几类重要蛋白质的分子动力学模拟研究
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摘要
酶是大分子蛋白的一种，它是由活细胞产生并具有催化功能的蛋白质。由于计算机技术的日益发展，计算机模拟方法被广泛应用于生物酶研究的科学领域。本文中，基于同家族的相关蛋白质晶体结构，我们利用如量子化学计算，分子模建，分子动力学模拟等多种计算机技术搭建几种高质量的人类生物酶的结构模型。同时，分子对接方法也被引入，用于生物分子复合物的获得及抑制剂的比对研究。主要结果如下：
1.谷胱甘肽硫转移酶家族几种等位基因蛋白酶的分子对接及分子动力学模拟研究
谷胱甘肽硫转移酶(Glutathione S-Transferases, GSTs, E.C.2.5.1.18)是由多个基因编码组成的,具有多种生理功能的家族酶。该家族酶广泛分布于哺乳动物体内,并能通过促进对有毒化合物的亲核攻击而参与细胞解毒过程。其中π家族中的成员GSTP1,因其与肿瘤耐药性密切相关,而被广泛研究。最近的研究结果表明, GSTP1在包括膀胱癌,口腔癌,食道癌,肺癌,肾癌,结肠癌,卵巢癌,睾丸癌,和胃癌等多种人类肿瘤细胞中,存在过度表达的现象。因此, GSTP1作为恶性肿瘤的标志,其耐药性及与肿瘤的关系链已成为肿瘤防治相关领域的研究热点。
借助分子动力学模拟的手段系统地研究了谷胱甘肽硫转移酶家族GSTP1的等位基因蛋白B(GSTP1*B)与抑制剂利尿酸(EA)及EA的谷胱甘肽共轭物EAG(I),EAG(O)的具体结合方式。抑制剂及其谷胱甘肽共轭物与蛋白的相互作用能计算和分子动力学轨迹的统计分析结果表明, GSTP1*B与EA的谷胱甘肽共轭物的结合能力高于EA的结合能力,残基Phe8, Arg13, Trp38和Tyr108是作用过程中的关键残基,对稳定抑制剂及其谷胱甘肽共轭物在GSTP1*B的G-位点和H-位点的构象有着重要的作用。通过对构象的统计分析发现残基Phe8和Tyr108与GSTP1*B酶对抑制剂的选择性密切相关.
另外，自从1991年第一个GSTP1的蛋白质晶体结构在0.23nm结晶条件下被获得,多达168个GSTP1的蛋白质晶体结构被发现。然而,人类GSTP1*D三维(3D)结构的一直未被确定。如果要详细地了解人类GSTP1*D结构—功能的关系，则需要其蛋白质的精确三维结构作为基础。本节中，我们利用如分子模建，分子动力学模拟等多种计算机技术搭建高质量的人类GSTP1的结构模型。同时，分子对接方法也被引入，用于生物分子复合物的获得及抑制剂的比对研究。本节中提出了GSTP1*D与五种抑制剂的相互作用模式，包括利尿酸(EA)，瘤可宁(CBL)，利尿酸的两种谷胱甘肽共轭物EAG(I)、EAG(O)，和瘤可宁的谷胱甘肽共轭物LZ6。这些发现将会为基于结构的GSTP1*D的相关研究提供较好的出发点。
2.人类犬尿氨酸转氨酶III（HKAT3）与底物及抑制剂相互作用的分子模拟
犬尿酸(Kynurenic acid, KYNA)，是唯一已知的内生拮抗剂N-甲基-D-天冬氨酸(NMDA)亚型谷氨酸受体,也可作为拮抗剂R7-烟碱的乙酰胆碱受体。最近,KYNA被确认为一种内源性配体的孤对耦合-G蛋白受体(GPR35)。根据报道，多种神经退行性疾病都与KYNA在中枢神经系统的异常表达水平密切相关,如亨廷顿症,阿尔茨海默症,精神分裂症和获得性免疫缺陷综合痴呆征。此外, KYNA可能对谷氨酸类和类胆碱类所控制的神经传递型心血管疾病的发病有相应的影响。KYNA是存在于大多数哺乳动物细胞组织中的色氨酸代谢途径中间体,该种化合物是由L-KYN配合维生素B6衍生物(pyridoxal5‘-phosphate, PLP)辅酶经由犬尿氨酸转氨酶家族(KATs)催化的不可逆反应生成。
在本文中，我们对来源于人类细胞内的犬尿氨酸转氨酶III(HKAT3)进行了深入研究。基于鼠类KATIII的晶体结构(PDB code:3E2Y)，模建了HKAT3的三维结构模型。此后，对HKAT3的初始模型进行能量最小化和分子动力学优化模拟。该模型通过了Verify-3D和Procheck程序评估。我们还使用CDOCKER方法将两种抑制剂与蛋白对接，获得了酶与配体的作用模型。尽管两种抑制剂作用于相同的活性位点区域，但两者却以不同模式与蛋白HKAT3结合。通过分子动力学的轨迹分析和相互作用能的计算，发现了几个与配体对接相关的关键氨基酸残基。我们所得的实验结果与以往的生物学实验数据十分吻合。此外,本节中还发现了一些对配体具有选择作用的氨基酸残基，包括Phe32，Tyr95，Thr269，Arg59(B)和Cys121。上述结果可能有助于对HKAT3的生物角色的进一步研究,并为新型抑制剂的设计提供新的探索方向。
