冷休克蛋白力致去折叠的动力学模拟
摘要
蛋白质折叠和去折叠机制是蛋白质研究的重要领域。蛋白质的正确折叠是体现生物功能的基础,也是生物学中最基本和最普遍的自组装模式。肽链在体内如何折叠主要取决于其一级结构和肽链所位于的细胞环境,一般来说,蛋白质能自发的折叠成具有特定空间结构和生物功能的分子。但是环境因素的改变会使肽链构象发生变化,也就是说蛋白质采取何种空间结构不仅受肽链自身热力学稳定性的控制,还受到蛋白质分子所处的微环境和动力学过程的影响。
蛋白质的构象转换在生物体内是一个普遍的现象,近年来的医学研究发现,蛋白质在人体内的错误折叠会引起严重的疾病;另一方面重组蛋白质的高效表达常常导致无活性的蛋白质聚集体生成。因此,研究蛋白质的折叠机理和促使蛋白质复性的方法无论在理论上还是在应用上都有很重要的意义。
除了一系列试验技术(例如原子力显微镜、光镊等等)以外,计算机模拟对于研究这些问题具有不可替代的作用,分子动力学模拟是研究蛋白质分子动态性质的主要方法之一,与实验方法互补,在生物大分子体系研究中得到了广泛的应用,它能够给出皮秒(10-12秒)到微秒(10-6秒)时间尺度内蛋白质在原子水平上的动力学信息。生物大分子的计算机模拟在这个领域开展时间并不是很长,但是已经在研究蛋白质折叠和去折叠以及功能因素等方面取得了很多成就,并且还在进一步的发展完善之中。
我们研究嗜热和嗜温两种冷休克蛋白在外力作用下的去折叠过程和机制,采用分子动力学软件包NAMD在相同的外力情况下进行两组分子动力学模拟,都以蛋白质的完全去折叠作为模拟终点。我们着重从氢键相互作用,静电相互作用和疏水相互作用这三个方面讨论了影响冷休克蛋白的去折叠因素,本论文主要包括以下部分:
1.概括的论述了分子动力学理论的基本原理,以及蛋白质的相关基本概念。
2.主要论述了嗜温冷休克蛋白在常速和常力两种动力学模拟中的去折叠过程,研究发现在两种拉伸过程中,嗜温冷休克蛋白都是C端β片层首先破裂,随后N端β片层破裂,然后讨论了决定嗜温冷休克蛋白去折叠的内部相互作用力。
3.论述了嗜热冷休克蛋白和嗜温冷休克蛋白在常速和常力两种动力学模拟中去折叠的异同,在常速去折叠的过程中,嗜温冷休克蛋白C端β片层的破裂需要更大的力,但是嗜热冷休克蛋白在N端β片层的破裂中需要更大的外力。
随着计算机运算能力的大幅度提高和算法的发展,计算机模拟技术将在更大体系,更长时间尺度内的蛋白质动力学研究方面发挥更大的作用。
The mechanisms of protein folding and unfolding, is the important field of protein research. The proteins must fold into their correct three-dimensional conformation in order to attain their biological function. Protein folding is the most fundamental and universal example of biological self-assembly. How a polypeptide chain folds into a stable, native structure in vivo is dependent on amino acid sequence and native solution environment. Generally, the polypeptide chain with given amino acid sequence can spontaneously fold into a certain three-dimensional structure with unique biological function. But structual transition could take place when the environment of protein is changed, that is to say, the three-dimensional strunture of protein is determined by not only its thermodynamic stability, but also the micro-environment of protein and kinetic process.
Structual transition of protein is common phenomena in organism. The research found that the structural transition and misfolding of protein could lead to serious diseases. On the other hand, the overexpression of recombinant proteins in Escherichia coli often results in the accumulation of the protein, producing inactive insoluble deposits inside the cells, called inclusion bodies. Therefore, the study on the mechanism of protein folding and the development of more efficient folding methods is very important in theory and practice.
Besides a series of experimental techniques(AFM, optical tweezers etc.), the molecular dynamics simulation posses irreplaceable effect for such research.Molecular dynamics, one of the most populars simulation methods, has been proved to be a p powerful tool in simulating dynamic properties of protein. Molecular dynamics simulations can provide a atomical realistic view of the folding and unfolding process from picosecond to millisecond. even though MD simulation about biomacromolecule is in a short time, MD simulations have succeed in these field, and it need further development to overcome its disadvantage.
Thermophilic and mesophilic cold shock protein,which have been employed to model forced unfolding of cold shock protein. We study the unfolding process and mechanism of the proteins by external force with dynamics software package NAMD. The completely unfolding of the proteins were thought as end of dynamics simulation.
We chiefly study the unfolding mechanism of the proteins under the interaction of hydrogen bond; electrostatic and hydrophobe, come to the conclusion as follow:
1. We not only introduced the basic principle of molecular dynamics simulation, concept of steered molecular dynamics simulation, and basic principle of protein.
2. Using steered molecular dynamics simulation, we explored the unfolding process of mesophilic cold shock protein by constant velocity and constant force. The results indicate thatβsheet of C terminal of mesophilic cold shock protein is reptured, susequentlyβsheet of N terminal. Then we explored the interior force that determine the unfolding process.
3. Using steered molecular dynamics in constant velocity and constant force, we explored the Similarities and Differences in the Forced Unfolding of Thermophilic and Mesophilic Cold Shock Proteins. The results indicate that the proteins follow same unfolding process, in the course of constant velocity unfolding, the C terminal is reptured at first, susequently N terminal. But the mestphilic cold shock protein need a bigger force in the beginning.
