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Locking Function of a Key Residue in Kinesin＇s Gating Mechanism

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Chinese Physics Letters 2014年第4期31卷 201-205页

作者： geng yi-zhao ZHANG Hui JI Qing YAN Shi-Wei College of Nuclear Science and Technology Beijing Normal University Beijing 100875 School of Science Hebei University of Technology Tianjin 300401 Institute of Biophysics Hebei University of Technology Tianjin 300401

In kinesin＇s mechanochemical cycle, ATP＇s binding to the nucleotide-free leading head is exquisitely gated so that futile hydrolysis is effectively avoided, Experiments show that, when both kinesin heads bind to a microtubule~ ATP cannot bind to kinesin＇s leading head when the neck linker （NL） of this head has a backward orientation. How NL＇s backward orientation is maintained needs understanding on a structural basis. By using steered molecular dynamics and rrmtation simulations, we investigate the backward-pointing conformation of the leading head＇s NL under different inter-head tensions. We find that the NL cannot keep in a strict backward orientation solely by the inter-head tension. LYS325 （amino acid sequence in 2KIN） has an assistant locking function which locks the NL and β0 to the β-domain. This locking function has an enhanced positive cooperation with the inter-head tension. When the inter-head tension is weakened, this locking function can be broken, resulting in a loose backward orientation of the NL. The difference between the strict and loose backward orientation of the NL might be a crucial factor in the gating mechanism. These results are consistent with relevant experiments and proposals.

关键词： KINESIN MICROTUBULES HYDROLYSIS NUCLEOTIDES -- Spectra CONFORMATIONAL analysis AMINO acid sequence

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p53活性四聚体全原子分子动力学分析

物理学报 2024年第4期73卷 300-313页

作者：周晗耿轶钊晏世伟北京师范大学物理学系北京100875 河北工业大学理学院天津300131 北京师范大学文理学院珠海519085

p53是一种肿瘤抑制蛋白,对阻碍癌症发展、维持遗传完整性起着至关重要的作用.在细胞核内,4个p53分子通过高度协同的方式、通过DNA结合域与DNA结合,形成稳定的四聚体活性结构,并转录激活或抑制其靶向基因.然而,大多数肿瘤细胞中存在大量... 详细信息

p53是一种肿瘤抑制蛋白,对阻碍癌症发展、维持遗传完整性起着至关重要的作用.在细胞核内,4个p53分子通过高度协同的方式、通过DNA结合域与DNA结合,形成稳定的四聚体活性结构,并转录激活或抑制其靶向基因.然而,大多数肿瘤细胞中存在大量p53的突变,其中绝大部分突变发生在p53的DNA结合域,而p53的DNA结合域又是p53形成四聚体活性结构、调控下游靶基因转录的重要区域.本文通过全原子分子动力学模拟,研究了野生型p53四聚体内分子间的相互作用机制.结果表明,位于DNA两侧的对称二聚体是一个稳定的二聚体,在与DNA结合前后都能维持稳定的结构.位于DNA同侧的两个单体依靠两个接触面提供的蛋白-蛋白相互作用和DNA的骨架作用使四聚体活性结构保持稳定,这些相互作用为四聚体的形成机制提供了重要支撑.该工作厘清了p53四聚体在动力学过程中的内部相互作用机制和关键残基,揭示了四聚化过程中各个相互作用界面的关键位点,对于理解p53的抑癌机制、探索有效治癌策略、发展治癌药物具有重要意义.

