葡萄糖苷酶催化机理及几类新型药物作用机制的理论研究
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摘要
低聚糖是各种有机体的主要能源物质,它可以由地球上最丰富的聚合物—维素的分解转化而得到,也可以由单糖的聚合而得到。这两种转化都要靠糖苷酶的催化作用来实现。在纤维素水解过程中起催化作用的酶称为糖苷水解酶,而在单糖聚合过程中起催化作用的酶称为糖基合成酶。目前实验上已经得到了许多糖苷水解酶和糖基合成酶的晶体结构,并且通过突变实验得到了活性口袋处起催化作用的残基,另外,人们从理论上也对一些糖苷酶的催化机理进行了研究。但是总的来说,仍然有很多糖苷酶的反应机理尚不十分明确。本论文利用量子力学和分子力学相结合的方法(QM/MM)对几种糖苷酶的催化机理进行了研究。
关于药物作用机制及生物大分子的分子模拟也是化学研究的一个热点领域,深入探索药物分子和受体蛋白之间的作用机制对于药物的筛选和设计具有重要的指导意义。维生素D受体、孕酮受体、人的EP3受体等均是重要的靶点,可用于治疗骨质疏松、乳腺痛、动脉硬化等一系列疾病,本论文用多种,理论化学方法(分子模拟、QM/MM和3D-QSAR)深入探索了几类新型药物分子与这些药物靶点的作用模式、生物大分子在药物作用下的构象变化以及在此研究基础上的药物设计。
本论文主要工作描述如下：
(1)水稻p-型葡萄糖苷酶催化机理研究。
◆糖基化和去糖基化机理研究。从微生物酶进化而来的水稻p-型葡萄糖苷酶(BGlul,即3Os3bglu7)比其它植物酶的同源性更好,在水解低聚糖方面更有效。水稻BGlul葡萄糖苷酶的催化水解过程遵循的是双取代机理,主要包括糖基化和去糖基化两个步骤。为了探索这种酶的催化机理,我们用联合的量子力学／分子力学(QM/MM)方法对水稻BGlul葡萄糖苷酶催化昆布二糖水解的糖基化机理进行了研究。计算结果表明,此反应的糖基化是一个协同反应,即作为酸碱催化剂(acid/base)的E176进攻糖基氧和作为亲核试剂的E386进攻异头碳是同步的；反应形成的过渡态具有阳离子特性,反应能垒为15.7kcal/mol;在过渡中端基糖环向椅式构象转化,平面化趋势加强。
本文对去糖基化过程也进行了研究。研究表明,此反应也经历一个协同过程到达最终的产物,反应能垒为21.4kcal/mol；反应形成的过渡态同样具有碳正离子特性;在过渡态中,E386与底物的C2-OH之间仍有氢桥相互作用。这种氢键相互作用有利于糖环由椅式构象变成半椅式构象,并且可以稳定过渡态的碳正离子,与实验结果相符。
至此,我们已经系统地研究了水稻葡萄糖苷酶催化昆布二糖水解的糖基化和去糖基化两个过程,反应物构型与传统的量子化学方法有相似之处,但是反应的能垒更低。希望我们的研究结果可以为今后人们更好地研究糖苷酶提供理论性的指导作用。
◆E386突变体催化寡糖合成机理研究。作为高效率的糖苷合成酶,β-型葡萄糖苷酶的亲核残基突变体可以用来合成低聚糖。我们采用QM/MM组合方法进一步研究了水稻BGlul葡萄糖苷酶亲核残基E386突变体(E386G、E386S和E386A)合成低聚糖的催化机理。研究结果表明,此合成机理是单步反应,即E176夺取氢质子和糖苷键的形成是一个协同过程；反应能垒受突变残基侧链空间位阻的影响比较大,突变体E386G、E386S和E386A的催化反应能垒分别为22.4、25.7和28.2kcal/mol,很好的解释了相关的突变实验活性的递变结果。
(2)多形拟杆菌α-型葡萄糖苷酶水解机理研究。作为重要的革兰氏阳性菌种,多形拟杆菌(B. thetaiotaomicron)是一种主要寄生在人的内脏器官的寄生菌。作为糖苷酶GH97家族中的一员,BtGH97a是一种α-型葡萄糖苷酶。这种酶可以把碳水化合物分解成可供寄主吸收的物质。因此,我们采用QM/MM组合方法对BtGH97a催化底物pNP-Glc水解的机理进行了研究,主要分析了两种可能的分步反应路径：亲核进攻优先路径和质子进攻优先路径。在第一种路径中,首先一个水分子被亲核碱残基(E439或E508)去质子化再进攻底物pNP-Glc的异头碳完成亲核进攻过程,然后酸性氨基酸残基E532进攻糖苷氧完成质子进攻过程。在第二条反应路径中,首先是E532进攻糖苷氧完成质子进攻过程,然后去质子化的水(亲核碱为E439或E508)进攻底物的异头碳完成亲核进攻过程。计算结果表明,亲核进攻优先路径是有利的反应路径,而其亲核进攻过程是速率决定步骤(能垒为15.4kcal/mol,E508作为亲核碱)。在这个决速步中,水分子去质子化和糖苷氧的质子化过程是协同的；在质子进攻优先路径中,质子进攻糖苷氧是速率决定步骤,能垒为24.1kcal/mol。所以,通过比较我们发现此水解反应遵循的是亲核进攻优先路径。本次研究工作主要回答了哪一个氨基酸残基是最可能的辅助亲核碱以及最可能的反应路径。
(3)维生素D受体构象变化和相关抑制剂的3D-QSAR研究。
◆维生素D受体配体结合区的构象变化研究。维生素D受体(VDR)是一种核激素受体。VDR需要结合一定的配体(天然激素或类似物)才能实现其功能表达。我们用分子动力学(MD)模拟方法研究了人类维生素D受体(hVDR)在与1α,25(OH)2D3(天然激素配体)及其两种类似物(在文章中用b和c表示)结合时配体结合区(LBD)的构象变化情况。MD模拟结果显示,这些配体可以引起LBD的不同构象变化：1α,25(OH)2D3只引起很小的的变化,这表明VDR结合天然配体时采取典型的活性构象；而b和c则会导致LBD结构的明显重排,这种结构重排现象明显地扩大了配体结合口袋,与实验测定结果一致。本文的计算结果可以帮助人们更好地认识VDR对于不同抑制剂分子的识别,并可以对人们设计低钙活性的VDR抑制剂提供参考信息。
