复杂受限体系中蛋白质折叠行为的动力学模拟研究

Protein folding is an important and challenging problem in molecular biology. Experiments indicate that the protein folding processes in the crowded cell controlled by both thermodynamic and kinetic effects strongly depend on its local environmental conditions. It is well known that the folding process of certain proteins in vivo requires the assistance from molecular chaperones providing the confined nanocage. Furthmore, some illnesses such as Parkinson's disease, Kreutzfeld-Jacob syndrome and mad cow disease are treated as the result of toxic protien misfolding in the cellular environment. Therefore, the investigation of protein folding behaviors in the complex confinement is significant for understanding the nature of life..The current research proposal carried out numerical analysis and computer simulations aspires to provide the theoretical support for the comprehension of protein folding process under the confined system. The replica-exchange strategies by coupling coarse grained and all-atomistic molecular dynamics simulations will be applied. The anticipated results achieved by computer simulations and theoretical studies are specified as follows (1) To establish the theoretical approach and molecular model concerning the improved expression of confining potential, optimized algorithm, and effective parameters to obtain the structural information. (2) To find the intrinsic relationship between the equilibrium configuration of the target protein under different geometrical confinements and the interactions between them. (3) To illuminate the physical mechanism of the protein folding in the complex confinement. .The molecular insight into the protein conformational transition, as established by the present research, could be used to anticipate the native structures, control the bilolgical processes and guide the design or application of surfactant in bioprocessing engineering.

蛋白质分子的折叠过程与所处的外部环境密切相关，是一个受到热力学和动力学双重制约的过程。蛋白质分子在复杂受限体系中的折叠行为研究，对认识生命现象、控制生物过程乃至发明新型药物和诊疗方法，都有着重要的意义。本项目拟采用结合粗粒化和全原子模型的副本交换分子动力学模拟，对蛋白质在复杂受限体系中折叠的动力学过程和热力学性质进行研究。通过计算机模拟和理论分析，达到以下目标：(1)建立一套较完整的研究蛋白质在复杂受限体系中折叠行为的理论方法和模型，包括确立复杂受限空间的势能函数表达式、优化算法、提供有效的结构分析手段。(2)揭示受限空间结构和相互作用方式与蛋白质稳定构型的内在联系。(3)阐明蛋白质在复杂受限体系中折叠过程的物理图像。通过上述研究，深入理解蛋白质的折叠机理，为蛋白质三维结构的预测、功能分析、以及药物设计提供理论依据。

蛋白质作为生命信息的载体，它折叠所形成的特定空间结构是其具有生物学功能的基础，此一维信息向三维信息的转化过程是表现生命活力所必需的。多肽链折叠成蛋白质特定三维结构的过程，是中心法则留下的空白，而这恰恰又是从“遗传信息”到“生物功能”的关键环节。阐明关于蛋白质折叠的过程将对相关疾病的预防和治疗都有重要意义。. 本研究基于NHP非格点和ODI格点模型对蛋白质链进行简化，通过分子动力学和动态蒙特卡罗模拟以及理论分析相结合的方法研究蛋白质的折叠过程和动力学行为。主要研究内容包括以下四个方面：(1)不同类型蛋白质链在折叠过程中的能量转变；(2)拥挤环境对蛋白质链传输过程的影响；(3)蛋白质在分子伴侣形成的管道中传输过程；(4)蛋白质链的柔性对其结构的影响。主要成果包括：(1)建立一套研究蛋白质折叠行为的理论方法和模型，包括确立受限体系的势能函数表达式、优化算法、提供有效的结构分析手段；(2)揭示空间结构、蛋白质链柔性及相互作用方式与蛋白质稳定构型的内在联系；(3)阐明蛋白质在分子伴侣形成的受限体系中输运过程的物理图像。通过上述研究，深入理解蛋白质的折叠机理，为蛋白质三维结构的预测、功能分析、以及药物设计提供理论依据。