The phototoxicity of polycyclic aromatic hydrocarbons: a theoretical study of excited states and correlation to experiment

Investigators using models to determine the phototoxic effects of sunlight on polycyclic aromatic hydrocarbons (PAHs) have invoked the excited states of the molecule as important in elucidating the mechanism of these reactions. Energies of actual excited states were calculated for ten PAHs by several ab initio methods. The main method used for these calculations was the Configuration Interaction approach, modeling excited states as combinations of single substitutions out of the Hartree-Fock ground state. These calculations correlate well with both experimentally measured singlet and triplet state energies and also previous HOMO-LUMO gap energies that approximate the singlet state energies. The excited state calculations then correlate well with general models of photo-induced toxicity based for the PAHs.     

分子动力学模拟HEWL晶体在不同环境中的动力学行为

简要阐述分子动力学模拟的原理及步骤,介绍研究溶菌酶的一般方法和优缺点。在Ubuntu操作系统环境下,利用Gromacs软件和其自带的Gromos96力场,通过分子动力学模拟(MD)鸡蛋清溶菌酶晶体(chicken egg-whitelysozyme,HEWL)溶液,考察真空、水溶液和加入NaCl 3种不同环境条件对溶菌酶晶体构象动力学行为的影响,发现无论从均方根位移(rmsd)、回旋半径、还是从B因子值的轨迹图分析,HEWL在水溶液特别是加入抗衡离子(Na~+,Cl~-)的水溶液的环境下的结构更稳定、合理,与(protein data bank)数据库的真实情况相符。原因是Cl~-与溶菌酶晶体在界面处发生了吸附现象,局部形成溶菌酶-Cl~-复合物,抑制了蛋白-水合物中水分子在相邻水合位置间的跳跃,从而使单晶体在离子液态中更加稳定。模拟结果表明,在pH值6.5,等电位点13.1,总电荷7.999 6的体系下,影响HEWL的吸附位点为123号残基(色氨酸),对从分子水平上解释HEWL晶体的动力学吸附行为具有重要指导意义。     

In silico modeling for the risk assessment of toxicity in cells

A cell is a complex biochemical reactor. Various biochemical reactions take place in it to carry out different tasks. One such task is the metabolism of the ubiquitous environmental carcinogenic compounds Polycyclic Aromatic Hydrocarbons (PAHs) in biological cells, which is crucial to model. These PAHs are lipophilic did partition into membranes and diffuse through them to demolish the DNA and thereby cause toxicity or tumors. Therefore there is a dire need of the development of a model for the assessment of these carcinogenic chemical compounds. Earlier, a 3D model was developed in order to investigate the cellular fate after being affected by PAHs, but this model was lacking the presence of Nucleolemma with its enzymatic reactions, which is an important factor to be considered. Thus, a new 3D model was developed which in addition to the other domains, consists of Nucleolemma along with its enzymatic reactions. A homogenization approach was used for the numerical treatment of cytoplasm to scale down the complexity of the model. The numerical results of the extended model were validated against the numerical results of the old model and the experimental results, where the results of extended model clearly show the improvement and convergence to the experimental results not only qualitatively but quantitatively as well.     

多层纳米银／壳聚糖膜用于芘的表面增强拉曼测定

多环芳烃类物质的高疏水性质使得其在金属表面吸附能力差,从而拉曼增强信号弱。该文针对此问题,制备了以壳聚糖为骨架,纳米银颗粒为热点的多层纳米银／壳聚糖复合膜表面拉曼增强基底,成功用于芘的表面增强拉曼检测。由于壳聚糖本身的富集作用,目标分子被吸附、富集于银纳米颗粒形成拉曼热点,可检测0．01μmol／L的芘。     

Three-dimensional models of histamine H3 receptor antagonist complexes and their pharmacophore

