在不同溶剂体系中PC脂肪酶对PBS基共聚物的催化降解和分子模拟

采用酶促降解实验、分子对接模拟和分子动力学模拟相结合的方法,分别研究了在氯仿和水溶剂体系中洋葱假单胞菌脂肪酶(Pseudomonas cepacialipase PC)对含六元环结构的1,4-环己烷二甲醇(CHDM)、1,4环己烷二甲酸(CHDA)、含醚键结构的一缩二乙二醇(DEG)和二乙醇酸(DGA)单体的聚丁二酸丁二醇酯(PBS)改性共聚物的降解规律,并对它们进行了比较,阐明了PC脂肪酶与不同底物的结合机制及其降解差异性。结果表明:PC脂肪酶可有效地催化降解不同结构的PBS基共聚物,氯仿中酶与底物结合自由能的大小顺序为CMSCMDGSDGBDABBCABBSB,水中二者的结合自由能大小顺序为CMSCMDGSDGBCABBDABBSB,其中CM单元的六元环状亚甲基的富集作用使得底物与酶活性位点的对接最为稳定,具有较大的结合能,且PBS-co-CHDMS降解率最大。受溶剂效应影响,酶与底物在氯仿中的结合更稳定,降解率远大于在水中的降解率。     

结合分子模拟探讨PC脂肪酶催化PBS基共聚物降解的主链异构效应

采用固定化洋葱假单胞菌脂肪酶(Pseudomonas cepacia lipase,PC脂肪酶)为催化剂,在有机溶剂体系中研究了环己烷二甲醇和环己烷二甲酸对聚丁二酸丁二醇酯(PBS)的改性共聚物,即聚(丁二酸丁二醇-co-丁二酸环己烷二甲醇酯)(PBS-co-CHDMS)和聚(丁二酸丁二醇-co-环己烷二甲酸丁二醇酯)(PBS-co-BCHDA)的降解规律及其差异性.通过共聚物降解率随时间的变化、降解产物的MALDI-TOF-MS分析研究了共聚物降解规律,并以分子模拟分别研究了降解差异性和PC脂肪酶与底物的结合机制.研究结果表明,PC脂肪酶均可催化PBS基共聚物降解;在降解60 h后,相比较于PBS-co-BCHDA,PBS-co-CHDMS降解率均更大;其中PBS-co-10%CHDMS降解率最大,为85%.共聚物降解不仅生成了线型小分子,还产生了部分环状低聚物;此外,PBS-co-CHDMS降解产生的低聚物种类比PBS-co-BCHDA的要多.分子对接模拟结果表明,在氯仿中,PC脂肪酶与底物结合自由能的大小顺序为CMSCMBSCMBCABBSB,即含有丁二酸环己烷二甲醇酯(CHDMS)单元的底物与PC脂肪酶活性位点的对接更为稳定.     

结合分子模拟探讨不同醚键PBS基共聚物的性能与酶催化降解

以硫二甘醇取代二甘醇,在聚(丁二酸丁二醇酯)(PBS)分子主链上分别引入硫醚和氧醚基团,得到聚(丁二酸丁二醇酯-丁二酸硫代二乙二醇酯)[P(BS-co-TDGS)]和聚(丁二酸丁二醇酯-丁二酸二乙二醇酯)[P(BS-co-DEGS)],通过热重分析(TG)和X射线衍射(XRD)测试比较了二者的结晶性能和热性能.采用南极假丝酵母脂肪酶N435(CALB)为催化剂,在水相中研究了P(BS-co-TDGS)和P(BS-co-DEGS)的降解规律及差异性.采用分子模拟方法研究了共聚物可能存在的聚集态以及N435酶与底物的结合,模拟结果验证了共聚物P(BS-co-TDGS)的结晶度下降及热稳定性降低的结论.分子对接模拟结果表明,N435酶与DEGSDEG单元的结合能更大,即含有丁二酸硫代二乙二醇酯键型底物P(BS-co-DEGS)与N435酶活性位点的对接更为稳定.     