◆维生素D326,23-内酯类抑制剂的3D-QSAR研究。三维定量构效关系(3D-QSAR)方法是药物设计领域一种非常有效的药物设计方法,基于它我们可以设计出具有更高预测活性的抑制剂分子。利用这种方法本文对82个25-脱氢-1α-羟基维生素D3-26,23-内酯类抑制剂进行了研究,并由此构建了比较分子场分析(CoMFA)(?)(?)比较分子相似性指数分析(CoMSIA)模型。CoMFA模型给出的交叉验证(q2)和非交叉验证(r2ncv)的参数值分别为0.516和0.667,而CoMSIA模型给出的q2和r2ncv值分别为0.517和0.632。这两个模型给出的预测性参数rpred2值分别为0.639和0.619。总体上来说,CoMFA模型的预测能力在这里要优于CoMSIA模型。所以,基于CoMFA模型,我们设计了一些高预测活性的维生素D3类抑制剂,并通过自由能围绕(FEP)模拟揭示了这些所设计分子的合理性。
(4)孕酮受体抑制剂的3D-QSAR研究。对于54种孕酮受体(PR)抑制剂,我们构建了基于受体的CoMFA和CoMSIA模型。CoMFA模型统计出的结果为：交叉验证系数q2=0.534,非交叉验证系数r2ncv=0.947。CoMSIA模型统计结果为：q2=0.615,r2ncv=0.954。这两个模型给出的预测相关系数r2pred分别为0681(CoMFA)和0.677(CoMSIA)。基于预测性较好的CoMFA模型,我们设计了两类PR抑制剂,均表现出较高的预测活性。对于两种典型的PR抑制剂,我们用QM/MM组合方法给出了其在活性位点处可能的结合模式。这将为PR类抑制剂分子的药物设计提供有用的理论信息。
(5)EP3受体抑制剂的3D-QSAR研究。本文对57个人的EP3受体抑制剂进行了3D-QSAR研究,并构建了CoMFA和CoMSIA模型。这两个模型统计出的交叉验证系数q2分别为0.505和0.492,非交叉验证系数r2ncv分别为0.937和0.921,这两个模型得到的预测相关系数分别为0.549和0.540。通过比较我们发现CoMFA模型的预测能力较好。所以,基于CoMFA模型,对相关EP3抑制剂的主要结构参数进行了确认,并设计了一些具有较高预测活性的抑制剂。这将为EP3类抑制剂的设计和开发提供有用的理论信息。
本研究论文的主要创新点如下：
◆用QM/MM组合方法系统地研究了水稻BGlul葡萄糖苷酶的保持型催化机理及其突变体催化低聚糖合成的机理。计算中充分考虑了蛋白质环境和活性中心残基对反应的影响,可以提供更加接近实验事实的结构和能垒数据,能够更好地揭示水稻BGlul葡萄糖苷酶催化作用的实质,并且可以得到一些单从晶体结构无法得到的信息(如对E386G、E386S (?)口E386A突变体催化低聚糖合成机理的研究,我们成功地解释三种突变体活性顺次减弱的原因),在分子水平上阐明了水稻葡萄糖苷酶的催化机制。
◆用QM/MM方法系统研究了多形拟杆菌α-型葡萄糖苷酶翻转型催化机理,在研究中我们设计了两种可能的反应路径,通过对对比四种可能进行的反应情况研究,得到了最可能的反应路径和对催化反应起关键作用的残基。
◆系统研究了几种重要靶蛋白如维生素D、孕酮受体和前列腺素受体与相应药物分子作用机制,应用3D-QSAR模型得到了这些药物分子的结构一活性关系并构建了具有高度预测性的构效关系模型,设计了药物活性更好的药物分子,引入QM/MM组合方法精确地给出了新设计抑制剂的结合模式,同时结合自由能围绕方法(FEP)来评价新设计抑制剂的合理性。这为今后相关的药物筛选和设计提供了有价值的理论指导信息。
As the main energy sources of a variety of organisms, the oligosaccharides may be converted from the most abundant biopolymers-cellulose on earth, or be obtained by the monosaccharide polymerization. The relizations of the two transformations are depended on the the catalytic effects of the glycosidases. The enzymes to hydrolyze the cellulose are called as glycohydrolase, and the monosaccharide polymerizations are catalyzed by glycosynthases. At present, various kinds of crystals for the glycohydrolases and glycosynthases have been crystallized and the catalytic residues in the active sites have been identifized by one point mutations. Though people have paied much attention to the catalytic reactions of glycosidases in theory, many reaction mechanisms of glycosidase are still not very clear. In this research, we used the combined quantum mechanics and the molecular mechanics (QM/MM) methods to study several kinds of glycosidases catalytic mechanisms.