Molecular modeling was used to analyze the binding mode and activities of histamine H₃ receptor antagonists. A model of the H₃ receptor was constructed through homology modeling methods based on the crystal structure of bovine rhodopsin. Known H₃ antagonists were interactively docked into the putative antagonist binding pocket and the resultant model was subjected to molecular mechanics energy minimization and molecular dynamics simulations which included a continuum model of the lipid bilayer and intra- and extracellular aqueous environments surrounding the transmembrane helices. The transmemebrane helices stayed well embedded in the dielectric slab representing the lipid bilayer and the intra- and extracellular loops remain situated in the aqueous solvent region of the model during molecular dynamics simulations of up to 200 ps in duration. A pharmacophore model was calculated by mapping the features common to three active compounds three-dimensionally in space. The 3D pharmacophore model complements our atomistic receptor/ligand modeling. The H₃ antagonist pharmacophore consists of two protonation sites (i.e. basic centers) connected by a central aromatic ring or hydrophobic region. These two basic sites can simultaneously interact with Asp 114 (3.32) in helix III and a Glu 206 (5.46) in helix V which are believed to be the key residues that histamine interacts with to stabilize the receptor in the active state. The interaction with Glu 206 is consistent with the enhanced activity resulting from the additional basic site. In addition to these two salt bridging interactions, the central region of these antagonists contains a lipophilic group, usually an aromatic ring, that is found to interact with several nearby hydrophobic side chains. The picture of antagonist binding provided by these models is consistent with earlier pharmacophore models for H₃ antagonists with some exceptions.     

Dynamic conformations of fluorocarbon molecules on magnetic hard disk surfaces with charged sites

To meet the demand of extremely high recording density of magnetic storage device, magnetic head is expected to reduce its flying height to sub 5 nm. Lubricant films in such system become more important and the conformation characteristics of lubricant molecules, which receive attractive forces both from the disk and the head, must be clarified for the stable flying of the head. In this report molecular dynamics simulations are carried out to investigate the conformation of lubricant molecules. The model is composed of solid surface and polar-ended fluorocarbon molecules. The surface has several reactive sites, which interact with polar end groups of fluorocarbon molecules. Varying the number of reactive sites, the processes that the reactive sites attract molecules are simulated. Results from the present simulations indicate that lubricant molecules tend to gathered and piled up. It is difficult to achieve 100% coverage.     

多环芳烃(PAHs)对虹鳟(Oncorhynchus mykiss)鱼腮细胞系细胞毒性的Fisher判别分析

采用量子化学PM3算法计算得到的多环芳烃(PAHs)的量子化学参数，应用逐步判别分析法分析PAHs的细胞毒性，建立了能成功预测PAHs细胞毒性的Fisher线性判别函数，函数预测结果的正确识别率达到100％。研究认为影响PAHs细胞毒性的主要因素是PAHs的分子量(Mw)、偶极矩(μ)、分子最高占据轨道能(EHDMO)、分子最低未占据轨道能(ELUMO)和(ELUMO-EHOMO)^2。     

Three-dimensional models of histamine H3 receptor antagonist complexes and their pharmacophore

Molecular modeling was used to analyze the binding mode and activities of histamine H₃ receptor antagonists. A model of the H₃ receptor was constructed through homology modeling methods based on the crystal structure of bovine rhodopsin. Known H₃ antagonists were interactively docked into the putative antagonist binding pocket and the resultant model was subjected to molecular mechanics energy minimization and molecular dynamics simulations which included a continuum model of the lipid bilayer and intra- and extracellular aqueous environments surrounding the transmembrane helices. The transmemebrane helices stayed well embedded in the dielectric slab representing the lipid bilayer and the intra- and extracellular loops remain situated in the aqueous solvent region of the model during molecular dynamics simulations of up to 200 ps in duration. A pharmacophore model was calculated by mapping the features common to three active compounds three-dimensionally in space. The 3D pharmacophore model complements our atomistic receptor/ligand modeling. The H₃ antagonist pharmacophore consists of two protonation sites (i.e. basic centers) connected by a central aromatic ring or hydrophobic region. These two basic sites can simultaneously interact with Asp 114 (3.32) in helix III and a Glu 206 (5.46) in helix V which are believed to be the key residues that histamine interacts with to stabilize the receptor in the active state. The interaction with Glu 206 is consistent with the enhanced activity resulting from the additional basic site. In addition to these two salt bridging interactions, the central region of these antagonists contains a lipophilic group, usually an aromatic ring, that is found to interact with several nearby hydrophobic side chains. The picture of antagonist binding provided by these models is consistent with earlier pharmacophore models for H₃ antagonists with some exceptions.     

