高氯酸锂-乙酰胺新型二元熔盐电解质的谱学研究

高氯酸锂与乙酰胺在适宜摩尔配比范围内可形成热稳定性良好、电化学性能优良的室温熔盐.从分析LiClO4与乙酰胺形成熔盐的作用机制出发,通过红外、拉曼光谱的谱学分析并应用非局部密度泛函理论方法进行量化计算对二者的相互作用进行了讨论.发现乙酰胺通过Li－O键与LiClO4中的Li＋配位而破坏了LiClO4的离子键,形成很大的配位阳离子,削弱了阴阳离子间的库伦作用力;同时Li－O也导致乙酰胺分子间的氢键断裂,因而体系的共熔温度较之纯物质熔点显著降低,部分样品室温下以液体状态稳定存在.     

高氯酸锂与1,3-氮氧杂环-戊-2-酮形成的二元熔盐电解质

制备了高氯酸锂(LiClO4)与1,3-氮氧杂环-戊-2-酮(OZO)形成的二元熔盐电解质, 虽然先导物具有较高的熔点, 但二者可形成均一、稳定的共熔体系, 测试结果表明该熔盐体系具有低的共熔温度(-50 益). 红外光谱分析表明OZO 通过Li—O 键与LiClO4中Li+配位而破坏了LiClO4的离子键,形成很大的配位阳离子,削弱了阴阳离子间的库伦作用力; 同时Li—O 配位也导致OZO 分子间的氢键断裂, 因而体系的共熔温度较之纯物质熔点显著降低, 部分样品室温下以液体状态稳定存在. 采用交流阻抗法和循环伏安法对其电化学性质进行研究, 结果显示, 配比n(LiClO4):n(OZO)=1:4.5 的样品室温(25 ℃)电导率为0.66×10^-3 S·cm^-1, 80 ℃电导率为7.33×10^-3 S·cm^-1; 其电化学稳定电位窗口约为3.5 V.     

铜离子(II)与Ab多肽形成可溶性配合物结构的理论研究

大脑中淀粉样Cross-β纤维沉淀是老年痴呆症(AD)的一个关键性病理特征. X射线分析显示有大量Cu^2＋和Zn^2＋集中到患者的大脑中, 暗示了这些失调的离子与AD疾病有关. 实验发现, 在适度酸性pH值下, Cu^2＋与组氨酸咪唑环上的Nt配位可诱导Ab多肽聚合成沉淀, 而在中性pH值下, Cu^2＋与组氨酸咪唑环上的Np及主链上的去质子N或O配位生成可溶的配位化合物. 本文应用密度泛函理论(B3LYP)方法, 研究了Cu^2＋与Ab多肽中的四肽(HHQK)形成可溶性配合物的结构, 结果得到N(3)O(1)及N(4)O(1)两类配位方式, 其中以N(3)O(1)配位形成变形的平面正方形配位结构, 而以N(4)O(1)配位形成变形的四方锥结构. 由于分子内氢键的形成, 优化得到了6个不同的结构, 通过能量对比找到了最稳定的结构, 并深入探讨了最稳定结构的原子电荷布居规律、一些前沿分子轨道以及配合物的振动光谱, 在振动光谱方面, 理论与实验符合得很好.     

单核Zn(Ⅱ)/Ni(Ⅱ)含氮配体配合物的合成、晶体结构及性质

合成了2个新的配合物[Zn(BPP)2(H2O)4](2,6-NDS)·0.5H2O(1)和[Ni(phen)2(H2O)2](A-2,5-DSA)·3H2O(2)(2,6-NDS=2,6-萘二磺酸根,A-2,5-DSA=苯氨-2,5-二磺酸根,BPP=1,3-二(4-吡啶基)丙烷,phen=1,10-邻菲咯啉),用X-射线单晶衍射结构分析方法测定了配合物的晶体结构。配合物1是单核分子,Zn2+离子与2个1,3-二(4-吡啶基)丙烷的2个N原子及4个水分子配位,形成单核配位阳离子。相邻配位阳离子通过配位水分子与氮原子的氢键作用联接成一维双螺旋阳离子链。双螺旋阳离子链与未配位的2,6-萘二磺酸根阴离子通过氢键作用形成二维超分子网。配合物2是单核分子,Ni2+离子与2个1,10-邻菲咯啉分子中的4个N原子及2个水分子配位,形成单核配位阳离子。配位阳离子与游离的水分子及苯氨-2,5-二磺酸根阴离子通过氢键作用构筑成二维超分子网。     

