细胞色素P450 2f1(CYP2f1)的三维结构模建和与维甲酸的对接研究

利用同源模建和分子动力学模拟方法，模建了细胞色素P450 2f1(CYP2f1)的三维结构．在此基础上，分析了活性位点的组成和结构，并进行了与小分子(维甲酸)的对接研究．研究结果表明，His328，Ser397和Arg417对复合物的结合起重要作用．     

人类细胞色素P450 2E1酶在不同乙醇浓度下构象变化的分子动力学模拟

细胞色素P450(CYP) 2E1家族酶是一种具有双重功能的单加氧酶, 能够参与市场上6%药物的代谢而具有重要的作用. 这类酶与酒精的消耗、 糖尿病、 肥胖症以及厌食症等密切相关, 引起了广泛的研究兴趣. 目前尚未见从原子水平上对这种酶在不同乙醇浓度下构象行为的研究. 基于此, 本文研究了花生四烯酸(AA)与CYP2E1复合物结构在不同乙醇浓度下构象与能量变化的特点. 对于在不同乙醇浓度下AA与CYP2E1的复合物结构, 采用分子动力学模拟结合自由能计算的方法进行研究. 分子动力学模拟结果表明, His109和Lys243氨基酸残基对AA与CYP2E1的结合起到了至关重要的作用. 当体系的乙醇浓度较高时, AA的结合能力有所下降, 这种结合能力的下降是由于AA与CYP2E1之间氢键相互作用力的减弱所致. 本研究对于AA与CYP2E1复合物结构在不同乙醇浓度下, AA分子与CYP2E1分子结合能力下降以及CYP2E1的构象变化给出了详细的解释. 本研究工作得到的结论对于实验和理论研究均有重要意义, 可为后续细胞色素P450酶类催化活性的研究提供理论支持.     

基于多光谱方法和计算模拟的细胞色素CYP1A2与阿奇霉素的结合机制研究

为了解阿奇霉素(AZI)在模拟的人体环境中与CYP1A2的结合情况,探索AZI在人体内的转化机制,本论文使用分子对接、分子动力学模拟、荧光光谱、紫外分光光度法、傅立叶变换红外光谱、圆二色光谱等多种实验方法,阐明AZI与CYP1A2之间的相互作用机制。分子对接结果表明AZI与CYP1A2的结合方式是半包裹并且以疏水作用力相结合。分子动力学模拟结果表明,CYP1A2-AZI复合物的均方根偏差(RMSD)值增大;均方根波动(RMSF)值表明复合物体系柔性较大;回旋半径(Rg)值表明蛋白质特定区域的结构松散。荧光猝灭光谱实验表明,CYP1A2与AZI是以静态猝灭机制结合在一起。热力学参数表明AZI与CYP1A2之间的主导作用力为疏水作用力。时间分辨光谱表明AZI对CYP1A2的机制为静态猝灭。紫外光谱实验表明AZI与CYP1A2反应生成了复合物。红外光谱实验结果表明CYP1A2的二级结构含量发生了改变。圆二色光谱证实AZI对CYP1A2的二级结构产生影响。     

人类细胞色素P450 2E1酶在不同乙醇浓度下构象变化的分子动力学模拟（英文）

细胞色素P450(CYP)2E1家族酶是一种具有双重功能的单加氧酶,能够参与市场上6%药物的代谢而具有重要的作用.这类酶与酒精的消耗、糖尿病、肥胖症以及厌食症等密切相关,引起了广泛的研究兴趣.目前尚未见从原子水平上对这种酶在不同乙醇浓度下构象行为的研究.基于此,本文研究了花生四烯酸(AA)与CYP2E1复合物结构在不同乙醇浓度下构象与能量变化的特点.对于在不同乙醇浓度下AA与CYP2E1的复合物结构,采用分子动力学模拟结合自由能计算的方法进行研究.分子动力学模拟结果表明,His109和Lys243氨基酸残基对AA与CYP2E1的结合起到了至关重要的作用.当体系的乙醇浓度较高时,AA的结合能力有所下降,这种结合能力的下降是由于AA与CYP2E1之间氢键相互作用力的减弱所致.本研究对于AA与CYP2E1复合物结构在不同乙醇浓度下,AA分子与CYP2E1分子结合能力下降以及CYP2E1的构象变化给出了详细的解释.本研究工作得到的结论对于实验和理论研究均有重要意义,可为后续细胞色素P450酶类催化活性的研究提供理论支持.     

诺氟沙星-DNA复合物的分子动力学模拟

采用分子模建的方法构建了诺氟沙星-DNA复合物的初始结构, 通过2 ns的分子动力学(MD)模拟研究表明: 诺氟沙星能够和双螺旋d[ATATCGATAT]₂形成稳定的复合物, 药物分子可紧密结合在DNA的小沟区域, 并且能够与DNA的鸟嘌呤碱基形成两个稳定的氢键. 在分子水平上提供了诺氟沙星直接与双螺旋DNA相互作用的结构及复合物的动态变化情况.     