Modelling β-1,3-exoglucanase–saccharide interactions: Structure of the enzyme–substrate complex and enzyme binding to the cell wall

Glycoside hydrolases are a class of enzymes that break/form the bond between sugar monomers (monosaccharides). Candida albicans's β-1,3-exoglucanase (Exg), a family 5 glycosidase, belongs to this class of enzymes. This small protein is an ideal computational model for its family of enzymes and was used here to create several enzyme–substrate models starting from a crystallographic glucanase-inhibitor structure. A series of enzyme–substrate complexes were generated using molecular docking, ranging from Exg–glucose (Exg–1Glc) to Exg–laminarihexaose (Exg–6Glc). Structure optimizations followed by molecular dynamics provided a picture of the way the enzyme and substrates interact.Molecular dynamics was conducted for each complex to assess the flexibility of the substrate, of the enzyme as a whole, and of enzyme–substrate interactions. The enzyme overall conformation was found to be quite rigid, although most enzyme residues increase mobility upon substrate binding. However, two surface loops stand out by having large fluctuations and becoming less flexible when the substrates were bound. These data point to a possible biological role for the mentioned loops, corresponding to amino acids 36–47 and 101–106.We propose that these loops could bind the enzyme to a glucan chain in the cell wall. The polysaccharide and enzyme structures have very complementary shapes and form numerous interactions; so it appears likely that the flexible loops connect the enzyme to the cell wall and allow it to navigate the wall to shape glucan structure.     

钾、钠、氯离子水化现象的分子动力学模拟

用Material Studio软件包中的COMP ASS力场提供的9/6 Lennard-Jones势能模型,分别模拟298 K,密度为1.0 g/cm~3的水溶液中K~+、Na~+、Cl~-水化现象的分子动力学和水分子配位的微观结构。发现阳离子周围的水分子以氧原子去靠近阳离子,而阴离子周围的水分子则以其中的一个氢原子去靠近阴离子,并获得了K~+、Na~+、Cl~-的径向分布函数和配位数曲线。计算得到的K~+、Na~+、Cl~-的水化数分别为2.53、3.64、3.66,它们的水化半径分别为0.272nm、0.299 nm、0.316 nm,自扩散系数分别为1.98×10~(-5)cm~2s~(-1)、1.04×10~(-5)cm~2s~(-1)、2.08×10~(-5)cm~2s~(-1)。结果表明,3种离子的水化能力顺序为:Cl~->Na~+>K~+,自扩散系数的计算值与实验值吻合较好。K~+、Na~+、Cl~-在海水中广泛存在,本文的研究结果可为海水资源的高效开发利用提供一定的理论基础。     

影响土壤中PAHs降解的环境因素及促进降解的措施

土壤中的多环芳烃(PAHs)类有机污染物的生物有效性低,不易降解。本文综述了影响污染土壤中多环芳烃降解的环境因素和促进降解措施的研究进展。影响土壤中多环芳烃降解的因素,包括水分、养分、土壤物理条件等;促进土壤中多环芳烃降解的措施有:向污染土壤添加有机溶剂、利用冯顿反应、添加堆肥和有机物料等。从目前研究来看,应当通过促进多环芳烃从土壤上解吸和培育具有较高多环芳烃降解能力的微生物来促进多环芳烃污染土壤的修复。     

Modelling β-1,3-exoglucanase–saccharide interactions: Structure of the enzyme–substrate complex and enzyme binding to the cell wall

