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A molecular dynamics and computational study of human KAT3 involved in KYN pathway

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Science China Chemistry 2013年第4期56卷 514-523页

作者： XU Yu zheng qingchuan YU LiYing ZHANG HongXing SUN ChiaChung State Key Laboratory of Theoretical and Computational Chemistry Institute of Theoretical Chemistry Jilin University

Kynurenine aminotransferases （KATs） catalyze the transamination of kynurenine （KYN） pathway and endogenous KYNs have been suggested to highly correlate to abnormal brain diseases. HKAT3 is a key member of KAT family, while the binding mechanism of KYN and cofactor with HKAT3 has not been determined yet. In this study, we focus on the structure-function relationship among KYN, cofactor and HKAT3. The binding models of KYN complex and KYN＆cofactor complex were ob- tained and were studied by molecular dynamics （MD） simulations. We identified several critical residues and influence of conformational changes in human kynurenine aminotransferase 3 （HKAT3） complexes. The cofactor may contribute largely not only to the catalysis, but also to the binding. In addition, a hypothesis is proposed that a strong hydrophobic interaction between Tyr159 and Lys280 may influence the binding mode and the binding region of the substrate and the cofactor. Our re- suits will be a good starting point for further determination of the biological role.

关键词： kynurenine (KYN) kynurenine aminotransferases (KATs) ^-~ interaction molecular dynamic (MD) simulation interaction energy

How Mutations Affecting the Ligand-receptor Interactions： a Combined MD and QM/MM Calculation on CYP2E1 and Its Two Mutants

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Chemical Research in Chinese Universities 2015年第6期31卷 1029-1038页

作者： WANG Yan zheng qingchuan ZHANG Jilong XIE Mo ZHAN Jiuyu ZHANG Hongxing Institute of Theoretical Chemistry Jilin University Changchun 130021 P. R. China

Cytochrome P450（CYP） 2El is a dual function monoxygenase with a crucial role in the metabolism of 6% of drugs on the market at present. The enzyme is of tremendous interest for its association with alcohol consumption, diabetes, obesity and fasting. Despite the abundant experimental mutagenesis data, the molecular origin and the structural motifs for the enzymatic activity deficiencies have not been rationalized at the atomic level. In this regard, we have investigated the effects of mutation on the structural and energetic characteristics upon single point mutations in CYP2E1, N219D and $366C. The molecular dynamics（MD） simulation combined with quantum mechanics/molecular mechanics（QM/MM） and noncovalent interaction（NCI） analysis was carried out on CYP2EI and its two mutants. The results highlight the critical role of Phe207, which is responsible for both structural flexibility and energetic variation, shortening the gap between the theory and the experimentally observed results of enzymatic activity decrease, The underlying molecular mechanism of the enzymatic activity deficiencies for mutants may be attributed to the changes of spatial position of Phe207 in the two mutants. This work provides particular explanations to how mutations affect ligand-receptor interactions based on combined MD and QM/MM calculations. Furthermore, the mutational effects on the activity of CYP2E1 obtained in the present study are beneficial to both the experimental and the computational works of CYPs and may allow researchers to achieve desirable changes in enzymatic activity.

关键词： Cytochrome P450(CYP) 2El Molecular dynamics(MD) simulation Quantum mechanics/molecular mechanics(QM/MM, ONIOM) calculation Noncovalent interaction(NCI) analysis

Insight into the Urea Binding and K166R Mutation Stabilizing Mechanism of TIpB： Molecular Dynamics and Principal Component Analysis Study

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Chemical Research in Chinese Universities 2014年第6期30卷 1011-1017页

作者： WU Yunjian zheng qingchuan XU Yu CHU Wenting CUI Yinglu WANG Yan ZHANG Hongxing State Key Laboratory of Theoretical and Computational Chemistry Institute of Theoretical Chemistry Jilin University Changchun 130021 P R. China