含有二维有序水层的癸二酸锌(Ⅱ)、钴(Ⅱ)超分子配合物的构筑

室温下,在醇水溶液中合成了2个新型配合物,[Zn(phen)3]2·[Zn(C10H16O4)·(H2O)3]·(C10H16O4)2·20H2O(C10H18O4=癸二酸)(1)和[Co(phen)3]2·[Co(H2O)6]·(C10H16O4)3·30H2O(2),并对配合物进行了元素分析分析、红外光谱分析、热重分析以及晶体结构研究.配合物(1)的基本结构单元中含有一个电中性配位单元[Zn(C10H16O4)·(H2O)3]、二个配位阳离子[Zn(phen)3]2+、二个游离的癸二酸根和20个晶格水.Zn原子有两种配位模式,在[Zn(phen)3]2+配位单元中Zn原子与三个邻菲啰啉的六个N原子配位,构成略有畸变的八面体,Zn原子位于八面体的对称中心;在[Zn(C10H16O4)·(H2O)3]配位单元中Zn原子采取五配位的三角双锥构型,两个羧基均采取单齿配位,同一个癸二酸根与相邻的不同Zn原子配位,将相邻的[Zn(C10H16O4)·(H2O)3]配位单元连接起来,自组装得到了无限链状结构.配合物以癸二酸根为模板在ab平面形成了有序水层,该水层由5元,6元水簇,以及其他由羧基参与的各元环组成.与一般常见的6元水簇不同,配合物1中的6元水簇采取了高能量的类似苯环的平面构象.配合物(2)的基本结构单元中含有一个[Co(H2O)6]2+配位阳离子、二个[Co(phen)3]2+配位阳离子、三个游离的癸二酸根和30个晶格水.Co原子也有两种配位模式.在[Co(phen)3]2+配位单元中,Co原子与三个邻菲啰啉的六个N原子配位,构成略有畸变的八面体,Co原子位于八面体的对称中心.在[Co(H2O)6]2+配位单元中Co(II)与6个配位水的氧原子配位,6个配位水中的6个原子和Co(Ⅱ)形成八面体结构.通过水分子之间及水分子和羧基阴离子间的氢键形成了二维有序水层,二维水层中最小的构筑基元为6元环的水,最大的构筑基元为16元环水,每个水环中分别含有6个和16个游离的没有配位的水分子,水分子之间通过很强的氢键作用形成环形的超分子水簇.这些基元片断在二维空间扩展开来,形成二维有序水层.有趣的是,在该水层上通过水分子之间的分子间氢键形成了16元大环水簇,它与两端的六元环共用六条边,每一个16元水环中含有16个游离的没有配位的水分子,水分子之间通过氢键作用形成环形超分子水簇,每个水分子同时作为氢键的给体和受体.[Co(H2O)6]2+和四个羧酸根离子位于十六元环水的中心,与其周围的游离水分子形成了十二个氢键,同时与环外的游离水和羧酸根形成了十个氢键,对大环水聚集体起到稳定作用.     

