single chain, symmetric, finite cluster is an effective model for the geometric and electronic properties of bulk and end TiO6 groups in ETS-10.     

Acetic acid vapor: 1. Statistical/quantum mechanical models of the ideal vapor

Two statistical mechanical/quantum computational models are developed for the ideal acetic acid vapor. One describes the equilibrium of the cis-monomer and the ring dimer and the other the equilibrium of a mixture of oligomers. Ten quantum computational models of the acetic acid ring dimer have been compared in developing these models. The end product of this work is a critical tool for assessing experimental vapor density studies of acetic acid reported in the literature.     

A QM/MM study of cisplatin-DNA oligonucleotides: from simple models to realistic systems

QM/MM calculations were employed to investigate the role of hydrogen bonding and pi stacking in several single- and double-stranded cisplatin-DNA structures. Computed geometrical parameters reproduce experimental structures of cisplatin and its complex with guanine-phosphate-guanine. Following QM/MM optimisation, single-point DFT calculations allowed estimation of intermolecular forces through atoms in molecules (AIM) analysis. Binding energies of platinated single-strand DNA qualitatively agree with myriad experimental and theoretical studies showing that complexes of guanine are stronger than those of adenine. The topology of all studied complexes confirms that platination strongly affects the stability of both single- and double-stranded DNAs: Pt-N-H...X (X = N or O) interactions are ubiquitous in these complexes and account for over 70 % of all H-bonding interactions. The pi stacking is greatly reduced by both mono- and bifunctional complexation: the former causes a loss of about 3-4 kcal mol(-1), whereas the latter leads to more drastic disruption. The effect of platination on Watson-Crick GC is similar to that found in previous studies: major redistribution of energy occurs, but the overall stability is barely affected. The BH&H/AMBER/AIM approach was also used to study platination of a double-stranded DNA octamer d(CCTG*G*TCC)d(GGACCAGG), for which an experimental structure is available. Comparison between theory and experiment is satisfactory, and also reproduces previous DFT-based studies of analogous structures. The effect of platination is similar to that seen in model systems, although the effect on GC pairing was more pronounced. These calculations also reveal weaker, secondary interactions of the form Pt...O and Pt...N, detected in several single- and double-stranded DNA.     

QM/MM based 3D QSAR models for potent B-Raf inhibitors

Three dimensional (3D) quantitative structure-activity relationship studies of 37 B-Raf inhibitors, pyrazole-based derivatives, were performed. Based on the co-crystallized compound (PDB ID: 3D4Q), several alignment methods were utilized to derive reliable comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models. Receptor-guided alignment with quantum mechanics/molecular mechanics (QM/MM) minimization led to the best CoMFA model (q ² = 0.624, r ² = 0.959). With the same alignment, a statistically reliable CoMSIA model with steric, H-bond acceptor, and hydrophobic fields was also derived (q ² = 0.590, r ² = 0.922). Both models were validated with an external test set, which gave satisfactory predictive r ² values of 0.926 and 0.878, respectively. Contour maps from CoMFA and CoMSIA models revealed important structural features responsible for increasing biological activity within the active site and explained the correlation between biological activity and receptor-ligand interactions. New fragments were identified as building blocks which can replace R1-3 groups through combinatorial screening methods. By combining these fragments a compound with a high bioactivity level prediction was found. These results can offer useful information for the design of new B-Raf inhibitors.     

Thermogravimetric method for a rapid estimation of vapor pressure and vaporization enthalpies of disubstituted benzoic acids: an attempt to correlate vapor pressures and vaporization enthalpies with structure

A rapid estimation of vapor pressure and vaporization enthalpies of some disubstituted benzoic acids (2,4-dihydroxybenzoic acid (2,4-DHBA), 2,6-dihydroxybenzoic acid (2,6-DHBA), 3,4-dihydroxybenzoic acid (3,4-DHBA), 2,4-dinitrobenzoic acid (2,4-DNBA), 3,4-dinitrobenzoic acid (3,4-DNBA), 2,5-dibromobenzoic acid (2,5-DBBA), and 3,5-dibromobenzoic acid (3,5-DBBA)) was made using a simultaneous TG/DSC apparatus operating with aluminum open crucibles under inert atmosphere in both isothermal and non-isothermal mode. No evidence of thermal decomposition (in the form of endo or exothermic effect) was found during each experiment. Vapor pressure was obtained in the range from some tenth to some hundreds of Pa after calibration with benzoic acid. All operative conditions (sample mass, temperature rage, and purge gas flow) were carefully checked in order to obtain reliable results. Internal consistency of the results obtained was checked by comparing the sublimation enthalpy obtained by the sum of the vaporization enthalpies derived by the global NITG and ITG data, the melting enthalpies from DSC adjusted at 298.15 using the molar isobaric heat capacities of both solid and liquid estimated according to a group additivity approach and that obtained from the sublimation enthalpies determined by torsion effusion corrected at 298.15 K using the same approach. Finally, some comments concerning the relationship between energetics and structure (substituent effect) are also reported.     

