Binding mode analysis of the NADH cofactor in nitric oxide reductase: a theoretical study

Nitric oxide reductase (Nor), a member of the cytochrome P450 superfamily, takes part in the denitrification process of fungi by reducing NO to N(2)O. Evidence indicates that Nor binds NADH, source of the reducing equivalents of the reaction, within its large hydrophilic ligand binding cavity on the distal side of heme and receives electrons directly from the cofactor. Here we present a binding mode analysis of the structure of the Nor-NO-NADH complex, performed in three steps. The NADH cofactor was first docked into the enzyme interior using the Monte Carlo multiple minimum algorithm, refined by low-mode conformational search and the final arrangement was obtained in a 5ns NPT molecular dynamics simulation. The NADH cofactor, in our results, is positioned--by Arg174, Lys291, Asp393 and several water molecules--within reactive distance of the NO binding spot suggesting a direct hydride shift mechanism between the two. The catalytically required water molecule is captured by NADH and the cofactor not only retains the suggested H-bonded proton transfer pathway between the active site and the solvent, but provides structural restraint for its members. We also found that direct interaction is formed between the cofactor and propionate A of the heme group, which flips from the proximal to the distal side of the heme plane in order to become an H-bonding partner of NADH. The role of Arg64 and Glu71 was suggested to be fixing the residues of the translocated helix B' to their new position.     

Long range molecular dynamics study of interactions of the eukaryotic glucosamine-6-phosphate synthase with fructose-6-phosphate and UDP-GlcNAc

Glucosamine-6-phosphate synthase (EC 2.6.1.16) is responsible for catalysis of the first and practically irreversible step in hexosamine metabolism. The final product of this pathway, uridine 5′ diphospho N-acetyl-d-glucosamine (UDP-GlcNAc), is an essential substrate for assembly of bacterial and fungal cell walls. Moreover, the enzyme is involved in phenomenon of hexosamine induced insulin resistance in type II diabetes, which makes of it a potential target for anti-fungal, anti-bacterial and anti-diabetic therapy.The crystal structure of isomerase domain from human pathogenic fungus Candida albicans has been solved recently but it doesn’t reveal the molecular mechanism details of inhibition taking place under UDP-GlcNAc influence, the unique feature of eukaryotic enzyme. The following study is a continuation of the previous research based on comparative molecular dynamics simulations of the structures with and without the enzyme's physiological inhibitor (UDP-GlcNAc) bound. The models used for this study included fructose-6-phosphate, one of the enzyme's substrates in its binding pocket.The simulation results studies demonstrated differences in mobility of the compared structures. Some amino acid residues were determined, for which flexibility is evidently different between the models. Importantly, it has been confirmed that the most fixed residues are related to the inhibitor binding process and to the catalysis reaction. The obtained results constitute an important step towards understanding of the inhibition that GlcN-6-P synthase is subjected by UDP-GlcNAc molecule.     

Identification of a potential proton donor to the linking oxygen atom in a three-metal ion assisted catalysis pathway catalyzed by Fructose-1, 6-bisphosphatase

In this paper, the dephosphorylation mechanism of FBP to F6P catalyzed by the Fructose-1, 6-bisphosphatase (St-Fbp) from Sulfolobus tokodaii was studied using quantum mechanical/molecular mechanical (QM/MM) approach. Based on the experimental results, total five possible catalytic mechanisms (path1-path4′) were designed. The most possible dephosphorylation reaction follows a two-step mechanism (path2): a dephosphorylation process (with D12 being an base of W6 and residue K133 being the proton donor of the linking FBP:O4) and a proton exchange process (between K133 and the water W1). Furthermore, the three-step of path4 is also possible: a dephosphorylation process (with D54 being the base of W6 and residue K133 being the proton donor of the linking FBP:O4) and two proton exchange processes (first between residues D54 and D12 then between K133 and the water W1). The relative low energy of this pathway suggests that D54 might also be a base except D12. Our calculations indicate that K133 is the preferred proton donor during the breaking of the phosphate bond O4-P1, with the W1 being an alternative proton donor to access to a more stable product. Findings here give a new insight into the understanding of catalytic mechanism of FBPase.     

Design of an interface peptide as new inhibitor of human glucose-6-phosphate dehydrogenase

Glucose-6-phosphate dehydrogenase (G6PDH) is an essential enzyme involved in the first reaction of the oxidative branch of the pentose phosphate pathway (PPP). Recently, G6PDH was suggested as a novel target protein for cancer therapy as one of the final products of the PPP, ribose-5-phosphate, is necessary for nucleic acid synthesis and tumor progression. After analyzing the protein–protein interface of the crystal structure of human G6PDH by means of molecular dynamics simulations, we designed six interface peptides based on the natural sequence of the protein. The three most promising peptides, as predicted by binding free energy calculations, were synthesized and one of them was confirmed as a novel inhibitor of human G6PDH in experimental assays. Together, the active peptide found and its suggested binding mode proposes a new strategy for inhibiting this enzyme and should aid the further design of novel, potent and non-peptidic G6PDH inhibitors.     