含有机胺的柔性配位聚合物: 热活化, 结构转变及质子转移

配体均苯三甲酸与醋酸镉或醋酸锌的溶剂热反应得到两个分子式分别为(Me₂NH₂)[Cd(btc)]-DMA (1)和(Me₂NH₂)[Zn(btc)]-DMF (2) (H₃btc, DMA和DMF分别代表均苯三甲酸, N,N-二甲基乙酰胺和N,N-二甲基甲酰胺)的化合物. 两个化合物都是具有金红石拓扑的三维骨架结构. 其骨架由6连接的二聚金属单元和3连接的配体btc3?连接而成, 溶剂分子和抗衡阳离子占据在骨架内的一维孔道中. 不过,两个化合物中金属原子与配体羧酸基团的配位形式存在细小的差别. 在1中, 每个镉原子与五个羧酸氧原子配位, 每个btc^3-配体通过两个双齿羧基和一个单齿羧基参与配位. 孔道中的抗衡阳离子二甲铵与一个配位的羧酸氧原子形成氢键. 对于2, 每个锌原子与四个羧酸氧原子配位, 每个btc^3-配体通过一个双齿羧基两个单齿羧基参与配位. 孔道中的二甲铵抗衡阳离子与一个未配位的羧酸氧原子形成氢键. 这一细小的结构差别导致了两个化合物骨架截然不同的柔性. 变温粉末X射线衍射研究表明1的骨架在180 °C下已经坍塌, 而2在380 °C以下却经历两次结构转变. 结合热重分析结果我们推测这两次结构转变是分别由于溶剂分子和抗衡阳离子的移除导致的. 热重红外联用光谱研究进一步表明, 在60~210 °C下, 溶剂分子DMF被移除, 得到对应分子式为(Me₂NH₂)[Zn(btc)]的相2a, 而在 210~340 °C之间, 二甲铵抗衡阳离子以二甲胺分子形式被移除, 得到对应分子式为[Zn(Hbtc)]的2b物相. 这些结果证实了上述推测. 由于二甲铵抗衡阳离子是以二甲胺分子形式被移除的, 这一过程中必然存在一个质子转移过程. 我们分别对2, 2a和2b的样品进行了红外光谱研究, 结果显示2a与2的IR光谱除了部分强度差异基本相象. 然而, 在2b的红外光谱上1710 cm^-1处却出现一个新的吸收峰, 这是典型质子化的羧酸基团峰. 这一结果明确地证明抗衡阳离子二甲铵在被移除的时候其质子转移到了骨架上btc^3-配体的羧酸氧原子上. 2比1呈现出的更好柔性可能归因于其结构特征. 如前文所述, 在2中, 每个btc^3-配体的三个羧酸基团有两个是通过单齿的形式与锌原子配位. 相对比1而言, 这可能赋予2更多在结构转变上的优势. 此外, 在2中, 抗衡阳离子二甲铵附近有一个与其形成氢键的未配位羧酸氧原子. 与配位的氧原子相比, 未配位的应该更电负性, 更容易接受质子. 因此, 这个包括质子转移过程的结构转换所需要的能垒可能相对低一些, 最后导致在这一过程中2的骨架没有被破坏. 另外, 由于1和2结构中含有孔道以及孔道中可能存在质子传导路径, 我们也对两个化合物吸附和质子导电性质进行了研究及讨论.     

1-乙基-3-甲基咪唑阳离子与天冬酰胺阴离子的相互作用

利用密度泛函理论B3LYP方法, 在6-311+G(d,p)水平上, 对1-乙基-3-甲基咪唑阳离子[Emim]+与天冬酰胺阴离子[Asn]-形成的氨基酸离子液体气态阴阳离子对([Emim][Asn])进行理论研究. 通过几何结构优化和频率分析得到势能面上的五个稳定构型. [Emim]+和[Asn]-之间能够形成较强的氢键相互作用, 零点能校正后的能量在-373.96至-326.28 kJ·mol-1之间. 其稳定化能主要来源于[Asn]-中羰基O的孤对电子lp(O)与[Emim]+中C—H反键轨道σ*(C—H)之间的相互作用: lp(O)→σ*(C—H). 红外光谱特征和自然布居分析(NPA)计算表明咪唑阳离子中参与形成氢键的C—H键振动的红移值、阴阳离子间的电荷转移与氢键相互作用能成正比关系. 分子中的原子(AIM)理论分析得到[Emim]+和[Asn]-之间的氢键相互作用以静电作用为主. 通过计算结果初步探讨影响氨基酸离子液体玻璃化温度Tg的结构因素.     

