Theory of Biomolecular Diffusion

描述（由申请人提供）：分子扩散，通常由溶质相互作用引导和加速，严重影响许多生物过程的结果。众所周知，扩散可以影响或控制许多酶的动力学，并且由于带电底物对酶活性位点的静电吸引，这些酶的作用速率可以提高几个数量级。同样，在细胞骨架重塑、货物运输、基因表达和信号转导的各种过程中，静电控制的扩散极大地加快了蛋白质与其他蛋白质、与核酸以及与膜上大分子组装的相互作用。所提议的工作的广泛目标是提供新的计算机模拟工具，使分子扩散在亚细胞和细胞水平的生物过程中的作用的详细分析，并将这些工具应用于与实验工作密切接触的选定问题。更具体地说，将开发一个新的布朗动力学模拟包，其中将包括许多新的理论方法，以提高扩散模拟的准确性和规模。一种独特的、统一的极性-极性隐式溶剂化理论（变分隐式溶剂法）将在许多重要的方向上得到扩展，以在未来的布朗动力学和其他模拟中提供前所未有的准确性。提出了一种独特的方法，将布朗动力学模拟在关键区域进行适当的随机处理，而在其他地方进行有效的连续处理。应用于研究从分子到细胞尺度的信号转导现象。这项工作的健康相关性在于扩散模拟的潜力，以揭示健康细胞内分子相互作用的详细动态，以及这些动态在病理情况下如何改变。这将为未来基于结构的药物发现工作提供基础，其中小分子被用来调节细胞内的动态过程。

DESCRIPTION (provided by applicant): Molecular diffusion, often steered and accelerated by solute interactions, critically influences the outcomes of many biological processes. Diffusion is known to influence or control the kinetics of many enzymes, and the rates of action of such enzymes may be increased by several orders of magnitude by electrostatic attraction of charged substrates toward the enzyme active sites. Likewise, electrostatically steered diffusion greatly speeds the interaction of proteins with other proteins, with nucleic acids, and with macromolecular assemblages on membranes in a variety of processes essential for cytoskeletal remodeling, cargo transport, gene expression, and signal transduction. The broad objectives of the proposed 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 and cellular levels, and the application of these tools to selected problems where close contact with experimental work is possible. More specifically, a new Brownian dynamics simulation package will be developed that will include many novel theoretical methods to increase the accuracy and scales of diffusional simulations. A unique, unified polar-apolar implicit solvation theory invented in the current grant period (the Variational Implicit Solvent Method) will be extended in a number of important directions to provide unprecedented accuracy in future Brownian dynamics and other simulations. A unique approach is proposed that will couple Brownian dynamics simulations for a proper stochastic treatment in critical domains with efficient continuum treatments elsewhere. Applications will be made to study signal transduction phenomena from molecular to cellular scales. The health relatedness of this work lies in the potential of diffusional simulations to reveal the detailed dynamics of molecular interactions within healthy cells and how these dynamics may be altered in pathological situations. This will provide a basis for future work in structure-based drug discovery, in which small molecules are used to modulate the dynamic processes within the cell.