Mathematical modeling of the voltage driven translocation of polyelectrolytes thr

电压驱动聚电解质易位的数学模型

• 批准号: 8436833
• 负责人: Sandip Ghosal
• 金额: $ 9.42万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-17 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8436833
• 关键词: Address; Agreement; Area; Automobile Driving; Base Sequence; Biological; Biophysical Process; Biotechnology; Budgets; Cell Cycle; Cell Nucleus; Cell physiology; Cells; Charge; Chemicals; Confined Spaces; Coupled; DNA; DNA Sequence; Data; Defect; Development; Diffusion; Disease; Drug Design; Electrophoresis; Eukaryotic Cell; Failure; Genome; Goals; Health; Human; Human Genome; Individual; Knowledge; Lead; Life; Liquid substance; Mediating; Methods; Mission; Modeling; Molecular; Paper; Pharmaceutical Preparations; Physics; Polymers; Probability; Process; Protein translocation; RNA; Reading; Research; Resolution; Sampling; Signal Transduction; Sorting - Cell Movement; Speed; Tail; Techniques; Technology; Theoretical model; United States National Institutes of Health; Work; base; cost; design; electric field; gene therapy; high risk; improved; insight; interest; mathematical model; molecular dynamics; nanopore; nanoscale; novel strategies; pathogen; single molecule; solid state; success; voltage

DESCRIPTION (provided by applicant): A number of applications of nanometer scale pores have emerged recently in biotechnology inspired partly by their function in the biological context. This proposal relates to an exploratory method for sequencing DNA and other linear polyelectrolytes of biological significance by driving them through a single nanopore using an electric field. Analogous field mediated transfer across nanopores is believed to be part of the normal molecular level machinery of eukaryotic cells. A fair amount of experimental data has accumulated since the landmark 1996 paper by Kasianowicz, Brandin, Branton and Deamer [Proc. Natl. Acad. Sci. 93, 13770 - 13773 (1996)]. demonstrating the possibility of detecting the passage of individual molecules through a nanopore by observing the current signal. Recent atomic level molecular dynamic simulations have enhanced our understanding of the detailed mechanism behind these translocations. Simple analytical models that result in explicit formulas for such things as translocation speeds and scaling exponents are however rare. This proposal seeks to address this gap in our knowledge. It is proposed that the translocation process may be understood as a problem of electrophoresis of charged objects through confined spaces in an ionic fluid. Using such a description, coupled with a drift diffusion model to describe the Brownian fluctuations, quantitative predictions are sought that can be directly compared to experimental data. Preliminary results indicating the success of such an approach are presented. The expected broad impact of the proposed activity are: (A) The theoretical models being developed would provide much needed guidance in the experimental efforts to develop a viable ultra rapid DNA sequencing technology based on the nanopore idea. The ability to sequence DNA at a fraction of the cost of current methods has vast and broad implications for human health that are well known. (B) The theoretical models would lead to valuable insight on a vital and essential part of the molecular level functioning of a living cell. Such understanding has a variety of known and as yet unknown practical implications: it could, for example, lead to improved methods of injecting DNA into the cell nucleus in gene therapy, it could result in the development of new drugs based on the principle of disrupting the protein translocation step in the cell cycle of pathogens and conversely cure diseases caused by the failure of the translocation process by designing chemicals to rectify the defect. PUBLIC HEALTH RELEVANCE: The proposed activity is aimed at furthering fundamental understanding of the biophysical process of voltage mediated transfer of linear polyelectrolytes across nanopores. This process is the basis for a proposed ultra-fast DNA sequencing method that has been the subject of intensive research for about a decade and is also a basic step in the normal functioning of a eukaryotic cell. Besides the ultra-fast DNA sequencing technology, the enormous potential impact of which has been widely discussed, improved understanding of the translocation process could lead to improvements in techniques of gene therapy as well as the designing of drugs meant to promote or disrupt (in case of pathogens) the translocation process in cells.

描述（由申请人提供）：最近在生物技术中出现了纳米级孔的许多应用，部分受到它们在生物背景中的功能的启发。该提案涉及一种探索性方法，通过使用电场驱动DNA和其他具有生物学意义的线性聚电解质通过单个纳米孔来对其进行测序。类似的场介导的跨纳米孔转移被认为是真核细胞正常分子水平机制的一部分。自 1996 年 Kasianowicz、Brandin、Branton 和 Deamer 发表具有里程碑意义的论文以来，已经积累了大量的实验数据 [Proc.国家。阿卡德。科学。 93, 13770 - 13773 (1996)]。展示了通过观察电流信号来检测单个分子通过纳米孔的可能性。最近的原子级分子动力学模拟增强了我们对这些易位背后的详细机制的理解。然而，能够得出易位速度和缩放指数等明确公式的简单分析模型却很少见。该提案旨在解决我们的知识差距。有人提出，易位过程可以理解为带电物体通过离子流体中的有限空间的电泳问题。使用这样的描述，结合漂移扩散模型来描述布朗涨落，寻求可以直接与实验数据进行比较的定量预测。初步结果表明这种方法是成功的。拟议活动的预期广泛影响是： (A) 正在开发的理论模型将为实验工作提供急需的指导，以开发基于纳米孔思想的可行的超快速 DNA 测序技术。众所周知，以当前方法成本一小部分的成本进行 DNA 测序的能力对人类健康具有巨大而广泛的影响。 (B) 理论模型将对活细胞分子水平功能的重要和重要部分产生有价值的见解。这种理解具有多种已知和未知的实际意义：例如，它可以改进基因治疗中将 DNA 注入细胞核的方法，它可以导致基于破坏原理的新药物的开发。病原体细胞周期中的蛋白质易位步骤，并通过设计化学物质来纠正缺陷，从而治愈因易位过程失败而引起的疾病。公共健康相关性：拟议的活动旨在进一步加深对电压介导的线性聚电解质跨纳米孔转移的生物物理过程的基本理解。这一过程是所提出的超快速 DNA 测序方法的基础，该方法已成为近十年来深入研究的主题，也是真核细胞正常功能的基本步骤。除了超快速 DNA 测序技术（其巨大的潜在影响已被广泛讨论）之外，对易位过程的进一步了解可能会导致基因治疗技术的改进以及旨在促进或破坏的药物的设计（如果病原体）细胞内的易位过程。

项目成果

Electrically generated eddies at an eightfold stagnation point within a nanopore.

• DOI: 10.1063/1.4901984
• 发表时间: 2014-11
• 期刊: Physics of fluids
• 影响因子: 4.6
• 作者: J. Sherwood;M. Mao;S. Ghosal

Hydrodynamic flow in the vicinity of a nanopore induced by an applied voltage.

• DOI: 10.1088/0957-4484/24/24/245202
• 发表时间: 2013-06-21
• 期刊: Nanotechnology
• 影响因子: 3.5
• 作者: Mao M;Ghosal S;Hu G
• 通讯作者: Hu G

Ion transport through a graphene nanopore.

通过石墨烯纳米孔的离子传输

• DOI: 10.1088/0957-4484/23/39/395501
• 发表时间: 2012-10-05
• 期刊: Nanotechnology
• 影响因子: 3.5
• 作者: Hu G;Mao M;Ghosal S
• 通讯作者: Ghosal S

A Landau-Squire nanojet.

• DOI: 10.1021/nl402350a
• 发表时间: 2013-11-13
• 期刊: Nano letters
• 影响因子: 10.8
• 作者: Laohakunakorn N;Gollnick B;Moreno-Herrero F;Aarts DG;Dullens RP;Ghosal S;Keyser UF
• 通讯作者: Keyser UF