亲水改性PBS基共聚物的N435酶降解差异性及分子模拟

在水相体系中, 采用脂肪酶Novozym435对聚丁二酸丁二醇酯(PBS)分子主链中氧醚键在醇段和酸段的不同位置的共聚物聚(丁二酸丁二醇-co-丁二酸二甘醇酯)[P(BS-co-BDGA)]和聚(丁二酸丁二醇-co-二甘醇酸丁二醇酯)[P(BS-co-DEGS)]进行酶促降解研究. 以分子对接模拟探讨了酶对亲水性底物的识别及相互作用机制. 通过对降解前后不同摩尔比的共聚物薄膜的质量损失率、 亲水性、 热性能以及降解产物的分析, 研究了PBS改性共聚物的降解规律. 结果表明, 随着降解时间的推移, 所有共聚物薄膜的质量损失率升高, 亲水性增强, 热分解温度升高; 降解5 d后, P(BS-co-BDGA)降解产生的低聚物种类比P(BS-co-DEGS)的多. 分子对接结果表明, 醚键在酸段的P(BS-co-BDGA)型酯键与Novozym435酶活性位点的结合比醚键在醇段的P(BS-co-DEGS)型酯键更稳定, 因此, 在N435脂肪酶作用下, P(BS-co-BDGA)比P(BS-co-DEGS)的降解效果好. 实验结果表明, 当DGA摩尔分数为20%时, 降解效果最佳.     

化学修饰法表征Bacillus smithii T7产耐热菊粉酶催化活性中心的必需氨基酸残基

采用化学修饰法研究了史氏芽胞杆菌Bacillus smithiiT7产耐热菊粉酶活性中心氨基酸残基,发现该酶活性中心存在一个组氨酸残基和一个谷氨酸(或天冬氨酸)残基.修饰前后的酶动力学参数变化表明组氨酸残基参与了底物的结合和催化过程,而谷氨酸(或天冬氨酸)的羧基亲核攻击促使底物分解.邹氏作图法证明酶活性中心存在两个必需的色氨酸残基,荧光和圆二色光谱研究表明色氨酸残基在酶的催化和酶的耐热性方面起重要作用.     

末端为磷酰胆碱基团的聚丁二酸丁二醇酯的酶促降解和热性能

以聚丁二酸丁二醇酯(PBS)为参照, 研究了酯酶Lipase AY30对亲水磷酰胆碱(PC)基团改性的聚丁二酸丁二醇酯(PBS-PC)的生物降解性能的影响. 结果显示, 在酯酶Lipase AY30作用下, 21 d后PBS的质量损失仅为1.9%, 而PBS-PC的质量损失了9.7%. 相同条件下扣除各自水解引起的质量损失(PBS 1.4%和PBS-PC 6.5%)后, PC亲水基团的引入对聚合物的降解起到了促进作用. 示差扫描量热(DSC)研究结果表明, 改性后的聚合物熔融温度和熔融焓降低, 玻璃化转变温度升高, 表明PC端基的引入降低了PBS的结晶能力, 非晶相结构的增多对聚合物降解有促进作用. 因此PBS-PC有望作为一种新的具有良好生物降解性和生物相容性的高分子材料, 应用于药物控释、基因治疗及组织工程等生物医用材料领域.     

CYP2C9酶与Warfarin结合模型的立体选择性理论研究

对CYP2C9酶与S-Warfarin复合物的晶体结构进行分子对接、分子动力学模拟、通道分析及结合自由能计算,发现原晶体结构中的结合模式为"亚稳态",提出了CYP2C9与S-Warfarin结合的可催化模式;比较了CYP2C9与S-和R-Warfarin结合的异同,确定了在结合过程中起重要作用的锚定氨基酸残基,尤其是位于活性位点区域的苯丙氨酸簇.在结合过程中这些残基通过芳香环的移动对稳定底物的结合模式起到至关重要的作用,阐明了该酶呈现相关底物选择性的原因.对于CYP2C9与底物对接模式及立体选择性的研究有助于在分子层面上理解特异性底物与酶的结合特点,为潜在的药物设计提供了合理可信的理论依据.     

末端带有磷酰胆碱基团的聚丁二酸丁二醇酯的合成、表征和性能研究

采用四步反应合成了一种新的具有良好生物相容性和生物降解性的末端带有磷酰胆碱(PC)基团的聚丁二酸丁二醇酯PBS-PC. 采用1H NMR、IR、凝胶色谱(GPC)和X射线光电子能谱(XPS)表征了聚合物的结构. 同时研究了聚合物的亲疏水性能、体外降解、溶胀率和对模型药物中性红的缓释性能. 结果显示: PC基团引入, 在一定程度上提高了PBS的亲水性、降解速率、溶胀率和对中性红的缓释性能.     

