摘要
本文运用一系列的理论化学方法研究了一些生物小分子(尼古丁、可卡因、神经递质等)和生物大分子(磷酸二酯酶)的结构及其相互作用。全文由三章构成：第一章简单介绍了溶液中从头算理论的最新进展以及磷酸二酯酶体系活性中心的结构；第二章采用几种溶剂化模型计算了一些生物小分子在溶液中的离解常数，通过溶液中频率的计算分析了组胺在溶液中的主要构象；第三章运用量子力学／分子力学和分子动力学模拟方法研究磷酸二酯酶-5(PDE5)活性中心的结构，利用分子对接和3D-QSAR方法研究了环鸟嘌呤衍生物同磷酸二酯酶-5(PDE5)之间的相互作用。
第二章的第一部分运用第一原理电子结构方法对24种胺类化合物，包括可卡因、尼古丁、10种神经递质和12种苯胺分子进行pK_a值的计算，采用了四种不同的自洽反应场溶剂化模型：表面极化和体极化作用(SVPE)的方法、极化连续介质模型(PCM)、积分连续介质模型(IEFPCM)、极化导体模型(COSMO，亦称为CPCM)。由SVPE方法计算的绝对pK_a值同实验值最接近，计算值和实验值之间的均方根差(RMSD)只有1.18，而用PCM、IEFPCM和COSMO方法计算的pK_a值和实验值之间的RMSD分别为3.21、2.72和3.08。当所有溶剂化模型所计算的pK_a值同实验值进行一元线性拟合后，RMSD都变小了，在0.51～0.83之间。最小RMSD的值(0.51)也是对应着表面极化和体极化作用(SVPE)的方法。所有的计算结果都表明运用SVPE模型的第一原理电子结构计算是预测胺类化合物比较合理的方法。第二部分利用第一原理电子结构方法计算了一价和二价组胺阳离子在气相和溶液中各种可能的构象，并且用IEFPCM模型对组胺一价阳离子进行了频率计算，根据校正的计算频率以及同位素的移动同实验的红外和拉曼光谱进行比较。最后的结果表明，g_3H构象在溶液中的自由能最低，溶液中约占57％的比率；根据计算频率和实验光谱的比较，g_3H构象的计算频率和实验光谱吻合的较好，平均偏差约为10cm~(-1)。所有结果都表明：在溶液中侧链质子化的一价组胺阳离子在溶液中主要是g_3H构象，而不是t_3H构象。这里所得到的溶液中侧链质子化的一价组胺离子详细的结构信息对将来研究组胺分子同各种生物大分子体系的相互作用具有重要的指导意义。
第三章的第一部分通过量子力学／分子力学(QM／MM)和分子动力学模拟计算得到了两种PDE5酶活性位点的结构。为了验证PDE5活性中心第二个桥配体(BL2)的性质：到底是氢氧根HO~-还是H_2O水分子?分别从X-射线的晶体结构和分子动力学模拟平衡后结构出发进行QM／MM优化计算。计算结果清楚的表明只有当BL2是氢氧根离子时，它才能真正的充当桥配体连接两个带正电的金属离子Zn~(2+)和Mg~(2+)；当BL2是水分子的时候，它只能同Mg~(2+)离子配位而离开Zn~(2+)离子。而且计算结果表明QM／MM优化的几何构型受到溶剂水分子、蛋白质的动力学环境以及embed MM部分电荷的影响，而且这几个因素是相互依赖的。当完全忽略或完全考虑这三种因素的QM／MM计算结果是一致的，表明这三种因素对几何构型优化的影响可以相互抵消。然而，如果仅仅考虑其中的几个，就会得到完全不同的结果。因此要么全部考虑，要么全部忽略。第二部分根据得到的PDE5活性中心的结构，运用分子对接和3D-QSAR分析来研究PDE5和PDE6酶同一系列环鸟嘌呤衍生物的相互作用。通过分子对接得到化合物的初始构象，运用CoMFA和CoMSIA分析得到定量构效关系式和定量结构选择性关系式模型(具有比较高的交叉验证系数q~2和传统的相关系数r~2的值)，这些关系式能够预测PDE5抑制剂的活性和PDE5同PDE6之间选择性的抑制剂。这些比较高的验证系数q~2和r~2的值以及后面所做的进一步的测试都表明所得的3D-QSAR和3D-QSSR模型是合理的，这些关系式在提高环鸟嘌呤衍生物对靶标蛋白质的抑制性和选择性方面具有很高的应用价值。
In this work, a series of theoretical methods were employed to study the structures andinteractions of some small biomolecules (including cocaine, nicotine and neurotransmitters ctc) andbiomacromolecules (PDE5). The thesis consists of three chapters: The first charpter is a briefintroduction of some recent progress of the development of ab initio electronic structure theory formolecules in solution and a summary of the active site structure of phosphodiesterase-5 and itsproblems to be solved. The second charpter is the computational determinations of the absolute pK_avalues of some amine compounds through first-principles electronic structure calculations usingfour different solvation models, along with an analysis of the most stable conformation of protonatedhistamine in solution based on the calculated Gibbs free energies and vibrational frequencies. Thethird charpter is computational studies of the dynamic structures of phosphodiesterase-5 (PDE5)active site by combined molecular dynamics simulations and hybrid quantum mechanical/molecularmechanical calculations and the structure-activity and structure-selectivity correlation of cyclicguanine derivatives as PDE5 inhibitors by molecular docking, CoMFA and CoMSIA analyses.
