Theory of Biomolecular Diffusion

项目总结 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。扩散是已知的影响或控制的动力学 许多酶，这些酶的作用速度可能会增加几个数量级 带电底物对酶活性部位的静电吸引的大小。同样， 静电引导扩散极大地加快了蛋白质与其他蛋白质的相互作用， 核酸，以及在各种过程中与膜上的大分子组装 对细胞骨架重塑、货物运输、基因表达和信号转导至关重要。 拟议工作的广泛目标是提供新的计算机模拟工具， 能够在亚细胞中详细分析分子扩散在生物过程中的作用 和细胞水平，以及这些工具对选定的问题的应用，这些问题与 实验工作是可能的。 将继续开发一种新的方法来处理流体动力相互作用 为了更好地描述这些相互作用在生物分子关联中的显著影响。一种独特的， 在过去和现在的赠款周期中发明和发展的统一的极-非极隐式溶剂化理论 (变分隐式溶剂法)将在几个重要方向推广到 在未来的布朗动力学模拟中提供前所未有的精度和速度。发展 将继续使用一种独特的方法来耦合适当的布朗动力学模拟 在关键领域进行随机处理，在其他地方进行有效的连续处理。我们会 利用布朗动力学发展了大分子柔性运动的一种方法 生物分子构象变化的马尔可夫状态模型。这些创新 将在我们的布朗动力学模拟程序包“Browndy”中实现，并将用于 研究各种生物系统。 这项工作的健康相关性在于扩散模拟的潜力，以揭示详细的 健康细胞内分子相互作用的动力学以及这些动力学可能如何改变 病态的情况。这将为基于结构的药物发现的未来工作提供基础， 这些小分子被用来调节细胞内的动态过程。

PROJECT SUMMARY 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. Development will continue on a novel approach to the treatment of hydrodynamic interactions in order to better describe the significant effects of these interactions in biomolecular associations. A unique, unified polar-apolar implicit solvation theory invented and developed in past and current grant cycles (the Variational Implicit Solvent Method) will be extended in a number of important directions to provide unprecedented accuracy and speed in future Brownian dynamics simulations. Development will continue on a unique approach for coupling Brownian dynamics simulations for a proper stochastic treatment in critical domains with efficient continuum treatments elsewhere. We will develop a method of adding flexible motion to large molecules in Brownian dynamics by making use of well-developed Markov State models of biomolecular conformational changes. These innovations will be implemented in our Brownian dynamics simulation package “Browndye”, and will be used to study a variety of biological systems. 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.