另一方面，在本节中，通过使用分子动力学模拟方法研究了由HKAT3参与催化的KYN转氨作用机理。我们还获得了详细的配体与蛋白的结合模型，并且比较了辅酶PMP对配体结合过程的影响。实验结果不仅揭示了蛋白酶HKAT3，配体KYN和辅酶PMP间的相互作用模式，更有助于了解在KYN代谢途径中配体存在情况下的酶的催化特性。此外，本节中的研究发现能够指向KYN代谢途径的重要中间产物KYNA，并且可能为进一步了解蛋白酶HKAT3生理地位的提供崭新的出发点。
3.钾离子通道KCNQ1/KCNE1对接模型的搭建及二者相互作用的分子动力学模拟研究
KCNQ1是典型的电压门控钾离子(Kv)通道，并在人体组织细胞内有着广泛表达。在KCNQ1和KCNE1共同表达的不同类型的细胞中，KCNQ1通道似乎需要辅助亚基KCNE家族的协同方能履行其功能。在心脏细胞中，KCNQ1与KCNE1(此处缩写为Q1和E1)结合形成了缓慢延迟整流型(IKs)通道。亚基E1从以下几个方面调节Q1通道功能：增高单一通道的电导和响应电流幅度；减缓的激活和去激活速度；使激活的电压依赖在正方向移动并延缓失活速度。研究发现，蛋白Q1和E1所涉及的丧失功能型突变可能导致先天性心率缓慢(LQT)综合征，并且，降低病变心脏组织中的IKs通道的数量也会促使心率缓慢速综合征的发生。另一方面，对Q1通道蛋白进行获得性通道功能型突变将引起心动过速综合征(SQT2)和家族性心房颤动综合征(fAF)。显然，适当的IKs的通道数量对于维持心脏的电稳定性至关重要，过多或过少都同样危险。由此，我们可以推断，在具体的情况下通过抑制和催化IKs通道蛋白可以防止心律失常症状。
在本文中，我们基于Kv1.2_2.1的Chimera结构(PDB code:2r9r)，利用MODELER程序模建了离子通道KCNQ1的三维结构模型。此外，我们还使用布朗尼动力学对接方法将辅基KCNE1与通道蛋白KCNQ1进行对接，获得了Iks通道的的作用模型。并且，对KCNQ1通道模型、KCNE1辅基蛋白晶体结构和Iks通道模型的初始模型进行能量最小化和分子动力学优化模拟的结果进行了相应的分析。通过对KCNQ1/KCNE1对接模型的分析表明，辅基KCNE1的细胞外N-端区域与通道蛋白KCNQ1的S5-P连接区域间的相互作用提高了复合通道在细胞膜表面的表达。此外，辅基KCNE1的跨膜螺旋区域以其高骨架柔性面与KCNQ1进行优化对接。结合布朗尼动力学蛋白质对接方法、实验所得的相关限制和分子动力学模拟的强大方法我们得出大量的实验结果，由此能够更为完整地探测Q1/E1的相互作用机制。
Enzymes are kinds of proteins that can act as catalysts and are produced byliving cells. Becaues of the development of the computer technology, computationalmethods have been widely used in scientific reseach fields of the enzymes. In thesisstudy, we constructed several high quality model structures of human enzymes byusing various computational techniques, such as homology modeling and moleculardynamics (MD) simulations. And the molecular binding modes has been adopted todetermine biomolecular complexes and to compare the inhibitors. We reveal themechanism of interaction between the protein and inhibitors. The finding might be agood starting point for further determination of the biological role and structure-basedinhibitor design of these human proteins.
