Characterization of the farnesyl pyrophosphate synthase of Trypanosoma cruzi by homology modeling and molecular dynamics

Chagas' disease, caused by the Trypanosoma cruzi parasite, is one of the largest public health problems in the Western hemisphere, with 16-18 million people infected, and approximately 100 million people at risk. Many efforts towards the development of targeted antiparasitic agents have recently been described. Of interest, bisphosphonates, pyrophosphate analogs in which the oxygen bridge between the two phosphorus atoms has been replaced by a carbon substituted with different side chains, are able to inhibit the growth of T. cruzi. The enzyme T. cruzi farnesyl pyrophosphate synthase (TcFPPS) involved in the mevalonate pathway, has been recently identified as the target of bisphosphonates. The protein has 362 amino acids and a molecular mass of 41.2 kDa. Several sequence motifs found in other FPPSs are present in TcFPPS. In this study we have modeled the structure of TcFPPS based on the structure of the avian FPPS. We have characterized the interaction with its substrates, isopentyl pyrophosphate and dimethylallyl pyrophosphate, and the mechanism of inhibition by the potent bisphosphonate risedronate (K(i) of 0.032+/-0.002 microM) by means of molecular dynamics techniques. We propose that homorisedronate, which has an extra methylene and a K(i) of 8.17+/-1.36 microM, does not form strong hydrogen bonds with TYR 211 and THR 208, which may be responsible for its lower activity as compared to risedronate. Moreover, we were able to reproduce the structural changes that occur upon the binding of the third Mg2+ to the active site of the protein. Taken together, our results provide a structural model for the design of novel inhibitors that may prove useful for the treatment of Chagas' disease.     

MOLMAP指数生成及其在化学反应分类和反应性预测中的应用

分子MOLMAP指数是通过递交一个分子中所有化学键描述符到Kohonen自组织映射,基于一个特定的算法所生成,其中Kohonen自组织映射已经预先由多种类型化学键所衍生的描述符进行了训练。化学键描述符由化学键的物理化学性质或(和)拓扑性质组成。MOLMAP指数是一个基于化学键类型的分子指数。若2个描述符相似的化学键激活同一个Kohonen自组织映射神经元,则2个化学键为同一类型。进一步,采用反应物与生成物的MOLMAP指数差异性描述化学反应,衍生了化学反应的MOLMAP指数。此指数能够在没有参与化学反应的化学键信息的情况下进行化学反应的相关研究,因而能够广泛地应用。本文从3个方面概述了MOLMAP指数的应用:1)在化学反应分类中的应用,例如:预测生物代谢反应分类;2)在化学反应性预测中的应用,化学反应性是指与化学反应有关的性质,例如:预测物质的变异性和抗氧化性;3)在三维数据处理中的应用,是基于MOLMAP指数算法进行的扩展,例如:预测氯酚类化合物的毒性。     

WorkSpace and the study of Chagas' disease

Chagas' disease afflicts more than 18 million people throughout South and Central America. Some areas of North America have also seen an increased incidence in recent years. The Trypanosoma cruzi (T. cruzi) parasite, which causes the disease, is most often transmitted by Triatomid bugs living in close proximity to humans. The T. cruzi parasite depends heavily on a small molecule called trypanothione to protect itself against damage from free radicals produced during normal metabolism. The concentration of trypanothione in the cell is carefully maintained by an enzyme called trypanothione reductase (TR). Drugs that inhibit TR should cause the parasite to die. Human cells have a similar enzyme-substrate pair: glutathione and glutathione reductase (GR). Fortunately, the enzyme GR differs electrostatically from TR, so there is hope of developing a drug that will be safe for human cells. The molecular structures of both TR and GR are known from ongoing X-ray crystallography studies. Both enzymes are dimers, that is, they consist of two equivalent domains, each having its own active site (the place where glutathione or trypanothione binds). One surprising feature of this system is a long tunnel passing through the center of the dimer and connecting the active sites of the two domains. While this is a naturally interesting feature to explore in a VR environment, the goal of the research is to evaluate the binding ability of particular drugs. For purposes of early testing, we chose chlorpromazine, an antidepressant drug. Large doses of the drug are known to kill the parasite, but are also toxic to the human host. It is possible that minor structural changes to this molecule would improve the selectivity and potency of the drug. For purposes of testing our VR environment, we present only a token calculation on chlorpromazine     

互信息在图像检索中的应用

介绍了一种用互信息来衡量相似性图像检索方法.该方法首先生成一种在统计上有代表性的视觉模式,使用这种模式的分布作为图像内容的描述符;基于该内容描述,设计了其互信息的计算方法以衡量图像的相似性.实验结果表明,在图像检索中,相对于其它如KL散度和L2规范等方法,互信息是一种更为有效的衡量相似性的方法.     

无机含氧酸pK1的定量构效关系(QSPR)研究

采用Tomasi的极化统一模型对20种无机含氧酸HnROm在水相条件下进行从头算,选取14个量化参数结合含氧酸非羟基氧原子数等2个重要结构参数对含氧酸pK1进行逐步回归,引入非羟基氧原子数No、非羟基氧原子将电荷数NCo、羟基氢原子将电荷数NCH(O)和氢氧间的重叠布居数POPR-O(H)4个参数建立QSPR方程,方程相关系数R为0.9946,且有F＞Fa,表明方程回归效果显著,对回归系数的双边t检验结果均有 P＜0.05,表明此4个参数对pK1影响显著.对引入参数的物理意义及其对含氧酸pK1的影响分析表明,此4个参数均与羟基氧原子电子密度相关;其中NCH(O)和NO是影响含氧酸强度的主要因素,且NCH(O)的影响更大;NCO和POPR-O(H)则是影响含氧酸强度的次要因素,可用于区分各含氧酸强度的细微差别.此外,将 NCH(O)、POPR-O(H)m用于对35种酸碱进行分类也获得了良好的效果,表明此2个参数可用于区分R-O-H的电离方式.     

用量子化学参数预测烯烃聚合物热容变化

在B3LYP/6-31G(d)水平上对烯烃聚合物单体进行密度泛函理论计算,得到2个量子化学参数,即分子的等容摩尔热容(Cv)和偶极矩(μ),并用来预测烯烃聚合物在玻璃化转变温度的热容变化(Cp,change).从训练集用逐步线性回归方法得到的、物理意义非常明确的结构与性能定量关系模型由测试集进行检验.预测值与实验值的相关系数为0.937.这结果表明由这些量子化学参数所建立的关于性能Cp,change的定量关系模型能用于聚合物Cp,change值的预测,这也证明了量子化学参数能在聚合物结构与性能定量关系研究中能起重要作用.     

区域高斯描绘子及其在物体识别中的应用

为了对几何变形的图像进行正确和有效的识别,对基于物体轮廓的高斯描绘子进行推广,构造了一种基于区域的新的不变量--区域高斯描绘子.构造思路主要有两点:①定义一个具有平移、尺度不变性的函数--区域高斯势函数;②分别计算区域高斯势函数在8个同心圆上的平均值,从而获得8个不变量.这些不变量不仅具有平移、旋转、尺度和反射不变性,而且对噪声不敏感,适用范围广.将区域高斯描绘子应用于物体识别,获得很高的识别率.