Glycoside hydrolases are a class of enzymes that break/form the bond between sugar monomers (monosaccharides). Candida albicans's β-1,3-exoglucanase (Exg), a family 5 glycosidase, belongs to this class of enzymes. This small protein is an ideal computational model for its family of enzymes and was used here to create several enzyme–substrate models starting from a crystallographic glucanase-inhibitor structure. A series of enzyme–substrate complexes were generated using molecular docking, ranging from Exg–glucose (Exg–1Glc) to Exg–laminarihexaose (Exg–6Glc). Structure optimizations followed by molecular dynamics provided a picture of the way the enzyme and substrates interact.Molecular dynamics was conducted for each complex to assess the flexibility of the substrate, of the enzyme as a whole, and of enzyme–substrate interactions. The enzyme overall conformation was found to be quite rigid, although most enzyme residues increase mobility upon substrate binding. However, two surface loops stand out by having large fluctuations and becoming less flexible when the substrates were bound. These data point to a possible biological role for the mentioned loops, corresponding to amino acids 36–47 and 101–106.We propose that these loops could bind the enzyme to a glucan chain in the cell wall. The polysaccharide and enzyme structures have very complementary shapes and form numerous interactions; so it appears likely that the flexible loops connect the enzyme to the cell wall and allow it to navigate the wall to shape glucan structure.     

Amplification of fluorescence emission of CdSe/ZnS QDs entrapped in a sol-gel matrix, a new approach for detection of trace level of PAHs

In this work, CdSe/ZnS core/shell QDs with emission wavelengths of 535 nm, 545 nm, 555 nm and 575 nm were synthesized and the ligands on their surface were exchanged with mercaptopropionic acid (MPA) to make them water-soluble. Hydrophilic QDs were incorporated into a sol-gel GA matrix of 3-aminopropyl trimethoxysilane (APTMS) and 3-glycidoxypropyl trimethoxysilane (GPTMS) to fabricate QD-entrapped membranes. The fluorescence intensity of the QDs entrapped in the sol-gel membrane was increased after being activated by the energy transfer from polycyclic aromatic hydrocarbon compounds (PAHs). The signal increase of the QDs was proportional to the increase in the concentration of the PAHs. Herein, trace levels of anthracene (ANT), phenanthrene (PHE) and pyrene (PYR) were detected through the enhancement of the fluorescence intensity of the CdSe/ZnS QD-entrapped membranes. The linear detection ranges were 0.01-0.1 μM for ANT and PHE and 0.005-0.05 μM for PYR. The QD-entrapped sol-gel membranes also showed quite good stability for the detection of PAHs over a period of 2 months.     

Critical assessment of thermodynamic properties of important polycyclic aromatic hydrocarbon compounds (PAHs) in coal tar pitch at typical temperature ranges of the carbonization process

Because of the importance of thermodynamic behavior of Polycyclic Aromatic Hydrocarbon (PAH) compounds in coal tar pitch carbonization process, a thermodynamic model for the prediction of thermodynamic properties of PAH compounds is developed. Heat capacity functions as well as standard thermodynamic properties of PAHs in solid, liquid, and gas states are estimated using modified group additivity algorithms first proposed by Richard and Helgeson and thermal physical data of those PAHs for which enough experimental data exists in the literature. For the first time, initial calculated thermodynamic properties of PAHs are optimized by applying the CALPHAD (CaLculation of PHAse Diagrams) approach where all thermodynamic data are rendered consistent with phase transitions and vapor pressure data. The heat capacity function of PAHs exhibiting thermal anomaly behavior is modeled as a specific case. This modeling is performed using an order-disorder approach with the Compound Energy Formalism (CEF). Good agreement has been obtained between the predicted thermodynamic properties of PAHs and available experimental data. The proposed model has improved the predictive capacity compared to that of the previous models predicting thermodynamic properties of PAHs at typical temperature ranges of the carbonization process. The application of the model to predict the thermodynamic properties of major and high molecular weight PAHs available in coal tar pitch has been discussed.     

Metamodels and emergent behaviour in models of conflict

In this paper, we develop a simplified mathematical model (a metamodel) of a simulation model of conflict, based on ideas drawn from the analysis of more general physical systems, such as found in fluid dynamics modelling. We show that there is evidence from the analysis of historical conflicts to support the kind of emergent behaviour implied by this approach. We then apply this approach to the development of a metamodel of a particular complexity based simulation model of conflict (ISAAC), developed for the US Marine Corps.The approach we have illustrated here is very generic, and is applicable to any simulation model which has complex interactions similar to those found in fluid dynamic modelling, or in simulating the emergent behaviour of large numbers of simple systems which interact with each other locally.     