基于ARM的SF6中微水含量检测系统

介绍了一种以ARM处理器S3C44B0为核心、利用红外光谱原理对SF6气体中水分含量进行监测的实时在线检测系统。系统运用基于分子辐射吸收理论的红外检测技术,设计了探测水分的光电传感器;开发了以S3C44B0为核心,包括A／D转换模块、LCD液晶显示模块、基于串口的GPRS通信模块等在内的ARM中央硬件处理平台。与传统检测设备相比,该系统灵敏度高,重复性好,实时性强,是测量精度达到0．001％,是测量SF6气体中微水分含量的理想设备。     

Design of fructose-2,6-bisphosphatase inhibitors: a novel virtual screening approach

Fructose-2,6-bisphosphatase (FBPase-2) is a switch between gluconeogenesis and glycolysis in the hepatic cells. The structural features required for inhibitory activity of FBPase-2 were unidentified; no leads are available for inhibiting this important enzyme. In this paper pharmacophore mapping, molecular docking methods were employed in a virtual screening strategy to identify leads for FBPase-2. A receptor based pharmacophore map was modeled which comprised of important interactions as observed in co-crystal of rat liver isozyme with the product inhibitor fructose-6-phosphate. The pharmacophore model was validated against two databases of best docked structural analogues of fructose-2,6-bisphosphate and fructose-6-phosphate. The query generated was submitted for flexible search of ligands in chemical databases, namely LeadQuest, Maybridge and NCI. The hits obtained were further screened by molecular docking using FlexX.     

Thermus thermophilus木糖异构酶复合物模型的建立与分析

Thermus thermophilus木糖异构酶在高果糖浆的工业生产及木糖发酵重组菌的构建方面具有极其广阔的应用前景．本文主要运用结构分析和分子对接及计算软件,确定了Mg~2及木糖异构酶天然底物D-木糖在1BXB晶体结构中的定位,构建出1BXB复合物模型并进行评价与分析．通过对1BXB复合物模型1与1XIC的结构进行比较,发现所构建模型中D-木糖周围的残基在木糖异构酶中高度保守,并且D-木糖的定位与取向与1XIC中底物分子基本一致．     

精甲霜灵的电子结构及圆二色谱性质

采用量子化学密度泛函理论在B3LYP/6-311++G**水平上对精甲霜灵分子几何构型进行优化;在优化的基础上进行圆二色谱究。计算结果表明:(1)C(8)=O(9)与N(1)、C(3)=O(4)与O(5)之间均存在p—π共轭,N原子上另外2个取代基分别位于苯环上下方为最稳定构型。(2)VCD谱中,C(10)—H沿C(8)—C(10)—O(11)平面的摇摆振动在1020cm-1处存在正性康登效应;垂直于该平面的摇摆振动在1273cm-1处出现负性康登效应。C(2)原子上的C—H摇摆振动在的1334cm-1处存在强的康登效应。C(3)=O(4)在的1788cm-1处出现较强的吸收峰;C(8)=O(9)由于与手性中心的间隔一个N原子,其在VCD谱中未出现康登效应。(3)甲醇溶液中的理论ECD谱,228nm处存在正性康登效应,与实验值符合较好;同时,理论计算还预测标题化合物在201nm处存在负性康登效应。     

Simulation of geometrical and electronic structure of quasi-two-dimensional layer consisting of fullerenes D6h-C36

This article describes a computer simulation of the geometrical and electronic structure of a quasi-two-dimensional carbon layer with a trigonal lattice consisting of fullerenes C36 (1) with topological symmetry D6h. Every polyhedral cluster 1 of this polymeric layer (2) is surrounded by six similar fullerenes and connected with every such a fullerene by two covalent bonds. Atomic coordinates of the repeating unit are estimated on the basis of MNDO/PM3 calculations of hydrocarbon molecule (D6h)-C132H48 (3). The carbon skeleton of 3 coincides with a sufficiently large fragment of the polymeric layer 2. The electronic spectrum of the quasi-two-dimensional layer 2 is calculated by the crystalline orbital method in the EHT approximation. The band gap in the electronic spectrum of 2 was found to be equal to 1.5 eV. The geometric and electronic structure of some oligomers of cluster C36, quasi-linear macromolecule [C36]n, and "hypergraphite" layer is also discussed.     

