拉伸力（streching force）作用下大分子构象变化动力学的介观统计理论研究

Single-molecule pulling experiments are capable of modeling the forces and strains that develop during many processes in a cell, and therefore have been widely used to directly observe the biomolecular reaction and conformational transitions in the presence of mechanical force. On the other hand, the controlled application of mechanical forces on single molecules provides a powerful tool to probe the kinetic information of rare molecular events, such as protein unfolding and ligand dissociation. To interpret the dynamic force spectroscopy accurately, an appropriate theory for biomolecular reaction and conformational transitions under the action of force is crucially significant. In this project, we study single-molecule experiments based on a generalized Langevin equation and the Kramers' model for the rate of chemical reaction. The dynamics of the stochastic variables will be computed by stochastic dynamic simulation. The main contents of our study include: (1) The dynamic disorder effect associated with the slow conformational fluctuation of macromolecules will be introduced into the study of single-molecule experiments. (2) The crowded effect of cellular environments to the kinetics of molecular transitions will be explicitly evaluated by the aid of mode-coupling theory. (3) A two-dimensional free-energy landscape description will be established, and the nonmonotonic variation of rupture rate with respect to force will be investigated. This project aims to provide a novel and effective theoretical method to study the biomolecular reactions and conformational transitions in cellular environments, and to provide an appropriate theory for an accurate interpretation of single-molecule experiments. Moreover, it makes also contribution to the development of the mesoscopic statistical mechanics for the study of complex systems.

单分子拉伸力实验是模拟生物大分子在活细胞复杂环境中受到应力作用下的反应及构象变化动力学，以及研究蛋白质解折叠、配体解离等过程，反推体系内秉动力学信息的重要手段。纳入大分子构型涨落及溶液环境等复杂因素，建立描述生物大分子在拉伸力作用下恰当的反应及构象转变动力学的介观统计理论，有重要学术意义和实际价值。本项目将立足广义郎之万方程，借助Kramers速率模型，采用随机动力学模拟，研究单分子拉伸力实验。主要内容包括（1）结合构型慢涨落，引入动力学无序效应。（2）运用模耦合理论，揭示细胞复杂环境拥挤效应。（3）建立有效二维势能面描述，研究构象转变速率等随外力非单调异常变化的内在机制。本项目的研究，将为研究活细胞应力环境下生物大分子反应及构象变化动力学，正确分析单分子拉伸力实验提供有效的新方法，同时为复杂体系中介观统计力学理论与方法的发展作出贡献。

单分子拉伸力实验是模拟生物大分子在活细胞复杂环境中受到应力作用下的反应及构象变化动力学，以及研究蛋白质解折叠、配体解离等过程，反推体系内秉动力学信息的重要手段。纳入大分子构型涨落及溶液环境等复杂因素，建立描述生物大分子在拉伸力作用下恰当的反应及构象转变动力学的介观统计理论，有重要学术意义和实际价值。本项目将立足广义郎之万方程，借助Kramers速率模型，采用随机动力学模拟，研究单分子拉伸力实验。主要内容包括（1）结合构型慢涨落，引入动力学无序效应。（2）运用模耦合理论，揭示细胞复杂环境拥挤效应。（3）建立有效二维势能面描述，研究构象转变速率等随外力非单调异常变化的内在机制。（4）研究内摩擦对生物大分子成环的影响。本项目的研究，将为研究活细胞应力环境下生物大分子反应及构象变化动力学，正确分析单分子拉伸力实验提供有效的新方法，同时为复杂体系中介观统计力学理论与方法的发展作出贡献。