1. Computational modeling of novel inhibitors targeting the human GSTP1variants homology domain
The glutathione transferases (GSTs, E.C.2.5.1.18), also known as a family ofenzymes involved in the mechanism of cellular detoxification, catalyze thenucleophilic attack of glutathione on the electrophilic center of a number of toxiccompounds and xenobiotics. The Pi-class GST enzyme (GSTP1) has beenextensively studied because of its potential role in disease research. Previous studiespredicted four human Pi gene variants from human normal cells and malignantgliomas.
We constructed a high quality model of human GSTP1*B (GlutathioneS-Transferases, Pi,1B) and revealed the interactions between protein and threeinhibitors including EA and its conjugate of Glutathione (EAG(I) and EAG(O)) toexplore the structure-function relationship by molecular dynamics (MD) simulations. Based on the results of interaction energy caculation and the analysis of MDsimulation trojactory, we identified several critical residues of stablizing the structureof G-and H-site, including Phe8, Arg13, Trp38and Tyr108. Our results also show thatthe conjutation of GSTP1*B protein may increase the binding ability of the inhibitorand the specific selectivity of Phe8and Tyr108to the substrate.
Meanwhile, a detailed understanding of human GSTP1*D requires an accuratestructure, which has not been determined yet. We constructed a high quality modelstructure of human GSTP1*D by molecular dynamics (MD) simulations and revealedthe interactions between the proteins and five inhibitors including CBL, EA, EAG andLZ6to explore the structure-function relationship. We identified several criticalresidues, including Phe8, Arg13, Val35, Ile104, Tyr108, and Val113. Our resultsrevealed the specific selectivity of Phe8and Tyr108to the substrate. And we provieda new explanation for how does Ile104influence the substrate binding and ahypothesis about the indirect interaction between Val113and Tyr108. These resultsmay illustrate the alteration of enzymatic activity in the variants of GSTP1. Inaddition, the influence of Glutathione conjugate on ligands was observed.. This workwill be a good starting point for further determination of the biological role andstructure-based inhibitor design of human Pi-class GST.
2. A Molecular Dynamics and Computational Study of Human KAT3homologymodel Involved in KYN Pathway and substrate binding study
Kynurenine aminotransferase III (KAT3) is a novel member of the kynurenineaminotransferase enzyme family. Its active site topology and structure characteristicshave not been established. In this study, with extensive computational simulations,including homology modeling and molecular dynamics simulations, a3D structuremodel of human KAT3(HKAT3) dimmer was created and refined. Furthermore,CDOCKER approach was employed to dock two ligands (L-methionine andL-tryptophan) into the active sites of human KAT III dimmer and uncover theligand-binding modes. The complexes were subjected to5ns MD simulation, and the results indicate that Tyr159and Trp53might be the key residues as they have the largecontributions to the binding affinity, which is in good agreement with theexperimental results. Moreover, another two residues (Asp160and Tyr97) are alsofound that their strong interactions stabilize the whole system. The structural andbiochemical insights obtained from the present study will be helpful for designing thespecific inhibitors of HKAT3.