重质油中的分子聚集结构及其对重质油稳定性的影响

重质油组分分子的聚集是重质油最显著的特征之一,重质油的高粘特性和相态稳定性均与此聚集行为有紧密的联系.为克服实验研究获得重质油微观聚集结构的困难,本文采用Zhang等人针对重质油体系改进的耗散粒子动力学(DPD)方法,研究重质油的分子聚集结构及其对重质油稳定性的影响.根据重质油组分的结构特征,可将重质油表达为其他轻组分...     

修正Cp_EA-PLS用于多环芳烃光解半衰期QSAR的研究

文章讨论了多环芳烃光解半衰期的QSAR模型.运用量子化学软件包以B3LYP/6-311+C(d)方法计算13种PAHs的量子化学描述符,用修正CP统计量作目标函数并用进化算法(EA)选择变量,然后应用偏最小二乘(PLS)方法给13种PAHs的光降解活性进行建模,模型的相关系数为0.9719,比直接用PLS方法所得到的模型更优越.结果表明模型预测PAHs的光解半衰期有效.     

Molecular modeling of enzyme attachment on AFM probes

The immobilization of enzymes on atomic force microscope tip (AFM tip) surface is a crucial step in the development of nanobiosensors to be used in detection process. In this work, an atomistic modeling of the attachment of the acetyl coenzyme A carboxylase (ACC enzyme) on a functionalized AFM tip surface is proposed. Using electrostatic considerations, suitable enzyme–surface orientations with the active sites of the ACC enzyme available for interactions with bulk molecules were found. A 50 ns molecular dynamics trajectory in aqueous solution was obtained and surface contact area, hydrogen bonding and protein stability were analyzed. The enzyme–surface model proposed here with minor adjustment can be applied to study antigen–antibody interactions as well as enzyme immobilization on silica for chromatography applications.     

Dynamical analysis of the conformation of the active site of porcine pancreatic elastase in native and Michaelis complex states. Molecular dynamics simulations

Mechanistic details of events preceeding and occurring during enzymatic catalysis are extremely difficult to obtain experimentally. While molecular dynamics methods permit the simulation of discrete steps along the catalytic pathway, they also can overwhelm the investigator with a mountain of structural details, necessitating the development of specific analytic tools. Based on recent crystallographic data, several molecular dynamics simulations have been performed using the AMBER 3.0 program package. Two different simulations for the hydrated native enzyme (100 and 50 ps) and two simulations (30 and 70 ps) of the Michaelis complex of this enzyme with the substrate (Thr-Pro-nVal-Leu-Tyr-Thr) have been performed. Dynamical properties of the active site (especially the catalytic tetrad: Ser-195, His-57, Asp-102 and Ser-214; chymotrypsinogen numbering system) have been examined using the program MD_ANALYSIS_1. It, together with the program MDKINO, facilitates analysis of dynamical changes of conformation (especially the hydrogen bond network) of the active site. Hydrogen bonding among Asp-102, Ser-214 and His-57 was quite stable, but the catalytic Ser-195 sidechain was flexible. Therefore the catalytically crucial H-bond between HO_γ (Ser-195) and N_ϵ (His-57) is relatively labile. In the native case (i.e. without substrate) this H-bond was never formed due to competition for the acceptor atom (N_ϵ) between water molecules and the HO_γ group. In the Michaelis complex the H-bond is more readily formed, although the sidechain (Ser-195) may sometimes change its conformation do to the influence of the carbonyl group of Ser-214. Due to the dynamical motion of the enzyme there were six different short periods in which the distance between both heavy atoms in this crucial H-bond was less than 2.6 Å, which may facilitate proton transfer from Ser-195 to His-57 (the first step during the proper catalysis). These results suggest mechanistic details about the precise clockwork of a functioning enzyme.