聚酯在超临界甲醇中的降解特性

研究在间歇高压反应器中聚对苯二甲酸乙二醇酯(PET)、聚对苯二甲酸丁二醇酯(PBT)及聚碳酸酯(PC)在超临界甲醇中的降解反应;通过建立聚酯在超临界甲醇中的降解反应模型,探讨了聚酯在甲醇中降解的机理。结果表明:PET、PBT和PC在甲醇溶液中的降解具有共性,均可分为超临界区、非临界区和中间过渡区三个区域。在超临界区聚酯完全溶于甲醇并降解为原料单体,且对苯二甲酸二甲酯(DMT)和碳酸二甲酯(DMC)的收率均大于90%;聚酯的降解是在聚合物分子链的无规断裂和聚酯进行酯交换反应的双重作用下发生的。     

水解酶在二乙基锌与芳香醛加成反应中的应用(英文)

报道了水解酶催化二乙基锌与芳香醛的加成反应,对反应条件进行了优化.在最适条件(嗜热酯酶APE1547为酶源,反应温度40℃,氯仿为溶剂,4-Cl-苯甲醛为底物)下,加成反应生成的光学活性醇产率最高达78%,ee值最高可达56%.通过实验结果和分子动力学分析对可能的反应机理进行了推测.本研究进一步拓展了酶的非专一性.     

I/V characteristics of a molecular switch

We present a study of the conduction properties of a class of aromatic compounds, whose conformation can be modulated with a transverse electric field, with strong effects on the molecular transport properties. The theoretical method includes the molecule–electrode interaction in a simple, although effective way: the coupling matrix elements are considered independent from the energy of the continuum spectrum of the lead. This results in a simple expression for the molecular Green’s function with a significant simplification in the expression of the transmission function. The effects of the voltage bias on the electronic molecular density is included through a uniform effective electric field. A simplified but accurate method for the evaluation of the molecular response to the field, which spares lengthy computations for each value of the voltage, is presented. The proposed method is calibrated on the widely studied benzene-1,4-dithiol molecule. The calculations on the selected molecular wire (a tetracyano derivative of 4,4′-di(mercaptoethynyl)tolan) show that conductivity is low for perpendicular rings, whereas conduction is allowed for the planar conformation, which corresponds to the equilibrium geometry in the absence of the transverse electric field.     

Towards an understanding of the molecular basis of hydrophobicity

Summary The modern view is stressed that the structuring of water around nonpolar solutes, a process called hydrophobic hydration, actually favors the solubility of nonpolar solutes in water, its associated positive free energy of transfer arising from the enthalpic input required to create a cavity in water to accommodate the solute. The results of a series of molecular dynamics simulations of methane in SPC/E water at different temperatures are reported. These results show the existence of a larger fraction of broken hydrogen bonds in the hydration-shell water of the nonpolar solutes with respect to the bulk water, the difference increasing with a rise in temperature. This supports Muller's modified hydration-shell hydrogen-bond model predictions, where hydration-shell water molecules have lower free energies of hydrogen-bond breaking than those in the bulk.This paper is based on a presentation given at the 14th Molecular Graphics and Modelling Society Conference, held in Cairns, Australia, August 27 September 1, 1995.     

分子力场发展的新趋势

分子模拟中的力场方法是用来精确计算分子结构和能量的计算方法,它通过原子核的位置来计算体系能量。最初的分子力场都是针对某一特定体系的,它们的许多参数要由观测数据拟合得到。当时要建立新的分子力场是十分困难的,因为实验归属振动谱带需要花费大量的时间。所以此后大多数工作者都致力于发展涵盖尽可能多体系的“求全”型分子力场,这种趋势一直延续至今。但是随着各个学科研究的不断深入,所需要研究的体系越来越复杂,要求的精度也越来越高。在保证相当精度的条件下,“求全”型的分子力场要想涵盖所有需要研究的体系常常是十分困难的事情。2003年问世的Direct Force Field软件包能够便捷的建立针对某一特定分子体系,并且有相当精度的分子力场。它的出现为分子力场从“求全”转为向“求精”发展提供了可能。     