However, KATs also catalyze the transamination of kynurenine (KYN) pathwayand endogenous KYNs have been suggested to correlate highly to abnormal braindiseases. HKAT3is a key member of KAT family, while the binding mechanism ofKYN and cofactor with HKAT3has not been determined yet. In this study, we focuson the structure-function relationship among KYN, cofactor and HKAT3. The bindingmodels of KYN complex and KYN&cofactor complex were obtained and werestudied by Molecular Dynamics (MD) simulations. We identified several criticalresidues and influence of conformational changes in human Kynurenineaminotransferase3complexes. The cofactor may play significant contributions notonly to the catalysis, but also to the binding. In addition, a hypothesis is proposed thata strong hydrophobic interaction between Tyr159and Lys280may influence thebinding mode and the binding region of the substrate and the cofactor. Our results willbe a good starting point for further determination of the biological role.
3. Building KCNQ1/KCNE1docking models and probing their interactions bymolecular dynamics simulations
The slow delayed-rectifier (IKs) channel is composed of KCNQ1(pore-forming)and KCNE1(auxiliary) subunits, and functions as repolarization reserve‘in the heart.Design of IKs-targeting anti-arrhythmic drugs requires detailed3-D structures of theKCNQ1/KCNE1complex, a task made possible by Kv-channel crystal structures(templates for KCNQ1homology modeling) and KCNE1NMR structures. PreviousKCNQ1/KCNE1models included only the KCNE1transmembrane domain(E1-TMD), despite data indicating the importance of extracellular N-terminal domain (E1-NT) in IKs function. Our goal is to build KCNQ1/KCNE1models includingE1-NT:(a) creating KCNQ1homology model based on new experimental restraints,(b) refining KCNE1NMR structures to correct non-native loop configurations,(c)docking E1-TMD and E1-NT to KCNQ1in a step-wise manner,(d) testing modelpredictions independent from restraints used in model-building,(e) subjecting thecomplex to molecular dynamics simulations in explicit lipid/solvent environment, andanalyzing KCNQ1/KCNE1contacts and impact of docking on their backbonefluctuations. Our analysis suggests two novel aspects of KCNQ1/KCNE1interactions:(1) Frequent contacts between E1-NT and KCNQ1S5-P linker may serve to stabilizethe docking conformation and enhance IKs expression in cell surface membrane,(2)E1-TMD uses one helical face of high backbone fluctuations to optimize contactswith KCNQ1during protein docking.
1.谷胱甘肽硫转移酶家族几种等位基因蛋白酶的分子对接及分子动力学模拟研究
谷胱甘肽硫转移酶(Glutathione S-Transferases, GSTs, E.C.2.5.1.18)是由多个基因编码组成的,具有多种生理功能的家族酶。该家族酶广泛分布于哺乳动物体内,并能通过促进对有毒化合物的亲核攻击而参与细胞解毒过程。其中π家族中的成员GSTP1,因其与肿瘤耐药性密切相关,而被广泛研究。最近的研究结果表明, GSTP1在包括膀胱癌,口腔癌,食道癌,肺癌,肾癌,结肠癌,卵巢癌,睾丸癌,和胃癌等多种人类肿瘤细胞中,存在过度表达的现象。因此, GSTP1作为恶性肿瘤的标志,其耐药性及与肿瘤的关系链已成为肿瘤防治相关领域的研究热点。
借助分子动力学模拟的手段系统地研究了谷胱甘肽硫转移酶家族GSTP1的等位基因蛋白B(GSTP1*B)与抑制剂利尿酸(EA)及EA的谷胱甘肽共轭物EAG(I),EAG(O)的具体结合方式。抑制剂及其谷胱甘肽共轭物与蛋白的相互作用能计算和分子动力学轨迹的统计分析结果表明, GSTP1*B与EA的谷胱甘肽共轭物的结合能力高于EA的结合能力,残基Phe8, Arg13, Trp38和Tyr108是作用过程中的关键残基,对稳定抑制剂及其谷胱甘肽共轭物在GSTP1*B的G-位点和H-位点的构象有着重要的作用。通过对构象的统计分析发现残基Phe8和Tyr108与GSTP1*B酶对抑制剂的选择性密切相关.
