_f-A_aD_d氢键体系的统计特征

基于氢键的形成和缩聚反应机理在统计意义下的相似性 ,利用高分子反应统计理论和反应动力学理论对氢键溶液的一个模型体系进行了相关讨论 .给出了体系的溶胶分数和发生溶胶 -凝胶相变的条件 ,指出质子受体基团间的竞争作用对溶胶凝胶相变点的影响 ,进而讨论了体系的数量分布函数和相关问题 .     

_f-A_aD_d氢键体系的统计特征

基于氢键的形成和缩聚反应机理在统计意义下的相似性,利用高分子反应统计理论和反应动力学理论对氢键溶液的一个模型体系进行了相关讨论.给出了体系的溶胶分数和发生溶胶-凝胶相变的条件,指出质子受体基团间的竞争作用对溶胶凝胶相变点的影响,进而讨论了体系的数量分布函数和相关问题.     

3DFs:用于药物设计的三维结构柔性搜索系统

在三维结构数据库中搜索含有某种药效团的分子的三维结构搜索法已经成为新药研制的重要手段，近年已有了广泛的发展。３ＤＦＳ是我室研制的用于药物分子设计的三维结构柔性搜索系统，该系统支持由化学功能基团定义的药效团，并详细定义了氢键给体、氢键受体、电荷中心、疏水区等重要化学功能基团的结构类型，并且具有三维构象柔性搜索功能。     

葡萄糖、果糖和蔗糖在甲酰胺溶液中的体积性质

报导了含葡萄糖、果糖和蔗糖的甲酰胺溶液的密度数据，无限稀释表观摩尔体积和体积第二维里系数．利用改进的定标粒子理论、基团几何模型和基团加合方法，求解了溶质的空腔生成体积，溶质-溶剂间的氢键作用对体积性质的影响，并和水溶液中的情况进行了比较．     

作用于秋水仙碱位点的微管蛋白抑制剂的结合模式 研究与结构模型的构建

采用对接的方法建立了秋水仙碱位点抑制剂与微管蛋白的结合模式, 并构建了其结构模型. 结果表明: 抑制剂主要借助于与口袋I和II的疏水作用, 以及同α-Thr178, α-Val181和β-Cys241之间的氢键来实现与微管蛋白的结合. 根据抑制剂的结合构象, 将抑制剂的结构分为A, B以及AB间的桥连三个部分, 从而建立了由A部分中的疏水中心H1、氢键受体A1, B部分中的疏水中心H2、疏水基团H3和极性原子P以及桥连结构中的氢键受体A2组成的结构模型. 并指出H1与H2对活性的影响因素分别为疏水基团的体积和平面特征, 而桥连部分则应以刚性的形式保证AB处于桥连的同侧(即顺式构象). 还提出在A2与loop区之间存在一个的潜在氢键受体A3. 研究结果为设计新型小分子微管蛋白抑制剂提供指导.     

_f-A_aD_d型氢键体系的网络结构参数

利用溶胶-凝胶分配理论对氢键溶液的模型体系进行研究,给出了凝胶点后氢键网络中各结构参数的计算方案,并进行相应的数值计算.结果表明,因受体基团本身的性质及两类质子受体基团的数量比不同,受体基团的竞争作用对网络结构有明显影响,这提供了控制氢键网络结构特征的可能方法.     

Af-AaDd型氢键体系的网络结构参数

利用溶胶-凝胶分配理论对氢键溶液的模型体系进行研究, 给出了凝胶点后氢键网络中各结构参数的计算方案, 并进行相应的数值计算. 结果表明, 因受体基团本身的性质及两类质子受体基团的数量比不同, 受体基团的竞争作用对网络结构有明显影响, 这提供了控制氢键网络结构特征的可能方法.     

Af-AaDd型氢键体系的网络结构参数

利用溶胶-凝胶分配理论对氢键溶液的模型体系进行研究, 给出了凝胶点后氢键网络中各结构参数的计算方案, 并进行相应的数值计算. 结果表明, 因受体基团本身的性质及两类质子受体基团的数量比不同, 受体基团的竞争作用对网络结构有明显影响, 这提供了控制氢键网络结构特征的可能方法.     

氢键簇生长的反应动力学和统计力学理论

分析氢键的形成机理与缩聚反应在统计意义下的相似性,以AaDd型氢键体系为例,分别应用反应动力学方法和统计力学理论研究了氢键簇的生长过程.两种方法给出的结果一致,由此说明,高分子反应统计力学理论可以用来研究氢键体系.然后,给出了AaDd型氢键体系中质子给体和受体官能团的反应程度与体系Gibbs自由能等热力学量之间的解析表达式.进一步预言一些氢键体系可以发生溶胶-凝胶相转变现象,并给出可以描述相变过程的广义标度律.     