Chemoreceptor TlpB（Tlp=transducer-like protein）, which has been demonstrated to respond to pH sensing function, is crucial for the survival ofHelicobacterpylori（H, pylori） in host stomach. Urea was proposed to be essen- tial for TlpB＇s pH sensing function via binding with the Per-ARNT-Sim（PAS） domain of TlpB. Additionally, KI66R mutation of the TlpB protein has also been proven to have a similar effect on TlpB pH sensing as urea binding. Al- though X-ray crystallographic studies have been carried out for urea-bound Tlpl3, the molecular mechanism for the stabilization of TIpB induced by urea binding and K166R mutation remains to be elucidated. In this study, molecular dynamics simulations combined with principal component analysis（PCA） for the simulation results were used to gain an insight into the molecular mechanism of the stabilization of urea on TlpB protein. The formed H-bonds and salt-bridges surrounding Aspll4, which were induced by both urea binding and K166R mutation of TIpB, were im- portant to the stabilization of TlpB by urea. The similarity between the urea binding and K166R mutation as well as their differences in effect has been explicitly demonstrated with computer simulations at atomic-level. The findings may Dave the wav for the further researches of TlpB.

关键词： TlpB Per-ARNT-Sim(PAS) domain Molecular dynamics simulation Principal component analysis

Theoretical Investigation on Binding Process of Allophanate to AUophanate Hydrolase

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Chemical Research in Chinese Universities 2015年第6期31卷 1023-1028页

作者： ZHANG Zidong ZHANG Jilong zheng qingchuan KONG Chuipeng LI zhengqiang ZHANG Hongxing MA Jianzhang College of Wildlife Resource Northeast Forestry University Harbin 150040 P. R. China International Joint Research Laboratory of Nano-miero Architecture Chemistry Institute of Theoretical Chemistry Jilin University Changchun 130021 P. R. China Key Laboratory for Molecular Enzymology and Engineering Ministry of Education Jilin University Changchun 130012 P. R. China

t Several molecular simulation methods were integrated to investigate the detailed binding process of allo- phanate to allophanate hydrolase and predict their stable complex structure. The optimal enzyme-substrate complex conformation demonstrates that along with Arg307 and Tyr299, Gly124 is also one of the key anchor residues in the stable complex. The energetic calculation suggests the existence of an intermediate state in the enzyme-substrate binding process. The further atomic-level investigation illuminates that Tyr299, Arg307 and Ser172 can stabilize the substrate in the intermediate state. By this token, the residues Arg307 and Tyr299 function in both binding process and getting stable state.

关键词： Allophanate hydrolase Molecular dynamics simulation Substrate binding Free energy Intermediate state

A Selective and Sensitive Fluorescence Probe for Se（IV） Based on Fluorescence Quenching of Gatifloxacin

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Chemical Research in Chinese Universities 2016年第5期32卷 736-741页

作者： LIU Qing HUAN Yanfu zheng qingchuan FEI Qiang FEI Yanqun FAN Qian FENG Guodong SHAN Hongyan College of Chemistry Jilin University Changchun 130021 P. R. China Laboratory of Theoretical and Computational Chemistry Institute of Theoretical Chemistry Jilin University Changchun 130021 P. R. China Changchun WeiersaiBiotec Pharmaceutical Co. Ltd. Changchun 130616 P. R. China Changchun Vocational Institute of Technology Changchun 130033 P. R. China

A novel high selective and sensitive fluorescence probe termed gatifloxacin was discovered based on fluorescence ＂on-off＂ phenomenon in the presence of Se（IV）. In the Tris-HCl/acetonitrile（3：7, volume ratio, Tris-HCl 0.05 mol/L, pH=7.3） system, the fluorescence intensity of gatifloxacin was linearly decreased with the concentration increase of Se（IV） in a range of 1.0×10-5--5.0×10-5 mol/L with a correlation coefficient of 0.9979（R2=0.9958） and in a range of 5.0×10-5--1.0 ×10-4 mol/L with a correlation coefficient of 0.9973（R2=0.9946）. The detection limit of Se（IV） was 1.70×10-6mol/L.

关键词： Gatifloxacin Fluorescence probe Quenching Selenium

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）

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高等学校化学学报 2015年第11期36卷 2226-2235页

作者：王衍郑清川吉林大学理论化学研究所长春130021 吉林大学分子酶学工程教育部重点实验室长春130021

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... 详细信息

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.