另外，自从1991年第一个GSTP1的蛋白质晶体结构在0.23nm结晶条件下被获得,多达168个GSTP1的蛋白质晶体结构被发现。然而,人类GSTP1*D三维(3D)结构的一直未被确定。如果要详细地了解人类GSTP1*D结构—功能的关系，则需要其蛋白质的精确三维结构作为基础。本节中，我们利用如分子模建，分子动力学模拟等多种计算机技术搭建高质量的人类GSTP1的结构模型。同时，分子对接方法也被引入，用于生物分子复合物的获得及抑制剂的比对研究。本节中提出了GSTP1*D与五种抑制剂的相互作用模式，包括利尿酸(EA)，瘤可宁(CBL)，利尿酸的两种谷胱甘肽共轭物EAG(I)、EAG(O)，和瘤可宁的谷胱甘肽共轭物LZ6。这些发现将会为基于结构的GSTP1*D的相关研究提供较好的出发点。
2.人类犬尿氨酸转氨酶III（HKAT3）与底物及抑制剂相互作用的分子模拟
犬尿酸(Kynurenic acid, KYNA)，是唯一已知的内生拮抗剂N-甲基-D-天冬氨酸(NMDA)亚型谷氨酸受体,也可作为拮抗剂R7-烟碱的乙酰胆碱受体。最近,KYNA被确认为一种内源性配体的孤对耦合-G蛋白受体(GPR35)。根据报道，多种神经退行性疾病都与KYNA在中枢神经系统的异常表达水平密切相关,如亨廷顿症,阿尔茨海默症,精神分裂症和获得性免疫缺陷综合痴呆征。此外, KYNA可能对谷氨酸类和类胆碱类所控制的神经传递型心血管疾病的发病有相应的影响。KYNA是存在于大多数哺乳动物细胞组织中的色氨酸代谢途径中间体,该种化合物是由L-KYN配合维生素B6衍生物(pyridoxal5‘-phosphate, PLP)辅酶经由犬尿氨酸转氨酶家族(KATs)催化的不可逆反应生成。
在本文中，我们对来源于人类细胞内的犬尿氨酸转氨酶III(HKAT3)进行了深入研究。基于鼠类KATIII的晶体结构(PDB code:3E2Y)，模建了HKAT3的三维结构模型。此后，对HKAT3的初始模型进行能量最小化和分子动力学优化模拟。该模型通过了Verify-3D和Procheck程序评估。我们还使用CDOCKER方法将两种抑制剂与蛋白对接，获得了酶与配体的作用模型。尽管两种抑制剂作用于相同的活性位点区域，但两者却以不同模式与蛋白HKAT3结合。通过分子动力学的轨迹分析和相互作用能的计算，发现了几个与配体对接相关的关键氨基酸残基。我们所得的实验结果与以往的生物学实验数据十分吻合。此外,本节中还发现了一些对配体具有选择作用的氨基酸残基，包括Phe32，Tyr95，Thr269，Arg59(B)和Cys121。上述结果可能有助于对HKAT3的生物角色的进一步研究,并为新型抑制剂的设计提供新的探索方向。
另一方面，在本节中，通过使用分子动力学模拟方法研究了由HKAT3参与催化的KYN转氨作用机理。我们还获得了详细的配体与蛋白的结合模型，并且比较了辅酶PMP对配体结合过程的影响。实验结果不仅揭示了蛋白酶HKAT3，配体KYN和辅酶PMP间的相互作用模式，更有助于了解在KYN代谢途径中配体存在情况下的酶的催化特性。此外，本节中的研究发现能够指向KYN代谢途径的重要中间产物KYNA，并且可能为进一步了解蛋白酶HKAT3生理地位的提供崭新的出发点。
3.钾离子通道KCNQ1/KCNE1对接模型的搭建及二者相互作用的分子动力学模拟研究
KCNQ1是典型的电压门控钾离子(Kv)通道，并在人体组织细胞内有着广泛表达。在KCNQ1和KCNE1共同表达的不同类型的细胞中，KCNQ1通道似乎需要辅助亚基KCNE家族的协同方能履行其功能。在心脏细胞中，KCNQ1与KCNE1(此处缩写为Q1和E1)结合形成了缓慢延迟整流型(IKs)通道。亚基E1从以下几个方面调节Q1通道功能：增高单一通道的电导和响应电流幅度；减缓的激活和去激活速度；使激活的电压依赖在正方向移动并延缓失活速度。研究发现，蛋白Q1和E1所涉及的丧失功能型突变可能导致先天性心率缓慢(LQT)综合征，并且，降低病变心脏组织中的IKs通道的数量也会促使心率缓慢速综合征的发生。另一方面，对Q1通道蛋白进行获得性通道功能型突变将引起心动过速综合征(SQT2)和家族性心房颤动综合征(fAF)。显然，适当的IKs的通道数量对于维持心脏的电稳定性至关重要，过多或过少都同样危险。由此，我们可以推断，在具体的情况下通过抑制和催化IKs通道蛋白可以防止心律失常症状。
在本文中，我们基于Kv1.2_2.1的Chimera结构(PDB code:2r9r)，利用MODELER程序模建了离子通道KCNQ1的三维结构模型。此外，我们还使用布朗尼动力学对接方法将辅基KCNE1与通道蛋白KCNQ1进行对接，获得了Iks通道的的作用模型。并且，对KCNQ1通道模型、KCNE1辅基蛋白晶体结构和Iks通道模型的初始模型进行能量最小化和分子动力学优化模拟的结果进行了相应的分析。通过对KCNQ1/KCNE1对接模型的分析表明，辅基KCNE1的细胞外N-端区域与通道蛋白KCNQ1的S5-P连接区域间的相互作用提高了复合通道在细胞膜表面的表达。此外，辅基KCNE1的跨膜螺旋区域以其高骨架柔性面与KCNQ1进行优化对接。结合布朗尼动力学蛋白质对接方法、实验所得的相关限制和分子动力学模拟的强大方法我们得出大量的实验结果，由此能够更为完整地探测Q1/E1的相互作用机制。
