分子对接法预测丹皮酚及其2个异构体与β-环糊精复合物结构（英文）

β-环糊精对丹皮酚和其异构体具有明显的分子识别能力,其复合物的构象也可以极大提高其溶解能力。为了调查3个异构体和β-环糊精之间的结合模式以及相互作用,进行了分子对接和分子动力学模拟计算。采用拉马克遗传算法进行复合物可能的构象搜索,采用分子动力学评估了对接结果。对接结果分析表明3个异构体的羟基和甲氧基等的相对位置对其结合模式起到关键作用。丹皮酚(Pae)和香草乙酮(Ace)只有1个稳定的结合方式,计算结果和1H-NMR预测的一致。而2-羟基-5-甲氧基苯乙酮(Hma)和β-环糊精的可能的作用方式都不稳定。主客体之间主要的作用力为分子间氢键和疏水相互作用。分子对接法和分子动力学结合是预测β-环糊精和其配体复合物结构的1种简单方便的方法。     

论吡咯与双卤分子间的卤键

运用量子化学微扰理论MP2方法,采用6-311++G(d,p)基组,对吡咯与双卤分子XY(XY=ClF,BrF,BrCl)形成的卤键复合物进行构型全优化,得到各分子的稳定几何构型和分子间相互作用能.利用电子密度拓扑分析方法分析卤键复合物的拓扑性质,探讨了该类分子间卤键的作用本质.证明吡咯与双卤分子间存在Y-X...N和Y-X...π2类相互作用,且后者比前者强.复合物中的卤键介于共价键与离子键之间,偏于静电作用成分为主.形成卤键后,2种类型卤键复合物中的电子受体X-Y键伸长,其振动频率发生红移.用电子密度拓扑分析程序GTA-2000,将π型卤键体系中π电子与σ电子分开处理,绘制出π电子密度等值线图和Laplacian量等值线图,更加形象地说明π型卤键的存在和作用本质.利用AIM程序计算了卤键复合物中各原子电子积分的性质,原子积分性质随着卤键形成发生了改变.     

羟基化树状大分子与布洛芬相互作用的分子模拟研究

采用分子对接和分子动力学(MD)的模拟方法研究了第四代羟基为末端基团的树状大分子(PAMAM-G4-OH)与布洛芬的相互作用机理并对形成的复合物稳定性进行研究,结果发现:布洛芬插入PAMAM-G4-OH树状大分子空穴,羧基基团靠近核心;对接过程中分子间的范德华力和分子间的氢键贡献很大;将复合物体系进行2000 ps的MD模拟,发现前1000 ps体系的势能、总能量和RMSD值持续下降趋于平衡,最后分别在-1639 kcal/mol～-1701 kcal/mol,-457.009 kcal/mol～-475.809 kcal/mol,0.487A～0.607A范围内波动:复合物的结构起先较松散,经过2000 ps的模拟后逐渐紧凑。结论:树状大分子(PAMAM-G4-OH)与布洛芬主要作用力主为静电力,该静电力主要由布洛芬的羧基去质子化后形成的负电离子和树状大分子内部碱性的叔胺离子产生的;经过2000 ps的分子动力学模拟后,该体系达到了稳定状态。     

C6H6和SO3相互作用的理论研究（英文）

采用B3LYP和MP2方法在6-31G*、6-31+G*和6-311+G**基组下对C6H6…SO3复合物体系的4种可能结构进行自由优化,得3种。在考虑基组重叠误差校正基础上,得结合能,并用自然键轨道分析方法讨论其相互作用。结果表明,用B3LYP/6-31G*计算3种复合物的结合能分别为-17.75, -18.33, -18.80 kJ/mol,且C6H6和SO3结合时电子从苯环向SO3转移,形成电荷转移复合物,它们之间的作用包含π-p作用方式。     

