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.     

静电和疏水效应对TGEV主蛋白酶二聚体稳定性的影响

从TGEV 3CL蛋白酶二聚体结构出发,研究了TGEV 3CL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TGEV 3CL蛋白酶二聚体静电和疏水相互作用的影响,在pH值为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较小,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,这符合实验结晶所需条件.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.     

三种金属硫蛋白聚合物静电效应的研究

考察了三种金属硫蛋白(大鼠金属硫蛋白亚型II,兔肝金属硫蛋白亚型I和兔肝金属硫蛋白亚型II)的单体、二聚体和三聚体在pH为5.6-8.5和10.6两种缓冲条件下的静电势分布。其中大鼠金属硫蛋白亚型II的结构直接来自于晶体数据,兔肝金属硫蛋白亚型I和II的结构则通过同源蛋白模型搭建。三种金属硫蛋白的静电势通过有限差分方法求解Poisson-Boltzmann方程得到。对于三种金属硫蛋白的二聚体,pH为5.6-8.5时,单体和单体之间的静电势分布具有明显的互补性;但pH≥10.6时,这种互补性会大大削弱。对于三种金属硫蛋白的三聚体,单体和二聚体之间主要表现为静电排斥,而且pH在10.6下的静电排斥力明显强于pH为5.6-8.5时的静电排斥。     

SARS 3CL蛋白酶同源二聚化与底物结合互为别构调控因素

研究了严重急性呼吸系统综合症(SARS)冠状病毒3C-Like蛋白酶(3CLpro)在存在底物或抑制剂时的二聚体形成情况. 通过测定酶活性随酶浓度的变化, 拟合出在底物存在下酶二聚体的解离常数约为0.94 μmol·L-1, 小于纯蛋白酶的二聚体解离常数(14.0 μmol·L-1), 表明底物对二聚体的形成具有增强作用. 选用与底物具有类似结合方式的靛红类抑制剂N-萘甲基靛红-5-甲酰胺(5f), 利用超速离心沉降速率方法定量测定了SARS 3CL蛋白酶单体和二聚体在不同浓度5f时的含量, 发现5f同样具有诱导二聚体形成的能力. 在3 μmol·L-1蛋白酶浓度下测定得到诱导二聚的EC50 值(半数有效浓度)约为1 μmol·L-1, 说明二聚体中只有一个单体与抑制剂结合. 研究结果表明, 随着底物浓度的升高, SARS 3CL蛋白酶会形成更多的二聚体, 而二聚体含量的提高又反过来提高酶的活性, 这种双向别构调控机制有可能是病毒用来调控多聚蛋白水解速率和组装时机的一种方法.     

SARS冠状病毒3CL蛋白酶及其抑制剂的理论研究

应用AutoDock程序将SARS冠状病毒3CL蛋白酶及其抑制剂配体和受体进行了对接,并用InsightⅡ中的Discover 3模块进行了分子动力学模拟,分析了蛋白酶活性口袋的形状,讨论了其亚基的氢键、静电、疏水等相互作用,为进一步设计药物提供了重要的参考信息.     

细菌化学趋向性受体聚集体的相互作用

细菌化学趋向性受体的最小结构单元为二聚体,在细胞膜上这些二聚体会聚集成大团簇. X射线晶体结构和低分辨电镜结构测定表明,这些团簇有两类不同的形式,一种是在晶体结构中观察到的倒金字塔式二聚体的三聚体重复形成的聚集,另一种为由二聚体尾部相互盘绕形成的拉链状聚集. 有关拉链状聚集的详细分子模型目前尚不清楚. 本文使用蛋白质-蛋白质对接的方法研究了大肠杆菌丝氨酸化学趋向性受体Tsr 二聚体之间的相互作用. 分子对接计算表明,倒金字塔式聚集和拉链状聚集的基本复合物都是可以出现的,相应复合物的分子动力学模拟表明这些结构都具有一定的稳定性. 对于所获得的拉链状聚集体的基本复合物结构模型进行了详细的二聚体作用界面分析,发现二聚体间主要通过静电和疏水作用形成复合物,其中Arg388、Phe373 和Ile377是形成拉链状聚集的关键作用残基. 所建立的Tsr 拉链状聚集的结构模型有助于揭示细菌化学趋向性受体在细胞膜上聚集的分子机制,为进一步的聚集理论及模拟研究提供了基础.     

固体的表面能及其亲水/疏水性

固体表面的亲水/疏水性质与表面分子与水之间的固/液界面相互作用自由能以及水介质中表面分子与空气之间的固/(液)/气界面相互作用自由能密切相关.水介质中固体表面与水之间存在范德华引力或疏水引力,与气泡之间存在范德华斥力、疏水引力以及静电斥力.在Lifshitz-范德华(LW)相互作用自由能、Lewis酸-碱(AB)相互作用自由能以及静电(EL)相互作用自由能3者之中,AB相互作用自由能比其它两者要大2～3个数量级以上.与固体表面能Lewis酸-碱分量相关的亲水指数√r_s~++√r_s~-可以成为衡量固体表面亲水/疏水性质的重要判据,水介质中固体表面疏水的必要条件是√r_s~++√r_s~-＜5mJ~(1/2)/m,指数大于或接近5mJ~(1/2)/m的表面必然是亲水的.     