Enzymes are kinds of proteins that can act as catalysts and are produced byliving cells. Becaues of the development of the computer technology, computationalmethods have been widely used in scientific reseach fields of the enzymes. In thesisstudy, we constructed several high quality model structures of human enzymes byusing various computational techniques, such as homology modeling and moleculardynamics (MD) simulations. And the molecular binding modes has been adopted todetermine biomolecular complexes and to compare the inhibitors. We reveal themechanism of interaction between the protein and inhibitors. The finding might be agood starting point for further determination of the biological role and structure-basedinhibitor design of these human proteins.
1. Computational modeling of novel inhibitors targeting the human GSTP1variants homology domain
The glutathione transferases (GSTs, E.C.2.5.1.18), also known as a family ofenzymes involved in the mechanism of cellular detoxification, catalyze thenucleophilic attack of glutathione on the electrophilic center of a number of toxiccompounds and xenobiotics. The Pi-class GST enzyme (GSTP1) has beenextensively studied because of its potential role in disease research. Previous studiespredicted four human Pi gene variants from human normal cells and malignantgliomas.
We constructed a high quality model of human GSTP1*B (GlutathioneS-Transferases, Pi,1B) and revealed the interactions between protein and threeinhibitors including EA and its conjugate of Glutathione (EAG(I) and EAG(O)) toexplore the structure-function relationship by molecular dynamics (MD) simulations. Based on the results of interaction energy caculation and the analysis of MDsimulation trojactory, we identified several critical residues of stablizing the structureof G-and H-site, including Phe8, Arg13, Trp38and Tyr108. Our results also show thatthe conjutation of GSTP1*B protein may increase the binding ability of the inhibitorand the specific selectivity of Phe8and Tyr108to the substrate.