光敏离子载体丹磺酰基-单氮杂-18-冠-6的阳离子识别性质研究

以DNS－MAC（O5）为主体,利用其荧光性质研究了该物质在乙腈和水溶液中对阳离子Li^ ,Na^ ,K^ ,Mg^2 ,Ba^2 和Pb^2 的识别性质,由改进的B－H方程计算了主－客体配合物的稳定常数和识别敏感因子,结果表明,阳离子的电荷密度和阳离子与冠醚环空间的匹配程度是影响其识别性质的最重要的两个因素,DNS－MAC（O5）与阳离子配位时荧光光谱的变化主要受迭于阳离子的电荷密度,阳离子与DNS－MAC（O5）配位时不仅使这种离子载体的偶极矩增大,而且更有利于其实现光谱导分子内的电荷转移,所以激发态稳定性增加,荧光光谱红移,同时测定也该发光离子载体在乙腈和水中的荧光量子产率。     

碱基腺嘌呤与多肽酰胺间氢键作用的最佳位点

正确理解核酸碱基和蛋白质多肽间的作用机制有助于人们利用这些生物分子有效地进行分子设计,进而制备具有特殊纳米结构和功能的生物分子材料.本文优化得到了碱基腺嘌呤与N-甲基乙酰胺、甘氨酸二肽、丙氨酸二肽形成的20个氢键复合物的结构并计算了结合能,探讨了腺嘌呤与多肽酰胺间氢键作用的最佳位点.研究发现:腺嘌呤可以使用两个不同位点(A1位点和A2位点)与N-甲基乙酰胺形成N―H…N型或者N―H…O=C型氢键复合物,腺嘌呤使用A1位点与N-甲基乙酰胺形成的N―H…N型氢键复合物更稳定;二肽分子可以使用主链上两个不同位点(丙氨酸的Ala7位点和Ala5位点或者甘氨酸的Gly7位点和Gly5位点)与腺嘌呤形成含有N―H…N和N―H…O=C两条氢键的复合物,二肽分子使用Ala7或Gly7位点与腺嘌呤形成的氢键复合物更稳定;腺嘌呤与多肽间的氢键作用强于其与N-甲基乙酰胺的作用.基于分子中的原子理论与自然键轨道计算结果分析了氢键作用的本质.     

新型1,10-菲罗啉铅配合物的合成、晶体结构及性质研究

1,10-菲罗啉与Pb(NO3)2反应合成了一种新型配合物C24H16N6O6Pb(1),其结构通过元素分析、红外光谱及X-射线单晶衍射等手段进行了表征。晶体结构解析表明,1属单斜晶系,空间群P21/n,晶胞参数为a=16.692(8),b=7.738(4),c=18.133(9),β=98.179(5)o,V=2318(2)3,Z=4,Dc=1.981 g/cm3,Mr=691.62,μ=7.332 mm-1,F(000)=1328,R1=0.0290,wR2=0.0629。1的不对称单元中含有1个Pb(II)原子,2个配位1,10-菲罗啉分子,1个配位硝酸根阴离子和1个游离硝酸根阴离子组成。中心Pb(II)的配位数为6,分别与来自于2个配位1,10-菲罗啉分子的4个氮原子和1个硝酸根离子的2个氧原子配位,以金属离子为中心形成了扭曲五角锥结构的配位几何构型,化合物分子之间通过π-π堆积作用形成了三维超分子结构。应用荧光光谱研究了该配合物与牛血清蛋白(BSA)分子间的相互作用,结果表明金属(Pb2+)配合物对BSA有较强的荧光猝灭作用,其相互作用导致的荧光猝灭为混合猝灭。     

Discovery of Anti-SARS Coronavirus Drug Based on Molecular Docking and Database Screening

The active site of 3CL proteinase (3CL^por) for coronavirus was identified by comparing the crystal structures of human and porcine coronavirus. The inhibitor of the main protein of rhinovirus (Ag7088) could bind with 3CL^pro of human coronavirus, then it was selected as the reference for molecular docking and database screening. The ligands from two databases were used to search potential lead structures with molecular docking. Several structures from natural products and ACD-SC databases were found to have lower binding free energy with 3CL^pro than that of Ag7088. These structures have similar hydrophobicity to Ag7088. They have complementary electrostatic potential and hydrogen bond aeceptor and donor with 3CL^pro, showing that the strategy of anti-SARS drug design based on molecular docking and database screening is feasible.     