Structure and dynamics of the GH loop of the foot-and-mouth disease virus capsid

The GH loop of VP1 of the foot-and-mouth disease virus capsid is important because it is a major antigenic site and an integrin recognition site. The GH loop is disordered in all X-ray structures of the capsid except for serotype O under reduced conditions in which the loop lies on the capsid surface. Although the structure of the capsid–integrin complex has not yet been determined, the GH loop is known to protrude from the capsid surface when the capsid is bound with an antigen-binding fragment (Fab). To clarify the structure and dynamics of the GH loop under natural unreduced conditions before binding to integrins or Fab fragments, we performed molecular dynamics simulation of 16.3 ns long under rotational symmetry boundary conditions for the capsid of serotype O using the X-ray structure of the reduced capsid for the initial coordinates. When the disulfide bond at the base of the GH loop was formed by the molecular mutation method, the loop protruded into the surrounding water, as reported for Fab–capsid complexes, and fluctuated like a tentacle. After equilibration, the GH loop overlapped the surface of the capsid but continued to fluctuate, being directed toward a 2-fold axis. The conformational change of the GH loop after formation of the disulfide bond was explained by a model of elastic tube. The side chains of arginine and aspartic acid of the integrin recognition residues (RGD tripeptide) extended in opposite directions, and the residues on the C-terminal side of the RGD tripeptide formed a hydrophobic cluster in close proximity of the arginine residue of the tripeptide.     

Structural modeling and docking studies of ribose 5-phosphate isomerase from Leishmania major and Homo sapiens: A comparative analysis for Leishmaniasis treatment

Leishmaniases are caused by protozoa of the genus Leishmania and are considered the second-highest cause of death worldwide by parasitic infection. The drugs available for treatment in humans are becoming ineffective mainly due to parasite resistance; therefore, it is extremely important to develop a new chemotherapy against these parasites. A crucial aspect of drug design development is the identification and characterization of novel molecular targets. In this work, through an in silico comparative analysis between the genomes of Leishmania major and Homo sapiens, the enzyme ribose 5-phosphate isomerase (R5PI) was indicated as a promising molecular target. R5PI is an important enzyme that acts in the pentose phosphate pathway and catalyzes the interconversion of d-ribose-5-phosphate (R5P) and d-ribulose-5-phosphate (5RP). R5PI activity is found in two analogous groups of enzymes called RpiA (found in H. sapiens) and RpiB (found in L. major). Here, we present the first report of the three-dimensional (3D) structures and active sites of RpiB from L. major (LmRpiB) and RpiA from H. sapiens (HsRpiA). Three-dimensional models were constructed by applying a hybrid methodology that combines comparative and ab initio modeling techniques, and the active site was characterized based on docking studies of the substrates R5P (furanose and ring-opened forms) and 5RP. Our comparative analyses show that these proteins are structural analogs and that distinct residues participate in the interconversion of R5P and 5RP. We propose two distinct reaction mechanisms for the reversible isomerization of R5P to 5RP, which is catalyzed by LmRpiB and HsRpiA. We expect that the present results will be important in guiding future molecular modeling studies to develop new drugs that are specially designed to inhibit the parasitic form of the enzyme without significant effects on the human analog.     

光盘镜像服务器的Cache技术研究与实现

本文提出了一种基于光盘镜像服务器系统的两级Cache结构，即在客户端建立一个小的Cache，通过预取机制增大一次请求的规模；同时，在服务器端设计一个大的Cache，加快数据请求的响应速度。实验证明，两级Cache结构大大提高了光盘镜像服务器系统的数据传输率。     

Chemical fragmentation in quantum mechanical methods

We give a survey on the application of the chemical fragmentation concept in computer modelling of extended covalent systems. It will be stressed that information on molecular topology, as well as location and composition of the reaction centre allows the construction of a reasonable initial guess for the wave function and thus facilitates the solution of the Schr?dinger equation. For systems, where the chemical changes are localised to a few atoms, while others play the role of essentially electrostatic perturbation, a partition into active site and environment is possible providing a background to hybrid quantum mechanical/molecular mechanical (QM/MM) methods. Full molecular orbital treatment of large covalent systems at the minimal basis, semiempirical level becomes possible in the frame of the fragment self-consistent field (FSCF) method which was developed in the past two decades in our laboratory. As an application, we discuss the hydride shift reaction step in xylose isomerase catalysis.     

1H与13C NMR谱图模拟程序

介绍由二维化学结构模拟＾１Ｈ和＾１３Ｃ谱图技术及软件。用户可通过用户界面调用ＩＳＩＳ／Ｄｒａｗ输入二维分子结构,通过运行谱图模拟程度得到化学位移和相应的Ｈ和＾１３Ｃ模拟谱图。这项工作有计算机辅助结构解析的热点,同时是结构解析系统所必须的基础工作     

Multi-isotopic modelling of mass spectra: a procedure for verification of the fragmentation hypothesis for the organometallic and coordination compounds

Interpretations of mass spectra usually depend on explanations of the molecular structure by determination of the fragmentation ions structures. Therefore, identification of fragmentation ions formulas is an initial step of such investigations. It seems that multi-isotopic modelling of all ions proposed in fragmentation data should lead to the theoretical mass spectrum. Good adjustment of experimental and predicted spectra proves the validity of the fragmentation table, whose contents are recognised as fragmentation hypothesis. This means that multi-isotopic modelling is a helpful tool for verification of proposed fragmentation data. Applications of the method are presented for 1,1',2,2',3,3'-hexachloro-ferrocene, C10H4Cl6Fe, and bis(dibutyldithiophosphate)-zinc(II), [(C4H9O)2PS2]2Zn.     