Meanwhile, a detailed understanding of human GSTP1*D requires an accuratestructure, which has not been determined yet. We constructed a high quality modelstructure of human GSTP1*D by molecular dynamics (MD) simulations and revealedthe interactions between the proteins and five inhibitors including CBL, EA, EAG andLZ6to explore the structure-function relationship. We identified several criticalresidues, including Phe8, Arg13, Val35, Ile104, Tyr108, and Val113. Our resultsrevealed the specific selectivity of Phe8and Tyr108to the substrate. And we provieda new explanation for how does Ile104influence the substrate binding and ahypothesis about the indirect interaction between Val113and Tyr108. These resultsmay illustrate the alteration of enzymatic activity in the variants of GSTP1. Inaddition, the influence of Glutathione conjugate on ligands was observed.. This workwill be a good starting point for further determination of the biological role andstructure-based inhibitor design of human Pi-class GST.
2. A Molecular Dynamics and Computational Study of Human KAT3homologymodel Involved in KYN Pathway and substrate binding study
Kynurenine aminotransferase III (KAT3) is a novel member of the kynurenineaminotransferase enzyme family. Its active site topology and structure characteristicshave not been established. In this study, with extensive computational simulations,including homology modeling and molecular dynamics simulations, a3D structuremodel of human KAT3(HKAT3) dimmer was created and refined. Furthermore,CDOCKER approach was employed to dock two ligands (L-methionine andL-tryptophan) into the active sites of human KAT III dimmer and uncover theligand-binding modes. The complexes were subjected to5ns MD simulation, and the results indicate that Tyr159and Trp53might be the key residues as they have the largecontributions to the binding affinity, which is in good agreement with theexperimental results. Moreover, another two residues (Asp160and Tyr97) are alsofound that their strong interactions stabilize the whole system. The structural andbiochemical insights obtained from the present study will be helpful for designing thespecific inhibitors of HKAT3.
However, KATs also catalyze the transamination of kynurenine (KYN) pathwayand endogenous KYNs have been suggested to correlate highly to abnormal braindiseases. HKAT3is a key member of KAT family, while the binding mechanism ofKYN and cofactor with HKAT3has not been determined yet. In this study, we focuson the structure-function relationship among KYN, cofactor and HKAT3. The bindingmodels of KYN complex and KYN&cofactor complex were obtained and werestudied by Molecular Dynamics (MD) simulations. We identified several criticalresidues and influence of conformational changes in human Kynurenineaminotransferase3complexes. The cofactor may play significant contributions notonly to the catalysis, but also to the binding. In addition, a hypothesis is proposed thata strong hydrophobic interaction between Tyr159and Lys280may influence thebinding mode and the binding region of the substrate and the cofactor. Our results willbe a good starting point for further determination of the biological role.
3. Building KCNQ1/KCNE1docking models and probing their interactions bymolecular dynamics simulations
The slow delayed-rectifier (IKs) channel is composed of KCNQ1(pore-forming)and KCNE1(auxiliary) subunits, and functions as repolarization reserve‘in the heart.Design of IKs-targeting anti-arrhythmic drugs requires detailed3-D structures of theKCNQ1/KCNE1complex, a task made possible by Kv-channel crystal structures(templates for KCNQ1homology modeling) and KCNE1NMR structures. PreviousKCNQ1/KCNE1models included only the KCNE1transmembrane domain(E1-TMD), despite data indicating the importance of extracellular N-terminal domain (E1-NT) in IKs function. Our goal is to build KCNQ1/KCNE1models includingE1-NT:(a) creating KCNQ1homology model based on new experimental restraints,(b) refining KCNE1NMR structures to correct non-native loop configurations,(c)docking E1-TMD and E1-NT to KCNQ1in a step-wise manner,(d) testing modelpredictions independent from restraints used in model-building,(e) subjecting thecomplex to molecular dynamics simulations in explicit lipid/solvent environment, andanalyzing KCNQ1/KCNE1contacts and impact of docking on their backbonefluctuations. Our analysis suggests two novel aspects of KCNQ1/KCNE1interactions:(1) Frequent contacts between E1-NT and KCNQ1S5-P linker may serve to stabilizethe docking conformation and enhance IKs expression in cell surface membrane,(2)E1-TMD uses one helical face of high backbone fluctuations to optimize contactswith KCNQ1during protein docking.
引文
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