Biomacromolecules, such as vitamin D receptor, progesterone receptor, human EP3receptor and so on, are served as the targets for drugs design and synthesis, which are mainly used to treat human major diseases, such as osteoporosis, Paget's disease of bone, mastalgia, peripheral arterial disease and so on. The investigations of interactions between drugs and biomacromolecules are thought to be important in treatment of major diseases and the foundation for drugs design and synthesis. In order to explore the binding modes and inhibition mechanisms of several inhibitors that interact with vitamin D receptor, progesterone receptor, human EP3receptor from molecular prespective, we use the theoretical chemistry methods (molecular simulations, QM/MM and3D-QSAR) to study the binding modes, conformational changes and3D-QSAR based drug designs. Many valuable results have been got, which are described as follows:
(1) The catalytic mechanism studies of the rice BGlu1β-glucosidase.
The glycosylation and deglycosylation mechanisms of the rice BGlu1β-glucosidase. The rice BGlu1(namely Os3bglu7), which evolves from the microbial enzymes, is more closely related to plant enzymes and more efficiently to hydrolyze cello-oligosaccharides. In order to explore the catalysis mechanism of this enzyme, the QM/MM method was used to study the glycosylation mechanism of rice BGlu1 P-glucosidase in complex with laminaribiose. The calculation results reveal that the glycosylation step experiences a concerted process from the reactant to the glycosyl-enzyme complex with an activation barrier of15.7kcal/mol, in which an oxocarbenium cation-like transition state (TS) is formed. At the TS, the terminal saccharide residue planarizes toward the half-chair conformation, and the glycosidic bond cleavage is promoted by the attacks of proton donor (E176) on glycosidic oxygen and nucleophilic residue (E386) on the anomeric carbon of laminaribiose. Both the nucleophilic glutamate (E386) and acid/base catalyst (E176) establish shorter hydrogen bridges with the C2-hydroxyl groups of sugar ring, which play an important role in the catalytic reaction of rice BGlul β-glucosidase. This study determines the pathway of the catalytic mechanism and achieves a better description of the glycosylation process.
It is proposed that the catalysis of BGlul follows a double-displacement mechanism involving a glycosylation and a deglycosylation steps. The deglycosylation step of the substrate laminaribiose catalyzed by rice BGlul β-glucosidase. by using QM/MM approach. The calculation results reveal that the nucleophilic water (Watl) attacks to the anomeric C1, and the deglycosylation step experiences a barrier of21.4kcal/mol from the glycosyl-enzyme intermediate to the hydrolysis product, in which an oxocarbenium cation-like TS is formed. At the TS, the covalent glycosyl-enzyme bond is almost broken (distance of2.45A), and the new covalent bond between the attacking oxygen of the water molecule and C1is basically established (length of2.14A). In addition, a short hydrogen bridge is observed between the nucleophilic E386and the C2-OH of sugar ring (distance of1.94A) at the TS, which facilitates the ring changing from a chair form to half-chair form, and stabilizes the oxocarbenium cation-like TS.
So far, we have studied the whole mechanism of the substrate laminaribiose catalyzed by rice BGlul β-glucosidase. We hope our studies could give a better understanding of the hydrolysis mechanism of β-glucosidase in future.
? The synthesis mechanism of the rice BGlul β-glucosidase E386mutants. The mutant of a β-glycosidase could act as the glycosynthase to efficiently synthesize oligosaccharides with high yields. In this study, the mechanisms of oligosaccharide synthesis promoted by rice BGlul E386mutants (E386G, E386S and E386A) have been studied by using QM/MM approach. This mechanism is a single step, in which the abstract of the proton by the acid/base E176, the formation of the glycosidic bond and the departure of the leaving group are concerted. The energy barriers are sensitive to sterically hindered interactions of the mutated residues. The energy barriers of E386Q E386S and E386A are calculated to be22.4,25.7and28.2kcal/mol, where the sequence is consistent with the experimental results. Besides, the role of the incoming crystal water Watl in the active site is also explored. Our results gives a good explanation of why the activity of Gly is better than Ser, and Ser than Ala, which cannot be explained from the crystal structure alone.
(2) The hydrolysis mechanism of Bacteroides thetaiotaomicron a-glucosidase BtGH97a. Bacteroides thetaiotaomicron (B. thetaiotaomicron), a Gram-negative anaerobe, is a bacterial symbiont. It is a dominant member of the intestinal microbiota of human gut. BtGH97a is one member of glycoside hydrolases (GHs) families GH97. This kind of enzyme plays a major role in the breakdown of polysaccharides ingested in the diet into a form that could be absorbed and utilized by the host. In this paper, the hydrolysis mechanism of pNP-Glc catalyzed by BtGH97a was firstly studied by using QM/MM approach. Two possible reaction pathways were considered. In the first pathway, a water molecule deprotonated by a nucleophilic base (here E439or E508) attacks firstly on the anomeric carbon of pNP-Glc, then a proton from an acid residue (E532) attacks on the glycosidic oxygen to finish the hydrolysis reaction (named as nucleophilic attack-first pathway). In the second pathway, the proton from E532attacks firstly on the glycosidic oxygen, then the water deprotonated by the nucleophilic base attacks on the anomeric carbon of pNP-Glc (named as proton attack-first pathway). Our calculation results indicate that the nucleophilic attack-first pathway is favourable in energy, in which the nucleophilic attack process is the rate-determining step with an energy barrier of15.4kcal/mol in the case of residue E508as nucleophilic base. In this rate-determining step, the deprotonation of water and the attack on the anomeric carbon are concerted. In the proton attack-first pathway, the proton attack on the glycosidic oxygen is the rate-determining step, and the energy barrier is24.1kcal/mol. We conclude that the hydrolysis mechanism would follow nucleophilic attack-first pathway. Our present work has answered some meaningful questions, such as which residue is the most favorable nucleophilic base to assist the hydrolysis reaction, and which pathway is the most possible.