Virtual screening of novel noncovalent inhibitors for SARS-CoV 3C-like proteinase

The SARS coronavirus 3C-like proteinase is considered as a potential drug design target for the treatment of severe acute respiratory syndrome (SARS). Owing to the lack of available drugs for the treatment of SARS, the discovery of inhibitors for SARS coronavirus 3C-like proteinase that can potentially be optimized as drugs appears to be highly desirable. We have built a "flexible" three-dimensional model for SARS 3C-like proteinase by homology modeling and multicanonical molecular dynamics method and used the model for virtual screening of chemical databases. After Dock procedures, strategies including pharmocophore model, consensus scoring, and "drug-like" filters were applied in order to accelerate the process and improve the success rate of virtual docking screening hit lists. Forty compounds were purchased and tested by HPLC and colorimetric assay against SARS 3C-like proteinase. Three of them including calmidazolium, a well-known antagonist of calmodulin, were found to inhibit the enzyme with an apparent K(i) from 61 to 178 microM. These active compounds and their binding modes provide useful information for understanding the binding sites and for further selective drug design against SARS and other coronavirus.     

SARS冠状病毒主要蛋白酶二聚体静电和疏水效应的研究

从三种冠状病毒主要蛋白酶SARS 3CL, HCoV 3CL和TGEC 3CL蛋白酶结构出发,着重研究了三种蛋白酶二聚体单体之间的静电和疏水相互作用.用连续介质模型有限差分方法计算得到三种蛋白二聚体界面处的静电势,发现三种蛋白酶单体和单体之间静电势分布具有明显的互补性,三种蛋白酶二聚体单体之间具有相同的静电相互作用能.用溶剂可及表面积模型分析了分子表面积及疏水性,发现三种蛋白酶具有相同的疏水分布,其中SARS 3CL蛋白酶疏水率为74%,驱动其单体聚合成二聚体.对三种蛋白酶的去溶剂化能疏水项的计算表明,三种蛋白酶二聚体单体之间具有相似的疏水相互作用能.     

Comprehensive structural analysis of the open and closed conformations of Theileria annulata enolase by molecular modelling and docking

Theileria annulata is an apicomplexan parasite which is responsible for tropical theileriosis in cattle. Due to resistance of T. annulata against commonly used antitheilerial drug, new drug candidates should be identified urgently. Enolase might be a druggable protein candidate which has an important role in glycolysis, and could also be related to several cellular functions as a moonlight protein. In this study; we have described three-dimensional models of open and closed conformations of T. annulata enolase by homology modeling method for the first time with the comprehensive domain, active site and docking analyses. Our results show that the enolase has similar folding patterns within enolase superfamily with conserved catalytic loops and active site residues. We have described specific insertions, possible plasminogen binding sites, electrostatic potential surfaces and positively charged pockets as druggable regions in T. annulata enolase.     

静电和疏水效应对SARS冠状病毒3CL蛋白酶二聚体稳定性的影响

从TGEV3CL蛋白酶二聚体结构出发,研究了TGEV3CL蛋白酶二聚体单体之间的静电和疏水相互作用.蛋白质的静电相互作用通过有限差分方法求解Poisson-Boltzmann方程得到,疏水相互作用通过分析溶剂可及性表面模型得到.考察了不同pH值对SARS3CL蛋白酶二聚体静电和疏水相互作用的影响,在pH=5.5～8.5时,二聚体静电相互作用能、静电去溶剂化能和疏水自由能都具有较小的数值,表明在该条件下静电和疏水相互作用有利于二聚体的稳定存在.由于SARS3CL蛋白酶活性模式为二聚体,因此,在该pH值范围内,有利于蛋白酶保持活性.在pH=7.0条件下,蛋白酶单体之间具有最强的静电和疏水相互作用,从而使蛋白酶具有最强的活性,这与实验结果相一致.pH值对静电去溶剂化能的影响大于疏水自由能,表明静电作用是造成强酸或强碱条件下二聚体不能稳定存在的主要原因.     