关键词：细胞色素P450 2E1酶分子动力学模拟结合自由能计算

CYP2C9酶与Warfarin结合模型的立体选择性理论研究

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高等学校化学学报 2014年第12期35卷 2605-2611页

作者：吴云剑崔颖璐郑清川张红星吉林大学理论化学研究所理论化学计算国家重点实验室长春130023

对CYP2C9酶与S-Warfarin复合物的晶体结构进行分子对接、分子动力学模拟、通道分析及结合自由能计算,发现原晶体结构中的结合模式为'亚稳态',提出了CYP2C9与S-Warfarin结合的可催化模式;比较了CYP2C9与S-和R-Warfarin结合的异同,确定了... 详细信息

对CYP2C9酶与S-Warfarin复合物的晶体结构进行分子对接、分子动力学模拟、通道分析及结合自由能计算,发现原晶体结构中的结合模式为'亚稳态',提出了CYP2C9与S-Warfarin结合的可催化模式;比较了CYP2C9与S-和R-Warfarin结合的异同,确定了在结合过程中起重要作用的锚定氨基酸残基,尤其是位于活性位点区域的苯丙氨酸簇.在结合过程中这些残基通过芳香环的移动对稳定底物的结合模式起到至关重要的作用,阐明了该酶呈现相关底物选择性的原因.对于CYP2C9与底物对接模式及立体选择性的研究有助于在分子层面上理解特异性底物与酶的结合特点,为潜在的药物设计提供了合理可信的理论依据.

关键词：分子对接分子动力学模拟细胞色素P450 结合自由能分析 CYP2C9酶和S-Warfarin复合物

烟草病程相关蛋白PR-1a的三维模型和荧光光谱

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应用与环境生物学报 2008年第4期14卷 466-468页

作者：李佳郑清川杜林方四川大学生命科学学院生物资源与生态环境教育部重点实验室四川成都610064 吉林大学理论化学研究所理论化学计算国家重点实验室吉林长春130023

利用同源模建和分子动力学模拟方法搭建了烟草病程相关蛋白PR-1a的三维结构,在此基础上预测出PR-1a具有2个可能的活性位点,进一步分析PR-1家族特异保守序列,结果显示位点1的可能性更大.利用蛋白质内源荧光为探针,对分离的重组表达PR-1a... 详细信息

利用同源模建和分子动力学模拟方法搭建了烟草病程相关蛋白PR-1a的三维结构,在此基础上预测出PR-1a具有2个可能的活性位点,进一步分析PR-1家族特异保守序列,结果显示位点1的可能性更大.利用蛋白质内源荧光为探针,对分离的重组表达PR-1a蛋白进行了热稳定性研究.低于60℃处理,PR-1a蛋白内源荧光只略微降低;70℃处理30min引起PR-1a蛋白内源荧光明显降低,结果显示,PR-1a中色氨酸残基主要处于蛋白质分子内部,这与三维结构模型预测结果相符.

关键词：病程相关蛋白分子动力学同源模建荧光发射光谱热稳定性

Study on Acoustic Emission Characteristics of Deformation Damage Process of Zirconia Ceramics

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Journal of Materials Science and Chemical Engineering 2024年第2期12卷 61-72页

作者： qingchuan Fu Yushu Lai School of Electronic Information and Engineering Chongqing Three Gorges University Chongqing China Key Laboratory of Signal and Information Processing School of Electronic and Information Engineering Chongqing Three Gorges University Chongqing China

Zirconia ceramics have become increasingly widely used in recent years and are favored by relevant enterprises. From the traditional dental field to aerospace, parts manufacturing has been used, but there is limited research on the deformation and damage process of zirconia ceramics. This article analyzes the acoustic emission characteristics of each stage of ceramic damage from the perspective of acoustic emission, and explores its deformation process characteristics from multiple perspectives such as time domain, frequency, and EWT modal analysis. It is concluded that zirconia ceramics exhibit higher brittleness and acoustic emission strength than alumina ceramics, and when approaching the fracture, it tends to generate lower frequency acoustic emission signals.

关键词： Zirconia Ceramics Acoustic Emission Monitoring Crack Damage