关键词： p53核心四聚体 p53核心结构域蛋白-蛋白相互作用分子动力学模拟

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Nutlin-3a对p53-MDM2复合物稳定性影响

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物理学报 2023年第6期72卷 359-366页

作者：周晗耿轶钊晏世伟北京师范大学物理学系北京100875 河北工业大学理学院天津300131

p53蛋白是一种与细胞周期停滞和细胞凋亡有关的蛋白质.在受到细胞压力或环境扰动后,p53促进下游多个靶基因的转录,介导肿瘤抑制.MDM2是主要的E3泛素连接酶,也是p53的负调控因子.MDM2可促进p53的泛素化和核输出,抑制p53的抑癌活性.因此M... 详细信息

p53蛋白是一种与细胞周期停滞和细胞凋亡有关的蛋白质.在受到细胞压力或环境扰动后,p53促进下游多个靶基因的转录,介导肿瘤抑制.MDM2是主要的E3泛素连接酶,也是p53的负调控因子.MDM2可促进p53的泛素化和核输出,抑制p53的抑癌活性.因此MDM2对p53的负调控始终是肿瘤治疗中急切需要解决的问题.Nutlin-3a是被证明可以有效抑制p53-MDM2相互作用的小分子抑制剂.本文使用全原子分子动力学模拟,研究Nutlin-3a对p53-MDM2复合物的稳定性的影响.结果表明,通过引起p53和MDM2间Phe19-Gln72的氢键和Glu17-Lys94的盐桥发生的断裂,Nutlin-3a可以削弱p53和MDM2间的相互作用.我们的工作对Nutlin-3a小分子抑制剂的作用机制进行了说明,揭示了抗癌药物Nutlin-3a介导的p53-MDM2复合物亲和力降低的分子机制,并为针对p53蛋白的有效抗癌治疗提供了理论基础.

关键词：治癌药物设计 p53-MDM2复合物 Nutlin-3a抑制剂分子分子动力学模拟

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驱动蛋白MCAK的微管解聚机制研究进展

生命科学 2022年第6期34卷 613-623页

作者：彭川耿轶钊河北工业大学理学院生物物理研究所天津300401

有丝分裂着丝粒相关驱动蛋白(MCAK)是驱动蛋白-13家族的代表性成员,在细胞分裂的多个过程中起作用。与传统的驱动蛋白不同,MCAK蛋白的生物学功能不是通过沿微管轨道的连续行走实现物质输运,而是从微管末端解聚微管蛋白,从而实现对微管... 详细信息

有丝分裂着丝粒相关驱动蛋白(MCAK)是驱动蛋白-13家族的代表性成员,在细胞分裂的多个过程中起作用。与传统的驱动蛋白不同,MCAK蛋白的生物学功能不是通过沿微管轨道的连续行走实现物质输运,而是从微管末端解聚微管蛋白,从而实现对微管动力学的调控。因此,MCAK蛋白是一种微管解聚蛋白,其沿微管轨道的运动过程以及解聚微管蛋白时的力学-化学循环过程都与其他驱动蛋白家族有很大的差异。该文对MCAK蛋白微管解聚过程的研究进展进行综述,尤其对高分辨率分子结构展现的MCAK蛋白在解聚微管末端蛋白时的1:2复合物模型进行了详细讨论。

关键词：有丝分裂着丝粒相关驱动蛋白驱动蛋白微管有丝分裂微管动力学

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驱动蛋白力产生机制的研究

物理学进展 2016年第6期36卷 157-201页

作者：耿轶钊晏世伟河北工业大学理学院北京师范大学核科学与技术学院

驱动蛋白颈链对接过程及其力产生机制的研究,是揭示驱动蛋白结构与功能的关系,认识生物体蛋白质中普遍存在的、高效的能量转化机制和精确的构象变化调控机制的一个基础性课题。本文中,我们对驱动蛋白颈链对接的过程及其力产生机制进行... 详细信息

驱动蛋白颈链对接过程及其力产生机制的研究,是揭示驱动蛋白结构与功能的关系,认识生物体蛋白质中普遍存在的、高效的能量转化机制和精确的构象变化调控机制的一个基础性课题。本文中,我们对驱动蛋白颈链对接的过程及其力产生机制进行了系统地分析研究。通过分子动力学模拟,得到了处于空态的马达头部的合理结构。在此结构的基础上,通过对颈链对接的启动机制以及具体实现过程、ATP结合引起的马达头部转动到颈链对接过程力传递路径的分析,从动力学上实现了驱动蛋白颈链对接;澄清了颈链对接的启动机制、颈链向马达头部对接的实现机制、驱动蛋白向前行走时的力产生机制、以及驱动蛋白双头力学化学循环调控机制。对文中所讨论的一些关键问题,给出了实验验证的可能方案。本文的研究结果对理解驱动蛋白结构与功能关系、分子马达的力产生机制、做功原理和高效的能量转换机制有重要的参考价值。