Unfavorable electrostatic and steric interactions in DNA polymerase β E295K mutant interfere with the enzyme's pathway

Mutations in DNA polymerase β (pol β) have been associated with approximately 30% of human tumors. The E295K mutation of pol β has been linked to gastric carcinoma via interference with base excision repair. To interpret the different behavior of E295K as compared to wild-type pol β in atomic and energetic detail, we resolve a binary crystal complex of E295K at 2.5 ? and apply transition path sampling (TPS) to delineate the closing pathway of the E295K pol β mutant. Conformational changes are important components in the enzymatic pathway that lead to and ready the enzyme for the chemical reaction. Our analyses show that the closing pathway of E295K mutant differs from the wild-type pol β in terms of the individual transition states along the pathway, associated energies, and the active site conformation in the final closed form of the mutant. In particular, the closed state of E295K has a more distorted active site than the active site in the wild-type pol β. In addition, the total energy barrier in the conformational closing pathway is 65 ± 11 kJ/mol, much higher than that estimated for both correct (e.g., G:C) and incorrect (e.g., G:A) wild-type pol β systems (42 ± 8 and 45 ± 7 kJ/mol, respectively). In particular, the rotation of Arg258 is the rate-limiting step in the conformational pathway of E295K due to unfavorable electrostatic and steric interactions. The distorted active site in the closed relative to open state and the high energy barrier in the conformational pathway may explain in part why the E295K mutant is observed to be inactive. Interestingly, however, following the closing of the thumb but prior to the rotation of Arg258, the E295K mutant complex has a similar energy level as compared to the wild-type pol β. This suggests that the E295K mutant may associate with DNA with similar affinity, but it may be hampered in continuing the process of chemistry. Supporting experimental data come from the observation that the catalytic activity of wild-type pol β is hampered when E295K is present: this may arise from the competition between E295K and wild-type enzyme for the DNA. These combined results suggest that the low insertion efficiency of E295K mutant as compared to wild-type pol β may be related to a closed form distorted by unfavorable electrostatic and steric interactions between Arg258 and other key residues. The active site is thus less competent for proceeding to the chemical reaction, which may also involve a higher reaction barrier than the wild-type or may not be possible in this mutant. Our analysis also suggests further experiments for other mutants to test the above hypothesis and dissect the roles of steric and electrostatic factors on enzyme behavior.     

Ligand atom partial charges assignment for complementary electrostatic potentials

Summary The design of molecules to fit into the active site of receptors is a rapidly developing area of pharmacology and medicinal chemistry. A good ligand needs a suitable geometry and also appropriate electrostatic properties. The electrostatic properties of the ligand should complement those of the receptor. We present a method for the assignment of atom-centred point charges for a ligand, based on the electrostatic potential of the receptor. These point charges are chosen to give the best possible complementarity to the receptor electrostatic potential over the van der Waals surface of the ligand. We demonstrate that point charges can be chosen to give good electrostatic complementarity, and suggest that a molecule with similar electrostatic properties should bind well to the receptor.     

The matching of electrostatic extrema: A useful method in drug design? A study of phosphodiesterase III inhibitors

Summary Ligands which bind to a specific protein binding site are often expected to have a similar electrostatic environment which complements that of the binding site. One method of assessing molecular electrostatic similarity is to examine the possible overlay of the maxima and minima in the electrostatic potential outside the molecules and thereby match the regions where strong electrostatic interactions, including hydrogen bonds, with the residues of the binding site may be possible. This approach is validated with accurate calculations of the electrostatic potential, derived from a distributed multipole analysis of an ab initio charge density of the molecule, so that the effects of lone pair and -electron density are correctly included. We have applied this method to the phosphodiesterase (PDE) III substrate adenosine-3,5-cyclic monophosphate (cAMP) and a range of nonspecific and specific PDE III inhibitors. Despite the structural variation between cAMP and the inhibitors, it is possible to match three or four extrema to produce relative orientations in which the inhibitors are sufficiently sterically and electrostatically similar to the natural substrate to account for their affinity for PDE III. This matching of extrema is more apparent using the accurate electrostatic models than it was when this approach was first applied, using semiempirical point charge models. These results reinforce the hypothesis of electrostatic similarity and give weight to the technique of extrema matching as a useful tool in drug design.     

甲硫氨酸-脑啡肽的活性位点

用ＡＭ１方法中计算静电势的ＰＭＥＰ子程序了甲硫氨酸－脑啡肽的活性位点。通过计算得到了整个分子的三维空间静电势分布和由静电势导出的各原子的电荷分布。进一步分析,确定模型分子活性位点为酪氨酸残在的叔氨原子和苯酚基、苯丙氨酸残基的苯基及部分氧原子。