(3) The Structural Rearrangement of vitamin D receptor and3D-QSAR study of its inhibitors.
The structural rearrangement of vitamin D receptor ligand binding domain. Vitamin D receptor (VDR) is a member of nuclear hormone receptor super family. The activity of VDR is induced by the natural hormone and its analogues. The structural rearrangement of the ligand binding domain (LBD) of human Vitamin D receptor (hVDR) complex ed with1α,25-dihydroxyvitamin D3(natural ligand) and its analogues (denoted as b and c) was studied by molecular dynamics (MD) simulations. MD simulations revealed that these ligands could induce different structural changes of LBD, in which la,25-dihydroxyvitamin D3only led to a minute change, suggesting that LBD adopted its canonical active conformation upon binding the natural ligand, while b and c could provoke a clear structural rearrangement of the LBD. In complex of hVDR-LBD/b, it is found that helix6(H6) and subsequent loop6-7shift outwards and the last turn of H11shifts away from H12, which generate a new cavity at the bottom of the binding pocket in order to accommodate the extra butyl group on the side chain of ligand b. As for hVDR-LBD/c, the steric exclusion of the second side chain of ligand c makes the N-terminal of H7move outsides and C-terminal of H11close to H12, expanding the bottom of the pocket. These calculation results agree well with the experimental observations. The results provide the train of thought for the understanding of the interactions between the inhibitors and VDR and further for the design of new VDR inhibitors with reducing the calcemic side effects.
3D-QSAR study of a series of vitamin D3-26,23-lactone analogs.3D-QSAR approach is one of the most useful tool for drug design. It can design potential molecules with high predictive activities. The ligand-based3D-QSAR for82inhibitors of25-dehydro-la-hydroxyvitamin D3-26,23-lactone analogs has been studied by using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models. The established CoMFA model in training set gives the cross-validated q2value of0.516and non-cross-validated r2ncv value of0.667, while the CoMSIA model represents a q2of0.517and r2ncv of0.632. In general, the predictive ability of CoMFA model is superior to CoMSIA model, in which the r2pred of CoMFA is0.639and that of CoMSIA is0.619. Based on the CoMFA contour maps, some key structural characters of vitamin D3analogs responsible for inhibitory activity are identified, and some new C2a-modified24-alkylvitamin D3lactone analogs with high predicted values are designed. The ligand functional group mutations by FEP simulation and docking studies reveal the rationality of the molecular design. In this study, we design some newly designed inhibitors not only possess higher predicted pIC50values but also with better binding model. We expect to give some targeted lead compounds for the drug design and discovery research.
(4)3D-QSAR study of progesterone receptor (PR) inhibitors. The receptor-based CoMFA and CoMSIA were performed on a series of54PR inhibitors. The established CoMFA model in training set gives statistically significant results with the cross-validated q2of0.534and non-cross-validated r2ncv of0.947. The best CoMSIA model was derived by the combination use of steric and hydrophobic fields with a q2of0.615and r2ncv of0.954. A test set of18compounds were utilized to validate the predictive abilities of the two models. The values of predicted correlation coefficient r2pred are0.681and0.677for CoMFA and CoMSIA, respectively. Based on the CoMFA maps, the key structural characters of PR inhibitors are identified. Two binding models of oxindoles and benzimidazol-2-ones are given by the QM/MM calculations. This may provide useful theoretical information for drug design of PR inhibitors.
(5)3D-QSAR study of human EP3receptor antagonists. Prostanoids generated in vivo act with EP3receptor, and play a key role in vascular homeostasis, such as platelet function regulation. In this study, the ligand-based CoMFA and CoMSIA methods were performed on a series of57selective human EP3receptor antagonists. The best CoMFA and CoMSIA models in training set derive statistically significant results with the cross-validated q2values of0.505and0.492, non-cross-validated r2ncv values of0.937and0.921, respectively. A test set of20compounds was utilized to validate the predictive abilities of the two models. The values of predicted correlation coefficient r2pred are0.549and0.540for CoMFA and CoMSIA, respectively. Based on the CoMFA maps, the key structural characters of human EP3inhibitors are identified. This may provide useful information for drug design.
The primary innovations are as follows:
? We systematically investigated the remaining hydrolysis mechanisms of the remaining glucosidase (rice BGlul β-glucosidase) as well as oligosaccharide synthesis mechanism catalyzed by the corresponding mutants by the combined QM/MM methods. Comparing to the traditional quantum chemistry methods, our research methods consider fully the interactions of the active center residues and the corresponding protonated states of the catalytic residues, which could provide much accurate data of the structures and energy barriers closer to the experimental fact. This could give better explanations of the catalysis essence of rice BGlul glucosidase, which could not be explained from the crystal structure alone (such as the order of the catalyzed oligosaccharide synthesis mechanisms of E386G, E386S and E386A mutant).
We systematically investigated the inverting hydrolysis mechanism of Bacteroides thetaiotaomicron a-glucosidase BtGH97a. Two possible reaction pathways were designed. The transition states and energy barriers for each pathway were investigated. The work resolved which residue was the most favorable nucleophilic base to assist the hydrolysis reaction, and which pathway was the most possible.