促红细胞生成素(EPO)受体(EBP)激活剂的理论突变设计

采用分子动力学模拟的方法, 构建了人促红细胞生成素模拟肽与其受体胞外结合片段的相互作用的分子动力学模型. 通过对该模型的结构研究和理论分析, 对模拟肽与受体结合机制提出了新的理论解释. 根据EBP活性口袋的静电势分布, 对二聚体小肽激活剂的每条链上的部分氨基酸进行了突变, 分别用电性更强的氨基酸来代替部分疏水氨基酸, 计算结果显示, 突变后的二聚体小肽激活剂对EBP的“亲和力”明显增强.     

细菌化学趋向性受体聚集体的相互作用

细菌化学趋向性受体的最小结构单元为二聚体,在细胞膜上这些二聚体会聚集成大团簇.X射线晶体结构和低分辨电镜结构测定表明,这些团簇有两类不同的形式,一种是在晶体结构中观察到的倒金字塔式二聚体的三聚体重复形成的聚集,另一种为由二聚体尾部相互盘绕形成的拉链状聚集.有关拉链状聚集的详细分子模型目前尚不清楚.本文使用蛋白质-蛋白质对接的方法研究了大肠杆菌丝氨酸化学趋向性受体Tsr二聚体之间的相互作用.分子对接计算表明,倒金字塔式聚集和拉链状聚集的基本复合物都是可以出现的,相应复合物的分子动力学模拟表明这些结构都具有一定的稳定性.对于所获得的拉链状聚集体的基本复合物结构模型进行了详细的二聚体作用界面分析,发现二聚体间主要通过静电和疏水作用形成复合物,其中Arg388、Phe373和Ile377是形成拉链状聚集的关键作用残基.所建立的Tsr拉链状聚集的结构模型有助于揭示细菌化学趋向性受体在细胞膜上聚集的分子机制,为进一步的聚集理论及模拟研究提供了基础.     

胰岛素单体、双体分子静电势的计算

计算了三方二锌胰岛素晶胞不对称单位中两个胰岛素分子单体及其双体的分子静电势。结果表明:胰岛素两个单体分子的构象不同,其分子表面静电势也不相同,由于它们的构象是类似的,所以其电势分布也是接近的,单体胰岛素分子的表面静电势呈偶极型分布,双体的表面静电势基本保持单体的特征。文中还比较了两个单体分子及其集聚后的静电势变化。     

DFT study of the monomers and dimers of 2-pyrrolidone: equilibrium structures, vibrational, orbital, topological, and NBO analysis of hydrogen-bonded interactions

A computational study of the monomers and hydrogen-bonded dimers of 2-pyrrolidone was executed at different DFT levels and basis sets. The above dimeric complexes were treated theoretically to elucidate the nature of the intermolecular hydrogen bonds, geometry, thermodynamic parameters, interaction energies, and charge transfer. The processes of dimer formation from monomers and concerted reactions of double proton transfer were considered. The evolution of geometry, vibrational frequencies, charge distribution, and AIM properties in going from monomers to dimers was systematically followed. The solvent effects upon dimer formation were investigated in terms of the self-consistent reaction field (SCRF Onsager model). For the monomers and three dimers, vibrational frequencies were calculated and the changes in frequencies of the vibrations most sensitive to complexation were discussed. The orbital interactions were shown to lengthen the X-H (X = N, O) bond and lower its vibrational frequency (a red shift). To better understand the nature of the corresponding intermolecular interactions, we performed natural bond orbital (NBO) analysis. Topological analysis of electron density at bond critical points (BCP) was executed for complex molecules using the Bader's atoms in molecules (AIM) theory. The interaction energies were calculated, and the basis set superposition errors (BSSE) were estimated systematically. Satisfactory correlations between the structural parameters, interaction energies, and electron density characteristics at BCP were found.     

Model chemistry calculations of thiophene dimer interactions: origin of pi-stacking

The intermolecular interaction energies of thiophene dimers have been calculated by using an aromatic intermolecular interaction (AIMI) model (a model chemistry for the evaluation of intermolecular interactions between aromatic molecules). The CCSD(T) interaction energy at the basis set limit has been estimated from the MP2 interaction energy near the basis set limit and the CCSD(T) correction term obtained by using a medium-size basis set. The calculated interaction energies of the parallel and perpendicular thiophene dimers are -1.71 and -3.12 kcal/mol, respectively. The substantial attractive interaction in the thiophene dimer, even where the molecules are well separated, shows that the major source of attraction is not short-range interactions such as charge transfer but rather long-range interactions such as electrostatic and dispersion. The inclusion of electron correlation increases the attraction significantly. The dispersion interaction is found to be the major source of attraction in the thiophene dimer. The calculated total interaction energy of the thiophene dimer is highly orientation dependent. Although electrostatic interaction is substantially weaker than dispersion interaction, it is highly orientation dependent, and therefore electrostatic interaction play an important role in the orientation dependence of the total interaction energy. The large attractive interaction in the perpendicular dimer is the cause of the preference for the herringbone structure in the crystals of nonsubstituted oligothiophenes (alpha-terthienyls), and the steric repulsion between the beta-substituents is the cause of the pi-stacked structure in the crystals of some beta-substituted oligothiophenes.     