基于分子力学的蛋白质分子场可视化

分子场是研究分子结构与功能的重要工具之一,已经成为药物设计和分子对接的常规方法。分子间作用力分布在3维空间,现有的蛋白质显示方法,如范德华表面,分子表面,球棍模型等,都难以对分子间作用力进行空间可视化分析。分子间各种相互作用中,静电力和范德华力在许多生物过程中都扮演着重要的角色,对蛋白质静电相互作用和范德华相互作用的正确计算模拟有着重要的理论和实践意义。分子场的计算分析从蛋白质分子结构出发,先经过分子模拟采样计算得到分子场,再对分子场进行可视化分析,提出针对分子场特点的分步式传输函数设计法,直观地反映了分子场在空间的分布,对于分析蛋白质结构功能、了解分子间相互作用机理以及进行药物设计和分子对接都有重要作用。     

胞嘧啶-巴比妥酸分子间相互作用的密度泛函理论研究

用密度泛函理论研究了胞嘧啶(Cyt)-巴比妥酸(BA)分子间相互作用,以期从理论上预测巴比妥酸类物质对核酸可能产生的影响.在B3LYP/6-311G* *理论水平上优化复合物构型,得到5个Cyt-BA1,8个Cyt-BA2和9个Cyt-BA3稳定复合物,经基组重叠误差和零点振动能校正后,发现在3个系列中最稳定的复合物分别是Cyt-BA1-Ⅳ,Cyt-BA2-Ⅲ和Cyt-BA3-ⅤⅢ,其结合能各自为53.98,96.48和92.50 kJ/mol,相互作用能主要由氢键贡献.cyt与BA2-Ⅲ、BA3-Ⅸ以三氢键,其余均以二氢键形成复合物,其稳定性与氢键强度关系非常密切.分析自然键轨道而揭示相互作用的本质.用统计热力学求出常温下从单体形成复合物的热力学性质的变化,发现除Cyt-BA3-Ⅰ、Ⅱ、Ⅵ外,Cyt与BA均可在常温下形成复合物.     

Leu-Phe分子印迹预组装体系热力学平衡的计算模拟

使用Gaussian03软件研究以Leu-Phe为模板,甲基丙烯酸为功能单体,乙二醇二甲基丙烯酸酯为交联剂,三氟乙酸为助溶剂的分子印迹预组装体系.计算了功能单体、助溶剂和交联剂加入量对各种模板复合物浓度的影响,进而确定了Leu-Phe分子印迹聚合物的合成条件.按条件合成聚合物后考察其识别性能,并结合计算模拟和实验结果解释实验现象.计算模拟可能有助于合成高特异性和亲和性分子印迹聚合物,探讨了分子印迹聚合物的分子识别机理.     

VEGF-B与去甲斑蝥素相互作用的分子动力学研究

利用分子对接(Molecular docking)结合分子动力学(Molecular dynamics,MD)模拟方法,建立去甲斑蝥素(Norcantharidin,NCTD)与血管内皮生长因子B(Vascular endothelial growth factor B,VEGF-B)的相互作用模型,分析二者的结合方式,结合能力,探究NCTD与VEGF-B的相互作用机制。结果表明,分子对接生成稳定的NCTD/VEGF-B复合物,NCTD与VEGF-B蛋白主链的Tyr117,Cys156,Gln46形成了氢键。经4ns的MD模拟后,NCTD/VEGF-B复合物体系达到了平衡,分析动力学轨迹并计算结合自由能证明了NCTD与VEGF-B的结合稳定合理。氢键、静电作用和疏水性为NCTD与VEGF-B稳定结合的主要贡献。本工作模建结果对开展NCTD抑制VEGF-B活性来控制肿瘤发生具有一定的理论意义。     