For a series of new drug molecules (vitamin D3inhibitors, progesterone receptor inhibitors and human EP3receptor inhibitors), the binding modes and highly predictive structure-activity relationship modes were constructed by the molecular docking and3D-QSAR methods, and some new inhibitors of vitamin D3inhibitors, progesterone receptor inhibitors and human EP3receptor inhibitors with higher predictive activities were designed. According the newly designed molecules, we introduce the combined QM/MM method to predict their binding modes, which may provide theoretical guidances for drug design and synthesis in the future.
关于药物作用机制及生物大分子的分子模拟也是化学研究的一个热点领域,深入探索药物分子和受体蛋白之间的作用机制对于药物的筛选和设计具有重要的指导意义。维生素D受体、孕酮受体、人的EP3受体等均是重要的靶点,可用于治疗骨质疏松、乳腺痛、动脉硬化等一系列疾病,本论文用多种,理论化学方法(分子模拟、QM/MM和3D-QSAR)深入探索了几类新型药物分子与这些药物靶点的作用模式、生物大分子在药物作用下的构象变化以及在此研究基础上的药物设计。
本论文主要工作描述如下：
(1)水稻p-型葡萄糖苷酶催化机理研究。
◆糖基化和去糖基化机理研究。从微生物酶进化而来的水稻p-型葡萄糖苷酶(BGlul,即3Os3bglu7)比其它植物酶的同源性更好,在水解低聚糖方面更有效。水稻BGlul葡萄糖苷酶的催化水解过程遵循的是双取代机理,主要包括糖基化和去糖基化两个步骤。为了探索这种酶的催化机理,我们用联合的量子力学／分子力学(QM/MM)方法对水稻BGlul葡萄糖苷酶催化昆布二糖水解的糖基化机理进行了研究。计算结果表明,此反应的糖基化是一个协同反应,即作为酸碱催化剂(acid/base)的E176进攻糖基氧和作为亲核试剂的E386进攻异头碳是同步的；反应形成的过渡态具有阳离子特性,反应能垒为15.7kcal/mol;在过渡中端基糖环向椅式构象转化,平面化趋势加强。
本文对去糖基化过程也进行了研究。研究表明,此反应也经历一个协同过程到达最终的产物,反应能垒为21.4kcal/mol；反应形成的过渡态同样具有碳正离子特性;在过渡态中,E386与底物的C2-OH之间仍有氢桥相互作用。这种氢键相互作用有利于糖环由椅式构象变成半椅式构象,并且可以稳定过渡态的碳正离子,与实验结果相符。
至此,我们已经系统地研究了水稻葡萄糖苷酶催化昆布二糖水解的糖基化和去糖基化两个过程,反应物构型与传统的量子化学方法有相似之处,但是反应的能垒更低。希望我们的研究结果可以为今后人们更好地研究糖苷酶提供理论性的指导作用。
◆E386突变体催化寡糖合成机理研究。作为高效率的糖苷合成酶,β-型葡萄糖苷酶的亲核残基突变体可以用来合成低聚糖。我们采用QM/MM组合方法进一步研究了水稻BGlul葡萄糖苷酶亲核残基E386突变体(E386G、E386S和E386A)合成低聚糖的催化机理。研究结果表明,此合成机理是单步反应,即E176夺取氢质子和糖苷键的形成是一个协同过程；反应能垒受突变残基侧链空间位阻的影响比较大,突变体E386G、E386S和E386A的催化反应能垒分别为22.4、25.7和28.2kcal/mol,很好的解释了相关的突变实验活性的递变结果。
(2)多形拟杆菌α-型葡萄糖苷酶水解机理研究。作为重要的革兰氏阳性菌种,多形拟杆菌(B. thetaiotaomicron)是一种主要寄生在人的内脏器官的寄生菌。作为糖苷酶GH97家族中的一员,BtGH97a是一种α-型葡萄糖苷酶。这种酶可以把碳水化合物分解成可供寄主吸收的物质。因此,我们采用QM/MM组合方法对BtGH97a催化底物pNP-Glc水解的机理进行了研究,主要分析了两种可能的分步反应路径：亲核进攻优先路径和质子进攻优先路径。在第一种路径中,首先一个水分子被亲核碱残基(E439或E508)去质子化再进攻底物pNP-Glc的异头碳完成亲核进攻过程,然后酸性氨基酸残基E532进攻糖苷氧完成质子进攻过程。在第二条反应路径中,首先是E532进攻糖苷氧完成质子进攻过程,然后去质子化的水(亲核碱为E439或E508)进攻底物的异头碳完成亲核进攻过程。计算结果表明,亲核进攻优先路径是有利的反应路径,而其亲核进攻过程是速率决定步骤(能垒为15.4kcal/mol,E508作为亲核碱)。在这个决速步中,水分子去质子化和糖苷氧的质子化过程是协同的；在质子进攻优先路径中,质子进攻糖苷氧是速率决定步骤,能垒为24.1kcal/mol。所以,通过比较我们发现此水解反应遵循的是亲核进攻优先路径。本次研究工作主要回答了哪一个氨基酸残基是最可能的辅助亲核碱以及最可能的反应路径。
(3)维生素D受体构象变化和相关抑制剂的3D-QSAR研究。
◆维生素D受体配体结合区的构象变化研究。维生素D受体(VDR)是一种核激素受体。VDR需要结合一定的配体(天然激素或类似物)才能实现其功能表达。我们用分子动力学(MD)模拟方法研究了人类维生素D受体(hVDR)在与1α,25(OH)2D3(天然激素配体)及其两种类似物(在文章中用b和c表示)结合时配体结合区(LBD)的构象变化情况。MD模拟结果显示,这些配体可以引起LBD的不同构象变化：1α,25(OH)2D3只引起很小的的变化,这表明VDR结合天然配体时采取典型的活性构象；而b和c则会导致LBD结构的明显重排,这种结构重排现象明显地扩大了配体结合口袋,与实验测定结果一致。本文的计算结果可以帮助人们更好地认识VDR对于不同抑制剂分子的识别,并可以对人们设计低钙活性的VDR抑制剂提供参考信息。
◆维生素D326,23-内酯类抑制剂的3D-QSAR研究。三维定量构效关系(3D-QSAR)方法是药物设计领域一种非常有效的药物设计方法,基于它我们可以设计出具有更高预测活性的抑制剂分子。利用这种方法本文对82个25-脱氢-1α-羟基维生素D3-26,23-内酯类抑制剂进行了研究,并由此构建了比较分子场分析(CoMFA)(?)(?)比较分子相似性指数分析(CoMSIA)模型。CoMFA模型给出的交叉验证(q2)和非交叉验证(r2ncv)的参数值分别为0.516和0.667,而CoMSIA模型给出的q2和r2ncv值分别为0.517和0.632。这两个模型给出的预测性参数rpred2值分别为0.639和0.619。总体上来说,CoMFA模型的预测能力在这里要优于CoMSIA模型。所以,基于CoMFA模型,我们设计了一些高预测活性的维生素D3类抑制剂,并通过自由能围绕(FEP)模拟揭示了这些所设计分子的合理性。
