THEORY OF BIOMOLECULAR DIFFUSION

扩散控制着许多具有生物医学重要性的分子过程的速率。这些过程包括乙酰胆碱酯酶等酶的作用速度，这在一定程度上是通过底物扩散到活性部位的静电引导实现其在突触活动中所需的高速功能。蛋白质之间、与脂质双分子层或与核酸的扩散相遇，在细胞生物学中的信号转导、基因表达、细胞骨架重塑和许多其他过程中起着核心作用。这项工作的广泛目标是提供新的计算机模拟工具，使能够在亚细胞水平上详细分析分子扩散在生物过程中的作用，并将这些工具应用于可能与实验工作密切接触的选定问题。下一个项目期的具体目标包括以下内容。(1)将对生成布朗动力学轨迹的方法进行几点改进。(2)将开发在模拟蛋白质-蛋白质相遇时考虑蛋白质表面环波动的方法。(3)将开发方法来模拟分子与延伸表面上的位置的结合。(4)将对拥有丰富实验生物物理数据的几个系统进行申请。本科生、研究生和博士后的培养将继续是该项目的一个关键方面。

Diffusion governs the rates of many molecular processes of biomedical importance. These processes include the rate of action of enzymes such as acetylcholinesterase, which achieves the high speed necessary for its function in synaptic activity in part by electrostatic guidance of substrate diffusion to its active site. The diffusional encounter of proteins with one another, with lipid bilayers, or with nucleic acids, plays a central role in signal transduction, gene expression, cytoskeletal remodeling, and a host of other processes in cell biology. The broad objectives of this work are to provide new computer simulation tools that will enable the detailed analysis of the role of molecular diffusion in biological processes at the subcellular level, and the application of these tools to selected problems where close contact with experimental work is possible. Specific aims for the next project period include the following. (1) Several improvements will be made in the methods for generating Brownian dynamics trajectories. (2) Methods will be developed to allow for the fluctuation of surface loops on proteins in simulations of protein-protein encounter. (3) Methods will be developed to allow simulations of molecular binding to sites on extended surfaces. (4) Applications will be pursued for several systems for which abundant experimental biophysical data are available. Training of undergraduate, graduate, and postdoctoral students will continue to be a key aspect of this project.