不同类型氨基酸网络参量与蛋白质折叠的关系研究
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摘要
蛋白质是生命系统中重要的生物大分子,它在生物体的繁衍、新陈代谢、生长发育等一切生命活动中发挥着重要的生物学功能。研究蛋白质结构的形成机制具有重要的理论和现实意义。自由能曲面理论为蛋白质折叠机理的研究提供了很好的理论框架,被广泛应用于蛋白质折叠热力学和动力学机制的研究。然而,能量函数和能量曲面的构建又存在一些困难。大量的实验和理论研究表明,蛋白质的折叠速率和机制在很大程度上是由天然态的拓扑结构所决定的,而不是完全取决于原子之间的精细的相互作用。因而,探究蛋白质拓扑结构和折叠机制之间的内在联系,通过蛋白质拓扑特征的分析获取折叠动力学信息,是一个很有意义的研究内容。
在本论文中,基于残基物理化学性质的差异性,分别构建了蛋白质氨基酸网、疏水网、亲水网、亲水-疏水网,进而计算了各网络的匹配系数和聚集系数,计算表明除了亲水-疏水网,其它类型的氨基酸网络的匹配系数均为正值。通过考察这两个参量与折叠速率之间的关系,发现疏水网的匹配系数与折叠速率之间有着非常明显的线性正相关关系。这说明了疏水残基之间相互作用的协同性对于蛋白质的快速折叠是有利的,可以促使蛋白质在非常短的时间内折叠成特定的三维空间结构。同时,亲水网的聚集系数与折叠速率有明显的线性负相关关系,表明疏水残基间三角结构的形成不利于蛋白质快速折叠。另外,我们还构建了相应的长程网络以观察各网络中长程残基间的相互作用对蛋白质折叠过程的影响,发现长程网络的平均聚集系数与折叠速率呈现出明显的负相关关系,说明序列上长距离残基之间接触的形成不利于快速折叠。
论文的研究结果表明,蛋白质的天然拓扑结构中蕴含了非常丰富的生物学信息,通过复杂网络的方法可以有效地提取并分析这些信息,进而有助于我们更进一步理解和揭示蛋白质折叠机理。
Proteins play an important role in the life system, and perform significant biological functions in all of the life activities, such as multiplication, metabolism, growth and development of life-forms. It is theoretically and practically significant to study the mechanism of protein folding. The theory of free energy surface has provided the theoretical framework to study protein folding mechanism, which has been widely used in the research of thermodynamics and kinetics of protein folding. However, there are still some troubles in constructing of the energy surface. Many experimental and theoretical studies have showed that the folding rate and mechanism of proteins are largely determined by their native structure topology, instead of the detail interactions between atoms. Therefore, it is meaningful to explore the relationship between protein structural topology and its corresponding folding mechanism, and then to obtain the information about folding dynamics through the analysis of protein topological features.
In this dissertation, according to the different physicochemical properties of different residues, we have constructed amino-acid network, hydrophobic amino acid network, hydrophilic amino acid network, and hydrophobic-hydrophilic amino acid network. Then, the assortative coefficient and clustering coefficient of these networks were calculated, respectively. It is found that the assortative coefficient of all these types of amino-acid network is positive except hydrophobic-Hydrophilic amino acid network. It is also found that there is clearly a linear positive correlation between the assortative coefficient of the hydrophobic amino acid network and the folding rate of the corresponding protein, which indicates that the cooperative interactions of the hydrophobic residues can promote the process of protein folding. Moreover, the results also show that the clustering coefficient of the hydrophobic network has an obviously linear negative correlation with the folding rate, which implies that the forming of the triangle structure in the protein was unfavorable for protein folding. In addition, we also constructed long-distance-in-sequence networks to study the influence of the interactions between long-distance residues in sequence on protein folding. It is found that the forming of the contacts between distant residues in sequence will delay the process of protein folding.
The above results show that the native topologic structure of proteins contains plenty of biological information, and it can be effectively obtained and analyzed by the introduction of complex network. The studies in this dissertation help us to further understand protein folding mechanisms.
在本论文中,基于残基物理化学性质的差异性,分别构建了蛋白质氨基酸网、疏水网、亲水网、亲水-疏水网,进而计算了各网络的匹配系数和聚集系数,计算表明除了亲水-疏水网,其它类型的氨基酸网络的匹配系数均为正值。通过考察这两个参量与折叠速率之间的关系,发现疏水网的匹配系数与折叠速率之间有着非常明显的线性正相关关系。这说明了疏水残基之间相互作用的协同性对于蛋白质的快速折叠是有利的,可以促使蛋白质在非常短的时间内折叠成特定的三维空间结构。同时,亲水网的聚集系数与折叠速率有明显的线性负相关关系,表明疏水残基间三角结构的形成不利于蛋白质快速折叠。另外,我们还构建了相应的长程网络以观察各网络中长程残基间的相互作用对蛋白质折叠过程的影响,发现长程网络的平均聚集系数与折叠速率呈现出明显的负相关关系,说明序列上长距离残基之间接触的形成不利于快速折叠。
论文的研究结果表明,蛋白质的天然拓扑结构中蕴含了非常丰富的生物学信息,通过复杂网络的方法可以有效地提取并分析这些信息,进而有助于我们更进一步理解和揭示蛋白质折叠机理。
Proteins play an important role in the life system, and perform significant biological functions in all of the life activities, such as multiplication, metabolism, growth and development of life-forms. It is theoretically and practically significant to study the mechanism of protein folding. The theory of free energy surface has provided the theoretical framework to study protein folding mechanism, which has been widely used in the research of thermodynamics and kinetics of protein folding. However, there are still some troubles in constructing of the energy surface. Many experimental and theoretical studies have showed that the folding rate and mechanism of proteins are largely determined by their native structure topology, instead of the detail interactions between atoms. Therefore, it is meaningful to explore the relationship between protein structural topology and its corresponding folding mechanism, and then to obtain the information about folding dynamics through the analysis of protein topological features.
In this dissertation, according to the different physicochemical properties of different residues, we have constructed amino-acid network, hydrophobic amino acid network, hydrophilic amino acid network, and hydrophobic-hydrophilic amino acid network. Then, the assortative coefficient and clustering coefficient of these networks were calculated, respectively. It is found that the assortative coefficient of all these types of amino-acid network is positive except hydrophobic-Hydrophilic amino acid network. It is also found that there is clearly a linear positive correlation between the assortative coefficient of the hydrophobic amino acid network and the folding rate of the corresponding protein, which indicates that the cooperative interactions of the hydrophobic residues can promote the process of protein folding. Moreover, the results also show that the clustering coefficient of the hydrophobic network has an obviously linear negative correlation with the folding rate, which implies that the forming of the triangle structure in the protein was unfavorable for protein folding. In addition, we also constructed long-distance-in-sequence networks to study the influence of the interactions between long-distance residues in sequence on protein folding. It is found that the forming of the contacts between distant residues in sequence will delay the process of protein folding.
The above results show that the native topologic structure of proteins contains plenty of biological information, and it can be effectively obtained and analyzed by the introduction of complex network. The studies in this dissertation help us to further understand protein folding mechanisms.
引文
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