基于双吡啶基双西佛碱通过氢键相互作用形成的有机超分子晶体

合成了双吡啶双西佛碱(bpbd)有机分子，并用该分子进行了超分子网络晶体的组装．X射线单晶结构分析表明：在bpbd晶体中存在着分子间氢键相互作用，该氢键由吡啶环上的N原子和西佛碱H—C—N基团上的H原子相互作用而成．每一个bpbd分子同另外4个bpbd分子通过氢键相连，构成了二维网状结构；在bpbd晶体中还存在分子间π…π相互作用，并导致一维分子柱的形成．二维氢键和一维π…π的协同作用，导致了三维超分子晶体的形成。     

利用样本成分耗散物的非线性化学指纹图谱原理及相似度计算与评价

在恒温恒压条件下,以丙酮和样本中底物作为主要耗散物的不同成分的样本对非线性化学反应机理产生不同影响,从而引起反应体系电位-时间曲线形状不同变化为特征的B-Z化学振荡体系为例,就非线性化学指纹图谱原理进行了详细研究和讨论,并提出了计算非线性化学指纹图谱系统相似度的通用方法.利用系统相似度和欧氏距离、相关系数及夹角余弦对不同生产批次古汉养生精和18种其他样本的非线性化学指纹图谱的相似度进行了计算与分析.结果表明,相关系数和夹角余弦都不能用来作为评价非线性化指纹图谱相似度的指标.利用欧氏距离公式计算指纹图谱的非参数型相似度时,能正确反映指纹图谱的特征差异,但用其计算参数型相似度时,则有时不能正确反映样本非线性化学指纹图谱特征差异的相对程度.系统相似度能最真实反映样本指纹图谱之间差异程度,是4种相似度计算方法中最好的,可用于非线性化学指纹图谱相似度计算与评价.成功提出了一种经济、简便、易行和有效的鉴别样本真伪与评价其质量的科学方法.     

Principle of nonlinear chemical fingerprint by using dissipative components in samples as well as calculation and evaluation of similarity

Under the conditions of constant temperature and pressure,different influences of samples with different chemical components on the mechanism of nonlinear chemical reaction will cause different changes of the potential-time relationship curve of the nonlinear chemical reaction system.Using it as the character,and using the B-Z nonlinear chemical system to use acetone and substrates in samples as main dissipative substances qua an example,the principle of nonlinear chemical fingerprint has been researched and discussed in detail.At the same time,the general method for calculating the system similarity about nonlinear chemical fingerprint was also put forward,and similarities of nonlinear chemistry fingerprints of different batches of Guhan Yangshengjing and 18 sorts of other samples were calculated by Euclidean distance,correlation coefficient,included angle cosine and system similarity,at the same time,the various similarities were analyzed.The results showed that,both of correlation coefficient and included angle cosine are unable to be used as the criterion for quantitatively evaluating the similarity of nonlinear chemistry fingerprint;as non-parametric similarity,Euclidean distance can accurately reflect the feature differences in the fingerprints,but as parametric similarity,sometimes,Euclidean distance can not accurately reflect the relative extent of characteristic difference in the nonlinear chemical fingerprints;system similarity can most truthfully reflect the characteristic difference in the nonlinear chemical fingerprints,and is the best evaluating method among the four ones.Therefore,system similarity can be used to quantitatively calculate the similar extent between the nonlinear chemical fingerprints.An economical,simple and convenient,easy pushing and effective method for identifying and evaluating complicated samples has successfully been put forward.     

Polarization response of water and methanol investigated by a polarizable force field and density functional theory calculations: implications for charge transfer

Electronic polarization response in hydrogen-bond clusters and liquid configurations of water and methanol has been studied by density functional theory (DFT) and by a polarizable force field based on the chemical potential equalization (CPE) principle. It has been shown that an accurate CPE parametrization based on isolated molecular properties is not completely transferable to strongly interacting hydrogen-bond clusters with discrepancies between CPE and DFT overall dipole moments as large as 15%. This is due to the lack of intermolecular charge transfer in the standard CPE implementation. A CPE scheme for evaluating the amount of transferred charge has been developed. The charge transfer parameters are determined with the aid of accurate DFT calculations using only hydrogen-bond dimer configurations. The amount of transferred charge is found to be of the order of few hundredths of electrons, as already found in recent studies on hydrogen-bond systems. The parameters of the model are then used, without further adjustment, to different hydrogen-bond clustered forms of water and methanol (oligomer and liquid configurations). In agreement with different approaches proposed in literature for studying charge transfer effects, the transferred charge in hydrogen-bond dimers is found to decrease exponentially with the hydrogen-bond distance. When allowance is made for charge transfer according to the proposed scheme, the CPE dipole moments are found to reproduce satisfactorily the DFT data.     

Ab initio molecular dynamics simulations and g-tensor calculations of aqueous benzosemiquinone radical anion: effects of regular and "T-stacked" hydrogen bonds

Car-Parrinello molecular dynamics (CP-MD) simulations of the benzosemiquinone radical anion in aqueous solution have been performed at ambient conditions. Analysis of the trajectory shows not only extensive hydrogen bonding to the carbonyl oxygen atoms (ca. 4-5.6 water molecules depending on distance criteria), but also relatively long-lived "T-stacked" hydrogen bonds to the semiquinone pi-system. These results are discussed in the context of recent findings on semiquinone-protein interactions in photosynthetic reaction centers, and of EPR and vibration spectroscopical data for the aqueous system. Snapshots from the CP-MD trajectory are used for the first quantum chemical analyses of dynamical effects on electronic g-tensors, using cluster models and a recently developed density functional method. In particular, the effects of intermolecular hydrogen-bond dynamics on the g-tensor components are examined, in comparison with recent EPR and ENDOR studies.     

