CAREER: Deciphering Ionic Current Signatures of Polymer Transport through a Nanopore

该职业奖支持聚合物通过纳米孔转运的计算和理论研究和教育。纳米孔在自然界和工程中无处不在。它们的功能范围从运送溶质进出活细胞到化学和生物分离以及药物输送。本研究计划通过实验研究电场驱动的典型聚合物DNA分子通过生物和合成纳米孔的传输，以及用于表征传输特性的共通过离子电流的变化。纳米孔易位实验能够在单分子水平上测试各种纳米尺度现象的物理模型。它们提供了关于纳米尺度静电和流体动力学、溶剂化和熵力、选择渗透效应、原子尺度摩擦、粘附和生物聚合物构象动力学的信息。解释纳米孔易位实验的根本困难在于，所研究的微观过程是通过测量它们对纳米孔电流的影响来间接表征的。为了更充分地利用纳米孔探针前所未有的灵敏度，需要一个定量的物理模型来将纳米孔中的微观事件与测量的离子电流联系起来。PI旨在通过结合全原子分子动力学、布朗动力学和多尺度模拟的创新建模方法，提供聚合物通过生物和合成纳米孔传输的全面物理描述。该方法既保留了分子动力学方法的原子级信息，又充分利用了布朗动力学和多尺度方法的计算效率。该方法将利用离子和聚合物传输时间尺度上的千倍差异。DNA通过纳米孔运输的过程将用统计学术语来描述。得到的DNA构象集合将用于计算相应的离子电流阻塞。该方法的最后一步是考虑到离子电流与聚合物构象耦合的电动力学效应。该方法与迄今为止提出的粗粒度模型的主要区别在于保留了溶质和纳米孔结构的全原子信息，并确定了实验精度的离子电流封锁。结合实验，这种预测能力将大大提高纳米孔作为探测纳米尺度系统和工艺的工具的实用性。这个研究项目可能会对纳米孔在生物传感和纳米技术中的应用产生直接影响，例如个人基因组学、纳米流体电子学和单分子操作的仪器。教育活动将集中在为本科生物物理课程开发实验课程和讲座演示。另一项主要任务是将研究生课程“纳米机器物理学”转化为教科书，该教科书将描述纳米级相互作用的物理学，这些相互作用支配着微型生物、合成和混合机器的操作。该计划的一个非常具体的目标是招募一名少数民族学生进行研究活动。该计划将为研究社区提供建模方法和工具，这些方法和工具由专业程序员在流行的开源程序中实现，包括一套包含所有必要说明和示例的独立教程。非技术总结：该职业奖支持计算和理论研究和教育，以模拟长链状分子被拉过直径与大分子大小相当的小孔。特别令人感兴趣的是由生物体产生的长链状分子。这些通常被称为生物聚合物。在一个短暂的时刻，分子被限制在由微小的分子大小的孔（也称为纳米孔）所定义的小体积内，并且它的性质可以被切片地检查。人们认为，通过将生物聚合物拉过小孔的过程，可以确定分子链的形状和化学组成。PI将专注于使用新颖的计算建模方法对这一过程进行全面的物理描述。所获得的理解可能会对生物传感和纳米技术的应用产生直接影响，例如DNA测序、未来的电子设备和单分子操作。教育活动将集中在为本科生物物理课程开发实验课程和讲座演示。另一项主要任务是将研究生课程“纳米机器物理学”转化为教科书，该教科书将描述控制微型生物、合成和混合机器操作的相互作用物理学。该计划的一个非常具体的目标是招募一名少数民族学生进行研究活动。该计划将为研究社区提供建模方法和工具，这些方法和工具由专业程序员在流行的开源程序中实现，包括一套包含所有必要说明和示例的独立教程。

TECHNICAL SUMMARYThis CAREER award supports computational and theoretical research and education on translocation of polymers through nanopores. Nanopores are ubiquitous in nature and engineering. Their functionality ranges from transport of solutes in and out of a living cell to chemical and biological separation and drug delivery. This research program investigates electric field-driven transport of a prototypical polymer DNA molecule through biological and synthetic nanopores and accompanying changes in co-passing ionic current used to characterize the transport by experiment. Nanopore translocation experiments enable testing of physical models of diverse nanoscale phenomena at the single-molecule level. They provide information about nanoscale electrostatics and hydrodynamics, solvation and entropic forces, selectro-osmotic effecs, atomic-scale friction, adhesion, and conformational dynamics of biopolymers. The fundamental difficulty in interpretation of the nanopore translocation experiments is that the microscopic processes of interest are characterized indirectly, by measuring their influence on the nanopore current. In order to more fully exploit the unprecedented sensitivity of nanopore probes, a quantitative physical model is required to relate the microscopic events in the nanopore to the measured ionic current. The PI aims to provide a comprehensive physical description of polymer transport through biological and synthetic nanopores through an innovative modeling method that combines all-atom molecular dynamics, Brownian dynamics, and multiscale simulations. This method will preserve the atomic-level information of the molecular dynamics method, while capitalizing on the computational efficiently of the Brownian dynamics and multiscale methods. The approach will exploit the thousandfold difference in the time scales of ion and polymer transport. The process of DNA transport through a nanopore will be characterized in statistical terms. The obtained ensemble of DNA conformations will be used to compute the corresponding ionic current blockades. The final step of the approach is to take into account the electro-kinetic effect that couples the ionic current to the polymer conformation. The main difference of this approach from the coarse-grained models that have been proposed to date is in preserving the all-atom information about the structure of the solute and nanopore and determining the ionic current blockade to the experimental accuracy. Combined with experiment, such predictive capability will greatly enhance utility of nanopores as tools to probe nanoscale systems and processes.This research program could have direct impact on nanopore applications in biosensing and nanotechnology, such as instrumentation for personal genomics, nanofluidic electronics, and single molecule manipulation. The educational activities will focus on developing a laboratory course and lecture demonstrations for an undergraduate biological physics course. Another major undertaking is transforming a graduate course "Physics of Nanomachines," into a textbook, which will describe the physics of nanoscale interactions that governs operation of miniature biological, synthetic, and hybrid machines. One very specific objective of the program is to recruit a minority student to carry out the research activities. The program will provide the research community with modeling methods and tools implemented by professional programmers in the popular Open Source programs, including a set of self-contained tutorials containing all necessary instructions and examples. NON-TECHNICAL SUMMARY:This CAREER award supports computational and theoretical research and education to simulate long chain-like molecules being pulled through tiny holes that have diameters the size of a large molecule. Of particular interest are long chain-like molecules produced by living organisms. These are often called biopolymers. For a brief moment, the molecule is confined to the small volume defined by the tiny molecule-sized hole, also known as a nanopore, and its properties can be examined section by section. It is thought that through the process of pulling the biopolymer through the tiny hole the shape and chemical makeup of the molecular string can be determined. The PI will focus on developing a comprehensive physical description of this process using novel computational modeling methods. The understanding that is gained could have direct impact on applications in biosensing and nanotechnology, such as sequencing DNA, future electronic devices, and single molecule manipulation. The educational activities will focus on developing a laboratory course and lecture demonstrations for an undergraduate biological physics course. Another major undertaking is transforming a graduate course "Physics of Nanomachines," into a textbook, which will describe the physics of interactions that governs operation of miniature biological, synthetic, and hybrid machines. One very specific objective of the program is to recruit a minority student to carry out the research activities. The program will provide the research community with modeling methods and tools implemented by professional programmers in the popular Open Source programs, including a set of self-contained tutorials containing all necessary instructions and examples.