卟啉超分子化合物在分子器件中的应用

分子电子器件已成为近年来的一个研究热点，卟啉类化合物因为光敏性好、性能稳定、易于修饰等优点成为分子器件研究的理想模型化合物。本文着重介绍了它在分子器件中的最新应用进展。     

分子纳米磁体的研究进展及应用

分子磁学主要研究无机配合物以及有机自由基的电子结构和磁性之间的关系。近些年发展起来的分子纳米磁体可以在单分子尺度上实现磁双稳态,独立作为一个磁功能单元,可能突破尺寸对传统磁性材料的制约,有望实现超高密度磁存储。分子纳米磁体中清晰的量子态也为量子退相干研究提供了化学调控的手段,这将为量子计算机提供物质基础。本文简要介绍了分子纳米磁体的概念和特征,并对研究进展进行了简要综述。     

分子印迹整体柱的制备、分类与应用

分子印迹整体柱在分离科学领域获得广泛应用,能够用于萃取分离有机小分子、特异性识别金属离子和蛋白质分离。本文综述了分子印迹整体柱的印迹策略、材料分类与应用,重点介绍了新型的分子印迹整体柱,并从特异性、分离效率、快速检测等方面讨论了分子印迹整体柱目前面临的挑战,展望了其发展前景和方向。     

Synthesis of covalently bonded nanostructure from two porphyrin molecular wires leading to a molecular tube

Molecular wire, diacetylene-linked porphyrin dimer 6 having terminal alkenes, was synthesized. Porphyrin dimer 6 formed the 1:1 double-stranded ladder complex with 1,4-diazabicyclo[2.2.2]octane (DABCO). The co-planar stacked two porphyrin molecular wires in the ladder complex were connected by olefin metathesis in the presence of the Grubbs catalyst in order to make a covalently bonded tubular nanostructure. The obtained molecular tube 7 was characterized by ¹H, ¹³C NMR spectroscopy, and MALDI-TOF MS spectrometry.     

Time-efficient flexible superposition of medium-sized molecules

We present an efficient algorithm for the structural alignment of medium-sized organic molecules. The algorithm has been developed for applications in 3D QSAR and in receptor modeling. The method assumes one of the molecules, the reference ligand, to be presented in the conformation that it adopts inside the receptor pocket. The second molecule, the test ligand, is considered to be flexible, and is assumed to be given in an arbitrary low-energy conformation. Ligand flexibility is modeled by decomposing the test ligand into molecular fragments, such that ring systems are completely contained in a single fragment. Conformations of fragments and torsional angles of single bonds are taken from a small finite set, which depends on the fragment and bond, respectively. The algorithm superimposes a distinguished base fragment of the test ligand onto a suitable region of the reference ligand and then attaches the remaining fragments of the test ligand in a step-by-step fashion. During this process, a scoring function is optimized that encompasses bonding terms and terms accounting for steric overlap as well as for similarity of chemical properties of both ligands. The algorithm has been implemented in the FLEXS system. To validate the quality of the produced results, we have selected a number of examples for which the mutual superposition of two ligands is experimentally given by the comparison of the binding geometries known from the crystal structures of their corresponding protein–ligand complexes. On more than two-thirds of the test examples the algorithm produces rms deviations of the predicted versus the observed conformation of the test ligand below 1.5 Å. The run time of the algorithm on a single problem instance is a few minutes on a common-day workstation. The overall goal of this research is to drastically reduce run times, while limiting the inaccuracies of the model and the computation to a tolerable level.     

Unified synthesis of diverse building blocks for application in the discovery of bioactive small molecules

The synthesis of large numbers of diverse molecular scaffolds with controlled molecular properties is a significant challenge in synthetic organic chemistry. A modular unified synthesis was developed, and was exploited in the synthesis of sixteen diverse three-dimensional scaffolds. The approach exploited two cyclisation precursors to be converted, using a toolkit of cyclisation reactions, into spirocyclic and fused-ring scaffolds. Remarkably, Pd-catalysed aminoarylation of substituted N-Boc-hex-5-enylamine cyclisation precursors to yield N-Boc piperidine-containing scaffolds was successful which was ascribed to a significant Thorpe−Ingold effect. Computational property analysis showed that the decorated scaffolds are shape-diverse, and enable diverse lead-like chemical space to be targeted.