(4)孕酮受体抑制剂的3D-QSAR研究。对于54种孕酮受体(PR)抑制剂,我们构建了基于受体的CoMFA和CoMSIA模型。CoMFA模型统计出的结果为：交叉验证系数q2=0.534,非交叉验证系数r2ncv=0.947。CoMSIA模型统计结果为：q2=0.615,r2ncv=0.954。这两个模型给出的预测相关系数r2pred分别为0681(CoMFA)和0.677(CoMSIA)。基于预测性较好的CoMFA模型,我们设计了两类PR抑制剂,均表现出较高的预测活性。对于两种典型的PR抑制剂,我们用QM/MM组合方法给出了其在活性位点处可能的结合模式。这将为PR类抑制剂分子的药物设计提供有用的理论信息。
(5)EP3受体抑制剂的3D-QSAR研究。本文对57个人的EP3受体抑制剂进行了3D-QSAR研究,并构建了CoMFA和CoMSIA模型。这两个模型统计出的交叉验证系数q2分别为0.505和0.492,非交叉验证系数r2ncv分别为0.937和0.921,这两个模型得到的预测相关系数分别为0.549和0.540。通过比较我们发现CoMFA模型的预测能力较好。所以,基于CoMFA模型,对相关EP3抑制剂的主要结构参数进行了确认,并设计了一些具有较高预测活性的抑制剂。这将为EP3类抑制剂的设计和开发提供有用的理论信息。
本研究论文的主要创新点如下：
◆用QM/MM组合方法系统地研究了水稻BGlul葡萄糖苷酶的保持型催化机理及其突变体催化低聚糖合成的机理。计算中充分考虑了蛋白质环境和活性中心残基对反应的影响,可以提供更加接近实验事实的结构和能垒数据,能够更好地揭示水稻BGlul葡萄糖苷酶催化作用的实质,并且可以得到一些单从晶体结构无法得到的信息(如对E386G、E386S (?)口E386A突变体催化低聚糖合成机理的研究,我们成功地解释三种突变体活性顺次减弱的原因),在分子水平上阐明了水稻葡萄糖苷酶的催化机制。
◆用QM/MM方法系统研究了多形拟杆菌α-型葡萄糖苷酶翻转型催化机理,在研究中我们设计了两种可能的反应路径,通过对对比四种可能进行的反应情况研究,得到了最可能的反应路径和对催化反应起关键作用的残基。
◆系统研究了几种重要靶蛋白如维生素D、孕酮受体和前列腺素受体与相应药物分子作用机制,应用3D-QSAR模型得到了这些药物分子的结构一活性关系并构建了具有高度预测性的构效关系模型,设计了药物活性更好的药物分子,引入QM/MM组合方法精确地给出了新设计抑制剂的结合模式,同时结合自由能围绕方法(FEP)来评价新设计抑制剂的合理性。这为今后相关的药物筛选和设计提供了有价值的理论指导信息。
As the main energy sources of a variety of organisms, the oligosaccharides may be converted from the most abundant biopolymers-cellulose on earth, or be obtained by the monosaccharide polymerization. The relizations of the two transformations are depended on the the catalytic effects of the glycosidases. The enzymes to hydrolyze the cellulose are called as glycohydrolase, and the monosaccharide polymerizations are catalyzed by glycosynthases. At present, various kinds of crystals for the glycohydrolases and glycosynthases have been crystallized and the catalytic residues in the active sites have been identifized by one point mutations. Though people have paied much attention to the catalytic reactions of glycosidases in theory, many reaction mechanisms of glycosidase are still not very clear. In this research, we used the combined quantum mechanics and the molecular mechanics (QM/MM) methods to study several kinds of glycosidases catalytic mechanisms.
Biomacromolecules, such as vitamin D receptor, progesterone receptor, human EP3receptor and so on, are served as the targets for drugs design and synthesis, which are mainly used to treat human major diseases, such as osteoporosis, Paget's disease of bone, mastalgia, peripheral arterial disease and so on. The investigations of interactions between drugs and biomacromolecules are thought to be important in treatment of major diseases and the foundation for drugs design and synthesis. In order to explore the binding modes and inhibition mechanisms of several inhibitors that interact with vitamin D receptor, progesterone receptor, human EP3receptor from molecular prespective, we use the theoretical chemistry methods (molecular simulations, QM/MM and3D-QSAR) to study the binding modes, conformational changes and3D-QSAR based drug designs. Many valuable results have been got, which are described as follows:
(1) The catalytic mechanism studies of the rice BGlu1β-glucosidase.
