Modeling Macromolecular Transport through Channels

模拟大分子通过通道的运输

• 批准号: 6897443
• 负责人: MURUGAPPAN MUTHUKUMAR
• 金额: $ 26.83万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-06 至 2007-05-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6897443
• 关键词: analytical method; biological signal transduction; biological transport; chemical models; chemical reaction; electric field; electrical conductance; electrophysiology; hemolysin; macromolecule; mathematical model; membrane channels; molecular assembly /self assembly; molecular dynamics; nanotechnology; nuclear membrane; polymers; protein transport

DESCRIPTION (provided by applicant): We propose to develop the macromolecular modeling needed for a fundamental molecular understanding of how electrically charged polymer molecules move through protein channels. Stimulated by prospects of direct high-speed detection of sequences in single polynucleotide molecules, and of stochastic sensing of single macromolecular analytes, very exciting single-molecule electrophysiology experiments have recently been reported. The results of these experiments are very puzzling and require an understanding of polymer physics, in combination with descriptions of chemical specificities. We propose to implement polymer physics concepts valid at large length and time scales, in conjunction with Brownian Dynamics simulations accounting for details at smaller length and time scales. The present proposal addresses a fundamental understanding of (1) how DNA/RNA molecules move through alpha-hemolysin channels under an electric field and computation of ionic current of channels with macromolecular transport, (2) origin of discrete conductance states and conformations of polymer tethers engineered into protein pores, and (3) development of coarse-grained models for RNA-carrying transport factors and their transport through nuclear pore complexes. Our unique combination of theory, simulations, and collaborations with active experimentalists, will have a direct and profound impact on understanding of signal transduction, high-speed sequencing of DNA/RNA and proteins, screening of biological warfare agents, pharmaceutical diagnostics, and macromolecular aspects of diseases and their control.

描述（由申请人提供）：我们建议开发大分子模型，以便对带电聚合物分子如何通过蛋白质通道进行基本的分子理解。由于对单个多核苷酸分子序列的直接高速检测和单个大分子分析物的随机感应的前景，最近报道了非常令人兴奋的单分子电生理实验。这些实验的结果非常令人困惑，需要了解聚合物物理学，并结合化学特性的描述。我们建议实现在大长度和时间尺度上有效的聚合物物理概念，并结合布朗动力学模拟，在较小的长度和时间尺度上解释细节。目前的建议解决了以下几个基本问题：(1)DNA/RNA分子如何在电场下通过α -溶血素通道移动，以及计算大分子运输通道的离子电流，(2)离散电导状态的起源和聚合物系链工程进入蛋白质孔隙的构象，以及(3)开发携带RNA的运输因子及其通过核孔复合物运输的粗粒度模型。我们独特的理论、模拟和与活跃的实验学家合作的结合，将对理解信号转导、DNA/RNA和蛋白质的高速测序、生物战剂的筛选、药物诊断和疾病的大分子方面及其控制产生直接而深远的影响。