关键词：驱动蛋白分子动力学模拟颈链对接机制力学化学循环调控机制力产生机制

Evolution of the elastic properties of lacustrine organic shales under different thermal maturity conditions

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Science China Earth Sciences 2025年第3期68卷 781-802页

作者： Zhenjia CAI Luanxiao zhao Jiqiang MA Fengshou ZHANG Jianhua geng State Key Laboratory of Marine Geology Tongji University School of Ocean and Earth Science Tongji University Department of Geotechnical Engineering College of Civil Engineering Tongji University

Research on the elastic responses of organic-rich shales during thermal evolution has predominantly focused on North American marine shales. However, the rock physics properties of lacustrine(continental) organic-rich shales with varying maturities, particularly under the unique geological conditions in China, have not yet been comprehensively explored. Therefore,characterizing the elastic properties of lacustrine organic-rich shales across various maturity stages is crucial for understanding their seismic rock physics responses and for enabling the identification of sweet spots in continental shale reservoirs using logging and seismic data, as well as facilitating geophysical monitoring of the in-situ conversion of oil shales. In this study,hydrous pyrolysis experiments were conducted on immature shales from the Chang 7 member of the Yanchang Formation in the Ordos Basin and the Jijuntun Formation in the Fushun Basin. Compressional and shear wave velocities, along with elastic anisotropy, were measured at various stages of thermal maturity to observe the evolution of the elastic properties. For the Chang7 shale(compacted shale), both P-and S-wave velocities perpendicular to the bedding decreased significantly during the oil and gas generation stages, with the S-wave velocity perpendicular to the bedding decreasing by over 40%. Meanwhile, the elastic anisotropy increased significantly, likely because of microcracks formed by hydrocarbon expulsion from the bedding-parallel organic matter. In contrast, the Jijuntun Formation shale(cemented shale) exhibited an increase in both P-and S-wave velocities during the oil generation stage. This trend could be attributed to early-stage cementation, which suppressed microcrack formation, while the increase in the elastic modulus of the organic matter became dominant. However, during the gas generation stage, both velocities decreased, while the anisotropy increased owing to the growth of organic pores and microcracks, which out

关键词： Lacustrine shales Thermal pyrolysis Elastic wave velocity Anisotropy In-situ conversion

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驱动蛋白颈链对接机制的研究进展

生命科学 2018年第6期30卷 615-620页

作者：张青张辉耿轶钊纪青河北工业大学生物物理研究所天津300401 河北工业大学理学院天津300401

驱动蛋白能够携带"货物"沿微管高速连续行走,在行走过程中,将ATP结合与水解释放的化学能转化为机械能。驱动蛋白的由十几个氨基酸组成的颈链周期性地与驱动蛋白头部对接和分离是其行走的关键步骤,也是驱动蛋白发力做功的关键环节。现结... 详细信息

驱动蛋白能够携带"货物"沿微管高速连续行走,在行走过程中,将ATP结合与水解释放的化学能转化为机械能。驱动蛋白的由十几个氨基酸组成的颈链周期性地与驱动蛋白头部对接和分离是其行走的关键步骤,也是驱动蛋白发力做功的关键环节。现结合本课题组最新的研究结果,对驱动蛋白颈链3个部分不同的对接机制的研究进展进行综述。驱动蛋白颈链对接机制的阐明,加深了人们对于驱动蛋白沿微管行走机制的理解,同时也为其他分子马达工作机理的研究提供了参考。

关键词：分子马达驱动蛋白颈链相互作用构象变化机制

A promising approach for quantifying focal stroke modeling and assessing stroke progression:optical resolution photoacoustic microscopy photothrombosis

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Neural Regeneration Research 2025年第7期20卷 2029-2037页