The glycosylation and deglycosylation mechanisms of the rice BGlu1β-glucosidase. The rice BGlu1(namely Os3bglu7), which evolves from the microbial enzymes, is more closely related to plant enzymes and more efficiently to hydrolyze cello-oligosaccharides. In order to explore the catalysis mechanism of this enzyme, the QM/MM method was used to study the glycosylation mechanism of rice BGlu1 P-glucosidase in complex with laminaribiose. The calculation results reveal that the glycosylation step experiences a concerted process from the reactant to the glycosyl-enzyme complex with an activation barrier of15.7kcal/mol, in which an oxocarbenium cation-like transition state (TS) is formed. At the TS, the terminal saccharide residue planarizes toward the half-chair conformation, and the glycosidic bond cleavage is promoted by the attacks of proton donor (E176) on glycosidic oxygen and nucleophilic residue (E386) on the anomeric carbon of laminaribiose. Both the nucleophilic glutamate (E386) and acid/base catalyst (E176) establish shorter hydrogen bridges with the C2-hydroxyl groups of sugar ring, which play an important role in the catalytic reaction of rice BGlul β-glucosidase. This study determines the pathway of the catalytic mechanism and achieves a better description of the glycosylation process.
It is proposed that the catalysis of BGlul follows a double-displacement mechanism involving a glycosylation and a deglycosylation steps. The deglycosylation step of the substrate laminaribiose catalyzed by rice BGlul β-glucosidase. by using QM/MM approach. The calculation results reveal that the nucleophilic water (Watl) attacks to the anomeric C1, and the deglycosylation step experiences a barrier of21.4kcal/mol from the glycosyl-enzyme intermediate to the hydrolysis product, in which an oxocarbenium cation-like TS is formed. At the TS, the covalent glycosyl-enzyme bond is almost broken (distance of2.45A), and the new covalent bond between the attacking oxygen of the water molecule and C1is basically established (length of2.14A). In addition, a short hydrogen bridge is observed between the nucleophilic E386and the C2-OH of sugar ring (distance of1.94A) at the TS, which facilitates the ring changing from a chair form to half-chair form, and stabilizes the oxocarbenium cation-like TS.
So far, we have studied the whole mechanism of the substrate laminaribiose catalyzed by rice BGlul β-glucosidase. We hope our studies could give a better understanding of the hydrolysis mechanism of β-glucosidase in future.
? The synthesis mechanism of the rice BGlul β-glucosidase E386mutants. The mutant of a β-glycosidase could act as the glycosynthase to efficiently synthesize oligosaccharides with high yields. In this study, the mechanisms of oligosaccharide synthesis promoted by rice BGlul E386mutants (E386G, E386S and E386A) have been studied by using QM/MM approach. This mechanism is a single step, in which the abstract of the proton by the acid/base E176, the formation of the glycosidic bond and the departure of the leaving group are concerted. The energy barriers are sensitive to sterically hindered interactions of the mutated residues. The energy barriers of E386Q E386S and E386A are calculated to be22.4,25.7and28.2kcal/mol, where the sequence is consistent with the experimental results. Besides, the role of the incoming crystal water Watl in the active site is also explored. Our results gives a good explanation of why the activity of Gly is better than Ser, and Ser than Ala, which cannot be explained from the crystal structure alone.
(2) The hydrolysis mechanism of Bacteroides thetaiotaomicron a-glucosidase BtGH97a. Bacteroides thetaiotaomicron (B. thetaiotaomicron), a Gram-negative anaerobe, is a bacterial symbiont. It is a dominant member of the intestinal microbiota of human gut. BtGH97a is one member of glycoside hydrolases (GHs) families GH97. This kind of enzyme plays a major role in the breakdown of polysaccharides ingested in the diet into a form that could be absorbed and utilized by the host. In this paper, the hydrolysis mechanism of pNP-Glc catalyzed by BtGH97a was firstly studied by using QM/MM approach. Two possible reaction pathways were considered. In the first pathway, a water molecule deprotonated by a nucleophilic base (here E439or E508) attacks firstly on the anomeric carbon of pNP-Glc, then a proton from an acid residue (E532) attacks on the glycosidic oxygen to finish the hydrolysis reaction (named as nucleophilic attack-first pathway). In the second pathway, the proton from E532attacks firstly on the glycosidic oxygen, then the water deprotonated by the nucleophilic base attacks on the anomeric carbon of pNP-Glc (named as proton attack-first pathway). Our calculation results indicate that the nucleophilic attack-first pathway is favourable in energy, in which the nucleophilic attack process is the rate-determining step with an energy barrier of15.4kcal/mol in the case of residue E508as nucleophilic base. In this rate-determining step, the deprotonation of water and the attack on the anomeric carbon are concerted. In the proton attack-first pathway, the proton attack on the glycosidic oxygen is the rate-determining step, and the energy barrier is24.1kcal/mol. We conclude that the hydrolysis mechanism would follow nucleophilic attack-first pathway. Our present work has answered some meaningful questions, such as which residue is the most favorable nucleophilic base to assist the hydrolysis reaction, and which pathway is the most possible.
(3) The Structural Rearrangement of vitamin D receptor and3D-QSAR study of its inhibitors.