Virtual screening for R-groups, including predicted pIC50 contributions, within large structural databases, using Topomer CoMFA

Multiple R-groups (monovalent fragments) are implicitly accessible within most of the molecular structures that populate large structural databases. R-group searching would desirably consider pIC50 contribution forecasts as well as ligand similarities or docking scores. However, R-group searching, with or without pIC50 forecasts, is currently not practical. The most prevalent and reliable source of pIC50 predictions, existing 3D-QSAR approaches, is also difficult and somewhat subjective. Yet in 25 of 25 trials on data sets on which a field-based 3D-QSAR treatment had already succeeded, substitution of objective (canonically generated) topomer poses for the original structure-guided manual alignments produced acceptable 3D-QSAR models, on average having almost equivalent statistical quality to the published models, and with negligible effort. Their overall pIC50 prediction error is 0.805, calculated as the average over these 25 topomer CoMFA models in the standard deviations of pIC50 predictions, derived from the 1109 possible "leave-out-one-R-group" (LOORG) pIC50 contributions. (This novel LOORG protocol provides a more realistic and stringent test of prediction accuracy than the customary "leave-out-one-compound" LOO approach.) The associated average predictive r(2) of 0.495 indicates a pIC50 prediction accuracy roughly halfway between perfect and useless. To assess the ability of topomer-CoMFA based virtual screening to identify "highly active" R-groups, a Receiver Operating Curve (ROC) approach was adopted. Using, as the binary criterion for a "highly active" R-group, a predicted pIC50 greater than the top 25% of the observed pIC50 range, the ROC area averaged across the 25 topomer CoMFA models is 0.729. Conventionally interpreted, the odds that a "highly active" R-group will indeed confer such a high pIC50 are 0.729/(1-0.729) or almost 3 to 1. To confirm that virtual screening within large collections of realized structures would provide a useful quantity and variety of R-group suggestions, combining shape similarity with the "highly active" pIC50, the 50 searches provided by these 25 models were applied to 2.2 million structurally distinct R-group candidates among 2.0 million structures within a ZINC database, identifying an average of 5705 R-groups per search, with the highest predicted pIC50 combination averaging 1.6 log units greater than the highest reported pIC50s.     

Parallel iterative reaction path optimization in ab initio quantum mechanical/molecular mechanical modeling of enzyme reactions

The determination of reaction paths for enzyme systems remains a great challenge for current computational methods. In this paper we present an efficient method for the determination of minimum energy reaction paths with the ab initio quantum mechanical/molecular mechanical approach. Our method is based on an adaptation of the path optimization procedure by Ayala and Schlegel for small molecules in gas phase, the iterative quantum mechanical/molecular mechanical (QM/MM) optimization method developed earlier in our laboratory and the introduction of a new metric defining the distance between different structures in the configuration space. In this method we represent the reaction path by a discrete set of structures. For each structure we partition the atoms into a core set that usually includes the QM subsystem and an environment set that usually includes the MM subsystem. These two sets are optimized iteratively: the core set is optimized to approximate the reaction path while the environment set is optimized to the corresponding energy minimum. In the optimization of the core set of atoms for the reaction path, we introduce a new metric to define the distances between the points on the reaction path, which excludes the soft degrees of freedom from the environment set and includes extra weights on coordinates describing chemical changes. Because the reaction path is represented by discrete structures and the optimization for each can be performed individually with very limited coupling, our method can be executed in a natural and efficient parallelization, with each processor handling one of the structures. We demonstrate the applicability and efficiency of our method by testing it on two systems previously studied by our group, triosephosphate isomerase and 4-oxalocrotonate tautomerase. In both cases the minimum energy paths for both enzymes agree with the previously reported paths.     

Similarity searching in databases of three-dimensional molecules and macromolecules.

This paper discusses algorithmic techniques for measuring the degree of similarity between pairs of three-dimensional (3-D) chemical molecules represented by interatomic distance matrices. A comparison of four methods for the calculation of 3-D structural similarity suggests that the most effective one is a procedure that identifies pairs of atoms, one from each of the molecules that are being compared, that lie at the center of geometrically-related volumes of 3-D space. This atom mapping method enables the calculation of a wide range of types of intermolecular similarity coefficient, including measures that are based on physicochemical data. Massively-parallel implementations of the method are discussed, using the AMT Distributed Array Processor, that achieve a substantial increase in performance when compared with a sequential implementation on a UNIX workstation. Current work involves the use of angular information and the extension of the method to field-based similarity searching. Similarity searching in 3-D macromolecules is effected by the use of a maximal common subgraph (MCS) isomorphism algorithm with a novel, graph-based representation of the tertiary structures of proteins. This algorithm is being used to identify similarities between the 3-D structures of proteins in the Brookhaven Protein Data Bank; its use is exemplified by searches involving the NAD-binding fold motif.