With continuing advances in both computers and algorithms, computer simulations will play an even more important role for understanding of protein folding/unfolding and functional motions in the future.
蛋白质的构象转换在生物体内是一个普遍的现象,近年来的医学研究发现,蛋白质在人体内的错误折叠会引起严重的疾病;另一方面重组蛋白质的高效表达常常导致无活性的蛋白质聚集体生成。因此,研究蛋白质的折叠机理和促使蛋白质复性的方法无论在理论上还是在应用上都有很重要的意义。
除了一系列试验技术(例如原子力显微镜、光镊等等)以外,计算机模拟对于研究这些问题具有不可替代的作用,分子动力学模拟是研究蛋白质分子动态性质的主要方法之一,与实验方法互补,在生物大分子体系研究中得到了广泛的应用,它能够给出皮秒(10-12秒)到微秒(10-6秒)时间尺度内蛋白质在原子水平上的动力学信息。生物大分子的计算机模拟在这个领域开展时间并不是很长,但是已经在研究蛋白质折叠和去折叠以及功能因素等方面取得了很多成就,并且还在进一步的发展完善之中。
我们研究嗜热和嗜温两种冷休克蛋白在外力作用下的去折叠过程和机制,采用分子动力学软件包NAMD在相同的外力情况下进行两组分子动力学模拟,都以蛋白质的完全去折叠作为模拟终点。我们着重从氢键相互作用,静电相互作用和疏水相互作用这三个方面讨论了影响冷休克蛋白的去折叠因素,本论文主要包括以下部分:
1.概括的论述了分子动力学理论的基本原理,以及蛋白质的相关基本概念。
2.主要论述了嗜温冷休克蛋白在常速和常力两种动力学模拟中的去折叠过程,研究发现在两种拉伸过程中,嗜温冷休克蛋白都是C端β片层首先破裂,随后N端β片层破裂,然后讨论了决定嗜温冷休克蛋白去折叠的内部相互作用力。
3.论述了嗜热冷休克蛋白和嗜温冷休克蛋白在常速和常力两种动力学模拟中去折叠的异同,在常速去折叠的过程中,嗜温冷休克蛋白C端β片层的破裂需要更大的力,但是嗜热冷休克蛋白在N端β片层的破裂中需要更大的外力。
随着计算机运算能力的大幅度提高和算法的发展,计算机模拟技术将在更大体系,更长时间尺度内的蛋白质动力学研究方面发挥更大的作用。
The mechanisms of protein folding and unfolding, is the important field of protein research. The proteins must fold into their correct three-dimensional conformation in order to attain their biological function. Protein folding is the most fundamental and universal example of biological self-assembly. How a polypeptide chain folds into a stable, native structure in vivo is dependent on amino acid sequence and native solution environment. Generally, the polypeptide chain with given amino acid sequence can spontaneously fold into a certain three-dimensional structure with unique biological function. But structual transition could take place when the environment of protein is changed, that is to say, the three-dimensional strunture of protein is determined by not only its thermodynamic stability, but also the micro-environment of protein and kinetic process.
Structual transition of protein is common phenomena in organism. The research found that the structural transition and misfolding of protein could lead to serious diseases. On the other hand, the overexpression of recombinant proteins in Escherichia coli often results in the accumulation of the protein, producing inactive insoluble deposits inside the cells, called inclusion bodies. Therefore, the study on the mechanism of protein folding and the development of more efficient folding methods is very important in theory and practice.
Besides a series of experimental techniques(AFM, optical tweezers etc.), the molecular dynamics simulation posses irreplaceable effect for such research.Molecular dynamics, one of the most populars simulation methods, has been proved to be a p powerful tool in simulating dynamic properties of protein. Molecular dynamics simulations can provide a atomical realistic view of the folding and unfolding process from picosecond to millisecond. even though MD simulation about biomacromolecule is in a short time, MD simulations have succeed in these field, and it need further development to overcome its disadvantage.
Thermophilic and mesophilic cold shock protein,which have been employed to model forced unfolding of cold shock protein. We study the unfolding process and mechanism of the proteins by external force with dynamics software package NAMD. The completely unfolding of the proteins were thought as end of dynamics simulation.
We chiefly study the unfolding mechanism of the proteins under the interaction of hydrogen bond; electrostatic and hydrophobe, come to the conclusion as follow:
1. We not only introduced the basic principle of molecular dynamics simulation, concept of steered molecular dynamics simulation, and basic principle of protein.
2. Using steered molecular dynamics simulation, we explored the unfolding process of mesophilic cold shock protein by constant velocity and constant force. The results indicate thatβsheet of C terminal of mesophilic cold shock protein is reptured, susequentlyβsheet of N terminal. Then we explored the interior force that determine the unfolding process.
3. Using steered molecular dynamics in constant velocity and constant force, we explored the Similarities and Differences in the Forced Unfolding of Thermophilic and Mesophilic Cold Shock Proteins. The results indicate that the proteins follow same unfolding process, in the course of constant velocity unfolding, the C terminal is reptured at first, susequently N terminal. But the mestphilic cold shock protein need a bigger force in the beginning.
With continuing advances in both computers and algorithms, computer simulations will play an even more important role for understanding of protein folding/unfolding and functional motions in the future.
引文
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