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驱动蛋白动态结构模拟与控制机制研究; Molecular dynamics simulations of the dynamic structures of kinesin and analysis of the underlying mechanisms
Thesis Advisor李静海 ; 任瑛 ; 徐骥
Degree Grantor中国科学院研究生院
Degree Discipline化学工程
Keyword驱动蛋白 分子马达 微管 分子动力学模拟 控制机制
Abstract驱动蛋白是一类能够利用三磷酸腺苷(adenosine triphosphate,ATP)水解释放的化学能驱动其所携带的“货物”分子沿着微管(microtubule,MT)定向运动的分子马达,在细胞器运输、有丝分裂、轴突运输等方面有着重要的生理作用。随着驱动蛋白结合二磷酸腺苷(adenosine diphosphate,ADP)、ATP和没有结合核苷酸(APO)三种特征状态的晶体结构的解析,驱动蛋白构象变化的研究得到了进一步发展。但是,在力产生机制和运动模型方面仍然存在较大争议,主要争论点在于颈链对接模型是否正确,驱动蛋白是以hand-over-hand方式还是inchworm方式向前运动。因此,本研究工作借助分子动力学(molecular dynamics,MD)模拟的方法,探索驱动蛋白这一复杂系统的运动控制机制和运动模型,分为以下几个章节:第1章综述了驱动蛋白体系的分类、结构、研究现状,以及三个研究热点:1、ATP释放的化学能如何转化为机械能;2、驱动蛋白在微管上的行走方式;3、驱动蛋白的定向运动机制。同时,还简单介绍了MD的基本理论。第2章介绍了驱动蛋白在ATP循环中的构象变化,包括ATP循环的四个阶段,分析了每一个阶段对应的构象变化,并研究发现构象变化主要发生在核苷酸结合位点、微管结合位点以及颈链结构,揭示了驱动蛋白在微管上的运动机理。第3章进一步探索了驱动蛋白在微管上的行走方式,分别模拟了驱动蛋白单个头部和二聚体结构与微管结合的过程,获得了驱动蛋白两个头部与微管结合的状态,并且发现驱动蛋白更容易以从旁边绕的方式沿微管(+)端运动,不太容易以向上跨的方式沿微管(+)端运动。第4章中构建了跨度更大、跨步更完整的驱动蛋白迈步体系,借助于拉伸分子动力学方法(steered molecular dynamics,SMD),实现了驱动蛋白在微管上行走的全过程模拟。第5章中对本论文进行了总结,并展望了驱动蛋白的研究方向。 
Other AbstractKinesin is a superfamily of microtubule-based molecular motor protein, which directionally transports various cargoes with the energy through hydrolyzing adenosine triphosphate (ATP) molecules, and plays very important roles in organelles transport, mitosis and axonal transport, etc. With the determination of the crystal structures of three characteristic states of kinesin systems, namely, adenosine diphosphate (ADP) bound state (Kinesin-ADP), adenosine triphosphate (ATP) bound state (Kinesin-ATP), and APO (without nucleotide) state (Kinesin-APO), the studies on the structural changes among these characteristic states have been promoted. However, the mechanisms of the directional walking of kinesin still remains unclear, including the molecular details of the force generation (whether the head-neck linker docking contributes to the force generation), the walking pattern (whether kinesin moves by a “hand-over-hand” or an “inchworm”). Here, based on our previous study of complex systems, namely, the evolution of complex systems are always governed by the compromise of competition between two or more different dominant mechanisms, we study the dynamic structures of kinesin during walking by atomic molecular dynamics (MD) simulations and examine the relevant underlying dominant mechanisms. .In chapter 1, we summarize the classification of kinesin superfamily, the structure of kinesins, and current research of kinesins, focusing on three aspects: the conversion of chemical energy into mechanical work in ATP cycle, the mode of kinesin walking and the underlying mechanisms. Besides, the MD method is simply introduced.In chapter 2, we study the structural changes among three characteristic states (Kinesin-ATP, Kinesin-ADP, and Kinesin-APO), and find that the structural changes mainly locate on neck-linker, ATPase-binding and microtubule-binding segment. These results give a basis of understanding the conversion of chemical energy into mechanical work.In chapter 3, we analyze two different microtubule-binding processes of kinesin monomer and dimer by atomic molecular dynamics simulations, and reach a conclusion that kinesin prefers to move forward from left or right side rather than move over the motor head.In chapter 4, we study kinesin walking by steered molecular dynamics (SMD), and realize kinesin walking along microtubule at molecular level.Finally, in chapter 5, we summarize the main results and prospect briefly the future investigations on kinesin walking. 
Document Type学位论文
Recommended Citation
GB/T 7714
曹添亮. 驱动蛋白动态结构模拟与控制机制研究, Molecular dynamics simulations of the dynamic structures of kinesin and analysis of the underlying mechanisms[D]. 中国科学院研究生院,2016.
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