In the first part of the second chapter, the absolute pK_a valucs of 24 representative aminecompounds in aqueous solution, including cocaine, nicotine, 10 neurotransmitters, and 12 anilines,were calculated by performing first-principles electronic structure calculations. Four differentsolvation models, i.e., the surface and volume polarization for electrostatic interaction (SVPE) model,the standard polarizable continuum model (PCM), the integral equation formalism for the polarizablecontinuum model (IEFPCM), and the conductorlike screening solvation model (COSMO) wereemployed to account for the solvent effect. Within the examined computational methods, thecalculations using the SVPE model lead to the absolute pK_a values with the smallestroot-mean-square-deviation (rmsd) value (1.18). When the SVPE model was replaced by the PCM,IEFPCM, and COSMO, the rmsd value of the calculated absolute pK_a values became 3.21, 2.72, and3.08, respectively. With the empirical corrections using the linear correlation relationships, thetheoretical pK_a values are much closer to the corresponding experimental data and the rmsd valuesbecome 0.51-0.83. The smallest rmsd value (0.51) is also associated with the SVPE model. All of theresults suggest that the first-principles electronic structure calculations using the SVPE model are areliable approach to the pK_a prediction for the amine compounds. In the second part of the secondchapter, first-principles electronic structure calculations were performed on a variety of possible molecular structures of side-chain protonated histamine and different conformers of thefully-protonated state (dication). The calculated results demonstrate that the solvent effectssignificantly affect the relative Gibbs free energies of different molecular structures and, therefore,change their relative concentrations. We also calculated the vibrational frequencies of monocationhistamine in aqueous solution. The calculated scaled theoretical wavenumbers are in good agreementwith the corresponding experimental values for both the natural and the N-deuterated g3I-I conformer.The average deviation was only 10 cm~(-1). All the calculated results indecate that the most stableconformation is the g3H conformer rather that the t_3H conformer. The detailed structural informationobtained from the present work might be a valuable reference for future computational studies ofhistamine binding with various biomacromolecular systems.
In the first part of the third chapter, various quantum mechanical/molecular mechanical(QM/MM) geometry optimizations starting from an x-ray crystal structure and from the snapshotstructures of constrained molecular dynamics (MD) simulations have been performed to characterizetwo dynamically stable active site structures of phosphodiesterase-5 (PDE5) in solution. The onlydifference between the two PDE5 structures exists in the catalytic, second bridging ligand (BL2)which is HO~- or H_2O. It has been shown that, whereas BL2 (i.e. HO~-) in the PDE5(BL2=HO~-)structure can really bridge the two positively charged metal ions (Zn~(2+) and Mg~(2+)), BL2 (/.e. 1-120) inthe PDE5(BL2=H_2O) structure can only coordinate Mg~(2+). It has been demonstrated that the results ofthe QM/MM geometry optimizations are remarkably affected by the solvent water molecules, thedynamics of the protein environment, and the embedded charges of the MM region in the QM part ofthe QMM/MM calculation. The PDE5(BL2=H_2O) geometries optimized by using the QM/MMmethod in different ways show strong couplings between these important factors. ThePDE5(BL2=H_2O) geometries determined by the QM/MM calculations neglecting these three factorsare all consistent with the corresponding geometries determined by the QM/MM calculations thataccount for all of these three factors. These results suggest the overall effects of these three importantfactors on the optimized geometries can be roughly canceled out. However, the QM/MM calculationsthat only account for some of these factors could lead to considerably different geometries. Theseresults might be useful also in guiding future QM/MM geometry optimizations on other enzymes. Inthe second part of the third chapter, molecular docking and 3D-QSAR analyses were performed tounderstand how PDE5 and PDE6 interact with a series of cyclic guanine derivatives. Using theconformations of the compounds revealed by molecular docking, CoMFA and CoMSIA analysesresulted in the first quantitative structure-activity relationship (QSAR) and first quantitativestructure-selectivity relationship (QSSR) models (with high cross-validated correlation coefficient q~2 and conventional correlation coefficient r~2 values) for predicting the inhibitory activity against PDE5and the selectivity against PDE6. The high q~2 and r~2 values, along with further testing, indicate thatthe obtained 3D-QSAR and 3D-QSSR models will be valuable in predicting both the inhibitoryactivity and selectivity of cyclic guanine derivatives for these protein targets.
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