β-环糊精对α-环己基扁桃酸异构体手性识别作用的计算机模拟研究

运用量子力学PM3方法模拟α-环己基扁桃酸((R/S)-CHMA)与β-环糊精(β-CD)的主客体相互作用,探讨(R/S)-CHMA在β-CD上的手性识别机理。模拟结果能够准确预测色谱出峰顺序从而能从原子层次上对手性识别机制给予理论解释。PM3方法的计算结果表明:(S)-CHMA与β-CD形成的结合物比(R)-CHMA与β-CD形成的结合物稳定。从模拟包结物的构型可以看出(R/S)-CHMA与β-CD结合方式完全不同:(R)-CHMA是将苯环插入β-CD空腔形成包结物,而(S)-CHMA是将环己基插入β-CD空腔形成包结物。此外,(S)-CHMA除了自身的分子内氢键外,与β-CD分子之间还存在分子间氢键作用;而(R)-CHMA与β-CD之间没有分子间氢键作用。从而说明疏水作用以及弱的分子间氢键作用是造成手性识别的主要驱动力。     

Cr(CO)_n(n=1-5)与C_6 H_6相互作用的密度泛函研究

用密度泛函理论在B3LYP/LANL2DZ基组水平上对(η~x-C_6H_6)Cr(CO)_n(x=1-6;n=1-5)复合物体系的可能构型进行了自由优化及相互作用能的计算,研究了不同羰基数对复合物稳定性、苯和羰基铬相互作用的影响,并对苯和羰基铬相互作用进行了NBO分析。得到以下结论:(1)当n≤3时,苯与Cr(CO)_n以η~6配位;当n≥4时,苯与Cr(CO)_n以η~2配位;(2)最稳定复合物中随羰基数的增加Cr-C_(benzene)平均键长增长,最大二面角H-C-C-H偏离碳环的角度随复合物对称性降低而逐渐增大;(3)当n为奇数时,复合物相互作用主要表现为苯C-C键的π轨道和Cr-CO键的σ反键轨道;当n为偶数时,复合物相互作用主要表现为苯C-C键的π轨道或π~*轨道与Cr的孤对电子轨道;(4)复合物羰基数越多,最稳定复合物的相互作用能数值越大,稳定性越小。     

Prediction of the binding mode of biarylpropylsulfonamide allosteric AMPA receptor modulators based on docking, GRID molecular interaction fields and 3D-QSAR analysis

A novel approach of combining flexible molecular docking, GRID molecular interaction fields, analysis of ligand-protein hydrogen bond interactions, conformational energy penalties and 3D-QSAR analysis was used to propose a binding mode in the dimer interface of the iGluR2 receptor for the biarylpropylsulfonamide class of positive allosteric AMPA modulators. Possible binding poses were generated by flexible molecular docking. GRID molecular interaction fields of the binding site, ligand-protein hydrogen bonding interactions and conformational energy penalties were used to select the most likely binding mode. The selected binding poses were subjected to a 3D-QSAR analysis using previously published activity data. The resulting model (2 LVs, R2=0.89, q2=0.61) predicted the activities of the compounds in the test set with a standard deviation on error of prediction of 0.17. The proposed binding mode was validated by interpretation of the PLS-coefficient regions from the 3D-QSAR analysis in terms of interactions between the receptor and the modulators.     

用分子对接方法研究肝素与孕激素受体相互结合模式(英文)

用分子对接模拟软件研究了肝素与孕激素受体的相互作用。以肝素中的一糖单位作为探针对孕激素受体蛋白进行搜索,获得肝素组成单位与孕激素受体的特异性结合模式。结果发现,2-O-硫酸-α-L 艾杜糖醛酸(2-O-sulfated iduronic acid,IdoA(2S))作为肝素的核心组成单糖之一,与孕激素受体的结合能力最好。分子对接结果显示 IdoA(2S)深入到孕激素受体的 helix2 和 helix 11 所包围的结合口袋,与孕激素受体结合结构域关键残基 Asn 719 形成稳固的氢键;并与孕激素受体结合结构域的关键残基 Met 909 残基侧链近距离接触,揭示了 IdoA(2S)可能具有的孕激素受体拮抗效应的分子作用机制。本模拟实验所建立的模型能够部分解释肝素抑制孕激素依赖性乳腺癌的现象,同时推测了其相应机理。     

Dissipative particle dynamics simulation of shear flow in a microchannel with a deformable membrane