基于二维码的数据传输系统设计

基于二维码的数据传输系统面向涉密场景,旨在实现涉密信息系统之间的自动数据传输。文中设计了涉密信息系统之间的数据通信流程,即发送端将传输数据按二维码帧容量切分为多帧,按序合成并显示二维码图像序列,接收端使用摄像头等设备采集二维码图像信息,合成传输数据,并按预定规则对接收情况进行反馈,完成收发两端之间的数据通信。与现有采用人工交互或安全铰链设备的方案相比,基于二维码的数据传输系统解决了自动化程度低、传输效率低、设备昂贵等问题,实现了网络隔离条件下自动高效的数据传输,适用于涉密信息系统中具有较高时效性要求的信息交互。     

面向UMPC的北大众志-SK系统芯片设计

如何更好地满足3C融合的需求,是超便携个人计算机(UMPC)普及的关键.北大众志-SK系统芯片,将传统个人计算机中分布在主板上的中央处理器、北桥与南桥芯片组、显示控制器和其它输入输出控制设备等众多芯片的功能集成到单一芯片中.该系统芯片采用2D/3D扩展指令、软硬协同视频解码加速部件、硬件视频编解码等方式,在高效完成多媒体处理的前提下,有效降低了对中央处理器性能的需求.通过在单芯片内部实现多层次的存储架构,简化了数据的传输路径,提高了数据传输的效率,从而提高系统性能.此外,在该系统芯片中还实现了众多主流的输入输出接口控制部件,以满足个人计算机的日常应用需求.该设计达到了高集成度、高性能、低功耗的设计目标,提供了面向教育、电子政务和个人信息处理等领域的低成本、低功耗、易使用、便于维护的UMPC解决方案.     

链烷烃分子结构设计(I)分子构成基团的确定

以链烃一阶分子连接性指数及其与状态方程参数的关系为基础，利用神经元网络预测与之对应的。然后根据、确定分子结构的路径指数并将其转换为与分子结构，构成基团相关的顶点度数，从而确定构成基团的种类与个数。     

钠离子在分子筛合成中的结构导向作用的分子模拟研究

利用分子力学和分子动力学计算工具,对钠离子的各种水合结构及能量进行了分子力学和动力学的计算,以此研究水合钠离子所起的结构生成剂的作用.用Monte Carlo Docking方法对各种结构的水合钠离子在MFI分子筛微孔结构内的附着行为模拟计算.结果表明,配位数为偶数时水合阳离子的结构较为合理,这种合理性体现在当配位数为偶数时,Na-+nH2O体系中金属离子的位置与氧原子的位置呈现对称结构,Na-+4H2O和Na-+6H2O是相对比较合适的结构;对于钠离子,配位数为4和6,当配位数大于6时,体系将自动转为6配位的情况;钠离子明显具有对周围的水分子结构进行重新排列的作用;钠离子的配位水分子数为4个或6个,而4配位结构是水合钠离子的主要存在方式之一;在MFI结构分子筛的合成中起模板剂作用的应该是Na-+4H2O结构;计算结果对分子筛合成研究中水合离子的结构生成和结构破坏具有重要的意义.     

二聚有机锡配合物[（n-Bu）2Sn（H2O）C5H3N（CO2）2]2的合成、结构和量子化学研究

吡啶-2,6-二甲酸与(n-Bu)2SnO反应合成标题化合物,并经元素分析、IR和X-射线衍射表征,该配合物晶体属四方晶系,空间群P42/n,晶胞参数:a=1.77103(6)nm,b=1.77103(6)nm,c=1.11717(7)nm,α=90°,β=90°,γ=90°,V=3.5041(3)nm3,Z=4,Dc=1.577g/cm3,μ(MoKα)=1.479mm-1,F(000)=1680andR1=0.0329,wR2=0.0852[对I>2σ(I)的衍射]和R1=0.0428,wR2=0.0937(对所有的衍射)。共收集12600个数据,其中独立衍射点3431个,可观察衍射[I>2σ(I)]点2723个用于结构精修。中心Sn原子形成七配位变形十面体,分子间通过氧原子的氢键作用形成三维网络结构。利用量子化学G98W软件,在Lanl2dz基组对化合物的稳定性、前沿分子轨道组成及能量进行研究。