人甲状腺旁素1型受体的结构特征

人甲状腺旁素1 型受体(PTH1R)是骨形成相关的B类G蛋白偶联受体, 其底物甲状腺旁腺素(PTH)及类似物具有抗骨质疏松作用. 由于此类受体的三维结构难以进行实验测定, 本文采用同源模建的方法, 完整构建了胞外区、跨膜区及其它相关区域, 并通过对接研究, 阐明复合物的氢键、疏水性相互作用及其与底物的相互作用关系和关键位点. 为进一步设计和发展此类药物提供理论依据.     

非对称二甲基精氨酸二甲胺水解酶-2的理论研究

利用同源模建的方法,构建了DDAH-2的三位结构.并与L-瓜氨酸、L-高半胱氨酸分别进行对接研究.其中,Asp77,Gly269,Glu27和Arg96是与L-瓜氨酸相互作用较强的残基,Asp77,His171,Asp125和Ala270是与-L高半胱氨酸相互作用较强的残基.尤其Asp77是在两种复合物中同时起重要作用的氨基酸,并且它与抑制剂之间都形成了氢键.     

Sirt1及Sirt2与活性分子INA的作用机制研究

应用分子模拟理论与方法研究了人类沉默信息调节因子2相关酶类Sirtuin家族成员Sirt1及Sirt2与一种活性分子(命名为INA)的作用机制.同源模建了Sirt1的三维结构,通过分子对接手段得到Sirt1(NAD+)-INA及Sirt2(NAD+)-INA的两种复合物体系,进行了分子动力学模拟.并且分别计算了两种体系中关键氨基酸残基与INA的结合自由能值,由此推测出Sirt1(NAD+)-INA、Sirt2(NAD+)-INA体系结合位点分别为Val72,Ser73和Arg272及Phe235,Leu264和Gly305,确证了两种体系的结合模式.模拟结果表明,在Sirt1(NAD+)-INA体系中,INA与催化底物NAD+距离较近,可以相互作用,具有较高活性;在Sirt2(NAD+)-INA体系中,INA与催化底物NAD+距离较远,与在Sirt1体系中比较,INA对Sirt2体系的活性较弱,结果与实验一致.本文的研究,对今后以去乙酰化酶Sirt1,Sirt2为靶点的新药开发具有一定指导意义.     

抑制剂BD2对PKA与PKCβⅡ的抑制选择性研究

蛋白激酶A(PKA)和蛋白激酶C(PKC)的过度表达导致细胞生长分化异常,是治疗肿瘤的潜在靶点.抑制剂BD2对PKA和PKC抑制作用存在高选择性.为了探讨BD2高选择性机制,本工作以PKA与BD2复合物的晶体结构为模板,通过同源模建结合分子对接的方法构建PKC βⅡ与BD2复合物的结构,并对PKA-BD2复合物和PKC-BD2复合物进行了2.5 ns的分子动力学模拟,运用MM-GBSA方法计算了结合自由能,通过能量分解的方法考察PKA和PKC的主要残基与BD2之间的相互作用和识别机制.结合能分析结果很好地描述了BD2对PKA抑制活性比其对PKC抑制活性高这一实验现象.氢键分析和能量分解结果共同说明了BD2的B环和酰胺链部分与PKA和PKC中相应位点的残基之间的相互作用存在差异,这是BD2存在选择性的内在因素.BD2高选择性作用机制的阐明为进一步基于结构的balanol类抑制剂的结构设计和优化提供了合理的指导.     

抑制剂BD2对PKA与PKC βII的抑制选择性研究

蛋白激酶A (PKA)和蛋白激酶C (PKC)的过度表达导致细胞生长分化异常, 是治疗肿瘤的潜在靶点. 抑制剂BD2对PKA和PKC抑制作用存在高选择性. 为了探讨BD2高选择性机制, 本工作以PKA与BD2复合物的晶体结构为模板, 通过同源模建结合分子对接的方法构建PKC βII与BD2复合物的结构, 并对PKA-BD2复合物和PKC-BD2复合物进行了2.5 ns的分子动力学模拟, 运用MM-GBSA方法计算了结合自由能, 通过能量分解的方法考察PKA和PKC的主要残基与BD2之间的相互作用和识别机制. 结合能分析结果很好地描述了BD2对PKA抑制活性比其对PKC抑制活性高这一实验现象. 氢键分析和能量分解结果共同说明了BD2的B环和酰胺链部分与PKA和PKC中相应位点的残基之间的相互作用存在差异, 这是BD2存在选择性的内在因素. BD2高选择性作用机制的阐明为进一步基于结构的balanol类抑制剂的结构设计和优化提供了合理的指导.     

Relativistic calculation of autoionization widths of 1s2s2pjJ, 1s2s2 2S1/2, and 1s2pJ 2pj′J levels

The autoionization widths of levels 1s 2s 2p_jJ, 1s2s^{2 2}S_1/2, and 1s2p_j2p_j′ J have been calculated for ions with Z = 6–30. The calculation has been carried out in intermediate coupling. The decay amplitudes have been calculated in a relativistic approximation.     