Retention-index based vapor pressure estimation for polychlorobiphenyl (PCB) by gas chromatography

Summary Vapor pressures for 133 individual polychlorobiphenyl congeners as subcooled liquids were determined by two different approaches on the basis of gas-chromatographic retention indices obtained with two different non-polar stationary phases. The approach which is based on the retention indices obtained on a methyl-50% octyl polysiloxane phase (SB Octyl 50) and on reference vapor pressures of PCB congeners, and thus contains less approximations, should yield more accurate results than the method which uses retention indices obtained on a methyl polysiloxane phase (OV 101) and reference vapor pressure data taken from the n-alkanes of the retention index system. A systematic deviation is observed between the values obtained by the two different methods. The first method gives constantly slightly higher values for the vapor pressure. This will be caused by the different separation characteristics of the two non-polar stationary phases used, as well as by uncertainties in the reference data for the vapor pressure calculations.     

pKa calculations in solution and proteins with QM/MM free energy perturbation simulations: a quantitative test of QM/MM protocols

The accuracy of biological simulations depends, in large part, on the treatment of electrostatics. Due to the availability of accurate experimental values, calculation of pKa provides stringent evaluation of computational methods. The generalized solvent boundary potential (GSBP) and Ewald summation electrostatic treatments were recently implemented for combined quantum mechanical and molecular mechanics (QM/MM) simulations by our group. These approaches were tested by calculating pKa shifts due to differences in electronic structure and electrostatic environment; the shifts were determined for a series of small molecules in solution, using various electrostatic treatments, and two residues (His 31, Lys 102) in the M102K T4-lysozyme mutant with large pKa shifts, using the GSBP approach. The calculations utilized a free energy perturbation scheme with the QM/MM potential function involving the self-consistent charge density functional tight binding (SCC-DFTB) and CHARMM as the QM and MM methods, respectively. The study of small molecules demonstrated that inconsistent electrostatic models produced results that were difficult to correct in a robust manner; by contrast, extended electrostatics, GSBP, and Ewald simulations produced consistent results once a bulk solvation contribution was carefully chosen. In addition to the electrostatic treatment, the pKa shifts were also sensitive to the level of the QM method and the scheme of treating QM/MM Coulombic interactions; however, simple perturbative corrections based on SCC-DFTB/CHARMM trajectories and higher level single point energy calculations were found to give satisfactory results. Combining all factors gave a root-mean-square difference of 0.7 pKa units for the relative pKa values of the small molecules compared to experiment. For the residues in the lysozyme, an accurate pKa shift was obtained for His 31 with multiple nanosecond simulations. For Lys 102, however, the pKa shift was estimated to be too large, even after more than 10 nanosecond simulations for each lambda window; the difficulty was due to the significant, but slow, reorganization of the protein and water structure when Lys 102 was protonated. The simulations support that Lys 102 is deprotonated in the X-ray structure and the protein is highly destabilized when this residue is protonated.     

Toward robust QSPR models: Synergistic utilization of robust regression and variable elimination

Widely used regression approaches in modeling quantitative structure-property relationships, such as PLS regression, are highly susceptible to outlying observations that will impair the prognostic value of a model. Our aim is to compile homogeneous datasets as the basis for regression modeling by removing outlying compounds and applying variable selection. We investigate different approaches to create robust, outlier-resistant regression models in the field of prediction of drug molecules' permeability. The objective is to join the strength of outlier detection and variable elimination increasing the predictive power of prognostic regression models. In conclusion, outlier detection is employed to identify multiple, homogeneous data subsets for regression modeling.     

液体的饱和蒸气压与内压

本文用统计热力学的方法, 建立了液体饱和蒸气压, 与内压间的关系式。对C6H6、CCl4、cy-C6H12、C(CH3)4、n-C6H14和(CH3)2CO等六种液体的检验结果表明, 上述关系式能适用于广阔的温度范围。