大分子自组织现象的分子动力学模拟及控制机制分析
文献类型：学位论文
| 作者 | 任瑛 |
| 学位类别 | 博士 |
| 答辩日期 | 2009-05-31 |
| 授予单位 | 中国科学院过程工程研究所 |
| 授予地点 | 过程工程研究所 |
| 导师 | 李静海 |
| 关键词 | 分子动力学模拟 自组织 协调 粗粒模型 联合原子模型 原子模型 表面活性剂 聚合物 蛋白质 |
| 其他题名 | Molecular dynamics simulation of macromolecular self-assembly in complex systems |
| 学位专业 | 化学工程 |
| 中文摘要 | 本文讨论的大分子自组织现象是指体系中的大分子在氢键、静电作用、范德华力等弱作用力推动下 ,自发地形成具有特殊形状和结构的聚集体的过程。本文从大分子自组织理论及控制机制协调形成复杂系统的多尺度结构的观点出发，分别采用粗粒化模型、联合原子模型和原子模型对表面活性剂体系、聚合物体系和蛋白质体系进行了分子动力学模拟，通过对体系进行结构、动力学和热力学以及控制机制的分析，探讨大分子体系自组织过程的共性规律。 第一章从实验、理论和模拟三个方面介绍了大分子自组织现象的研究现状，并对研究该问题常用的分子动力学模拟、蒙特卡罗模拟及耗散粒子动力学模拟等模拟方法进行了简要概述。 第二章采用粗粒化模型研究表面活性剂体系的自组织过程，能够在抓住表面活性剂双亲特性的同时最大限度地降低体系计算量。对微乳液体系和胶团溶液体系分别进行机理分析，其多尺度结构及控制机制均可以分为两个层次，即大尺度（团聚物尺度）上表面活性剂分子在聚团和体相溶液中不断交换，体系处于动态平衡，该现象源于“反应－扩散”控制机制的协调机制；小尺度（链分子尺度）上表面活性剂的亲水基团暴露在水中，亲油基团浸入油中（微乳液体系）或隐藏在聚团的内部（胶团溶液体系），该结构源于“亲水－亲油”控制机制的协调机制。 第三章采用联合原子模型研究单个疏水性聚合物分子在体相水溶液中及亲水性纳米窄缝中如何由延展的线性结构自组织为特定的三维构象。通过模拟聚合物在缝宽介于~1.5 Rg0到~4.0 Rg0（Rg0为聚合物在体相空间内的回转半径）的纳米窄缝中的自组织过程并同其在体相空间内的折叠情况相比较，发现该过程中聚合物分子内部自相作用，溶剂及壁面对聚合物的作用三者的协调导致了聚合物的稳态结构：聚合物分子沿壁面方向延展，沿垂直于壁面的方向收缩；被挤压成若干层，层与层之间的键长多与壁面垂直，层内的键长多与壁面平行；链分子在折叠过程中构象熵明显降低，溶剂分子所占体积增大，同链分子熵减相抗衡，导致体系整体熵的增加。 第四至六章以双结构域蛋白质―硫氰酸酶为研究对象，采用原子模型分别研究其高温去折叠、温度对体相溶剂中折叠过程的影响、在稀溶液中同生理环境中的结构比较、分子伴侣复合物辅助底物蛋白折叠这四个生物现象，并同相应的实验和理论结果进行对比分析。第四章通过模拟硫氰酸酶高温去折叠过程分析其结构变化、去折叠中间体的特点以及结构域间的协同效应；对蛋白质在278-368 K温度区间的折叠过程进行两阶段模拟表明，高温有利于疏水塌缩过程中多肽链上一级序列相邻较远的残基间相互作用形成塌缩的折叠中间体，但同时不利于随后的高级结构的形成，温度过低时情况相反，故存在一个最佳折叠温度，使蛋白质能以较快的速度折叠至天然构象。第五章探讨了硫氰酸酶在大分子拥挤环境中形成复合物的过程，并同其在稀溶液中的蛋白质结构进行比较，表明大分子复合物的形成会在某种程度上改变蛋白质的结构和稳定性。第六章对硫氰酸酶在分子伴侣复合物内的折叠过程进行了模拟，首次分析了该过程中分子伴侣自身的形变效应；指出A-domain的多个亚基通过对底物蛋白施加作用力而调整蛋白质的结构；探讨了空腔体积大小和空腔内壁静电效应对硫氰酸酶折叠速度的影响。 综上所述，无论是单个大分子自组织（如蛋白质折叠），还是多个大分子自组织（如活性剂聚集为胶团），都会形成复杂的多尺度结构且该动力学过程受大分子自身性质、溶剂性质、温度、受限空间等多种因素的影响。从控制机制协调形成复杂系统的多尺度结构的角度对以上各体系进行分析表明，体系中复杂结构的形成源于大分子内部自相作用及外部环境对大分子的作用的综合影响，多种控制机制在协调中实现体系的动态结构，对该控制机制的认识有助于调控复杂系统的结构以进一步改变其功能。 |
| 英文摘要 | Self-assembly of macromolecules can be defined as the spontaneous organization of macromolecules into ordered structures by weak interactions like hydrogen bonding, electrostatic interactions, Van der Waals forces, etc.. Three model systems, covering the self-assembly process of surfactants, polymer and protein, have been investigated by coarse-grained, united-atomic and atomic Molecular Dynamics (MD) simulations respectively. A combined analysis of the structure, dynamics and energies of these systems results in a general framework which permits extension to more complicated self-assembly macromolecular systems. In chapter 1, a summary of the experimental, theoretical and simulation investigations on macromolecular self-assembly is given, and the simulation methods frequently used for these problems, e.g., MD, Monte Carlo (MC) and Discrete Particle Dynamics (DPD), are briefly introduced. In chapter 2, the self-assembly processes of surfactants in both aqueous solution and microemulsion have been investigated by coarse-grained MD simulations, which can capture the amiphilic characteristics of surfactant molecules with a considerable reduction in computational cost. The formation of the complex structures in microemulsion or surfactant aqueous solution can be depicted on two distinct spatial scales. On molecular scale, the hydrophobic group tends to be driven away from water and the hydrophilic group tends to be driven away from oil in microemulsions, implying a compromise between hydrophobicity and hydrophilicity, which can be simplified as a single extreme tendency of hydrophobicity in surfactant aqueous solution because of the lack of oil molecules in the system. On a larger scale, the aggregations are in dynamic equilibrium with surfactant