Regioselectivity prediction of CYP1A2-mediated phase I metabolism

A kinetic, reactivity-binding model has been proposed to predict the regioselectivity of substrates meditated by the CYP1A2 enzyme, which is responsible for the metabolism of planar-conjugated compounds such as caffeine. This model consists of a docking simulation for binding energy and a semiempirical molecular orbital calculation for activation energy. Possible binding modes of CYP1A2 substrates were first examined using automated docking based on the crystal structure of CYP1A2, and binding energy was calculated. Then, activation energies for CYP1A2-mediated metabolism reactions were calculated using the semiempirical molecular orbital calculation, AM1. Finally, the metabolic probability obtained from two energy terms, binding and activation energies, was used for predicting the most probable metabolic site. This model predicted 8 out of 12 substrates accurately as the primary preferred site among all possible metabolic sites, and the other four substrates were predicted into the secondary preferred site. This method can be applied for qualitative prediction of drug metabolism mediated by CYP1A2 and other CYP450 family enzymes, helping to develop drugs efficiently.     

Long-range interaction between 1s and 2s or 2p hydrogen atoms

Long-range interaction energy between two hydrogen atoms has been computed in the second order of the perturbation theory. All states of the system arising when one of the atoms is in the 1s and the other in the 2s or 2p state have been considered. The energy represented by a series expansion in inverse powers of the internuclear distance, R, has been computed up to the terms in R^?8. The results are believed to give reliable interaction energies for R > 15 a.u. Accurate interaction energy for two ground-state hydrogen atoms has also been obtained up to the terms in R^?10. Results for the B′ ¹∑ state are employed to discuss the experimental ground-state dissociation energy of H₂, D₂, and HD. For H₂ all values of the dissociation energy obtained from various experimental absorption limits, by using the computed potential energy curve to separate off the effect of rotation, are shown to be satisfactorily consistent. The resulting total energy of H₂ is, however, higher than the most accurate theoretical value.     

Accurate variational calculations of the ground 2Po(1s22s22p) and excited 2S(1s22s2p2) and 2Po(1s22s23p) states of singly ionized carbon atom

In this article we report accurate nonrelativistic variational calculations of the ground and two excited states of C(+) ion. We employ extended and well optimized basis sets of all-electron explicitly correlated Gaussians to represent the wave functions of the states. The optimization of the basis functions is performed with a procedure employing the analytic gradient of the energy with respect to the nonlinear parameters of the Gaussians. The calculations explicitly include the effects due to the finite nuclear mass. The calculated transition energies between the three states are compared to the experimentally derived values. Finally, we present expectation values of some small positive and negative powers of the interparticle distances and contact densities.     

The large effects of electron correlation on the multiplet generalized oscillator strengths of non-closed shell systems: Be 1s22s21S → 1s22s2p 1P0 and B 1s22s22p 2p0 → 1s22s2p22D

Correlation effects are shown to change generalized oscillator strengths and inelastic form factors by large factors as large as 10, from the Hartree-Fock values. The effects are fully included in the charge wavefunctions of the non-closed shell many-electron theory by Sinano?lu. We calculate the charge wavefunctions and obtain from the generalized oscillator strength F_0η(q) versus ln q² and the integrated cross section σ_0η(E) versus lnE₁ for BeI 2s²¹S → 2s2p ¹P⁰ and BI 2s²2p ²P⁰ → 2s2p²²D cases, exemplifying the method.     

Self-consistent calculation of 1s2s1S state wave function of helium

A simple self consistent variation perturbation method in the coupled Hartree–Fock scheme has been proposed to calculate 1s2s ¹S state of the He atom. The present paper deals with an 1s2s ¹S wave function in which all the relevant orthogonality conditions are imposed in successive stages. The resulting wave functions together with some interesting features are discussed.     

A theoretical investigation of the singly excited two-electron atomic states 1s2s3S and 1s3s3S

The singly-excited two-electron states 1s2s ³S and ls3s ³S have been investigated by means of the variational perturbation theory procedure. The wave functions have been constructed as linear combinations of Hylleraas terms with hyperbolic factors in t, and the results obtained by carrying the computations through to 10th perturbation order and with 36(37)- 57(58)- and 85(86)-term basic sets, respectively, are reported. These results compare favourably with the corresponding best values from previous conventional variational calculations.     

HFS constants of Be I 1s22s2p 3p0, B I 1s22s2p24P and B I 1s22s2p22D obtained from the non-closed shell many-electron theory for excited states

Using the non-closed shell many-electron theory for excited states of Sinano?lu we compute the hyperfine structure constants of Be I 1s²2s2p ³P⁰, B I 1s²2s2p²⁴P and B I 1s²2s2p²²D. The quadrupole moment of ⁹Be is also newly determined to be, Q = 0.05494 barns.