Thin deformable membranes are encountered in a number of microfluidics-based applications. These are often employed for enhancing sorting, mixing, cross-diffusion transport, etc. Microfluidic systems with deformable membranes can be better understood by employing simple models and efficient computational procedures. In this paper, we present a dissipative particle dynamics model to simulate the interaction between a deformable membrane and fluid flow in a two-dimensional microchannel. The membrane is modeled as a bead-spring system with both extensional and torsional springs to simulate extensional stiffness and bending rigidity, respectively. By performing detailed simulations on a membrane pinned at both ends and oriented parallel to the flow, we observe different steady state conformations. These membrane deflections are found to be relatively large for low bending stiffnesses and small for high stiffnesses. The membrane was found to exhibit a simple bowing out mode for high stiffness values and more complex conformations at lower stiffnesses.     

Interactive design of intelligent machine vision based on human–computer interaction mode

The intelligent machine vision technology based on man-machine interaction mode has the advantages of weak intrusion, low adhesion and no device binding. With the development and progress of science and technology, the intelligent machine vision technology has become one of the most important directions in the field of human–computer interaction. Compared with the traditional interactive mode, the intelligent machine vision interaction technology is quite convenient, and the existence of these problems can also influence the vision of the intelligent machine to a certain extent. And the wide application of the sense interaction. At present, the operation precision is the main basis of the machine vision interaction design. Therefore, this paper studies the precision of the visual interaction of the intelligent machine. In this paper, three point-to-click experiments will be carried out on the basis of the Fitts' Law. The accuracy of the machine vision algorithm is experimentally studied from the operating direction, the mapping scale equation and the machine vision algorithm, and a reasonable suggestion is made for the intelligent machine vision interactive design of the human interaction mode.     

CLiBE: a database of computed ligand binding energy for ligand-receptor complexes

Consideration of binding competitiveness of a drug candidate against natural ligands and other drugs that bind to the same receptor site may facilitate the rational development of a candidate into a potent drug. A strategy that can be applied to computer-aided drug design is to evaluate ligand-receptor interaction energy or other scoring functions of a designed drug with that of the relevant ligands known to bind to the same binding site. As a tool to facilitate such a strategy, a database of ligand-receptor interaction energy is developed from known ligand-receptor 3D structural entries in the Protein Databank (PDB). The Energy is computed based on a molecular mechanics force field that has been used in the prediction of therapeutic and toxicity targets of drugs. This database also contains information about ligand function and other properties and it can be accessed at http://xin.cz3.nus.edu.sg/group/CLiBE.asp. The computed energy components may facilitate the probing of the mode of action and other profiles of binding. A number of computed energies of some PDB ligand-receptor complexes in this database are studied and compared to experimental binding affinity. A certain degree of correlation between the computed energy and experimental binding affinity is found, which suggests that the computed energy may be useful in facilitating a qualitative analysis of drug binding competitiveness.     

Conformational analysis and docking study of potent factor XIIIa inhibitors having a cyclopropenone ring

A conformational analysis and docking study of potent factor XIIIa inhibitors having a cyclopropenone ring were carried out in an attempt to obtain structural insight into the inhibition mechanism. First, stable conformers of the inhibitors alone were obtained from the conformational analysis by systematic search and molecular dynamics. Next, a binding form model of factor XIIIa was built based on an X-ray crystal structure of the enzyme. Finally, the docking study of the inhibitors into the model’s binding site was performed. From the resulting stable complex structures, it was found that the cyclopropenone ring fits the active site located at the base of the binding cavity with high complementarity. The carbonyl oxygen of the cyclopropenone ring formed a hydrogen bond to the indole NH group of Trp279 and the terminal carbon atom of the reactive C=C double bond was in close proximity to the sulfur atom of the catalytic residue, Cys314. This binding mode suggests a possible inhibition mechanism, whereby the cysteine residue reacts with the cyclopropenone ring of the inhibitor, forming an enzyme-ligand adduct. In addition, the higher interaction energies between factor XIIIa and the inhibitors alluded to the probable binding sites of the ligand side chain.     