monomers, implying a compromise between “reaction” and “diffusion”, where both hydrophobicity and hydrophilicity belongs to “reaction”. In chapter 3, the self-assembly process of a single hydrophobic polymer in nano-slits with a thickness ranging from ~1.5 Rg0 to ~4.0 Rg0 (Rg0 is the radius of gyration of the polymer in bulk solution) has been investigated by united-atomic MD simulations, and the results have been compared to polymer folding in bulk solution. The polymer is flattened parallel to the wall and shrunk normal to the wall. Monomers are compressed into several layers and the preferred bond orientations alternate between parallel and normal to the walls accordingly. The polymer collapses and suffers great loss in entropy during the folding process, and the free space water gains accordingly may compete with the entropy loss of the polymer, leading to an increase of the system entropy. The compromise between three factors, say, intra-molecular interactions in the polymer, solvent and wall effect on the polymer, together leads to the stable structure of the polymer in confined space. In chaper 4-6, a double-domain protein, rhodnaese, is taken as a paradigm to study a series of biological events, including thermal unfolding of proteins, effect of temperature on protein folding in bulk, the difference of protein structures in dilute solution and in living cells, protein folding in molecular chaperonins, and the simulatation results are compared with experimental observations and theretical or other simulation results. In chaper 4, the structural changes, unfolding intermediates and cooperativity between neighboring domains are discussed through rhodanesee unfolding; and high temperature is identified to play a double-faced role, acceperating hydrophobic collapse meanwhile decelerating formation of high-order structures during protein folding in bulk, resulting in an optimized temperature for protein folding to the native state. In chapter 5, the formation of protein complex in macromolecular crowded environment is simulated and the results are compared with isolated proteins in dilute solution, suggesting a profound effect of macromolecular crowding on protein stability and conformations. In chapter 6, chaperonin-assisted rhodanese folding is simulated and the conformational change of the chaperonin during the folding process is identified for the first time. The multiple A-domains exert a stretching force on the residues interacting with the chaperonin, leading to folding or unfolding of the substrate. Two factors affecting rhodanese folding, the geometrical confinement of the folding cavity and the charge effect of the inner surface, have also been discussed. In summary, self-assembly of macromolecular, no matter intra-molecular self-assembly like protein folding, or inter-molecular self-assembly like surfactants aggregation, can lead to multi-scale structures and the dynamic process is affected by many factors like charateristics of the macromolecule and the solvent, temperature, grometrical confinement. The compromise between various mechanisms of intra-molecular interactions in macromolecules and the effect of environment on macromolecule together leads to the structural change in complex systems, which provides a way to manipulate the structures and thus improve the function. |
| 语种 | 中文 |
| 公开日期 | 2013-09-13 |
| 页码 | 163 |
| 源URL | [http://ir.ipe.ac.cn/handle/122111/1242]  |
| 专题 | 过程工程研究所_研究所（批量导入） |
| 推荐引用方式 GB/T 7714 | 任瑛. 大分子自组织现象的分子动力学模拟及控制机制分析[D]. 过程工程研究所. 中国科学院过程工程研究所. 2009. |
入库方式： OAI收割
来源：过程工程研究所
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