作者： Xiao Liang Xingping Quan Xiaorui geng Yujing Huang Yonghua zhao Lei Xi Zhen Yuan Ping Wang Bin Liu Faculty of Health Sciences University of MacaoMacao Special Administrative RegionChina Center for Cognitive and Brain Sciences University of MacaoMacao Special Administrative RegionChina Department of Biomedical Engineering Southern University of Science and TechnologyShenzhenGuangdong ProvinceChina State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoTaipaMacao Special Administrative RegionChina Department of Emergency Zhujiang HospitalSouthern Medical UniversityGuangzhouGuangdong ProvinceChina

To investigate the mechanisms underlying the onset and progression of ischemic stroke,some methods have been proposed that can simultaneously monitor and create embolisms in the animal cerebral ***,these methods often require complex systems and the effect of age on cerebral embolism has not been adequately studied,although ischemic stroke is strongly *** this study,we propose an optical-resolution photoacoustic microscopy-based visualized photothrombosis methodology to create and monitor ischemic stroke in mice simultaneously using a 532 nm pulsed *** observed the molding process in mice of different ages and presented age-dependent vascular embolism ***,we integrated optical coherence tomography angiography to investigate age-associated trends in cerebrovascular variability following a *** imaging data and quantitative analyses underscore the differential cerebrovascular responses to stroke in mice of different ages,thereby highlighting the technique's potential for evaluating cerebrovascular health and unraveling age-related mechanisms involved in ischemic strokes.

关键词： age-dependent cerebral cortex ischemic stroke mouse model optical coherence tomography angiography photoacoustic microscopy photothrombosis vascular imaging

The association of isocarbophos and isofenphos with different types of glucose metabolism:The role of inflammatory cells

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Journal of Environmental Sciences 2025年第1期147卷 322-331页

作者： Jintian geng Dandan Wei Lulu Wang Qingqing Xu Juan Wang Jiayu Shi Cuicui Ma Mengzhen zhao Wenqian Huo Tao Jing Chongjian Wang Zhenxing Mao Department of Epidemiology and Biostatistics College of Public HealthZhengzhou UniversityZhengzhou 450001China Department of Occupational and Environmental Health Sciences College of Public HealthZhengzhou UniversityZhengzhou 450001China School of Public Health Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430074China

To investigate the associations between isocarbophos and isofenphos with impaired fasting glucose(IFG)and type 2 diabetes mellitus(T2DM),and to assess the mediation roles of inflammation *** were 2701 participants in the case-control study,including 896 patients with T2DM,900 patients with IFG,905 subjects with *** isocarbophos and isofenphos concentrationsweremeasured using gas chromatography and triple quadrupole tandem mass *** linear models were used to calculate the relationships between plasma isofenphos and isocarbophos levels with inflammatory factor levels and *** cell was used as mediators to estimate the mediating effects on the above *** and isofenphos were positively related with T2DM after adjusting for other *** odds ratio(95%confidence interval)(OR(95%CI))for T2DM was 1.041(1.015,1.068)and for IFG was 1.066(1.009,1.127)per unit rise in *** prevalence of T2DM increased by 6.4%for every 1 unit more of ln-isofenphos(OR(95%CI):1.064(1.041,1.087)).Additionally,a 100%rise in ln-isocarbophos was linked to 3.3%higher ln-HOMA2IR and a 0.029 mmol/L higher glycosylated hemoglobin(HbA1c)(95%CI:0.007,0.051).While a 100%rise in ln-isofenphos was linked to increase in ln-HOMA2 and ln-HOMA2IR of 5.8%and 3.4%,***,white blood cell(WBC)and neutrophilic(NE)were found to be mediators in the relationship between isocarbophos and T2DM,and the corresponding proportions were 17.12%and 17.67%,*** and isocarbophos are associated with IFG and T2DM in the rural Chinese population,WBC and NE have a significant role in this relationship.

关键词： Isocarbophos Isofenphos Type 2 diabetes mellitus Inflammatory cells Mediation effect