Three-dimensional micro-self-assembly using hydrophobic interaction controlled by self-assembled monolayers

This paper describes three-dimensional micro-self-assembly using hydrophobic interaction. The interaction between microparticles was controlled using self-assembled monolayers formed on the particles. The particles were stirred in a dispersion liquid to create a binding for connecting their surfaces directly. The interaction between the particles was described by the thermodynamic free energy of adhesion, which was calculated using the surface free energies of the solids and the liquid. The calculated free energy was then used to predict the bindings between particles. The binding probability was estimated by counting the number of microparticles that became bound to hydrophobic and to hydrophilic areas patterned on a substrate. The ratio of the bound particles was correlated to the difference between the free energies of the two areas, as predicted using the free energy calculation. This means that microparticle binding is controlled by the surface properties. Structures composed of several microparticles were successfully self-assembled using this principle. Hydrophobic interaction can thus be applied to micro-scale self-assembly.     

基于Web Service的异构工作流管理系统的集成和互操作研究

本文首先分析了分布、异构工作流管理系统的互操作对各种交互模式的需求，针对 现有的工作流管理系统的分布式应用解决方案的不足之处，提出了一种基于Web Service的支持分布、异构工作流管理系统之间集成和互操作的实现方法．Web Service因其开放、标准化而受到业界广泛重视，已成为新一代基于Internet建立分布式应用的规范．本文从异构工作流管理系统之间的信息集成、工作流引擎之间调用语义的实现、工作流执行服务的描述、发布和绑定等方面，论述了Web Service对异构工作流管理系统之间集成和互操作的支持．     

A theory of mode of action of azolylalkylquinolines as DNA binding agents using automated flexible ligand docking

Azolylalkylquinolines (AAQs) are a family of quinolines with varying degrees of cytotoxic activity (comparable or moderately superior to adriamycin in some cases) developed in the past decade in our group where their exact mode of action is still unclear. In this study the most probable DNA binding mode of AAQs was investigated employing a novel flexible ligand docking approach by using AutoDock 3.0. Forty-nine AAQs with known experimental inhibitory activity were docked onto d(CGCAAATTTGCG)(2), d(CGATCG)(2) and d(CGCG)(2) oligonucleotides retrieved from the Protein Data Bank (PDB IDs: 102D, 1D12 and 1D32, respectively) as the representatives of the three plausible models of interactions between chemotherapeutic agents and DNA (groove binding, groove binding plus intercalation and bisintercalation, respectively). Good correlation (r(2)=0.64) between calculated binding energies and experimental inhibitory activities was obtained using groove binding plus intercalation model for phenyl-azolylalkylquinoline (PAAQ) series. Our findings show that the most probable mode of action of PAAQs as DNA binding agents is via intercalation of quinolinic moiety between CG base pairs with linker chain and azole moiety binding to the minor groove.     

Insight into the structural mechanism for PKBα allosteric inhibition by molecular dynamics simulations and free energy calculations

Protein kinase B (PKB/Akt) is an attractive target for the treatment of tumor. Unlike PKB's ATP-competitive inhibitors, its allosteric inhibitors can maintain PKB's inactive state via its binding in a pocket between PH domain and kinase domain, which specifically inhibit PKB by preventing the phosphorylations of Thr308 and Ser473. In the present studies, MD simulations were performed on three allosteric inhibitors with different inhibitory potencies (IC₅₀) to investigate the interaction modes between the inhibitors and PKBα. MM/GB(PB)SA were further applied to calculate the binding free energies of these inhibitors binding to PKBα. The computed binding free energies were consistent with the ranking of their experimental bioactivities. The key residues of PKBα interacting with the allosteric inhibitor were further discussed by analyzing the different interaction modes of these three inhibitors binding to PKBα and by calculating binding free energy contributions of corresponding residues around the binding pocket. The structural requirements were then summarized for the allosteric inhibitor binding to PKBα. A possible structural mechanism of PKBα inhibition induced by the binding of allosteric inhibitor was formulated. The current studies indicate that there should be an optimum balance between the van der Waals and total electrostatic interactions for further designing of PKBα allosteric inhibitors.