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.     

Adsorption of Dimers at Surfaces

A model for the adsorption of dimers at a surface is presented. The model is based on a generalization of the Ono-Kondo lattice theory. The densities of dimer molecules that are parallel to the surface, x parallel, and perpendicular to the surface, x perpendicular, are calculated. It is shown that symmetric dimer molecules adsorb preferentially parallel to the surface at all densities. The model also predicts that the Gibbs adsorption is negative for small interaction energies between dimers and the surface. Copyright 1999 Academic Press.     

Substituent effects in the benzene dimer are due to direct interactions of the substituents with the unsubstituted benzene

The prevailing views of substituent effects in the sandwich configuration of the benzene dimer are flawed. For example, in the polar/pi model of Cozzi and co-workers (J. Am. Chem. Soc. 1992, 114, 5729), electron-withdrawing substituents enhance binding in the benzene dimer by withdrawing electron density from the pi-cloud of the substituted ring, reducing the repulsive electrostatic interaction with the nonsubstituted benzene. Conversely, electron-donating substituents donate excess electrons into the pi-system and diminish the pi-stacking interaction. We present computed interaction energies for the sandwich configuration of the benzene dimer and 24 substituted dimers, as well as sandwich complexes of substituted benzenes with perfluorobenzene. While the computed interaction energies correlate well with sigmam values for the substituents, interaction energies for related model systems demonstrate that this trend is independent of the substituted ring. Instead, the observed trends are consistent with direct electrostatic and dispersive interactions of the substituents with the unsubstituted ring.     

Mpro-C蛋白三维结构域交换的机理: 来自分子模拟的线索

SARS冠状病毒主蛋白酶(M^pro)在病毒的蛋白酶切过程中发挥着重要作用. M^pro的晶体结构显示它存在两种形式的二聚体: 一种是发生三维结构域交换的形式, 另一种是非交换的形式. M^pro的C端结构域(M^pro-C)单独表达时也能形成与全长M^pro类似的三维结构域交换二聚体. 三维结构域交换通常发生在蛋白质的表面, 但M^pro-C 的结构域交换却发生在疏水核心. 在本文中, 我们利用分子动力学模拟及三维结构域交换预测算法研究了M^pro-C 中被高度埋藏的核心螺旋片段发生交换的机理. 我们发现基于结构与基于序列的已有算法都不能正确预言出M^pro-C和M^pro中发生结构域交换的铰链区位置. 分子模拟结果表明M^pro-C中的交换片段在天然态下埋藏得很好, 但在变性单体中则会被释放并暴露在外面. 因此, 在完全或部分解折叠状态下交换片段的打开有助于促进单体间的相互作用及结构域交换二聚体的形成.     

Theoretical study on mesogenic core structures of nematic liquid crystalline compounds

The structures and intermolecular interaction energies of 10 dimers, included in the mesogenic core structures of typical liquid crystalline (LC) compounds, are obtained at the MP2/6-31G(d) level of theory. It is proved that the dispersion energy significantly contributes to the total interaction energy of these dimers. Even when bulky substituents are introduced into the core part, the interaction energy is still large. It is also revealed that when a long intermolecular distance is provided by a high steric repulsion originating from the linkage of two phenyl groups, the dispersion energy is significantly small. However, in this range of intermolecular distances, the electrostatic energy caused by a strong quadrupole-quadrupole attractive interaction plays a dominant role, and as a result, a rather stable dimer is formed. In all 10 dimers, the dispersion, electrostatic, and exchange-repulsion energies strongly depend on the geometrical orientation of the molecules. The calculated interaction energies of these dimers are also compared with the corresponding experimentally measured viscosities. The results suggest an explicit linear relationship between the interaction energies and viscosities.     

Theoretical study of peptide model dimers. Homo versus heterochiral complexes

The study of possible chiral recognition of a series of peptide models (For-Gly-NH₂, For-Ala-NH₂ and four of their fluoro substituted derivatives) has been carried out by means of DFT calculations. Homo (L,L) and heterochiral (L,D) dimers formed by hydrogen bond (HB) complexation have been considered. Initially, the conformational preferences of the monomers have been calculated and used to generate all the possible homo and heterochiral dimers. The energetic results show that in most cases, the β monomers are the most stable while in the dimers, the γ–γ complexes show the strongest interaction energies. In three of the four chiral cases studied, a heterochiral dimer is the most stable one. In addition, the electron density and nuclear shielding of the complexes have been studied.