The structural rearrangement of vitamin D receptor ligand binding domain. Vitamin D receptor (VDR) is a member of nuclear hormone receptor super family. The activity of VDR is induced by the natural hormone and its analogues. The structural rearrangement of the ligand binding domain (LBD) of human Vitamin D receptor (hVDR) complex ed with1α,25-dihydroxyvitamin D3(natural ligand) and its analogues (denoted as b and c) was studied by molecular dynamics (MD) simulations. MD simulations revealed that these ligands could induce different structural changes of LBD, in which la,25-dihydroxyvitamin D3only led to a minute change, suggesting that LBD adopted its canonical active conformation upon binding the natural ligand, while b and c could provoke a clear structural rearrangement of the LBD. In complex of hVDR-LBD/b, it is found that helix6(H6) and subsequent loop6-7shift outwards and the last turn of H11shifts away from H12, which generate a new cavity at the bottom of the binding pocket in order to accommodate the extra butyl group on the side chain of ligand b. As for hVDR-LBD/c, the steric exclusion of the second side chain of ligand c makes the N-terminal of H7move outsides and C-terminal of H11close to H12, expanding the bottom of the pocket. These calculation results agree well with the experimental observations. The results provide the train of thought for the understanding of the interactions between the inhibitors and VDR and further for the design of new VDR inhibitors with reducing the calcemic side effects.
3D-QSAR study of a series of vitamin D3-26,23-lactone analogs.3D-QSAR approach is one of the most useful tool for drug design. It can design potential molecules with high predictive activities. The ligand-based3D-QSAR for82inhibitors of25-dehydro-la-hydroxyvitamin D3-26,23-lactone analogs has been studied by using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models. The established CoMFA model in training set gives the cross-validated q2value of0.516and non-cross-validated r2ncv value of0.667, while the CoMSIA model represents a q2of0.517and r2ncv of0.632. In general, the predictive ability of CoMFA model is superior to CoMSIA model, in which the r2pred of CoMFA is0.639and that of CoMSIA is0.619. Based on the CoMFA contour maps, some key structural characters of vitamin D3analogs responsible for inhibitory activity are identified, and some new C2a-modified24-alkylvitamin D3lactone analogs with high predicted values are designed. The ligand functional group mutations by FEP simulation and docking studies reveal the rationality of the molecular design. In this study, we design some newly designed inhibitors not only possess higher predicted pIC50values but also with better binding model. We expect to give some targeted lead compounds for the drug design and discovery research.
(4)3D-QSAR study of progesterone receptor (PR) inhibitors. The receptor-based CoMFA and CoMSIA were performed on a series of54PR inhibitors. The established CoMFA model in training set gives statistically significant results with the cross-validated q2of0.534and non-cross-validated r2ncv of0.947. The best CoMSIA model was derived by the combination use of steric and hydrophobic fields with a q2of0.615and r2ncv of0.954. A test set of18compounds were utilized to validate the predictive abilities of the two models. The values of predicted correlation coefficient r2pred are0.681and0.677for CoMFA and CoMSIA, respectively. Based on the CoMFA maps, the key structural characters of PR inhibitors are identified. Two binding models of oxindoles and benzimidazol-2-ones are given by the QM/MM calculations. This may provide useful theoretical information for drug design of PR inhibitors.
(5)3D-QSAR study of human EP3receptor antagonists. Prostanoids generated in vivo act with EP3receptor, and play a key role in vascular homeostasis, such as platelet function regulation. In this study, the ligand-based CoMFA and CoMSIA methods were performed on a series of57selective human EP3receptor antagonists. The best CoMFA and CoMSIA models in training set derive statistically significant results with the cross-validated q2values of0.505and0.492, non-cross-validated r2ncv values of0.937and0.921, respectively. A test set of20compounds was utilized to validate the predictive abilities of the two models. The values of predicted correlation coefficient r2pred are0.549and0.540for CoMFA and CoMSIA, respectively. Based on the CoMFA maps, the key structural characters of human EP3inhibitors are identified. This may provide useful information for drug design.
The primary innovations are as follows:
? We systematically investigated the remaining hydrolysis mechanisms of the remaining glucosidase (rice BGlul β-glucosidase) as well as oligosaccharide synthesis mechanism catalyzed by the corresponding mutants by the combined QM/MM methods. Comparing to the traditional quantum chemistry methods, our research methods consider fully the interactions of the active center residues and the corresponding protonated states of the catalytic residues, which could provide much accurate data of the structures and energy barriers closer to the experimental fact. This could give better explanations of the catalysis essence of rice BGlul glucosidase, which could not be explained from the crystal structure alone (such as the order of the catalyzed oligosaccharide synthesis mechanisms of E386G, E386S and E386A mutant).
We systematically investigated the inverting hydrolysis mechanism of Bacteroides thetaiotaomicron a-glucosidase BtGH97a. Two possible reaction pathways were designed. The transition states and energy barriers for each pathway were investigated. The work resolved which residue was the most favorable nucleophilic base to assist the hydrolysis reaction, and which pathway was the most possible.
For a series of new drug molecules (vitamin D3inhibitors, progesterone receptor inhibitors and human EP3receptor inhibitors), the binding modes and highly predictive structure-activity relationship modes were constructed by the molecular docking and3D-QSAR methods, and some new inhibitors of vitamin D3inhibitors, progesterone receptor inhibitors and human EP3receptor inhibitors with higher predictive activities were designed. According the newly designed molecules, we introduce the combined QM/MM method to predict their binding modes, which may provide theoretical guidances for drug design and synthesis in the future.
引文
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